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THE

EVOLUTION OF DISEASE

DISCUSSION OF THE IMMUNE REACTIONS OCCURRING
IN INFECTIOUS AND NON-INFECTIOUS DISEASES

A THEORY OF IMMUNITY, OF ANAPHYLAXIS
AND OF ANTIANAPHYLAXIS

BY

PROF. J. DANYSZ

CHEF DE SERVICE, INS'm'UT PASTEUR, PARIS

TRANSLATED BY

FRANCIS M. RACKEMANN, M.D.

ASSISTANT IN MEDICINE IN THE HARVARD MEDICAL SCHOOL; ASSISTANT IN
MEDICINE IN THE MASSACHUSETTS GENERAL HOSPITAL, BOSTON, MASS.

LEA & FEBIGER

PHILADELPHIA AND NEW YORK
1921

COPYBIGHT

LEA & FEBIGER

1921

TRANSLATOR'S NOTE

In translating this work of Professor Danysz from French
into English, an attempt has been made to preserve carefully
the original meaning. The original work contains much
repetition arising from the desire to emphasize and elucidate
the author's theories and deductions on the evolution of
disease: the translation also contains repetition but the
translator has taken the liberty of omitting sentences, para-
graphs and, in certain instances, whole sections, in order to
present the book to the American profession in a more read-
able form. In particular, the case reports in the second
section of the second part have been greatly shortened and
many have been omitted.

In this book Professor Danysz has traced in a clear and
logical manner the various stages in the development of acute
infectious diseases; and proceeding along the same course,
has developed an interesting theory of the evolution of
chronic morbid states whose etiology and pathogenicity are
today so little understood and whose treatment is therefore
as difficult as it is unsatisfactory.

The book should be of interest to those who recognize
the importance of a comprehension of the principles under-
lying the study and treatment of disease.

The translator wishes to thank Mr. G. S. S. Playfair for
much valuable assistance in the translation.

F. M. R.

35901

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in 2007 with funding from

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PREFACE.

As 'the study of physical and biological phenomena, of
the constitution of matter and of its manifestations becomes
more extended and more precise, it tends to prove that the
perpetual changes noticed in all things, consist in an uninter-
rupted series of decompositions and syntheses; and as the
transformations of any one substance have a beginning and
an end, it can be said that any substance in process of change
undergoes an evolution of which the different successive
phases are determined by the physical and chemical proper-
ties of its constituent elements.'

Decompositions follow, as a rule, a very uniform path and
lead to simple elements which may be considered as definite.
Synthesis, on the other hand, is itself subject to evolution;
it leads step by step to compounds that are more and more
complicated, varied and numerous, and it is impossible to
predict any end to these changes.

The final result of natural synthesis, the most complicated
and the most perfect product known to us, is the chemical
species which we may call "albuminoid micelle."^ Its
characteristic is that it rebuilds itself as it wears out, or, in
other words, that it is continuously undergoing partial
decomposition and at the same time a reconstruction of the

^ The word "micelle" is used to define the units of albuminoid matter of
every colloid in the same sense that the word "molecule" expresses the
unit of chemical compounds. The word "particle" is used by many Ameri-
can authors in the same sense.

vi PREFACE

decomposed elements with simpler elements found in its
environment, so that although always in an unstable equilib-
rium, it constantly retains its initial composition and
structure.

It is easy to conceive that if the conditions of this " nutri-
tion" of the "micelle" depend on what is provided by the
surrounding matter, the "micelle" may decrease or increase
in volume; that is to say, it may decompose faster or slower
than it is constructed . When a sufficient quantity of building
material is at hand, the increase in volume will predominate ;
and when its volume will have reached certain limits capable
of modifying its conditions of normal nutrition, the "micelle"
will split into two equal parts.

It is this muUiplicaticm which together with nutrition
constitutes life.

The "micelle" develops as an individual and as a species;
in its evolution it must obey the law which obliges every
substance to replace in its complexes, the less stable or more
soluble compounds by more stable or less soluble compounds.

The "micelle" will "age" because, as its elements become
more stable, substitution becomes slower and slower; it will
"die" when stabilization will have passed beyond certain
Hmits, because a certain rapidity of exchange, producing a
certain amount of heat, in a given time, is an indispensable
condition of life.

The individual may die under these conditions; the species
likewise, because the child-" micelles" will inherit the degree
of stability acquired by the parent-" micelles."

When a cell's "micelles" find in their surrounding medium
elements of which they are composed themselves, or other
elements for which their own elements have no affinity, they
can find nourishment and can develop in a normal manner;
but when, on the contrary, they find strange elements,

PREFACE vii

requiring fixation by their affinities, the nutritive equilibrium
will be modified; and when the proportion of * 'micelles" so
affected among the "micelles" composing the plasma of the
cell, will have passed beyond certain limits, the cell itself will
become diseased and may die.

These are the general ideas which have guided us in the
following study of pathological states.

In Part II the secondary consequences in the organism of
the conditions of immunity and anaphylaxis, which result
from recovery in infectious disease, or from an habitual or
periodical digestion of antigens are discussed.

The study of these questions has led to the conclusion that
all the chronic morbid states with their periods of acute crises
alternating with longer or shorter remissions, originate from
antigens, and are determined by the state of immunity-
anaphylaxis of the organism. The necessary experimental
confirmation of this hypothesis has shown in reality that the
anti-anaphylactic treatment is of unquestionable efficacy
in all those chronic diseases in which we have been able to
apply it up to date (except organic mental diseases) and a
long series of observations corroborates this.

We have obtained these results by non-specific antigens
and in order to explain the curative action of these antigens,
we have been obliged to assume the direct and predominating
intervention of the nervous centers.

The work is concluded by a general theory of immunity,
anaphylaxis, and anti-anaphylaxis, based on the structure,
properties and function of the organism, and of the structural
and functional units composing it.

J. Danysz.

CONTENTS.

PART I.

CHAPTER I.

The Theories of Immunity (Metchnikoff and Ehrlich). Experi-
mental Researches Inspired by These Theories.

Pathogenic Mechanism of Bacterial Infection. Toxic
Action. Action of Bacterial Bodies and of the Products
of Bacteriolysis when Considered as Heterogeneous
Albumins. Properties of the Mixtures of Antigens with
Their Antibodies. Ricin. Antiricin. Phenomena of
"Surcharge" 17-32

CHAPTER II.

Physicochemical Properties. Transformation of the
Arsenobenzenes "In Vitro" and in the Organism.

Physicochemical Properties and Constitution. Transforma-
tions "In Vitro." Transformations in the Organism
Toxicity. Relations between Apparent Toxicity and
Formation of Precipitates. Reactions of the Organism.
Formation of a Specific Antibody. Experiments on the
Fixation and Elimination of Luargol by the Organism . 33-44

X CONTENTS

CHAPTER III.

Evolution of the Infectious Diseases.

(1) Diphtheria. Action of Toxin on the Tissues. Fixation

"en Surcharge" of Toxin. Experiments. Properties
of Mixtures of Toxin with Antitoxin. Immunity.
Cure by Antitoxin.

(2) TuhercuLosis. Action of Tuberculin. Action of Bacter-
ial Bodies. Antituberculin and Antibacillin. The Sur-
charge of the Organism by Antibodies Causes Patho-
logical Manifestations. Auto-reinfections.

(3) Typhoid and Paratyphoid Fevers. Cholera. Mechanism
of Gastro-intestinal Infections. Formation and Action
of Precipitating Antibodies. Exotoxins and Endotoxins.
Nature of the Pathological Symptoms in the Period of
Disease. Mechanism of Spontaneous Cure. Patho-
genicity of Ahmentary Poisoning by Paratyphoid.
Pathogenicity and Nature of Cholera Crisis . . . 45-73

CHAPTER IV.

Mechanism of Infection. Infection or Contagion. Virulence.
Immunity. Refractory State.

Means of Adaptation of Bacteria to the Interior of the
Organism. Origin of the Affinities between the Anti-
gens and the Normal Antibodies. Immunity and
Reciprocal Anaphylaxis of Infecting Bacteria and of
Infected Organisms. Experiments on the Pathogenesis
of Paratyphoids and of Rat Anthrax 74-81

CHAPTER V.

Immunity and Anaphylaxis.

Formation of Immunizing and Anaphylactic Antibodies.
Reason for the Existence of Anaphylaxis. Nature of
the Antigens. Colloids. Constitution and Physico-
chemical Properties of Particles. Combinations of
Colloids with Salts in Varying Proportions. Action
. and Nature of Antibodies 82-108

CONTENTS xi

CHAPTER VI.

Influence of the Central Nervous System on Immunizing
Reactions and on Anaphylaxis.

Pathological Manifestations Caused by Emotion. Action of
Hypnotic and Anesthetic Agents on Anaphylactic Shock.
Experiments by Roux and Besredka. Action of Violent
Emotions on the Metabolism of the Suprarenal Capsules.
Kendall's experiments 109-113

CHAPTER VII.

Therapeutic Measures.

Latent Anaphylaxis. Actual Anaphylaxis. Specificity of
Antigens in their Vaccinating and Curative Action.
Preventive and Curative Action of Non-specific Anti-
gens. Skepto- or Tachyphylaxis. Anti-anaphylatox-
ins. Uniformity of Reactions in Anaphylactic and
Anaphylatoxic Crises. Chemotherapy. Bacteriother-
apy. Serum Therapy 114-123

CHAPTER VIII.

Principles of the Classification of Infectious Diseases.

Constitution and Physicochemical Properties of Albuminoid

Particles. Normal and Abnormal Nutrition .... 124-127

CHAPTER IX.

General Conclusions.

The Organism. Its Physicochemical Composition. Prop-
erties of the "Micelle" 128-134

xii CONTENTS

PART 11.

CHAPTER X.
Evolution of Theories Concerning Immunity, Anaphylaxis

AND AnTI-ANAPHYLAXIS.

Introduction. Researches by Pasteur, Roux and Yersin,
Behring and Kitasato. Transfusion of Blood and Injec-
tion of Heterologous and Homologous Sera and Other
Proteins. Anaphylaxis. Anti-anaphylaxis and the
Immunization of Animals. Mechanism of Anti-ana-
phylaxis. Tachyphylaxis or Skeptophylaxis. Physio-
logical and Physicochemical Causes of the Formation
of Antibodies in Excess by Antigenic Action. Immed-
iate and Secondary Results of the Condition of Immun-
ity-anaphylaxis. Origin of Chronic Non-contagious
Diseases 135-161

CHAPTER XL

Principles of the Anti-anaphylactic Treatment of Chronic
Diseases by Entero-antigens.

Case Reports. A. Dermatoses (Cases 1 and 2, 4 to 7 inclu-
sive, and 9). B. Asthma (Cases 10 to 12 inclusive).
C. Other Cases. Summary of Observations. General
and Local Reactions Caused in the Organism by Entero-
antigens. Theory of Curative Reactions. Kendall's
Experiment. The Influence of the Nervous System . 162-184

CHAPTER XII.

General Summary: Theoretical Deductions.

Theory of Immunity, of Anaphylaxis and of Anti-anaphy-
laxis 185-194

EVOLUTION OF DISEASE,

PART L

CHAPTER I.

THEORIES OF IMMUNITY OF METCHNIKOFF
AND EHRLICH.

Experimental Researches Inspired by These Theories y/ It Si l\ (r

Medical science has for its object to teach us why and ^j/
how an organism becomes diseased, what constitutes this Wf
disease, and how cure is effected. It is only by knowing how
to answer these three questions that it is possible to treat
disease successfully either by preventing its occurrence or
by assisting the organism in recovering from it. Up to the
time of Pasteur we knew as pathogenic agents only poisons
as such; chemically crystallizable products and venins, all
of unknown composition, but which with the crystalloids
have this fact in common, that the diseases of which they
are the cause are non-contagious.

With the discovery of bacteria we began to know the origin
of contagious diseases and it was recognized at about the
same time, that if a certain microbe was the primary cause
of the disease it could act only by means of its soluble secre-
tions or by products which were allowed to escape at its
death; that is to say, by poisons of an unknown composition
analogous to the venins. But although we know the cause of
disease, we do not know the mechanism by which the patho-

18 THEORIES OF IMMUNITY

logic state is brought about. The symptoms and the ana-
tomical lesions of disease were recognized but it was not known
how these symptoms and lesions were produced. It was
learned how to "accustom" the organism to certain poisons,
to "vaccinate" against certain diseases and to effect cure by
certain antidotes. But we have been obliged to recognize
that methods, either preventive or curative, applied with
success in certain cases, do not give any appreciable result
in others.

Thus neither the mechanism of the pathogenicity nor that
of the pathologic state nor that of the cure was understood,
so that curative measures were necessarily limited to attempts
to relieve symptoms and to the treatment of lesions by means
found by chance experiments.

In order to throw light on the mechanism of cure, especially
in the infectious diseases, Metchnikoff put forth his phago-
cytic theory, according to which, the leukocytes, the only
cells of the organism provided with a membrane which could
engulf microbes, digested these microbes and thus destroyed
the primary cause of the disease.

However, much before the phagocytic theory, vaccina-
tion of the organism against smallpox, anthrax, erysipelas,
chicken cholera, carbuncle, had been successful. The first
practical results in the curative treatment of an infectious
disease, viz., the cure of diphtheria by antitoxic serum, did
not result from the conception of immunization by leukocytes.

Vaccination by soluble bacterial secretions had been
observed in numerous diseases, as for example: by Chauveau
in lambs born of ewes inoculated with anthrax during ges-
tation; by Salmon and Smith in their experiments in hog
cholera; by Charrin in pyocyaneous infection and by Roux
and Chamberland in symptomatic anthrax and the infection
by septic vibrio. Moreover the production of an antitoxin
"in excess" for diphtheria and tetanus following injection
of toxins filtered from both living and dead organisms was
demonstrated; as well as the fact that these bacterial poisons
might be fixed to and might act not only on the leukocytes
but also on every other cell.

These observations inspired Ehrlich to a more general

THEORIES OF IMMUNITY 19

conception not only of the mechanism of cure but also that
of the pathogenicity. Without denying the possibility of
the intervention of leukocytes Ehrlich propounded the idea
of indispensable chemical affinities for every reaction between
two substances: taking the same point of view for every
reaction, whether immunizing or pathogenic, between bac-
terial poisons and the cells : namely, that some one substance
of the cell possesses a chemical affinity for these poisons.
Pathologic symptoms are then the result of fixation of poisons
by cellular substance and cure is the result of the multiplica-
tion of this cellular substance neutralized by poison, which
the cell produces in excess. The product of the combination
ought necessarily to be neutral. .

We shall see further what there is to take or leave in this
theory which Ehrlich formulated. It will suffiiqe to note,
at the moment, that Ehrlich's theory was no more capable
than that of Metchnikoff of explaining the evolution of every
disease, and that it could not explain the reaction provoked
in the organism by bacterial poisons, or the necessity or
possibility of the organism reacting to certain poisons in a
way different from that in which it reacts to many other
poisons.

But even if the purely biologic theory of Metchnikoff as
well as the purely biochemical theory of Ehrlich cannot
explain the entire mechanism of pathogenicity and immunity,
yet each contains certain truths which have been the basis
of countless studies in the domains of biology, biochemistry
and biophysics. These studies have made possible the dis-
covery and the definition of a great number of facts concern-
ing the properties of pathogenic agents, the nature and the
mechanism of their action on the organism, the reactions
which they provoke, the nature and properties of the products
of their reactions with the fluids of the organism both in
vitro and in vim.

Notably so, these studies have allowed us to establish a
very fine distinction between these pathogenic agents, which
are cry stalliz able and those which are not: these latter being
grouped under the general name of colloids. These studies
have permitted us to enlarge the horizon, to clarify and to

20 THEORIES OF IMMUNITY

better understand the true significance of facts in daily
experience and to better group these facts in order to con-
struct a general idea which in its turn will point the way
toward new researches. In the discussion which follows we
shall try to recall the merits of the two theories of Metchnikoff
and Ehrlich and of the experimental researches which these
have inspired. We shall try to interpret the results of these
researches in the light of new facts and to draw from the total
of these studies conclusions which are necessarily logical.

Metchnikoff 's theory of immunity attributed the defensive
mechanism of the organism against pathogenic germs exclu-
sively to the leukocytes. Leukocytes engulf the germs,
digest them and there results an overproduction of a specific
digestive ferment which renders this digestion more and more
easy and active. When all the microbes are thus destroyed,
there is cure and the organism remains immunized against
the same germ because the leukocytes which have learned
to digest these germs retain this new property for a certain
time and transmit it by heredity to their descendants so that
they also will be able to attack a small quantity of the same
parasites in case the organism again becomes spontaneously
infected.

We may easily understand the destruction of the microbes
in the interior of the leukocytes. The role of these latter in
the defense of the organism is certainly very important but
we must recall that if the phagocytic theory contains one
part of the truth it cannot include the whole problem of
pathogenicity and immunity because the struggle between
microbes and organism does not take place exclusively in
the blood. If we must assume that it is the microbe which
is the origin of disease and that its destruction by the white
blood corpuscles can lead to cure, it is by no means less
certain that it is not only the microbe body but also and often
principally the soluble products or poisons which it secretes
during its life or which are allowed to difflise after its death
that by acting not only on the leukocytes but also on a large
number of other cells, produce the lesions and symptoms
characteristic of each disease.

Pathologic manifestations can be only the results of reac-

THEORIES OF IMMUNITY 21

tions between cells and bacterial poisons. When the cells
do not succumb in the struggle they become more resistant
to the action of the same poison. But the presence and the
destruction of bacteria in the organism may provoke reactions
of still another nature. The poisons which they excrete are
not the only substances of which the protoplasm and the
membrane of the bacterial body are composed. There are
albumins which without being poisonous are not harmless
for the organism. These albuminous substances themselves
must be transformed in order to be assimilated and there
may result from them disturbances which we will discuss
later when we come to treat of pathologic states provoked
by the injection of albumin. It is sufficient to note here
provisionally that we have to consider an intravascular
immunity which may be explained in many cases by the
phagocytic theory of Metchnikoff as well as a cellular immun-
ity which is not so explained and which is the object of the
biochemical theory formulated by Ehrlich.

Ehrlich's theory has for its basis, as we have seen, the
general conception that a reaction between two substances
is possible and can be determined only by chemical affinities
between these substances: and it would seem evident that a
body which is insoluble in the fluids of the organism can
exercise only a purely mechanical action on the fluids and
the tissues. Not being able to form any combination, it
cannot produce a reaction or any disturbance in the existing
equilibrium.

Ehrlich pictures the process of immunization in the follow-
ing manner: a toxin is attracted and fixed by a cellular sub-
stance which possesses a chemical affinity for it: the toxin
neutralizes this substance and is itself neutralized. The
neutral product thus formed is expelled from the cell as use-
less and as the cell cannot be permanently deprived of the
substance which the toxin has neutralized and which we will
call normal antibody, it reproduces not only as much as is lost,
but a little more; it is the custom of every living cell to react
to any sort of excitation by a multiplication of the substance
excited, or, in other words, by a reinforcement of the tis-
sues and of the organs excited in order to be able to support

22 THEORIES OF IMMUNITY

future excitations with less danger and fatigue. But it often
happens that the cell in this process of defense and rehabili-
tation exceeds the normal reaction: it makes a "normal
antibody" in much larger quantity than it can use and then
expels the excess, which passes into the blood and the fluids
to become antibody in excess or antitoxin, which, is found in the
serum of a hyperimmunized animal and which may be used
to cure disease in another subject, provided this disease is
caused by the same toxin secreted by the same germ.

Antibody-in-excess is then a substance which, according
to its definition, does not need to be transformed in order to
be assimilated. It is "homologous" for the organism and
may be considered as a sort of "substance in reserve" which
the organism may resorb according to its need.

Such as it was formulated by Ehrlich the theory of immun-
ity based on the general principles of chemical affinities is
applicable in reality to only a small number of special dis-
eases caused exclusively by certain toxins as diphtheria and
tetanus and even in these cases Ehrlich was obliged to add
purely hypothetical distinctions between certain properties
"toxophores" and " haptophores" of each toxin to explain
and distinguish their pathogenic and their immunizing
action.

As to the mechanism by which a pathologic state could
be provoked in an organism by infection; as to the question
of knowing why different diseases differed from each other
by a special evolution and by a total of symptoms more or
less characteristic to each; why in certain cases the processes
of immunization are complicated by an inverse process known
since the time of Charles Richet as "anaphylaxis"; and
finally, why there are certain substances for which the organ-
ism makes specific "antibodies" and others for which it does
not make them, as well as other questions, neither the one
nor the other of the two theories can explain.

Should we conclude that these theories cannot be of any
use because they are almost always incomplete and inade-
quate? Certainly not!

General ideas are always necessary to stimulate the studies
of new generations along new lines.

THEORIES OF IMMUNITY 23

All the works on serum diagnosis by Bordet and Gengou,
Besredka, Widal, Wassermann, and others, are the direct
emanation from the ideas of Metchnikoff. Modern chemo-
therapy is a creation of Ehrlich and his pupils. And all these
studies which have confirmed in part the theories of these
two great savants have had at the same time the result of
exposing their faults and discrepancies which it has been
necessary to correct with new researches, which in their turn
have permitted us to formulate a theory more complete for
the actual state of our knowledge.

Today we may conceive of a process of immunity in the
most general manner as a necessary reaction of the whole
organism against each and every substance which is not a
part of the organism and which is introduced into its interior
in any way whatsoever. From our present point of view we
may divide all these substances into two great groups:

First, those which on injection into the organism provoke
the formation of "specific antibodies," that is to say, of sub-
stances which appear in the fluids and tissues of the organism,
some time after the introduction of the foreign substance and
form with these substances products which are neutral or
active toward the organism.

Second, those to which the organism may accustom itself
in a certain measure but to which "specific antibodies" are
not formed. To this last group belong all those substances
of a relatively simple and well defined chemical composition
such as alkaloids, glucosides, mineral salts, in a word, crys-
talloids, which from the biophysical point of view, have the
common property of traversing dialyzing membranes and
of being able to be directly assimilated or eliminated. All
these substances if they are poisonous belong to the domain
of toxicology and will not be discussed here.

The substances of the first group including albumins of
every sort, bacterial secretions, venins, etc., have a composi-
tion and physicochemical constitution which is much more
complicated and even today imperfectly understood. From
the biochemical point of view, they have the common prop-
erty of not being able to traverse dialyzing membranes and
under the ultramicroscope they appear as very fine granules.

24 THEORIES OF IMMUNITY

To these substances of biologic origin have been added,
quite recently, several organic compounds obtained synthet-
ically and notably substances of the series of arsenobenzenes,
either simple or multimetallic, of which the chemical com-
position is well defined but of which the constitution is still
imperfectly understood.

The ability or lack of ability to traverse dialyzing mem-
branes is the most important distinctive characteristic of
these two categories of substances in their reaction on the
organism. Those which can traverse membranes rapidly
penefrate into the tissues, combining with substances of the
organism according to the laws of their chemical affinities
and produce immediately or at least very rapidly, effects
which are nutritive, exciting, toxic, hypnotic, or anesthetic
according to the nature of the products which they form
with the cell contents and according to the role of the cells
in the life of the organism. That part which is not fixed by
the tissues is quite rapidly eliminated by the kidne}^ or the
intestines.

On the other "hand the colloids, which do not traverse the
cell membranes which enclose each cell, cannot be either
assimilated or fixed by the tissues or eliminated without
being subjected to a special transformation. The charac-
teristic feature which results is the relative delay of the
reactions which they provoke in the organism. Furthermore,
we must well understand that there are no absolutely sharp
distinctions between colloids and crystalloids.

In setting up a series of more or less permeable dialyzing
membranes it is recognized that certain colloids traverse
certain membranes which others do not traverse, and that
the same membranes may allow one part of one colloid to
pass without the other. Thus a given membrane may pass
diphtheria toxin more easily than antitoxin and the toxin
will be only partially eliminated or dialj^zed. We must
necessarily conclude that all colloids, from the point of view
of the size of the granules of which they are composed are
not identical, that a colloid is not absolutely homogeneous
in all its parts, that it is composed of granules larger or smaller,
that is to say, of granules containing a larger or smaller
number of molecules.

THEORIES OF IMMUNITY 25

When a certain quantity of such a product is injected into
the blood of an animal it is found at the end of twenty-four
hours that one part has been able to penetrate into the tis-
sues and has been fixed in the cells, a second part has been
eliminated, while a third part is still found to circulate in
the blood. Thus in the case of disodoluargol (the disodium
salt of dioxydiaminoarsenobenzene-antimonious-silver-bro-
mide) ; if 10 eg. are injected into a rabbit's vein, after twenty-
four hours there will be found of it about a quarter in the
excretions and a quarter in the blood and we ought to con-
clude that the other two quarters have been absorbed and
fixed by the organs and tissues. Three-quarters of the
injected product have thus been able to traverse cellular
membranes within twenty-four hours while the final quarter
composed of larger granules has not been transformed into a
dialyzable product.

For each colloid the proportions may be different but for
the colloids of biologic origin we are unable to evaluate them
accurately because we do not know the chemical constitution.
We cannot conceive an idea of their quantity by biologic
reactions which are always uncertain. But w^e do know with
certainty that, as in the case of the arsenobenzenes, albumins,
like the toxins injected into the blood, are partly fixed by the
tissues some hours or some days after the injection; because
we see these tissues react with characteristic symptoms and
we know that no part of these products circulates for a long
time in the blood without being modified. Toxins generally
remain longer in circulation than albumins (white of egg,
serum, etc.). Thus we may conclude that they are more
fluid and less colloidal, than these latter.

We have seen above that all colloidal substances on which
experiments have been made up to the present time have,
from a biological point of view, another character in common:
injected into the blood or under the skin of an animal, they
cause, after a variable incubation period, the formation of
"antibodies in excess," that is to say, of products which
exert certain specific actions on themselves.

For want of a better term all these substances have been
grouped as "antigens" precisely because they provoke the

26 THEORIES OF IMMUNITY

formation of "antibodies" and at the moment they can
hardly be called anything else because all we know of them
except in the case of arsenobenzene, is that they are recipro-
cally *'anti." When after a preparatory treatment, the in-
tensity and duration of which may vary widely for different
antigens and different animals, the prepared animal is bled
and the blood serum mixed with the antigen in a test-tube,
reactions are seen which are not produced with the serum of a
normal animal and which are different according to the nature
of the antigen injected.

Toxins (diphtheria, tetanus, botulism), soiiie venins and
poisons of certain mushrooms cause the formation of anti-
bodies which neutralize the pathogenic effects of these poisons
without visible change. The mixture of the two liquids
remains clear and one can determine neutralization of the
"antigen" only by injecting the mixture into a susceptible
animal. After a sufficient preparation, a relatively very
small quantity of the blood serum of the treated animal is
able to neutralize a large number of "lethal doses" of the
antigen. One cubic centimeter of antitetanic serum may,
for example, often neutralize a thousand or even more times
the dose of toxin necessary to kill a guinea-pig and it is this
property of the antibody discovered by Behring and Kitasato
which E. Roux first utilized in the practical serum treatment
of diphtheria arid in the preventive treatment of tetanus
and which Calmette also used in the preparation of anti-
venomous serum.

Ricin, a vegetable antigen extracted from rice, whose com-
position is unknown but whose effects on the organism pre-
sented many analogies with that of diphtheria toxin, forms
with its antibody an insoluble compound. When antiricin
serum is added to a solution of ricin a precipitate is formed
and if the two solutions have been mixed in suitable propor-
tions the supernatant fluid will contain neither ricin nor free
antiricin. We have been able to conclude then that a part
if not all the antigen and antibody are combined or fixed one
by the other and are contained in the precipitate and this
supposition has been confirmed by experiment. By sub-
mitting the precipitate to the action of gastric juice which

THEORIES OF IMMUNITY 27

destroys the antibody and does not destroy the riein, it is
possible to recover the ricin which the precipitate contains.

Ricin presents another peculiarity which permits us to
study with a little more precision what it has not been possible
to study with diphtheria and with tetanus toxin. Ricin
dissolves red blood corpuscles in the test-tube. This pecu-
liarity is very precious because it permits us to make a large
number of tests under identical conditions and which are in
consequence exactly comparable; for example, to estimate
the pathogenic dose of diphtheria toxin or, in other words,
to establish a "unit of measure," it is necessary to inject
different quantities into a very large number of animals.
Each animal can be injected only once and as there are very
appreciable individual differences between the animals from
the point of view of their sensitiveness to the action of toxin,
even when they are of the same age, of the same weight and
apparently of the same species, one can obtain units of meas-
ure of only an approximate value, sufficiently exact for the
practical use of antitoxic serum but insufficient for the study
of the mechanism of the reactions.

With ricin the same solution (relatively more stable than
that of bacterial toxins) can be made to act in the test-tube on
the same blood cells of the same animal and these tests can
be multiplied almost indefinitely so that ''units of measure"
can be much more exactly obtained.

By studying the reaction of ricin and antiricin in the pres-
ence of blood cells it has been made possible to discover what
one may call the phenomenon of surcharge, that is to say, the
property of antigens to combine with their antibodies in
variable proportions and not according to the immutable
law of equivalents established for chemical combinations
as such. Thus, for example, when we mix one hundred toxic
units of ricin with one hundred antitoxic units, presumably
well titrated, a neutral mixture is obtained; but when the
hundred toxic units are added in fractions of five or of ten
units to one hundred units of antitoxin, a mixture is obtained
in which there will be a certain number (five to fifty accord-
ing to circumstances) of free toxic units. This fact has been
verified for other toxins and antitoxins and the conclusion

28 THEORIES OF IMMUNITY

follows that in mixtures of toxins with their antitoxins or in
general, of antigens with their antibodies, there are not
produced chemical combinations in the ordinary sense but
certain states of equilibrium which are variable for each
concentration or proportion of one product in the other;
in other words, if in certain proportions, two products can
exactly neutralize each other, either of them can fix its "anti"
en surcharge.

We will see further how this theory which results from
facts established by very exact experiments is important in
explaining the biologic action of antigens. For the moment,
it is necessary to remember that antigens may form with
their antibodies compounds which are soluble (in the cases of
diphtheria toxin, tetanus toxin, or venins) or compounds
wTiich are insoluble (in the cases of ricin or abrin). We may
also say in this last case that the antibody precipitates its
antigen and all precipitating antibodies are called "pre-
cipitins."

The discovery of antidiphtheritic serum gave birth to the
hope that it would be possible to prepare antibodies specific
for every infectious disease of which the bacteria were known.
Thus after the discovery of anthrax vaccine, it was hoped
that man and the domestic animals could be vaccinated
against all the contagions. It has been established that not
only all the microbes and their secretions are "antigens''
but that many other substances have a similar property of
causing the formation of specific antibodies. But we have
been obliged to remember that processes so simple and so
efficacious as vaccination against anthrax and serum therapy
in diphtheria cannot be applied to every infection.

The action of antigens on the organism including the
reactions which they provoke as well as the properties of
antibodies and the compounds which they form with their
antigens differ widely among themselves and produce many
contrary effects. Thus it is known that the injection of
bacteria, killed or living, as well as bacterial secretions pro-
vokes in the injected animal the formation of antibodies
which agglutinate and precipitate these bacteria "in vitro'';
that in certain cases (cholera) microbes are destroyed by

THEORIES OF IMMUNITY 29

their antibodies while in others (typhoid) they continue to
live and multiply without losing any of their virulence. With
rare exceptions, antibacterial sera not only do not cure dis-
eases but are rather more harmful than curative (typhoid,
plague cholera, tuberculosis). Thus preventive vaccination,
however efficacious and durable in small-pox and anthrax, is
usually very precarious and transient in many other diseases.

A series of facts have been discovered which without
touching infectious diseases directly have, from the theoretical
and practical point of view, given interesting results. Thus
it has been recognized (Bordet) that the serum or the blood
of an animal of another species provokes on injection the
formation of an antibody which can precipitate the serum
or dissolve the blood cells and can precipitate the serum of
the first animal and these researches, as well as the discovery
of bacterial precipitins, have led to the serum diagnosis of a
large number of infectious diseases, as well as to the reaction
called "complement fixation" (Bordet and Gengou, Wasser-
mann and others).

In order to understand the biologic action of antigens in
general, it is necessary to consider at first the characters of
the reactions which are common to each of them and then
for each antigen to study:

1. Its direct and immediate action on the blood and the
tissues; in other words, on the normal antibodies in the blood
and cells.

2. Its delayed action, that is to say, its action on the
''antibodies in excess" which, after a variable incubation
period, will have appeared in the organism.

3. The nature of its compounds with these ''antibodies in
excess" as well as the reactions which these compounds may
call forth in the tissues and in the blood.

It is very difficult to appreciate accurately the direct and
immediate action of antigens on the organism because we
have no idea of the quantity of actual antigen, that is of the
really active substance which is only part of a mixture and
which we cannot extract in pure state.

For example, we do know that a cubic centimeter of a
broth culture of diphtheria bacilli contains two or three hun-

30 THEORIES OF IMMUNITY

dred doses, lethal for a guinea-pig, while in the case of typhoid
or plague 2 or 3 c.c. of a broth culture are necessary to kill,
but we do not know to what quantity of active substance a
fatal dose corresponds nor whether typhoid or plague bacilli
produce quantities of toxins greater in the organism than in
artificial cultures. We cannot then know whether typhoid
or plague toxin produces on the organism effects analogous
to those of diphtheria toxin even if it were possible to obtain
typhoid and plague toxin in very much greater concentration
than other more or less poisonous substances in our culture
media.

At all events, however much we can judge by the apparent
results of present experiments, we may admit that the prod-
ucts of the secretions of certain bacteria as well as certain
other antigens may exercise a direct action on the organism,
while in the case of other bacteria the pathogenic reaction
manifests itself only after a special preparation — an indirect
action.

Thus, for example, we know that the toxins of diphtheria
and tetanus act quite quickly on normal tissues while tuber-
culin, malein, and very probably also the secretion of the
treponema of syphilis do not act under the same conditions,
but only on infected tissues and only in a longer or shorter
time after the infection. In the first case the tissue is sus-
ceptible without preparation of any sort; in the other it
becomes susceptible only after a specific preparation. The
action of antigens on tissues may then be direct or indirect
and this difference can be determined only by the physico-
chemical properties of these substances, or by the nature
of the compounds which they form with their "normal anti-
bodies," or finally, by the biologic properties of the compounds
thus formed which may be neutral or more or less pathogenic
to the organism.

In order to fully understand the first stages in the evolution
of a disease as well as the mechanism of the defense of the
organism, the question of the infecting dose is of capital
importance. We may assume that no antigen is exclusively
pathogenic as none is exclusively harmless. We can always
find for the most active toxin a dose, which will provoke no

THEORIES OF IMMUNITY 31

appreciable trouble in the organism, and the injection of the
apparently most innocuous albumin will disturb the normal
equilibrium whenever a certain dose is exceeded.

If then we assume with Ehrlich that a cell can be attacked
by an antigen only in case it possesses a substance (normal
antibody) which has a special chemical affinity for that
antigen, and if we complete this hypothesis by the experi-
mental fact analyzed above under the name of "phenomenon
of surcharge'^ we may easily explain the immunizing and
pathogenic action of the antigen. This action will be exclu-
sively immunizing when the quantity of antigen fixed by the
cell does not exceed or is less than the capacity of neutraliza-
tion by the antibody; it will be pathogenic when a quantity
of antigen fixed is larger than the neutralization capacity.
The normal functions of the cells will then be disturbed and
they will suffer more or less. Experience has shown that we
obtain an active immunity all the more intense and all the
more rapidly, in other words, we obtain a quantity of "anti-
body in excess" all the greater, when injections are restricted
and when they never exceed the w^ell-tolerated dose. We
may say, in a word, that immunization will be always
inversely proportional to intoxication or that the quantity
of "antibody in excess" will be directly proportional to the
intensity of the immunizing action of the antigen.

The study of certain infectious diseases will permit us to
better define our thought. Finally, we may conclude from
what precedes that every pathologic state caused by an
antigen is determined by the reactions which this antigen
may provoke in the organism and that the nature and the
gravity of these reactions must necessarily depend upon:

1. The affinities of the antigen for some other substance
intravascular or intracellular in the organism.

2. The nature of the reactions of the antigen with pre-
existing, that is to say, normal antibodies.

3. The importance of the role which the antibodies play
in the life of the cells and of the cells in the organism.

4. The nature and properties of the compounds which
the antigen may form with "antibodies in excess."

Any of these reactions may present special peculiarities

32 THEORIES OF IMMUNITY

in each pathologic state. It will be necessary to analyze
in detail a certain number of pathologic states caused by
different antigens in order to study their differences and
their common characteristics. We will begin this study by
the analysis of the action on the organism of the arseno-
benzenes because we know the chemical composition of these
substances. We will continue the studies by a series of
monographs having for their subjects the pathogenicity and
evolution of the better known infectious diseases: diphtheria,
tuberculosis, typhoid fever, with other intestinal infections
and septicemias caused by various parasites such as plague,
malaria and trypanosomiasis.

I

CHAPTER II.
PHYSICOCHEMICAL PROPERTIES

Transformations of the Arsenobenzenes "in Vitro" and in the Organism.

The discovery of the arsenobenzenes and especially of
their physicochemical and biological properties has opened
new horizons for the study of the transformation of anti-
gens. It has been recognized that certain arsenobenzenes,
more particularly arsenophenylglycin and dioxydiamino-
arsenobenzene (salvarsan) or its compounds, mono- bi- or
trimetallic luargol or cupriluargol are colloids and may
cause the formation of specific antibodies under the same
conditions as the biologic antigens which we have studied
heretofore. These substances possess properties essentially
analogous to every other antigen. Let us see how it has been
possible to consider them in this way.

The product which has been most particularly studied
from this pK)int of view is dioxydiaminobenzene-antimonious-
silver-bromide (luargol) because it is a strongly colored
red-brown solution which allows us to follow it in its trans-
formations much easier than simple arsenobenzene or arseno-
phenylglycin, the color of which does not differ essentially
from that of serum or other organic fluids. Luargol is a
yellow powder more or less dark colored, insoluble in the
basic state but soluble when slightly acidified with hydro-
chloric, phosphoric or citric acid; insoluble as a sulphate,
but soluble as a sodium compound when made slightly
alkaline.

The most convenient preparations for treatments and

experiments are the sodium compounds and monosodium

or disodium solutions can be obtained as well as intermediary

'alkalies between these two limits as well as hyperalkaline

solutions.

When intravenous injections of these different alkaline
3

34 PHYSICOCHEMICAL PROPERTIES

solutions are given to a series of animals, the apparent toxicity
of these products diminishes as their alkalinity increases.
Thus the rapid intravenous injection of 5 eg. of m6no-
sodium luargol will kill a rabbit in a few minutes while an
injection of 40 eg. of the same disodium product or a little
hyperalkaline will not kill the rabbit. Moreover, it is not
the addition of the soda which has rendered this product
less toxic because monosodium compounds are ordinarily less
toxic than the disodium, provided the injections are made
in minutes rather than in some seconds.

We must conclude, therefore, from this primary series of
experiments that the rapid death of an animal by no means
indicates the degree of toxicity of a product hut this rapid death
may he a phenomenon of some other nature.

In order to understand the causes of this rapid death it
has been necessary to undertake other experiments and
especially to study more closely the physicochemical proper-
ties of the arsenobenzenes as well as the transformations
which these products undergo "in vitro'' and "in vivo."
When we seal in a series of tubes, various solutions of sodium
luargol of different degrees of alkalinity in very pure distilled
water we find that these solutions remain for a long time
perfectly clear and when we expose them to the air and to the
light, they undergo no alteration for several minutes. On
the other hand, if instead of dissolving these products in
distilled water the solutions are prepared with salt solution
(6 to 10 per thousand of sodium chloride) we find that the
monosodium compounds precipitate in a few minutes; the
disodium in a few hours; the hyperalkaline in a few days.
Other salts, especially those of calcium are still more active
in this regard.

The rapidity with which a precipitate is formed in vitro
in salt mixtures coincides perfectly with the apparent toxicity
of the solutions and when an autopsy is made on an animal
which has succumbed in a few minutes to a large dose of one
of these solutions, precipitates are easily found in the heart
and in the pulmonary vessels as well as numerous infarcts in
all the tissues and organs. (Ch. Fleig, "Toxicite du Sal-
varsan.")

PHYSICOCHEMICAL PROPERTIES 35

What makes us hesitate to assume that the precipitant
action is the only cause of death, is that we may kill the test
animal by relatively small doses of the product and under
these conditions, although infarcts are found at autopsy,
intravascular precipitates are never found. Furthermore,
solutions of luargol in serum or in salt solution added to
normal serum retain their clarity longer than in pure dis-
tilled water. It seems certain that if the precipitate is not
found in serum it is only because of the difficulty of demon-
strating it and if serum does not precipitate luargol in vitro,
it is because it has lost the salts which play the greatest role
in the formation of the precipitate and which are retained
by the coagulum, and because albumins prevent precipita-
tion of colloids.

In fact when instead of treating the solution of luargol
with serum it is treated with fresh whole blood recently
drawn from the carotid and when after violently shaking
and centrifuging the mixture, the parts are analyzed sepa-
rately, much more luargol is found in the sediment than in
the supernant fluid and microscopic examination of the
sediment shows finely granular viscous masses.

To sum up, one may assume with certainty that the rapid
death of experimental animals caused by the sudden injec-
tion of monosodium preparations is caused only by the pre-
cipitate which fills the capillaries and thus produces con-
gestion and infarcts in different parts of the organism. The
symptoms observed: dyspnea, congestion of the mucous
membranes, epileptiform convulsions, gastro-intestinal dis-
turbances, fall of blood-pressure, subnormal temperature
are identical to those symptoms which are observed in the
phenomenon of "anaphylactic shock." The explanation
of the mechanism of the reaction and of the crisis which
results from it, is, in these cases, easy and simple. We have
seen that the arsenobenzenes, soluble in the state of di- or
even monosodium salts, are insoluble as neutral bases.
The weakest acids replace the sodium of the sodium com-
pounds. Consequently when injected into the blood the
compound loses its sodium by reason of the carbonic and
other organic acids of Ithe plasma, and becomes insoluble.

36 PHYSICOCHEMICAL PROPERTIES

It is then evident that the monosodium compounds will be
much more easily and rapidly transformed to bases than the
disodium or hyperalkaline compounds.

But as the monosodium compounds cause crises only when
injected rapidly and do not produce them when injected
slowly, we can draw logically this third conclusion, that, if
the formation of the precipitate is the primary cause, the
origin and the intensity of the disturbance is determined only
by the duration of the reaction. And to this conclusion
Doerr, Besredka, Mutermilch, and others, have come in
order to explain anaphylactic shock as caused by biologic
antigens. Thus we see :

1. That intravenous injections can cause immediate dis-
turbance.

2. That this disturbance arises by the transformation of a
soluble sodium compound to an insoluble base, that is to say,
to a precipitate.

3. That the degree of the disturbance is caused by the
rapidity with which the reaction takes place.

And we may therefore conclude that death or non-fatal
crisis which immediately follows injection is determined by
a reaction which is exclusively intravascular; that it does not
result from any toxic reaction of the product but from its
mechanical action on the capillary circulation.

Moreover, this is not the only expfanation which can be
given to this phenomenon. The reactions of the organism,
however localized they may be, are never simple. The
arsenobenzenes can be combined with a series of other sub-
stances which exist in the blood plasma and especially with
the calcium salts and can thus form compounds which are
more or less insoluble. By removing these substances from
the blood the injection causes a rupture of equilibrium and
especially a modification of plasma coagulability which
necessarily reacts on the intracellular fluids. The purely
mechanical intravascular action of emboli may therefore be
complicated by intimate and complex intracellular reactions
as in the case of biologic antigens. And in this case also, it
is the factor ''time," the rapidity of the reaction, which plays
the principal role in the severity of pathologic manifestations.

PHYSICOCHEMICAL PROPERTIES 37

The first stage of the transformation which the sodium
compounds of the arsenobenzenes undergo in the organism
consists then in making them change from the soluble state
to the insoluble state. They form precipitates or coagula
in the interior of vessels and these then provoke disturb-
ances which are more or less severe according to the in-
jected dose, the degree of alkalinity of the product, or what
amounts ultimately to the same thing, to the quantity
variable from one individual to another, of precipitating
substances which preexist in the blood: Other conditions
being the same, the reaction will depend also upon the rapid-
ity with which the injection is made.

There is thus a primary analogy between the action of
the arsenobenzenes and of biologic antigens and for greatet-
convenience in the discussion which follows we may call
the disturbances which immediately follow the injection
primary intravascular disturbances and we may group the
total of substances in the organism which concur in the forma-
tion of the precipitate under the name of preexisting or normal
antibody (and we know that in this case, these include acids
and salts, sodium chloride, calcium phosphate, etc.)

Arsenobenzene which becomes insoluble in the blood
plasma does not remain indefinitely in the organism in the
precipitated state. We may assume that only one part of
the injected product becomes insoluble; another part remains
in solution or passes to the precipitated state only after a
very short time, a fraction of a second.

In fact when we inject an animal intravenously with a
series of small doses of luargol, we obtain after a certain
incubation period a serum w^hich precipitates luargol of the
same alkalinity in vitro. But at the same time we know as a
result of seeking to define the conditions of the formation of
this precipitate, that the reaction is not simple; whatever
may be the proportions of sera and luargol in mixtures, total
coagulation of the latter is never obtained. It is found, further-
more, that in certain mixtures the precipitate already formed
redissolves in some minutes or some hours afterward.

In order to explain the cause of the particular nature of
all these reactions, we must remember these facts: That in

38 PHYSICOCHEMICAL PROPERTIES

a serum there are both acid functions and alkaline functions
in unstable equilibrium which may act more or less rapidly
on disodium luargol. That luargol is soluble in the mono-
and disodium state and also in the state of a mono- and di-
acid compound (hydrochloric, phosphoric or citric); and
that in the presence of the salt contained in the blood the
"mono" compounds precipitate more easily than the diacid
or dialkaline compounds.

The acid function acts first because there is in serum a
little free carbonic acid which precipitates one part of the
luargol as a base but soon afterward it is the alkaline function
which appears to hinder the coagulation of the part which
still remains in solution, and even to redissolve a part of the
precipitate already formed. In case the serum is hyperacid,
the precipitate will not form because certain acid compounds
of luargol are soluble.

It is important to note that this state of equilibrium
between the acid and alkaline functions may be different in
the serum of each normal animal, whether prepared by one
or several previous injections. The formation of a heavier
precipitate in the sera of prepared animals would indicate a
temporary predominance of the acid function or the presence
of a larger quantity of substances which form with the arseno-
benzenes, compounds less soluble (lime salts, etc.), or, what
is more probable, the two factors at once.

Heating to 60° or 65° has the effect of stabilizing or fixing
the acid and alkaline functions of serum and rendering it
neutral toward luargol. By adding acid to such a serum it
is possible to reactivate this precipitate again; by adding
sodium one reactivates the solvent action. By treating in
this way a serum normally neutral, whether heated or
unheated, we find that when heated in order to give us a
precipitate more acid is needed and in order to redissolve,
more alkali than in unheated serum.

So much of the chemical constitution of serum and anti-
body remains unknown that it will be hardly possible for us
to grasp an exact idea of the chemical mechanism of these
reactions. The key to the problem lies in researches of this
.kind in which the composition of one of the elements of the

PHYSICOCHEMICAL PROPERTIES 39

reaction is exactly known. For the moment it seems to us
important to recall the complete identity of the reactions
between serum and arsenobenzene on the one hand and
between serums and biologic antigens (albumins, microbes
and their secretions) on the other.

In fact it is more than probable that in the two cases the
nature and the mechanism of the reactions are the same. It
is the reaction of the acid and the alkaline functions of the
antibody, favored by the chlorides and phosphates of sodium
and calcium as well as certain substances, such as lipoids,
lecithin, cholesterin, which cause coagulation or dissolution
of the antigen; the action of the acid and alkaline function
ought to be fundamental and always the same. Thus should
be explained complement or alexine which is found indiffer-
ently in every normal serum, which disappears on heating and
which can reactivate the action of a specific serum antibody
when this is heated. Specific precipitant action should be
determined by the salts of calcium and other substances in
the plasma which form with arsenobenzenes, more stable,
less soluble combinations of which the quantity increases
as the result of a series of injections. Thus should be
explained the sensitizing substances or amboceptors which do
not disappear on heating, which combine with antigen, but
whose action must be assisted first by acids and oxidizing
agents, finally by alkalies in order to become appreciable.

Dioxydiaminoarsenobenzene has several afiinities. Tri-
valent arsenic can fix two molecules of metallic salts; amines
can be bound by acids or by formic aldehyde and through
this latter can fix a series of other substances. The oxyhy-
drate radicals may exchange their hydrogens for a series of
inorganic or organic bases. We know for example that when
one binds to the amines of arsenobenzene one or two molecules
of formaldehyde sulphonate of sodium, the product becomes
soluble in neutral medium and passes from the colloidal
state to the state of a salt and that by the substitution for
the hydrogen of the oxyhydrate radical one may make these
combinations soluble with salts of calcium.

A non-lethal dose of luargol injected into the blood of an
animal in the form of a sodium compound ought then to

40 PHYSICOCHEMICAL PROPERTIES

undergo a series of successive transformations without the
whole of the injected product ever being able to take part
simultaneously in each of the reactions which follow. We
may outline this transformation in a schematic method as
follows :

1. One part of the injected product, the more colloidal,
combines with the calcium salts, loses its sodium and thus
becomes rapidly an insoluble base of which one part continues
to circulate in the blood, while the other part is taken up by
leukocytes in the liver, the spleen, the lymphatic glands and
finally in the local lesions which become the site of an inflam-
matory process at the point of injection.

2. Another part of the product is not precipitated and
continues to circulate in the blood as a sodium compound.
This is probably the least colloidal part. It can traverse
certain membranes and thus penetrate to the interior of cells
where it is fixed as a base; that is to say, as a new insoluble
compound.

3. A third part finally becomes rapidly and almost simul-
taneously a base and a salt and as such may be partially
assimilated, that is to say, fixed by certain cells, partially
eliminated by the kidneys and intestines. In point of fact,
some minutes after the injection, traces of arsenobenzene
are found in the urine, to be sure in a soluble state, because
when one adds directly to the same urine a little of the
same solution of arsenobenzene there immediately forms an
abundant precipitate. The product has thus passed into the
urine in the form of a compound which is no longer precipi-
tated by salts.

The proportion of the product which is either engulfed by
leukocytes as a precipitate, or which continues to circulate
in the blood as a precipitate or which passes out and precipi-
tates in the cells of different tissues as a colloidal solution or
as a salt and finally the proportion which is immediately
eliminated, vary widely according to the injected doses,
the degree of alkalinity of the product, and the composition
of the blood of the injected animal at the time of the primary
injection (or later if injections are made in series). Thus
symptoms may vary infinitely.

PHYSICOCHEMICAL PROPERTIES 41

Experiments with doses of arsenic made by Mile. Michel
(by the method of Bougault) have given the following
results.

Experiment 1.— The whole blood of a rabbit bled white
is added to 10 eg. of luargol in a solution of 10 c.c. of distilled
water, is shaken violently to prevent coagulation and allowed
to stand for twenty-four hours. The fluid is centrifuged and
38 c.c. of dark liquid and 30 c.c. of precipitate are obtained
in which are found :

Arsenic, mg.

In the fluid 4.62

In the precipitate 15.37

in all the same 20 mg. of arsenic contained in the 10 eg. of
luargol of which about one-quarter remains in solution in
the serum and the other three-quarters have been partly
fixed by the formed elements of the blood and partly pre-
cipitated as finely granular viscous masses. Only a very
small quantity of coagulated fibrin is formed.

Experiment 2.— A rabbit is injected intravenously with
10 eg. of luargol dissolved in 10 c.c. of distilled water and is
bled twenty-four hours afterward. At the same time the
urine for the twenty-four hours is collected and is added to
the feces as well as to the intestinal contents after the bleed-
ing. The blood is centrifuged and we find :

In 55 c.c. of coaguium about 1 . 0 mg. of arsenic ^ •? r

In 37 c.c. of serum 2.5 " " r<*omg.

In 275 c.c. of urine 2.3

In 90 gr. of fecal matter 3 . 2

5 . 5 mg.

which means that a little more than a quarter of the injected
luargol has been eliminated in twenty-four hours by the
kidneys and intestines; about one-eighth remains in the
serum as un transformed luargol and one-sixteenth has been
absorbed and fixed in the elements of the circulating blood at
the moment of bleeding. In estimating at 10 per cent, the
quantity of blood remaining in the vessels, we may assume
that after twenty-four hours approximately one-half of the
luargol originally injected has remained fixed in the organs
or tissues.

42 PHYSICOCHEMICAL PROPERTIES

By comparing the doses of this second experiment with
those of the first, that is to say, by recognizing the large
proportion (three-quarters) of luargol fixed by the cells of
the blood in a mixture in vitro and the very small proportion
(one-sixteenth) found in the coagulum in the injected rabbit
twenty-four hours after the injection, we may assume that
the largest part of the luargol remaining in the organism has
been fixed by other elements, probably by leukocytes and
transported to the liver, spleen, and to the hemopoietic
organs.

By estimating the arsenic eliminated day by day following
a single injection, Mile. Michel found in certain cases traces
of arsenic in the urine twenty-four days after the injection
of a dose of 10 eg. in a rabbit weighing 2500 gm. In these
cases the elimination is not regular but takes place by suc-
cessive discharges (Emery and Jeanselme) at intervals of
three, four or even eight days. The largest quantity is
eliminated in the first sixty hours. By estimating the total
quantity of eliminated arsenic, we find that up to some
tenths of a milligram, the organism retains none of an arsenic
compound injected as luargol.

In man therapeutic doses of luargol exactly disodic (5 to
30 eg.) never provoke primary reactions but very small doses
of 5 to 10 eg. may produce a slight reaction of another nature,
rarely in two to three hours, generally in twelve to twenty-
four hours after the injection. These reactions are mani-
fested generally only after the first injection and consist of a
mild and transient fever (38° to 38.5° C.) for one to two hours
accompanied sometimes by chills and mild headache, very
rarely by nausea and diarrhea, corresponding to the fixation
of the product by the cells. The nature of the symptoms
leads us to suppose principally a reaction of the cells of the
central nervous system.

There is not generally a reaction to the second injection
nor to following injections even if the doses are progressively
increased because as we have seen above the elimination of
the product is very slow so that each of the successive doses
may be considered as a preparation or vaccination for the
following injection. There is even a sort of tolerance or a

PHYSICOCHEMICAL PROPERTIES 43

cellular immunity identical to that which is observed to
toxins and other biologic antigens. Cells multiply their anti-
bodies and may transform larger and larger quantities of
antigen (up to a certain limit) without being disturbed in
their normal functions.

Thus as far as it is possible to judge by repeated daily
analyses of urine and intestinal contents, of blood, organs
and tissues in a series of animals from the time of injection
to the total elimination of the injected product, we may
assume that arsenobenzene injected into the blood as a
soluble colloid passes partially as a precipitate into the
organs (liver, spleen, etc.) and partially as a solution into the
cells of different tissues where it becomes insoluble. That
part fixed by organs and tissues is transformed either into
soluble crystalloids which again pass into the blood and are
eliminated by the kidneys and intestines, because they have
no longer any affinity for the contents of the cells, or into
soluble semi-colloidal products which also pass into the
circulation but may again be fixed by the cells to be finally
transformed into neutral salts and eliminated as such. Some
of the injected arsenobenzene is transformed directly in the
blood to a neutral salt which is rapidly eliminated without
passing through the tissues. It is this last portion which
forms the primary discharges of the product eliminated in
the first twenty-four hours and which marks the first summit
of the elimination curve. The second summit which is
generally ended on the third or fourth day after the injection
indicates the second discharge of the product which has been
fixed and dissolved in the organs and tissues. Little summits
which are noted up to the tenth and thirteenth day corre-
spond to little successive discharges of the product which
have once or twice been refixed and redissolved in the tissues.

Summary.— Arsenobenzene is an arseniated or arseno-
antimonious or multimetallic amine which in the form of a
sodium compound does not exist as a free molecule but whose
component molecules in greater or less number, form col-
loidal granules. When injected into the blood, the colloidal
granule passes through a series of transformations which
lead to its disintegration and to the liberation of its molecules.

44 PHYSICOCHEMICAL PROPERTIES

From the physical point of view the transformation consists
of a series of successive passages from the state of colloidal
solution to the state of coagulum and from this latter to the
state of crystalloid solution.

From the chemical yoint of view, judging by experiments in
vitro the disintegration of colloids and the liberation of mole-
cules takes place by a binding of amines and the fixation of
bases by oxyhydrate radicals.

From the physiological point of view, the formation of
coagula may cause intravascular and intracellular disturb-
ances because in the blood, the reactions are rapid and sud-
den. In the interior of cells reactions may be also violent
but take place only after a longer or shorter incubation
period.

When at the end of these transformations, the molecule
of arsenobenzene has fixed to itself substances for which it
has an affinity, it becomes neutral for the organism and is
eliminated.

In a word, the processes are of exactly the same sequence and
of the same nature as those which an albumin undergoes when
submitted to digestion.

Digestion has no other effect than to liberate molecules of
amino acids. By certain substitutions of unsatisfied bonds,
these molecules are rebound by certain lateral chains to form
colloidal aggregates. It is very probable that these chains
which vary infinitely, constitute the specificity of albumins
and of antigens in general and that antibodies are thus noth-
ing else than the substances of the organism which replace
the chains and bind the affinities of the amino groups.

CHAPTER III.
EVOLUTION OF THE INFECTIOUS DISEASES.

DIPHTHERIA.

When one injects a non-fatal, but at the same time, a
highly pathogenic dose of diphtheria toxin under the skin of
a guinea-pig one sees a large edema develop at the site of
injection four to six hours afterward. From this edema and
at this time, almost all the injected toxin, can be extracted.
The edematous fluid injected into a second guinea-pig will
produce the same effect as the toxin injected into the first.
After a maximum development which is reached at the third
day, the edema is resorbed little by little and finally disappears
at the end of fifteen to twenty days. The quantity of toxin
which may be extracted diminishes at the same time.

When this edema is allowed to develop normally we will
find from the center to the periphery every degree of reaction
which toxin can produce on the cellular tissues of the guinea-
pig. At the center the most concentrated solution will
destroy the cells; there will be necrosis of the epidermis and
even of the dermis and the area will be marked by an eschar ;
at the periphery where the limit is marked by pallor, the
tissue will appear normal. When we try to produce the
Schick reaction at the site occupied by the edema after the
complete subsidence of the latter, we find that the zone
limited by the pallor neutralizes more of the toxin than the
central part formerly occupied by the eschar and more than
every other part of the animal's skin. The center of the
area previously occupied by edema will give a positive reac-
tion to a dose which gives a negative reaction on the per-
iphery. That is to say, there is a local immunity at the site
of the injection of the toxin and this immunity is most
marked at the site which has suffered least by the injection.

46 EVOLUTION OF THE INFECTIOUS DISEASES

This fact agrees with the observation of L. Martin^ that in
mild cases of disease immunity is estabHshed more rapidly
than in severe cases.

We may thus consider as proved :

1. That a certain pathogenic dose of diphtheria toxin is
fixed by the cellular tissues of the guinea-pig and that it is
retained in place eight or ten days without being either
neutralized or transformed.

2. That immunization or, in other words, the excess pro-
duction of the "normal antibody" is inversely proportional
to the intensity of the reaction and to the gravity of the
lesion.

These facts which do not accord with the theory of Ehrlich
are very easily explained in the light of experiments con-
cerning the nature and properties of mixtures of toxins and
antitoxins. We have seen in fact^ that diphtheria and tetanus
antitoxins as well as antiricin can ^x their toxins en surcharge;
that is to say, in a quantity greater than they can neutralize.

The passage into the wash water of tetanus toxin fixed
en surcharge by the nervous tissue in vitro^ as well as the
toxicity of the edematous fluid in the experiment above are
explained very simply in the following manner:

Normal antibody contained in the nervous cells or in the
cellular tissue (diphtheria in a guinea-pig, horse or man) can
neutralize a definite quantity of toxin. The product of this
combination is neutral for the cell and if the quantity does
not exceed its digestive capacity, the cell digests it, eliminates
it and reproduces the substance neutralized in a little larger
quantity than it normally contained. The cell will then be
capable of neutralizing and digesting without difficulty a
larger quantity of toxin. In this way it will establish a
certain local immunity and the tissue so immunized will give
a Schick reaction negative for a dose of toxin which otherwise
would give a positive reaction. But we have seen that the
rwrmal antibody can fix more toxin than it can neutralize

1 Bull, med., 1917, 10 fevrier.

2 Danysz, J. : Les proprietes et la nature des melanges de toxines avec
leurs antitoxines, Ann. dc I'lnst. Pasteur, mai, 1902.

' Danysz, J.: L'etude de Taction de la toxine tetaniquc sur la sub-
stance nerveuse, Ann. d. I'lnst. Pasteur, 1899, p. 15f).

DIPHTHERIA

47

and the more it fixes, the more difficult it is for the cell to
transform and eliminate the compounds thus formed. The
cell may then succumb to the task, that is to say, to a veri-
table indigestion and may even become incapable of repro-
ducing antibodies in excess.

It is useless to complicate the problem by assuming with
Ehrlich the existence in every toxin of a haptaphore group
which is exclusively immunizing and of a toxophore group
which is exclusively pathogenic, but we may certainly con-
clude from what precedes that the same substance will cause
one or the other of these reactions following doses measured
according to the degree of sensitiveness of the animal, that,
in a word, the immunizing or pathogenic reaction is a func-
tion of quantity and not of quality.

We may represent the process which can go on in the
edematous tissues of the above experiment according to the
following scheme:

'AT ANTIBOOV

T. TOXIN

T, toxin; AT, antitoxin. 1, 'pathogenic compound; the antibody is
surcharged with toxin; 2, 3, intermediate compounds; 4, non-pathogenic
compound; the antibody has fixed the quantity of toxin necessary only
to produce an immunizing reaction.

Between the two extremes, all intermediary steps are
possible but the quantity of toxin which an antibody can fix
en surcharge is not boundless and certain facts lead us to
suppose that this faculty of a tissue to fix larger or smaller
quantities of antigen depends not only on the local condition
of this tissue but rather on the general state of the organism.
Thus a dose of toxin fatal for a guinea-pig in three or four
days will produce on the second day an edema less volu-

48 EVOLUTION OF THE INFECTIOUS DISEASES

minous than a non-fatal dose. A dose fatal in thirty-six to
forty-eight hours will not produce edema at all. We must
assume first that the cellular tissue can retain only a maximum
of toxin beyond which the excess will be fixed by other tis-
sues more vital to the life of the animal and second, that this
general reaction of nervous origin influences the local reaction
by diminishing the fixation capacity of the cutaneous cellular
tissue.

There is no doubt but that all these reactions depend upon
physicochemical affinities and if we do not know the exact
mechanism we can at least say for the present that toxins
as well as antitoxins are colloidal substances, are aggregates
of molecules of varying size, and as seen in the ultramicro-
scope are spherical in form. We know that when causing toxins
and antitoxins to dialyze across collodion or gelatin mem-
branes of greater or less density, toxins pass easier than anti-
toxins, from which we can conclude that toxins form aggre-
gates less voluminous than antitoxins. The recognition of
these facts is sufficient for the moment to explain the curious
properties of mixtures of toxins with their antitoxins which
we have noted above.

In a rabbit treated by diphtheria toxin, the phenomena
observed are quite different from those in the guinea-pig.
Hypodermic injections provoke only a little redness at the
point of inoculation and if the dose is not speedily fatal the
rabbit succumbs almost always some weeks afterward to a
cachexia accompanied by nervous disturbances. In this
animal, the toxin is not retained in the cellular tissue, but
passes to the nervous tissue and produces disturbances which
are relatively much more severe. The same result may be
obtained in the guinea-pig by injecting a mixture of toxin and
antitoxin containing a slight excess of toxin or of toxin fixed
en surcharge. In this case the toxin fixed by antitoxin (in
vitro) is retained to a less extent by cellular tissue; it diffuses
into other regions of the organism and may produce in the
guinea-pig the same cachectic state and the same nervous
disturbances as toxin of itself produces in the rabbit.

The susceptibility of man seems to be intermediary between
that of the guinea-pig and that of the rabbit. In man toxin

DIPHTHERIA 49

is fixed by the cellular tissue but may also be fixed by nervous
tissue. The preventive vaccination of children by mixtures
of toxin and antitoxin may have, as noted by L. Martin^
consequences which are disagreeable if not serious. The
susceptibility of the horse is intermediary between that of
man and of the guinea-pig. In a horse treated by diphtheria
toxin nervous symptoms are less common than in man.
Edema of the subcutaneous cellular tissue develops in almost
the same way as in the guinea-pig.

We may thus explain why an exactly neutral mixture, that
is, one which contains no excess of antitoxin but may contain
an excess of toxin which is not pathogenic for the guinea-pig
will be also neutral for the horse, slightly pathogenic for
man, more so for the rabbit, and frankly toxic for birds which
are the most sensitive animals. For the same reasons, fixa-
tion of diphtheria toxin by cellular tissue should be considered
a reaction of preservation against reactions more pathogenic
for nervous tissue. The larger and stronger the barrier
which holds toxins in place in cellular tissue, the less will be
the chance for these toxins to approach nervous tissue.

The total of these facts permits us to represent the patho-
genicity and evolution of diphtheria in the following manner.
•Toxins secreted by bacteria are developed in the mucous
membranes of the throat, penetrate to the subjacent cellular
tissue and combine with the normal antibody of this tissue.
The two extreme things which may then happen are :

1 . The quantity or the virulence of the toxin secreted may
correspond exactly to the quantity of normal antibody which
can neutralize and digest it without difficulty and there will
thus be local immunity; and if the process lasts long enough
for the antibody to be able to reproduce itself in excess and
to pass into the blood as antitoxin there will also be general
immunity.

2. The quantity or the virulence of the secreted toxin or
rather the rapidity of the secretion may be too great for the
cellular tissue to be able to fix and retain it, so that a part of
this toxin will then pass into the organism and will produce

1 Loc. cit.

50 EVOLUTION OF THE INFECTIOUS DISEASES

severe disturbances which, if there is no timely intervention,
may result fatally. Between these two extremes we may
imagine an infinite variety of pathologic manifestations and
local or general immunizations. As we have indicated above,
acquired immunity will always be inversely proportional to
the severity of the attack.

But in this short discussion which has at the moment no
other object than to present in a certain order and to corre-
late a total of experimental and clinical facts most of which
result from the memorable researches of Roux and Yersin,
Behring and Kitasato, Vaillard, Ehrlich, L. Martin, Grancher,
Marfan and others: and to bring out the difference in the
evolution of diphtheria and most of the other infectious dis-
eases, we must dwell upon the exact significance of the
"incubation period" in pathologic states caused by antigens.

We are accustomed to designate the time which intervenes
between contagion and the appearance of the first symptoms
or, in other words the onset of disease, as the "period of
incubation." The studies of Ch. Richet, Hamburger and
Moro, Krauss, Besredka and Mile. Harde, Vaughan, Jobling
and others have shown that in the great majority of infectious
diseases as well as in pathologic states caused by previous
injections of heterologous albumins, of antigens, the " period
of disease" coincides almost exactly with the appearance of
specific antibodies in excess in the blood and we have been
able to establish that the symptomatology of all these patho-
logic states is determined by the nature and the site of* the
reaction between antibodies and antigens.

We may thus characterize the "period of incubation" by
reactions of antigens with normal antibodies; and the "period
of disease" by the reaction of antigens with antibodies in
excess.

But if we admit these distinctions and this seems neces-
sary, we assume that in diphtheria and in the diseases analo-
gous by the nature and action of their antigens (tetanus and
botulism), the pathological manifestations appear during
the "period of incubation" while the "period of disease" is
concerned with recovery; all of which is contrary to what
happens in the great majority of infectious diseases and in

TUBERCULOSIS 51

every case of anaphylaxis. This fact is explained quite natu-
rally when we assume that toxins form with their antitoxins
compounds which are absolutely neutral for the organism
and that antitoxins in excess can neutralize not only the
excess of toxins which has passed into the circulation but also
by virtue of its mass action the toxins fixed "en surcharge"
by the cells.

To summarize. By taking as a basis, the nature of the
infection, the nature and physicochemical as well as bio-
logical properties of the secretions of the diphtheria bacillus,
in other words, of its antigen as well as the nature and the
physicochemical properties of the compounds which this
antigen can form with its normal antibody and with the
antibody in excess (antitoxin), we may characterize diph-
theria in the following way :

Diphtheria— local, infectious disease.

Antigen colloidal, soluble, directly toxic. Without incu-
bation. Affinity especially for the cells of tissues of ecto-
dermic origin.

Normal an/i6o<:Zi/— intracellular. Can fix the antigen "en
surcharge." Compounds of the antigen with antibodies are
soluble.

Intracellular Reactions:

1. Immunizing for the cells and for the organism, if the
quantities of antigen and antibody are equivalent or if there
is an excess of antibody.

2. More or less pathogenic if there is an excess of antigen
and fixation of this latter by the cellular antibody "en sur-
charge."

Intravascular Reactions. — y^eutral compounds soluble and
directly assimilable or eliminable provided the quantities of
antigen and antibody (antitoxin) are equivalent or if the
latter are in excess. Can never provoke anaphylactic hyper-
sensitiveness.

TUBERCULOSIS.

A type of evolution quite different is represented by
tuberculosis.

Contrary to what we have seen for diphtheria toxin, the

52 EVOLUTION OF THE INFECTIOUS DISEASES

tuberculous antigen, tuberculin, exerts apparently no direct
pathogenic action on organs or normal tissues. But we know
that a dose of tuberculin known to be harmless for the normal
organism, or even a much smaller dose, will provoke in a tuber-
culous patient a general reaction more or less severe when
injected under the skin or into the blood and a local reaction
when a drop of it is placed on a break in the skin (cuti-
reaction) or on the cornea (oculoreaction). We also know
by the reaction of complement fixation that this general and
local hypersensitiveness coincides with the existence of a
specific antibody in the blood.

But this antibody does not neutralize tuberculin in vitro,
A mixture of it with tuberculin will cause a general and local
reaction identical to those provoked by tuberculin alone.
We have a total of facts which seem contradictory. The prob-
lem of the evolution of tuberculosis is much more compli-
cated than that of diphtheria. To solve it, it is necessary
to analyze carefully each of the elements which compose it.
Before beginning this study it is necessary to explain the
exact meaning of the terms which will be employed in what
follows.

We will define :

1. Artificial tuberculin as the total of the secretions of the
tubercle bacillus obtained in vitro, whatever may be the
culture medium and the method employed in its preparation.

2. Natural tuberculin, as the total of the products secreted
by the bacilli in vivo during infection.

3. Normal antibody, as the intracellular substance which
possesses a specific affinity for tuberculin and which combines
with it in the interior of cells; and

4. Antibody in excess, or antituberculin as the same sub-
stance as the normal antibody but multiplied and existing
in excess in the tissues and in the blood of the diseased.

After reviewing the total of experunental work and clinical
observations published on tuberculosis and tuberculin since
Koch's discovery of the germ and the facts well established
and verified by numerous experiments; we know that artificial
tuberculin does not act on normal tissues and that repeated
injections of this product do not provoke the formation of an

TUBERCULOSIS 53

antibody in excess comparable, for example, to diphtheria
antitoxin in the organism. But that natural tuberculin
becomes pathogenic for these tissues after a longer or shorter
incubation and that this natural tuberculin provokes in the
affected organism the formation of specific antibodies in excess
which can be found in the blood (reaction of fixation) and in
the tissues (cutireaction) .

From the fact that a true antigen can act only on a sus-
ceptible organism, one ought to assume that artificial and
natural tuberculin are two different substances since the
normal organism seems insensible to the action of the first
and on the contrary, acquires a specific sensitiveness to the
action of the second.

This suggests that there is in the cells a normal antibody
for natural tuberculin but no normal antibody for artificial
tuberculin and from the point of view of specificity of antigens
this would be a very important point of difference. Moreover
we know with some certainty that artificial tuberculin pro-
duces on the tissues of an organism infected by tuberculosis,
reactions which are identical to those which natural tuber-
culin produces in tuberculous foci. There is then a contra-
diction, but a close analysis of the known facts will easily
demonstrate that this contradiction is only apparent.

By studying the development of a tuberculous lesion, we
find, according to the researches of Besredka and others, that
lesions around tuberculous foci become manifest only some
time after the appearance in the blood of patients of the anti-
body in excess and a positive cutireaction shows at the same
time that the tissues of a tuberculous individual are impreg-
nated with this antibody in excess at a time when not a single
clinical symptom reveals the presence of a tuberculous focus.
The jjresence of antibody in excess in the blood is thus anindis-
pensable condition to pathogenic reaction and if this is so, we
may represent the evolution of the tuberculous lesion in the
following manner:

The bacteria of a tuberculous focus secrete natural tuber-
culin of which a part is fixed by the cells of the surrounding
tissue while another part, "the excess," diffuses into the gen-
eral economy. We will see later what happens to this excess.

54 EVOLUTION OF THE INFECTIOUS DISEASES

For the moment we can say with certainty that this natural
tuberculin is no more pathogenic for healthy tissues than
artificial tuberculin. The one and the other become patho-
genic only when in combination with tuberculous antibody
in the interior of cells. If natural tuberculin provokes the
formation of antibodies in excess, and if it has not been pos-
sible up to the present time to obtain an analogous hyper-
sensitization by repeated injections of artificial tuberculin, it
is very probably because the injections, even if often repeated,
do not act in the same way as the slow but steady diffusion
of the bacterial secretion from a tuberculous focus. We can
also say with certainty that it is in consequence of the action
of these bacterial secretions, harmless for normal tissues, that
antibody in excess is formed and we must necessarily con-
clude that normal intracellular antibody can fix tuberculin
in quantity strictly immunizing or, in other words, easily diges-
tible and hence not pathogenic for the cell. There is here no
fixation by the normal antituberculin of tuberculin "en
surcharge," which might be directly toxic as in the case of
diphtheria antitoxin and toxin. This immunizing action has
the effect of multiplying the normal antibody of which a
certain quantity remains in the sensitive cells and of which
the surplus passes into the circulation. Experience has
shown that tuberculin secreted by a tuberculous focus pene-
trates throughout the organism and that it provokes immu-
nizing reactions in every tissue, especially in those of ecto-
dermal origin.

At a given moment after an incubation period, longer or
shorter according to the virulence of the bacteria and the
number of foci, all the sensitive cells of the organism especially
those near the infectious foci are surcharged with antituber-
culin. That phase of the evolution of the disease which
corresponds in diphtheria to immunization and recovery
(because the combination of toxin with an excess of antitoxin
is completely neutral for the organism) determines in tuber-
culosis the beginning of the pathologic state because the
compound of tuberculin and antituberculin fixed in the cells-
is pathogenic for the cells.

Thus for diphtheria it is the surcharge of toxin; for tuber-

TVBEltCULOStS 55

culosis it is the surcharge of antibody in the interior of the cells
which determines the pathologic moment and the lesion.

It seems that this intracellular surcharge of antituberculin
is not indifferent for the organism even without the inter-
vention of tuberculin. In fact although an animal strongly
immunized and surcharged with diphtheria or tetanus anti-
toxin does not seem to suffer at all, a man or an animal sur-
charged with tuberculous antibody becomes rapidly hyper-
sensitive to all sorts of external agents such as changes in
temperature, fatigue and especially a series of non-specific
products such as the antigens of pneumococci, pyocyaneous,
Metchnikoff's vibrio, divers sera, creosote, etc. This non-
specific hypersensitiveness may be explained by the hypo-
thesis that the substance which constitutes the tuberculous
antibody in the cell is called upon to play a more important
role in the life of this cell than, for example, diphtheria anti-
body, and that the cell cannot easily rid itself of the excess
of antibody which it has produced. In a word there results
a sort of hypertrophy of an intracellular organ and of a
function which thus becomes abnormal and harmful for the
cell and for the organism.

An interpretation according to these theories of some of
the facts determined experimentally by A. K. Krause^ may
serve to clarify the discussion:

This investigator found that a subcutaneous injection of
living tubercle bacilli into a normal guinea-pig will cause in
this animal a local lesion (reaction) which will appear only
after a relatively long incubation period.

However, a guinea-pig treated in this way, will, after the
healing of this local lesion or tubercle, always react to a new
dose of tubercle bacilli (or tuberculin) in a very different
way from the first reaction.

The second dose, if given subcutaneously, will produce a
second tubercle but in a very short time and the lesion w^ill
be by comparison, large and severe. However, instead of
slowly progressing in size perhaps until the death of the
animal, the initial severity will soon subside and the
"tubercle" will heal.

1 Kraiise, A. K.: Jour. Med. Research, 1916.

I
56 EVOLUTION OF THE INFECTIOUS DISEASES

Another point: Artificial tuberculin applied to the skin or
the eye of the first guinea-pig will not evoke a reaction until
after the tubercle has been established and has begun to
heal— and this test can thereafter be elicited throughout the
life of this guinea-pig unless at some time the animal is over-
whelmed by a "miliary tuberculosis."

In a normal pig, a "tubercle" does not appear until the
production of antituberculin in excess. This antituberculin
in excess remains in all the cells of the guinea-pig " en sur-
charge" and can fix to these cells in equal quantity its own
"anti"— that is to say, tuberculin whether artificial or natural
whenever injected. And in this way is explained the local
and general reactions of the second injections. That this
second dose produces only a temporary reaction and that the
animal ultimately recovers (showing immunity) is explained
by the persistence of antituberculin.

However, when the available antituberculin is less than the
new dose of tuberculin, the organism will be overwhelmed,
local skin and eye reactions can be no longer produced and
the animal will die.

Let us now return to the tuberculous focus. The bacteria
of this focus secrete tuberculin which spreads to the sur-
rounding tissues and causes in the cells a multiplication of
antibodies. These cells then become capable of fixing larger
and larger quantities of tuberculin without pathologic mani-
festation up to a certain limit (greater and greater immunity
to tuberculin). When this limit is passed the quantity of
antituberculin en surcharge forms with tuberculin pathogenic
compounds and it is only then that the lesion appears.

The first phase of the infection, therefore, corresponds
to the incubation period, the second phase to the period of
disease. It is thus evident that from the beginning of the
infection, the evolution of a tuberculous focus will be deter-
mined by the three following factors :

1. The quantity of tuberculin secreted by the bacteria.

2. The multiplication of the antibodies in the cells which
surround the focus.

3. The quantity of tuberculin which is fixed by the cells
and which will diffuse into the general economy.

TUBERCULOSIS 57

Experience shows clearly that the production of antibody
far exceeds the production of tuberculin. Besredka deter-
mined that in the blood of guinea-pigs, antituberculin in
excess appeared four days after the infecting injection and
before any pathologic manifestation, either local or general.
In consequence there is in the evolution of a tuberculous
focus a period during which all the tuberculin secreted by the
bacteria will be fixed in the focus or the surrounding tissue.
During this period the excess production of antituberculin
will be forcibly stopped, the quantity of it which circulates
in the blood will progressively diminish and at the same
time, thanks to the intervention of leukocytes, the tuber-
culous focus can be isolated from the remainder of the
organism without forming a sequestrum. The lesion may
definitely heal by a mechanisin which we will examine later
leaving a scar, or a focus can remain in a latent condition
for a longer or shorter time and can be revivified by the onset
of another disease or sometimes even by a simple traumatism.
The excess production of antibody in the cells thus becomes
the cause of the lesion and of a possible cure.

Summary. — There results from the total of studies on
the properties of tuberculin and antituberculin as well as on
the reciprocal reactions of these substances on the organism :

First.— That all tuberculins, regardless of their method of
"preparation and origin {in artificial broth cultures or infectious
foci) J act by the same principle of pathogenicity, and that the
observed difference of action results only from their concentra-
tion and from the medium in which they are placed. The
biologic differences which are observed may be of the same
sort as those, for example, which are found in wines of differ-
ent ages in which the alcohol, always the same, but in greater
or less quantity may be associated with all sorts of substances
which modify its action in a very definite way. We may
assume with the certainty that the virulence of all germs
depends only on the quantity of the pathogenic sub-
stance secreted which passes to the free state in the external
medium.

Second.— That antituberculin which multiplies in the cells
by the action of tuberculin remains attached in the cells probably

58 EVOLUTION OF Tti^ INFECTIOUS DISEASES

by bonds which have vitally important functions to fulfill; the
cells may thus be surcharged mth antituberculin.

Third.— That the cells surcharged with antituberculin fix
corresponding quantities of tuberculin and that it is on account
of this abnormal quantity that the compound of tuberculin and
antituberculin becomes pathogenic for the cells.

Fourth.— That the excess of antituberculin confers on the
cells and on the organism a nonspecific hypersensitiveness to
every sort of foreign agent as well as a specific hypersensitiveness
to tuberculin.

Fifth.— That granting this is true, the impossibility of an
antituberculin immunity such as one finds in d phtheria is
easily explained.

Moreover the studies of Koch, Neufeld, Klimmer, Behring,
F. Arloing, Chauveau, Calmette and Guerin, Vallee and
others, on vaccination of calves have shown that it is possible
to increase the resistance of these animals to experimental
tuberculous infection or to natural contagions and although
it is impossible to obtain this relative immunity by bacterial
secretions, it ought to be obtained by the intervention of
bacterial bodies, in other words, by the reactions of the
organism against the germ.

What are these reactions? The study of this question is
less advanced than that of the reactions between tuberculin
and antituberculin although it has been established with
certainty.

First, that the "preparatory" injections of tuberculous
cultures, dead or alive, but not virulent, provoke in the
organism the formation of an antibody which agglutinates
and precipitates the germs in vitro.

Second, that the bacteria, dead or alive and a virulent, are
more or less rapidly absorbed; that is to say, digested by the
organism.

Third, that if this absorption is complete, acquired immun-
ity is of short duration, less than one year.

Fourth, that if, on the other hand, digest' on of living germs
injected as a vaccine is not complete there are formed small
latent infectious foci. Immunity against one injection or one
virulent contagion lasts a long time as the bacteria in these
foci live.

I

TUBERCULOSIS 59

Fifth, and finally, an attack of tuberculosis spontaneously
cured does not confer a longer immunity than a healed vac-
cination (Calmette, Vallee). Tuberculosis thus resembles
syphilis in which the possibility of a spontaneous reinfection
is considered as a proof of previous cure.

In considering the total of reactions provoked in the
organism by the secretion of living tubercle bacilli and by
the digestion of these bacilli which goes on under conditions
which are as yet impossible for us to define in a wholly satis-
factory way, we can represent the evolution of spontaneous
tuberculous infection in the following manner:

The bacteria which penetrate into the organism by the
digestive of respiratory tracts are taken into the circulation
and may remain there for a longer or shorter time before
being fixed in the different tissues, glands and organs. A
certain proportion of these fixed bacteria, all the greater
when the bacteria are less virulent (when they secrete less
pure tuberculin), and mce versa are certainly digested and
produce a precipitating antibody which w^e may call anti-
bacillin. This function belongs properly to the bacteria
fixed in the organs. Those which are fixed in the tissues
secrete tuberculin and become the origin of infectious foci
and of lesions, whose evolution has been analyzed above.
The successive phases of the disease are thus determined
first by the digestion of bacteria and the production of anti-
bacillin, and second by the secretion of tuberculin and the
production of antituberculin.

If the bacteria are less virulent the proportion of those
which are digested and which produce antibacillin is greater
than the proportion of those which are fixed in the tissues and
which produce the formation of antituberculin in excess.
On the contrary, when the bacteria are virulent it is the anti-
tuberculin reaction which predominates; infectious foci be-
come more numerous and lesions more severe.

The experiments of Besredka, and of Manoukhine show
with sufficient precision the evolution of the antituberculin
reactions in the successive phases of tuberculosis in the
guinea-pig. In these very sensitive animals antituberculin
appears in the blood four days after the injection of the virus;

60 EVOLUTION OF THE INFECTIOUS DISEASES

its quantity increases up to the fiftieth or eightieth day, falls
and increases again at about the ninetieth day and disappears
completely some few days before death. Thus the disease
develops parallel to the production of antituberculin. The
temporary disappearances of antituberculin from the blood
are the consequence of the limitation of the bacterial secre-
tions to the tissues which surround the infectious foci because
of antituberculin in excess and as soon as this excess dis-
appears from the circulation the same process begins again
if not finally stopped by the death of the animal. The
extreme susceptibility of the guinea-pig for tuberculosis
probably arises from the almost absolute incapacity of this
animal to digest Koch's bacillus and to produce antituber-
culin.

Such are the general principles which determine the evolu-
tion of pathogenicity of tuberculosis in so far as experiments
and clinical observations permit us to formulate them. They
may be summarized in a few lines :

1. Infection is followed by an incubation period during
which the digestive attack of the bacterial secretions and of
the bacteria themselves results in the production of anti-
tuberculin and antibacillin.

2. The period of disease begins at the moment when
intracellular antituberculin in excess has fixed a sufficient
quantity of tuberculin so that the compound of tuberculin
with antituberculin which is fixed in the cell can become
pathogenic (undigestible) for the cells themselves.

3. Antibacillin aids in the destruction of the bacteria
which are multiplied in the organism.

4. The different phases of the evolution of the disease are
determined on the one hand by the number and the stage of
development of the tuberculous foci (that is to say by reac-
tions successively immunizing and pathogenic between
tuberculin and antituberculin): on the other hand by the
reactions of the antituberculin with the bacteria. During
this disease period pathologic impulses which follow one
another at longer or shorter intervals and characterized by
fever, lassitude, sweats, etc., are provoked by the local or
general rupture of the antituberculin blockade. In case

TUBERCULOSIS 61

of local rupture the tuberculin thus liberated provokes a con-
gestive reaction in all the other foci; quite as an artificial
injection of tuberculin.

5. Each of these impulses may be followed by a definite
recovery, thanks to the intervention of antibacillin or by an
aggravation of the disease caused by the bacteria thus
liberated and not destroyed, which become centers for new
foci and new lesions.

6. Immunity acquired by the healing of a spontaneous
or artificia' infection is of short duration, most probably
because the production of antibacillin is rapidly stopped after
the disappearance of bacteria.

7. We may consider it as proved that the presence of living
avirulent bacteria in the organism confers on cattle a com-
plete immunity against virulent reinfections.

Tuberculosis may be characterized in the following
manner :

Disease of local infectious foci which may give rise to septi-
cemic metastases.

Antigen soluble (tuberculin), non-pathogenic for normal
tissues as it cannot be fixed by antibodies en surcharge.

Normal antibody intracellular can multiply in the cells in
excess and remain fixed in the interior of cells "en surcharge."

Intracellular antibody "en surcharge" (antituberculin) is
pathogenic for the cells— hypersensitiveness non-specific.

Intracellular compound of normal antibody and antigen is
non-pathogenic (digestible) and causes the multiplication of
antibodies.

Intracellular compound of antibody en surcharge and of
antigen is pathogenic (non-digestible) for the cells and causes
the destruction of the cells.

Bacterial antigen (bacterial bodies cause the formation of
a specific agglutinating antibody (antibacillin) .

Antibacillary immunity not antitoxic immunity.

Intracelhdar anaphylaxis and not intravascular anaphylaxis.

From the total of the theories which we have just reviewed
we are forced to conclude that in tuberculosis it may not only

62 EVOLUTION OF THE INFECTIOUS DISEASES

be a question of an immunity from antituberculin but since
it is shown that tuberculosis can heal spontaneously and
that a certain relative immunity may be obtained by bac-
terial vaccination we should necessarily assume that a
bacterial therapy and a specific chemotherapy should very
appreciably aid the destruction of the bacteria. Serum
therapy would be applicable only in the stages of the disease
during which one could establish the absence in the organism
of antibody in excess.

TYPHOID FEVER.

We know that completely digested albumins, that is to
say, those which are transformed to their amino-acids are
not antigens, while albumins themselves as well as all incom-
pletely digested compound are antigens. We must suppose
that in infections of intestinal origin bacteria as well as the
products of bacteria can resist digestion and can penetrate
into the cells and capillaries of the intestinal mucosa and
that only the individual and the species unable to digest the
bacteria and reduce them to amino-acids can be infected in
this way. It is at present not possible to follow all the phases
of the pathogenicity of typhoid fever in man, but it can be
done in paratyphoid fever of young rodents and the patho-
genicity can be represented as follows :

Bacteria enter by the mouth, are in large part destroyed
in the stomach but the products of this destruction are not
completely digested and pass with the surviving bacteria
into the intestines where these latter can multiply until the
bacterial products which resist intestinal digestion are in
part absorbed by the cells of the mucosa.

This primary absorption determines the formation of
more or less severe areas of congestion analogous to those
which are observed when a small quantity of dead bacteria
are introduced under the skin. This congestion favors in
its turn the penetration into the mucosa and into the capil-
laries of fresh quantities of bacterial products and even of
living bacteria. The result is that the severity of the con-
gestion is increased.

TYPHOID FEVER 63

The first bacteria which penetrate into the blood are
engulfed by leukocytes and taken to the hemopoetic organs
where they are more or less completely destroyed and where
those which remain viable produce little foci of infection
and lesions. During all this period typhoid antigens, bac-
terial secretions as well as products of bacteriolysis are found
in excess of the normal a7itibodies which preexist in the cells
of every organism susceptible to the action of antigens. The
areas of congestion are caused by the fixation "en surcharge"
of antigens by normal antibodies. Thus, for example, when
an injection of antigen is made into or under the skin, a mild
local congestion is produced; but when it is given into a vein,
there will be no appreciable reaction because here the antigen
will be distributed to a much larger number of cells and will
therefore never be in excess.

Under the continued action of new quantities of antigen
which increase steadily until the spontaneous death or destruc-
tion of the bacteria, there are formed in the organism larger
and larger quantities of antibodies. The excess of these is at
first stored "en surcharge" in the cells in which it is formed;
but after a certain maximum is reached, this excess is finally
thrown off into the blood by a series of sudden discharges.

At a certain given moment the antibody thus appears in
excess in the blood in spite of the continued multiplication
of bacteria and we must necessarily conclude that the pro-
duction of antibody is more rapid than that of antigen. The
moment at which we begin to find antibody in excess in the
blood coincides generally with the appearance of the first
severe symptoms which characterize the disease. This is
the end of the period of incubation and the beginning of the
period of disease.

If then one could describe the condition in which the
infected organism is found from the point of view of immunity
and anaphylaxis or if we could stop the evolution of the
infection at the end of the incubation period or at the moment
of the appearance of antibodies in excess we would find that
the organism had developed a greater resistance to a new
infection, in other words, that it had acquired a certain
degree of active anti-infectious immunity, and also that it
had become susceptible to active anaphylaxis.

64 EVOLUTION OF THE INFECTIOUS DISEASES

The theories of this condition cannot be demonstrated by
experiment but the result would be the same if in place of an
infection by living bacteria the organism had received an
injection or a series of injections of dead bacteria. At the
moment of the appearance of antibodies in excess it would
be immunized against the dose of living bacteria pathogenic
for controls and would be hypersusceptible (anaphylactic)
to a non-pathogenic dose of dead bacteria and finally hyper-
susceptible to a dose of living bacteria greater than its degree
of anti-infectious immunity.

Whether the bacteria be living or dead at the end of the
incubation period, the organism will be exactly in the same
condition from the point of view of immunity and anaphylaxis.
If the results are different it is because living bacteria con-
tinue to multiply, but if the injections of dead bacteria in
considerable doses were continued after the time when the
organism became surcharged by an excess of antibodies the
picture of spontaneous infectious disease would be very
probably and almost certainly duplicated. In fact practical
antityphoid vaccination has shown that the subjects more or
less immunized by a previous healed typhoid infection are
infinitely more sensitive to the vaccine than normal subjects
and in the cases of alimentary poisoning caused by para-
typhoid swallowed in modified doses the crises are all the
more severe if the subjects are already strongly immunized.^

But then one may ask why does a spontaneous infection
not stop at the end of the incubation period since the patient
is at this moment more immunized than at the start of the
infection? This very thing happens much more often than
has been supposed at the present time not only in typhoid
but in every other infectious disease. In certain cases the
few mild symptoms permit the recognition of a disease which
aborts, but the great majority of these cases escape observa-
tion and acquired immunity can be revealed only by a study
of the serum, by vaccine reaction or by the opsonic index.

^ A dozen persons, at least one of whom was immunized normally against
paratyphoid, swallowed by accident a heavy dose of paratyphoid bacilli
in milk. All of them were more or less indisposed, but only the immu-
nized individual was severely ill.

TYPHOID FEVER 65

The explanation of these facts appears very simple. The
continued development of the disease after the end of the
incubation period or the abortment necessarily depends upon
the degree of acquired immunity or on the quantity of formed
antibody and on the quantity of bacteria which exist at this
moment in the organism because immunity is only relative
and the protection is only against a certain minimum dose
of bacteria. Thus the relation between these two quantities
which tip the balance to one side or the other, individual
differences between the degrees of natural or acquired immun-
ity at the moment of infection and finally differences of
quantity or virulence of the infecting bacteria may be very
variable.

In the explanation of the results of these reactions it is
necessary to note: on the one hand, the fact, proved by
experiment, that the quantity of antibody formed at a given
moment as well as the rapidity with which it is formed is,
within certain limits, inversely proportional to the quantity
or the virulence of the injecting antigen; and, on the other
hand that the final result of all these reactions may depend
not only upon the direct action of the antigen upon the anti-
body or the cell which contains it but on the disturbance
which the lesion or the "complication" once produced will
cause in the function of the organism. If this is true, how
can we represent the causes and the origin of each pathologic
manifestation which characterizes the septicemic infectious
diseases, typhoid fever in particular?

We know that, for the diseases caused by toxins (diph-
theria), cure begins with the appearance of antibodies in
excess while in the case of typhoid it is the disease which
begins precisely at this moment. We then afRrm that the
incubation period of typhoid coincides with the disease period
of diphtheria or, to be more exact, that in diphtheria there is
simultaneously incubation, from the point of view of produc-
tion of antibodies, and disease with its pathologic manifes-
tations. And if this is true, we may assume by correlating
what precedes that in diphtheria pathologic manifestations
result from the direct action of the antigen-toxin on the
normal intracellular antibody and that the compounds of
5

66 EVOLUTION OF THE INFECTIOUS DISEASES

this antigen with antibody in excess do not produce an active
anaphylactic state. In typhoid, however, we may suppose
that the bacterial antigen secretion is not pathogenic for
nonnal tissue or else that this secretion is not the whole
antigen and that the pathologic symptoms which are mani-
fested at the moment of appearance of antibodies in excess
can be only the result of the combination of these antibodies
with antigens produced by bacteriolysis. Thus the syndrome
of the period of disease in typhoid in exclusively anaphylactic.
From the point of view of pathogenicity we may thus review
the two cases by the following formulae :

Diphtheria: Toxin + Normal antibody = Disease.
Toxin + Antibody in excess = Immunity and cure
Typhoid: Toxin (?) + Normal antibody = O ?
Products of bacteriolysis + Normal antibody = Incubation.
Products of bacteriolysis + Antibody in excess = Immunity and
anaphylaxis.

Thus we have seen that in typhoid there is no toxin-
secretion nor bacterial-antigen analogous to that of diph-
theria or if there is one, it is neutralized at the end of the
incubation period by the appearance of antibody in excess
(as in diphtheria) and can no longer produce any apparent
disturbance. If at this moment it becomes pathogenic it
will produce only anaphylactic disturbances. But in typhoid
there is certainly penetration and multiplication of bacteria,
or at least of products of bacteriolysis in the form of albumin
and it is absolutely certain that there are albumins which
cause disturbances characteristic of the period of disease as
in the case of every other heterologous albumin when com-
bined with its antibodies in excess.

Thus we may conclude with certainty that in typhoid the
disease consists of an anaphylactic crisis which is chronic or,
in other words, of a succession of anaphylactic crises which
are determined at each moment by the three following factors:

1. The appearance of the albumin antigen as a result of
the'multiplication of bacteria.

Il 2. The quantity of antibodies in excess formed by the
organism.

TYPHOID FEVER 67

3. The influence of the lesions in the different tissues and
organs on the general state of the organism.

Most if not all septicemic infectious diseases belong neces-
sarily in the same class. A septicemic bacteria can be patho-
genic only in case its albumin is antigenic for the organism;
in which case there will always be anaphylaxis.

It is possible that in certain cases the action of albumins
may be completed by that of toxic secretions but the study of
these secretions in the pure state, that is to say, completely
separated from the products of bacteriolysis is still too incom-
plete to enable us to know whether or not they may be toxic
and may produce antibodies. At all events, and we cannot
repeat it too often, this question can have only a secondary
importance in the pathogenicity of disturbances observed
during the disease period because as these appear simul-
taneously with the appearance of antibodies in excess, they
must be of an anaphylactic nature. And it is of little impor-
tance whether these products originate exclusively from
albumins or from exotoxins.

St)ontaneous Cure.— Immunity and anaphylaxis are phe-
nomena of a general nature which may be applied to all living
beings, vegetable or animal, uni- or pluricellular; to bacteria
as well as to man. A bacterium which has penetrated into the
interior of a higher organism must adapt itself to this interior.
The organism will produce an intracellular antibody and will
be surcharged with it and this surcharge will increase the
degree of its immunity but at the same time it will also
increase the degree of its anaphylaxis. The antibody of the
infected organism will become antigenic for the bacteria in
exactly the same way and will produce on the bacteria the
same effects as the bacterial antibody produces on the
organism.

It is this balance between the degrees of immunity and
anaphylaxis of the infecting bacteria on the one hand and
the infected organism on the other, that determines the issue
in the struggle between the two opponents. A bacterium
surcharged with its antibody, will fix a quantity of antibody
of the organism (which is antigenic for itself) all the greater
if its degree of immunity-anaphylaxis is higher. It will be

68 EVOLUTION OF THE INFECTIOUS DISEASES

"sensitized" and when this surcharge exceeds certain limits
it will burst by autolysis or will become the easy prey of
leukocytes according to the phenomenon of positive chemo-
taxis (Ch. Bordet and Massart). In this way, the source of
the infecting antigen will be exhausted. How can we inter-
vene successfully in order to throw the balance toward the
recovery of the organism?

Therapy. — To judge by the results of experiments and
clinical observations we are obliged to assume that the pres-
ence of a great excess of antibodies on the exterior of a cell
hinders hydrolysis of the antigen fixed to the interior of this
cell; in other words, if an infecting bacteria has produced an
excess of its intracellular antibody (which is antigenic for the
organism) and if it has fixed to this antibody a corresponding
quantity of antigen (which is the antibody produced by the
organism) it will not suffer until there is antigen in excess on
its exterior (antibody of the organism in the plasma). Bac-
tericidal anaphylactic shock is produced only when there is
an excess of antibody in the exterior.

Numerous studies have shown that when one injects a
typhoid patient with a certain quantity of dead bacteria the
content of antigen is increased and, by the same amount,
the quantity of antibody contained in the blood is diminished.
At the same time a diminution or even a complete disappear-
ance of bacteria and a rapid amelioration of all pathologic
manifestations is found. This result is obtained very often,
but there are also failures, relapses and sometimes complica-
tions and this is not surprising because to obtain a result
which is constant and proved beforehand it would be neces-
sary to know the exact quantity of antigen to inject in each
special case in order to produce an anaphylactic crisis fatal
to the bacteria. Thus the antibody of the organism may act
on the bacteria as an anaphylactic or anaphylatoxic antigen
and in order to provoke an anaphylactic crisis fatal for the
bacteria, certain optima proportions between the quantity
of antibody and fixed antigen held by the bacteria and the
excess of this antigen in the plasma, its external medium,
are necessary. But these optima proportions may vary
widely in different cases and as there is no theory to explain

TYPHOID FEVER 69

the therapeutic action of antigens, we can estabHsh only an
empirical means which may not always be the best.

In laboratories it would not be difficult to estimate the
excess of antibody in the blood of the organism, as well as
the degree of immunity anaphylaxis of the bacteria and by
always using the same antigen in exact titer one would obtain
essentially comparable results. In the practical medical
clinic all complications would very probably be avoided by
injecting the antigen in progressively increasing doses at
intervals of some minutes. The injections of dead bacteria
ought to be given intravenously and if the total dose was,
for example, 500 millions, one might begin by injecting 1, or
2, then in ten minutes 10 and finally 40 and 450 millions at
intervals of five minutes. Two successive injections, 1 of 5,
the other of 500 millions at ten-minute intervals might be
perhaps sufficient. If the principle of skepto- or tachy-
phylaxis is good, the technic would be easy to work out.

Preventive Vaccination.— The effects of preventive vac-
cination on the morbidity of typhoid are today indisputable;
what is not indisputable is the method of preparation of
vaccine and the technic of vaccination. The heated bac-
terial bodies of Chantemesse and Widal; the more or less
autolized bacteria of Vincent; the lipovaccines of LeMoignic
and Pinoy may confer the same degree of immunity on the
organism but never lasting very long.

It would be perhaps more interesting to try to make the
human organism refractory to typhoid fever as all other
mammals are refractory to typhoid and for that it would
suffice to teach it to completely digest typhoid and para-
typhoid bacteria as it, for example, digests plague bacilli.
Bacteriotherapy by mouth practiced successfully by Dr.
L. Fournier at the Cochin Hospital for more than three years,
proves indisputably that the products of bacteriolysis of
Eberth's bacillus are absorbed by the intestinal mucosa as
antigens and it is very possible to assume that one would be
able to stimulate complete gastro-intestinal digestion of
bacteria by a suitable means by causing children to ingest
more or less autolyzed bacterial bodies in progressively
increasing doses. By proceeding in this way, one would

70 EVOLUTION OF THE INFECTIOUS DISEASES

perhaps anticipate a two-fold result, a certain degree of
immunity for an infection by inoculation and a refractory
state for an infection by ingestion.

PARATYPHOID FEVERS.

The evolution of these diseases is as a rule very analogous
to that of typhoid fever. So that it is sufficient to repeat in a
few words the differences sometimes observed in those dis-
eases caused by paratyphoid which are commonly called
"ptomaine poisoning." In these cases the ingestion of
infected food is followed very rapidly in a few hours by a
violent crisis which simulates an acute attack of cholera.
When all the elements are analyzed it is found that the
evolution of these crises is only a repetition of the typical
evolution of a normal typhoid infection. There is no incu-
bation period; the disease begins full blown. The differences
in the progress of the evolution of infection will be determined
in the two cases :

1. By the difference of the ingested infecting dose.

2. By the degree of the permeability of the intestinal
mucosa at the moment of infection, and

3. Especially by the preexistence of a certain quantity
of antibodies in the blood.

Bacteria ingested in massive doses are in part destroyed
and in part digested. The colloidal products of this digestion
pass rapidly into the intestinal mucosa and into the blood
causing congestion and facilitating the passage of living
bacteria. Bacteria in the blood are rapidly "sensitized" by
antibodies in excess and autolized and the crisis may be
terminated by death or recovery in a few hours or few days
at most. Repeated intravenous injection of specific antigens
or heterologous antigens should be the most appropriate
treatment in these cases.

CHOLERA.

The same point of view of the pathogenicity of the evolu-
tion of intestinal infectious infections which we have just

CHOLERA 71

discussed in typhoid is equally applicable to cholera. The
cholera vibrio is very proteolytic. It will destroy itself in
its own culture. It is unable to penetrate alive into the
blood and the products of its bacteriolysis find in the blood
precipitating antibodies already preformed in combination
with which they produce all the known disturbances. They
act like the arsenobenzenes which have been insufficiently
alkalhiized. In the case of fulminating cholera, the crisis is
caused by the rapid passage into the blood of a great quan-
tity of products of bacteriolysis and in fact here we find none
or very few living bacteria in the intestines (at autopsy) .

It is impossible to know today whether the subjects over-
whelmed in this way have been more or less immunized by
spontaneous immunizing infections but it is very probable
that if they had been immunized, we should find that the
reaction would be here exclusively intravascular.

When the crisis lasts for several hours it begins with
intravascular reactions which cause disturbances of the
circulation: embolism, dilatation of capillaries, congestion
of mucous membranes and, in consequence, gastro-intestinal
disturbances and fall in temperature: sometimes dyspnea,
convulsions, and syncope which may result fatally. When
the crisis is prolonged, there are very probably intracellular
reactions which are expressed by fever and may in turn lead
to death. But in the latter case, the pathologic state may
result, not from the direct action of the cholera antigen but
from lesions more or less severe and numerous or from com-
plications produced by the reactions.

To sum up: the total of our knowledge concerning the
pathogenicity and evolution of gastro-intestinal infections
produced by the bacteria of the typhoid-colon and cholera
group permits us to conclude:

1. Only the animal species or individuals which are incap-
able of completely digesting, that is to say, of transforming
into non-specific amino-acids the albumins of certain bac-
teria can be spontaneously infected by those bacteria.

2. The severity of the disease is determined on the one
hand by the dose of bacteria injected as well as by the inten-
sity and rapidity of bacteriolysis; on the other hand, by the

72 EVOLUTION OF THE INFECTIOUS DISEASES

quantity of normal, antibodies or those which preexist in
excess; in other words, by the degree of immunity, natural
or acquired.

3. By taking into consideration:

(a) The frequency of these different bacteria in nature
and consequently the frequency of infections and of possible
spontaneous vaccinations :

(b) The gastro-intestinal digestibility of bacterial bodies
and of the products of their cleavage.

(c) The permeability of the intestinal mucosa for these
products.

(d) Finally the digestibility of these products which have
passed as antigens into the interior of the organism ; we may
classify these organisms in the following way:

1. The bacilli of Eberth are the least frequent, giving the
poorest growths in all the known culture media. The prod-
ucts of their proteolysis are most difficult to digest in the
digestive apparatus of man. The products of bacteriolysis
always begin by penetrating in small quantity (immunizing
quantity) into the blood where they stay during a relatively
long incubation period. The compounds of the antigen
which have penetrated into the blood with their antibodies
are digestible with difficulty in the interior of the organism;
on account of which lesions are severe and the period of
disease is relatively long.

2. Paratyphoid bacilli are more frequent, giving more
rapidly most potent cultures, are perhaps more proteolytic
and more difficult of digestion for certain animals (hog
cholera, typhoid of mice, psittacosis) and spontaneous
vaccination is more frequent. The products of bacteriolysis
may penetrate from the intestines into the blood in massive
doses and cause rapid crises of considerable violence but of
short duration, since the subject contains a larger quantity
of antibody in his blood and in his tissues, or, in other words,
is more strongly immunized. The compounds of antigen with
antibody are more easily digested and in consequence less
pathogenic than those of typhoid.

3. Colon bacilli are the most widely distributed of this
group of organisms and the easiest to cultivate. The prod-

CHOLERA 73

nets of their bacteriolysis are very probably completely
digested in the digestive apparatus and do not penetrate
into the blood as antigens and are only very exceptionally
pathogenic when taken by mouth.

4. Cholera vibrio are very widespread in nature, and very
often provoke apparently spontaneous vaccinations, they are
very proteolytic and the products of bacteriolysis are not
completely digested in the human gastro-intestinal tract.
These products penetrate into the blood as antigens and
provoke (as in the alimentary intoxications caused by para-
typhoid) various circulatory disturbances more or less severe
according to the quantity of antigen absorbed and the
quantity of preexisting antibody. The living germ does
not penetrate into the blood.

We may conclude that for every disease of intestinal
source, the most convenient and efficacious method of vac-
cination would be the prolonged ingestion of dead bacteria,
while the most efficacious method of treatment would be
specific bacterial therapy by fractionated intravenous
injections.

I

CHAPTER IV.
MECHANISM OF INFECTION.

Infection or Contagion — Virulence — Immunity — Refractory State,

We may deduce from what has preceded that, if vacci-
nations, either spontaneous or artificial, can increase the
resistance of the organism against spontaneous infection
by increasing within certain limits the parenteral digestive
power and probably also the digestive power of the intestines :
for the cells of the mucosa and of the intestinal glands may
quite as well as those of other tissues and organs participate
in the production of antibodies and distribute them partly
into the circulation and partly into the intestinal contents;
they (vaccinations) may at the same time increase the sus-
ceptiblity of the organism to the reaction of albumins and
thus put the organism into a state which we may rightly
call ''anaphylactic."

If then, as seems probable, bacteria of the colon-typhoid
group as well as cholera vibrios do not secrete a toxin-
antigen of a crystalloid poison, diseases caused by these
bacteria are nothing else than anaphylactic crises, whose
violence and duration is determined by the total of conditions
which we have analyzed above.

In typhoid fever these crises may last for several weeks
and there is not one single crisis but a series of successive
crises. Paratyphoid may develop in the same way as
typhoid or much more quickly (in one or a few days) accord-
ing to the state of sensitiveness of the subject and the dose
of bacteria injected and the differences of development
depend principally upon differences in the rapidity with which
bacteria multiply. Cholera develops always very rapidly,
because the bacteria rapidly yield very abundant cultures
and also because bacteriolysis takes place rapidly. Colon

J

MECHANISM OF INFECTION 75

bacilli only rarely become pathogenic, because the digestion
of the bacterial body and the products of bacteriolysis ought
to be complete in the intestine.

A true and lasting immunity would consist in rendering
the organism refractory to anaphylactic hypersusceptibility;
that is to say, to render the organism capable of completely
digesting bacteria or products of bacteriolysis in the stomach
and intestines so as to hinder these products from penetrat-
ing in the form of specific colloids into the blood as well as
into the cells of the mucosa and of the intestinal glands.

Some experiments on mouse typhoid permit the hope that
this will be not impossible of accomplishment. One may
demonstrate that if some or rather some dozens of bacteria
are necessary to infect an animal by subcutaneous injection,
several thousand times as many are necessary to infect an
animal by the ingestion of a pure culture and several millions
if this pure culture is mixed with another substance of
whatever nature.

If then, after having determined the minimum lethal
dose by ingestion of a pure culture, the animal is treated
during and after by hypodermic injections of sodium caco-
dylate or calcium glycerophosphate in convenient doses, it
is found that the animal thus treated resists doses which
are very fatal for controls. It is also found that animals
treated in this way are not vaccinated and have no specific
antibodies in their blood which proves that the bacteria
or their antigens have not been able to penetrate into the
interior and that they have been very probably digested in
the stomach and intestines, or perhaps evacuated without
havings been attacked by digestion.

From another aspect it is possible to determine by a
series of tests that the same paratyphoid pathogenic for
mice and completely harmless in the beginning for Mus
Decumanus and Mus Rattus can little by little become
more and more pathogenic for these species by ingestion
as a result of a series of alternate passages: (1) In vitro
in a broth culture prepared with the flesh of the animals of
this species; and (2) in collodion sacs inclosed for twenty-
four hours in the peritoneal cavity of these animals. Cul-

76 MECHANISM OF INFECTION

tures are finally obtained, of which a small dose will kill
by ingestion field and white mice in four to six days and
rats in six to twelve days.

These cultures have been preserved in sealed ampoules for
one to ten years and tested as to their virulence once to
twice a year. They have always preserved their virulence
and have even become a little more pathogenic for mice,
but at the same time they lose their virulence for rats, so
that after ten years they have become completely avirulent
for these animals. By passing a culture, virulent for the two
species, through ordinary broth, the virulence for the rats
remains constant for one or two years, but finally diminishes
and almost disappears at the end of a longer or shorter
time. Thus we conclude:

1. That the bacterial substance virulent for mice is
difi^erent from that which is virulent for rats.

2. That the bacteria can produce, augment and lose
this specific pathogenicity substance.

3. That this property is progressively acquired by being
nourished with the "substance rat" and that it is lost
when not nourished in this way.

By analyzing these facts we are obliged to assume that
in order to nourish itself with the "substance rat," the
bacteria has been obliged to learn to fix this substance by
a special chemical affinity, and the fact that the bacteria
can multiply this fixation substance, even when trans-
planted into a non-specific nutritive medium, obliges us to
assume that the fixation is intracellular.

Thus, in the last analysis, the substance of the bacteria
acquires a specific affinity for the "substance rat" and it is,
thanks to this acquired affinity, that the bacteria, or more
exactly, its own specific substance, can fix and digest the
"substance rat" and render it assimilable.

But it is evident that affinities ought to be always recipro-
cal and that in consequence the fixing substance of the
bacteria, freed by bacteriolysis, can fix itself by the same
affinity and produce reactions of the same nature in an extra-
or intracellular substance of the rat when it finds itself in
the organism of this animal.

MECHANISM OF INFECTION 77

The '^ substance rat" may thus be considered Hke an anti-
gen for paratyphoid and this antigen provokes the formation
of an antibody exactly in the same way, and by the same
mechanism, as the fixing substance of the bacteria becomes
antigenic for the rat and produces in the organism of the
rat the formation of a specific antibody.

We may assume that bacteria become pathogenic for an
animal species exactly in the same way as the organism of
these species becomes in its turn pathogenic for the bacteria.
The procedure which we have employed for rendering para-
typhoid, which is primarily pathogenic only for field mice,
virulent for rats does not apply only to this particular case.

Dujardin and Beaumetz have rendered virulent, for
sheep and goats, a culture of pleuropneumonia which had
been considered as pathogenic exclusively for cattle, by
cultivating the bacteria of this disease in incompletely
digested mutton broth, and we know from Pasteur that
anthrax may become avirulent and may re-acquire its lost
virulence by passages through more sensitive animals. We
know that the bacillus of tuberculosis may lose its virulence
after a long series of passages in exclusively crystalloid
media, and that the tubercle germ of cold-blooded animals
is entirely harmless for the guinea-pig, but may become
pathogenic for this animal by appropriate cultures and
passages.

The processes may vary for each particular case in their
details, but the principle ought to be a general one and
should apply to all living beings. The indispensable condi-
tion under which bacteria can become pathogenic and
under which an organism can produce a specific antibody
consists in penetration into the interior of the bacteria or
into the interior of the organism of a substance in colloidal
state, that is to say, incompletely digested, whose digestion
can be completed by the cell. Thus, bacteria which are
completely transformed into amino-acids by gastro-intestinal
digestion cannot become pathogenic, nor can bacteria
nourished exclusively by the amino-acids split off from
animal albumins become pathogenic for this animal.

The study of bacteriolysis in anthrax as well as the study

78 MECHANISM OF INFECTION

of the evolution of anthrax in the white rat has given us the
most interesting side lights on the nature of the reciprocal
relations between bacteria and organism. We know by the
studies of Savtchenko that anthrax bacilli are very rapidly
destroyed in rat sera. However, by starting the first
cultures in a mixture of a very small quantity of serum with
a large quantity of ordinary bouillon, and by continuing
passages through mixtures containing relatively larger and
larger quantities of serum, we finally obtain a fairly abund-
ant culture in pure-rat serum; that is, we obtain a race of
bacteria which resists the destructive action of this serum.
If we again transplant this race into ordinary bouillon and
if we make several transplants in it, we find that even in
spite of the change in media, that the properties of serum
resistance are obtained.

If one of these twenty-four-hour cultures is filtered through
a porcelain bougie so as to completely remove the bacteria
and if a small amount of the filtrate is added to rat serum,
and this mixture is added to broth which is then inoculated
with a non-serum-resistant strain, a growth will be obtained
quite as abundant as in ordinary broth. Anthrax bacilli
can thus acquire the ability little by little to fix and digest
rat serum by increasing the quantity of a "fixing substance."
The ability to produce this substance is retained even when
there is no longer any rat serum to stimulate it. The excess
given off to the exterior and when added to rat serum, can
neutralize in vitro the bactericidal properties of the serum,
and again render it all the more assimilable for a non-serum-
resistant race. Finally a filtered broth culture originating
from a non-serum-resistant culture mixed in equal propor-
tions with rat serum will hinder the bactericidal action of
the latter, but in a much less degree.

Anthrax bacilli can produce then a specific antibody
under different conditions, but by the same process as para-
typhoid as studied above. Moreover, contrary to suppo-
sition, a culture of anthrax avirulent for rats does not
become virulent when rendered serum-resistant; so that we
must conclude that it is not by acquiring an affinity for
any animal substance that a bacterium can become patho-
genic for the animal, and that it is not by virtue of its

MECHANISM OF INFECTION 79

combination with this substance or with all the bactericidal
substances in rat serum that bacteria become pathogenic
for these animals.

What proves this is that, in spite of the bactericidal
property of their serum, rats do not generally resist a
virulent inoculation of anthrax. Another peculiarity, all
the more important from this point of view is that when
a rat has resisted a primary inoculation it becomes more
sensitive to a second inoculation of the same virus. It
happens sometimes that an animal can resist three or four
successive injections and succumbs only to the fifth. There
is here a collection of facts which could not be correlated
and which puzzled bacteriologists of the period of 1889-1890.
It was not known by what mechanism bacteria might
become pathogenic for an animal. Today this mechanism
can be explained in the following way:

Rats in general, especially white rats, resist virulent
inoculations of anthrax better than all the other test animals
and they owe this relative resistance to the more or less
marked bactericidal properties of their plasma. If the dose
is not too large the bacteria are destroyed by bacteriolysis
and by phagocytes before being able to develop into a more
resistant race and the rat recovers. But although the
living bacteria may disappear in this way products of
bacteriolysis remain in the organism. The products pro-
voke the formation of specific antibodies which are not
bacteriolytic, but which neutralize a certain quantity of the
normal bacteriolytic substance of the organism. The same
phenomenon is seen in vitro when the same tube of serum
is mixed several times. The second or third mixing will
give a culture.

Something happens here very analogous to what we have
seen in the first stage of typhoid infection when bacterial
products are incompletely digested in the stomach and
intestines, and have penetrated into the blood and into
the cells of the intestinal mucosa, and by the formation of
an antibody, have rendered the organism more sensitive to
bacterial invasion. The bacteria of the second injection
will thus resist better and longer the bactericidal^ properties
of the organism; their more rapid multiplication will sue-

80 - MECHANISM OF INFECTION

cessfully resist destruction and each successive generation
will be more resistant to bacteriolysis. At the same time
the compounds of the bacterial products with antibodies
will cause the formation of more and more severe lesions.
Infections, at first local, may become generalized and the
animal may die.

The numerous experiments of Loeffler, Behring, Metchni-
koff and others on anthrax in rats do not give us a sufficiently
accurate explanation of all the conditions of the evolution
of this disease in animals, because all their experiments
were in reply to other questions which need not occupy us
here. But such as they are, they permit us to conclude that
hypersensitization of the white rat to anthrax, by one or
several inoculations which may be considered as vaccina-
tions, is not in contradiction to the principle of vaccination
which makes no exception for anthrax in animals nor for
any other known septicemic infection.

Relapses in typhoid, auto-reinfections in tuberculosis
and syphilis, reinfections in cyclic diseases (malaria, try-
panosomiasis) and all the chronic infections in which attacks
alternate with more or less prolonged remissions (gonorrhea,
infiuenza) are all phenomena of the same category. They
all presuppose a certain reciprocal adaptation or a symbiosis
of the parasites and the organism: The difference in the
observed results, that is to say, the increase or diminution of
resistance or of sensitization of the parasite or the organism,
the final destruction of one or the other are determined only
by secondary factors, notably: By the degree of reciprocal
adaptation of the parasite and the organism at the moment
of infection; by the infecting dose; by the general condition
of the organism before the infection and the severity of
the lesions which are produced during the period of disease
or during the attacks. The mechanism of these reactions
will be under all circumstances the same.

Resume and Conclusions.

1, A yathologic state can be caused only by:
(a) The penetration into the interior of the organism of
bacteria or of bacterial products in a colloidal state.

MECHANISM OF INFECTION 81

(b) The existence in the organism of chemical affinities for
these bacterial products.

2. Infection or contagion is brought about by the pene-
tration of bacteria or colloidal bacterial products across
the mucous membranes of the digestive or respiratory-
apparatus or by means of intra- or hypodermic inoculations.

3. Incubation in infection is the time necessary for a
bacterium with the products of its secretion or bacteriolysis
to adapt itself to its medium and to cause in the organism
the formation of specific antibodies in excess.

4. The preexistence of antibodies in certain organisms for
certain bacteria can be explained:

(a) By heredity, and

(6) By individual spontaneous vaccinations.

5. The formation of normal antibodies, or in other words,
specific affinities, when they do not preexist, can be explained
by the infection itself, or, in other words, by the penetration
into the interior of the organism of colloidal bacterial pro-
ducts in immunizing doses during the incubation period.
In this case the bacterium itself will create the affinity.

6. Every bacterium which can adapt itself to an animal
medium, that is to say, which can digest and assimilate
certain animal substances in the colloidal state, can become
pathogenic for that animal.

7. The state of resistance on ingestion to bacteria when
ingested is due to the complete digestibility of all bacteria
and all their products by gastro-intestinal digestion.

The state of resistance on inoculation results from the
absolute inability of the bacteria to be nourished in the
animal medium.

8. Active immunity is a state of resistance of the organism
to a certain dose of infecting bacteria which is rapidly and
easily digestible. It will be complicated by an anaphy-
lactic hypersensitiveness whenever the compound of antigen .
with antibody in excess is insoluble, and therefore, more
or less difficult to digest. There will be no hypersensitive-
ness when this compound is soluble and neutral.

CHAPTER V.
IMMUNITY AND ANAPHYLAXIS.

If we analyze the total of studies accumulated to the
present time on immunity and anaphylaxis we may isolate
a certain number of facts which we will review as briefly
as possible with the interpretations which have been given
them. But first let us see if it is possible to separate from
the total facts a general idea which will explain the nature
and the mechanism of the reactions which determine the
different phases of evolution of the infectious diseases and
of the various pathologic states no matter whether these
states are caused by animal or vegetable albumins con-
sidered as normally toxic, such as venins, the serum of
eels and turtles, ricin, abrin, etc. ; by synthetic colloids such
as the arsenobenzenes; or, finally, by albumins considered
as exclusively nutritious when they penetrate into the internal
substance of the organism by the intestines after complete
digestion, but which provoke anaphylactic states when
made to penetrate into this interior by subcutaneous, intra-
venous or even intrarectal injections.

We have not failed to notice how difficult it is to define the
limits between the different groups of substances just enum-
erated. Thus, a certain number of toxic albumins or of
pathogenic bacteria may be absorbed by mouth without
causing symptoms, others remain pathogenic after having
undergone gastric and intestinal digestion. All possess a
certain number of characteristics in common and the value
"of these characteristics for any classification whatever
will always furnish material for endless discussions. It is
necessary to note that the distinctions indicated above and
now made again have no absolute value and that they
are made only provisionally for the clarity of the discussion
which follows.

I

IMMUNITY AND ANAPHYLAXIS 83

We have then the following facts:

1. The toxins of tetanus and diphtheria may be injected
into sensitive animals in non-toxic or toxic doses and then:

(a) Each injection of a non-toxic or slightly pathogenic
dose protects the injected animal after a certain incubation
period against a larger dose: active immunity.

(b) The serum of the animal thus actively immunized
will neutralize the pathogenic action of thfe toxin in vitro,
and if injected prophylactically into a new animal will protect
this animal against a pathogenic dose : passive immunity.

(c) The injection of toxic mixtures of toxins with their
antitoxins as well as the preventive injections of "anti"
sera from animals of the same species never causes ana-
phylactic disturbances.

Thus for tetanus and diphtheria toxins there is active and
passive immunity; but there is never anaphylaxis, either active
or passive.

2. Living pathogenic bacteria may be easily injected in
non-pathogenic doses, but in the technic of vaccinations it
is convenient to employ either living cultures with attenu-
ated virulence, or bacterial bodies killed by heat or other
procedures or filtered broth cultures without bacteria.
The injection of all these products in non-pathogenic doses
provokes in part reactions of the same nature as in the
preceding section, that is to say:

(a) An active anti-infectious immunity in the treated
animal.

(6) The serum of the treated animal can confer a passive
immunity on a normal animal but at the same time this
same treatment has caused

(c) A state of active anaphylaxis in the treated animal
and the serum of this animal has become able to transfer
passively anaphylaxis to a new animal.

Thus, for all living or dead pathogenic bacteria as well
as for their filtered broth cultures there is at one and the
same time active and passive anti-infectious immunity and
active and passive anaphylaxis.

3. Pathogenic albumins behave, from the point of view of
their immunizing or anaphylactic reactions, exactly the

84 IMMUNITY AND ANAPHYLAXIS

same way as pathogenic bacteria and it is natural that it
should be so, because bacteria can act only through their
soluble products of secretion or through bacteriolysis.
There is at once antitoxic immunity and anaphylactic sen-
sitization, active and passive.

4. For exclusively nutritive albumins there can be no active
and passive immunity, but there is active and passive ana-
phylaxis.

All these substances have a common property. Injections
of them into a normal animal in non- or slightly pathogenic
doses always causes a reaction of the same nature: the
formation of an antibody which is specific without being
always exclusively specific. They are all grouped under
the name of antigens. The substances which are formed
in the organism by these antigens and which possess a
special, if not always exclusive, affinity for the corresponding
antigens are called antibodies.

In attempting to define the physicochemical properties of
antigens, it is recognized that they are always albumins or
colloids; as to antibodies it is not possible to isolate them
from the albumins of the serum in which they are found.
They should be considered as colloids or at least having
an action like colloidal action.

All albumins are not ''antigens." This property belongs
only to albumins called heterologous while homologous
albumins — that is, belonging to the individual of the same
species — do not produce the formation of antibodies, and
therefore do not produce anaphylaxis. The reaction which
causes the formation of antibodies and which confers immun-
ity alone, or both immunity and anaphylaxis, or finally
anaphylaxis alone, is not determined solely by the physico-
chemical nature of antigens since homologous albumins are,
from this point of view, identical with heterologous albu-
mins. This reaction depends upon the state of the treated
organism with reference to the injected antigen.

For example, an organism strongly (actively) immun-
ized against tetanus or diphtheria toxin will react in the
same way to a second dose of one of these toxins as a normal
organism would react to a homologous albumin. In other

IMMUNITY AND ANAPHYLAXIS 85

words, the transformation by which toxins and albumins
after injection become either assimilated or eliminated is
accomplished by a reaction of the same nature.

It is hardly probable that an albumin, even homologous,
when injected into the blood or under the skin can be assimil-
ated without undergoing some sort of transformation and
the mild anaphylactic disturbances which are seen after
the transfusion of 100 c.c. or 200 c.c. of whole blood: chills,
excitement, dyspnea, peripheral pallor seem to show that
in this case there is no assimilation without previous trans-
formation. In every normal organism there is an antibody
in excess for homologous albumins and this antibody reacts
with these albumins in a way quite analogous to the reac-
tion of toxin with antitoxin.

We will return later to this question which we can only
indicate here. For the moment it is important to recall
from what has preceded, that if the nature of the reactions
caused by antigens seems to be determined by the physico-
chemical properties of the colloidal state of these substances,
the effects of these reactions on the organism will depend
principally, if not exclusively, on the nature, the biologic
properties and the quantity of antibodies, normal or in excess.

From the biologic point of view, we may divide the reac-
tions between antigen and antibodies into two great groups:

1. Those which produce immunity alone— diphtheria,
tetanus toxins, perhaps botulism and homologous albumins.

2. Those which produce immunity and anaphylaxis or
only anaphylaxis— all the other antigens, bacteria and
heterologous albumins.

From the physicochemical point of view it may be said
that:

1. Antigens which are exclusively immunizing form with
their antibodies soluble compounds.

2. Those which are immunizing and anaphylactic or
exclusively anaphylactic form with their antibodies insoluble
compounds.

In the first instance the antibodies in excess dissolve the
colloidal antigens; in the second, they precipitate and this
difference in the nature of the resulting compounds is of the

86 IMMUNITY AND ANAPHYLAXIS

greatest importance from the biologic point of view as well
as from the point of view of evolution of pathologic states.

When antibodies form with their . antigens soluble com-
pounds, the appearance of antibodies in excess coincides
with the cure. But in all the other cases when insoluble
compounds are formed, the appearance of antibodies in
excess always coincides with the beginning of the disease
period or, in other words, with the first appreciable patho-
logic symptoms.

Up to the present we have had no idea of considering these
reactions together and in detail. There is, to be sure, a
theory (Ehrlich) to explain the origin of the pathologic
state or the recovery in diseases caused by the true toxins
(diphtheria and tetanus). It was assumed generally that
in the other infectious diseases the different aspects of the
pathologic state were caused by the combination of differ-
ent bacteria and by exo- and endotoxins produced in the
organism by these bacteria without attempting to explain
the mechanism of the reactions. After Ch. Richet, several
theories were formulated to explain the nature and the
mechanism of anaphylactic reactions but without attempt-
ing to explain the exact nature of the origin of these reactions.

And although clinicians have, at one time or another,
called attention to "anaphylactic syndromes" in some infec-
tious diseases (Ivanoif in malaria) or to " anaphylactic crises,"
following the injection of certain drugs (iodine, antipyrin,
arsenobenzene)j the true students of anaphylaxis could see
only superficial or accidental analogies because these ana-
phylactic crises were not produced under the same conditions
as in their experiments.

But we have seen that immunizing or anaphylactic reac-
tions with production of antibodies can be provoked only
by colloids and that crystalloids never cause analogous
reactions, because an antigenic albumin loses its antigenic
properties at the time when it ceases to be a colloid, that is
to say, when it is transformed into free amino-acids. The
nature of all these reactions ought thus to be sought in
the colloidal state of antigens and it is only by attempting
to analyze the physicochemical properties of colloids as

ANAPHYLAXIS 87

well as the transformations which these substances undergo
in the interior of the organism that it will be possible to
discover why the organism is obliged to produce antibodies in
excess, what the role of these antibodies is and what the
nature of the reaction between antibodies and antigens.

These reactions can be reduced to three different types
which we have treated in detail in the preceding chapter:
The evolution of diphtheria, of tuberculosis and of typhoid
fever. These types differ among themselves according to
the primary and secondary action of the antigen on the
organism and to the action of the antibody in excess on the
antigen.

These differences can be reviewed in a few words : In diph-
theria the antigen acts directly on the tissues and the anti-
body in excess neutralizes the antigen without precipitating
it. The appearance of the antigen in excess coincides with
recovery. There is no anaphylaxis.

In tuberculosis and in typhoid the antigen is not directly
toxic. In these cases the antigen is not an exotoxin as in
diphtheria, but is the albumin of the bacterial body w^hose
pathogenic action on the organism is manifested only by the
appearance of antibody in excess. The antigen (bacillin)
forms with antibody in excess insoluble compounds. All the
symptoms of the disease are anaphylactic in nature.

ANAPHYLAXIS.

The study of the pathogenicity of infectious diseases
has led us irresistably through a series of logical deductions
drawn from exact experiments to the conception that the
pathologic manifestations in disease are exclusively ana-
phylactic in nature.

To explain the nature, the mechanism and the basis of
anaphylaxis demands a knowledge of the nature of all the
septicemic diseases, and a general idea of all the researches
concerning these diseases. Let us see w^hat this knowledge
includes:

To Charles Richet, to w^hom belongs the credit for the
discovery of the biologic importance of the subject and of

88 . IMMUNITY AND ANAPHYLAXIS

the word, "anaphylaxis" was a state of hyperseiisitiveness
in which an organism found itself as a result of a series of
preparatory injections of an antigen. The same antigen,
non- or very slightly toxic in the first injection was very
toxic in the second or "shock" injection and, according to
Richet, this toxicity resulted from the formation of a particu-
lar poison "apotoxin" which was formed by the combination
of the antigen with a hypothetical "toxogenine."

According to Besredka there is no poison in anaphylactic
hypersensitiveness. He said, some years ago (1907), "In a
general way, the majority of the reported facts seem to
indicate that the formation of anaphylaxis and of anti-
anaphylaxis may be reduced to the actions of precipitation
and absorption which resist the reactions of colloids between
themselves." He had, as he said in a quite recent work,^
" A single purpose ; to contrast the idea of a physical process
with that of a poison determined chemically."

Finally, after having analyzed with clarity and customary
ability the numerous studies of P^riedberger, Neufeld and
Dold, Doerr and Russ, Levaditi and Mutermilch, Bordet,
Kraus, Nicolle, Vaughan and Wheeler and others and
selected the theories of these authors, whether chemical
or physical, Besredka completed his first conception by
saying, "What dominates anaphylaxis and anti-anaphylaxis
is neither poison nor antipoison but it is on the one hand
the rapidity with which the union of ' sensibiligen' and ' sen-
sibilisin' takes place and, on the other hand, the site of this
union which is probably the nervous system."

The causes of the crises of anaphylactic shock are then,
according to Besredka, partly physical; at all events we
read a few lines further in the same work (page 142):
"What happens after the test injection? The new antigen
meets the sensibilisin already transformed. Their affinity
results in an intense reaction. Whether this reaction rup-
tures the equilibrium of certain nervous cells in which the
combination takes place or whether it is accompanied by
a loss or by an absorption of caloric or other energy, there

^ Anaphylaxis et Anti-anaphylaxie, Masson et cie. ed. Paris, 1917.

ANAPHYLAXIS 89

takes place a series of phenomena always the same, which
constitutes anaphylactic shock."

Besredka does not explain either by physical or by chemi-
cal means or by both together the affinities and combina-
tions which he considers take part in the reaction, but the
apparent contradiction expressed in the two phrases which
precede may be explained with a little latitude. The affin-
ities are very probably chemical in nature and the combi-
nations as well; but in Besredka's conception the product
formed by the combination does not act by its chemical
properties (poison), but only by its physical properties
(precipitate). It is not the product already formed which
causes the pathologic manifestations of the anaphylactic
state, but only the rapidity with which products are formed ;
in his opinion, precipitates are not necessary.

Thus, in the last analysis whether a precipitate is formed
or not, the experiments of Besredka and the intrepretations
which he himself puts on them indicate that it is the factor
time which is at least one of the conditions of the reaction,
and may be the single cause of anaphylactic shock. (This
one factor ought, we think, to be chemical or rather physico-
chemical since the reaction concerns colloids.)

F. G. Novy and P. H. de Kruif^ return again in an exten-
sive work which has just appeared, to the idea of a soluble
anaphylatoxin or ''taraxin" formed in the organism by a
substance "taraxigen." Anaphylactic shock would be the
result of a sort of tautometric intramolecular rearrangement
of certain very labile substances contained in the blood.

Fundamentally it is evident that all these different ideas
are only plays on words. There has been, and is, much
discussion in current chemical literature on the subject of
the different phenomena and processes surrounding immun-
ity and anaphylaxis just as our fathers and grandfathers
discussed symptoms, pathogenicity and evolution of infec-
tious diseases before the discovery of bacteria, and in order
to explain these things there has been created a complicated
and barbarous terminology which has incidentally the great

^ Anaphylatoxin and Anaphylaxis, Jour. Am. Med. Assn., May 26, 1917.

90 IMMUNITY AND ANAPHYLAXIS

inconvenience of giving grand illusions with a precision which
does not exist.

Confusion and misunderstandings result in the vast
majority of cases from the forced use of inaccurate terms
which are necessary in order to visualize reactions between
substances of which only a few biological properties are
known.

And the differences which we have desired to establish
in the nature of the reactions of anaphylactic shock and
of chronic anaphylaxis (Arthus phenomenon) between the
guinea-pig, rabbit, goat, horse or rat, and even between
French and American guinea-pigs could arise only from
the fact that up to the present we have had only a general
idea of the interpretation of various observed phenomena,
clinical or experimental.

But although the words, "anaphylaxis," "taraxis,"
"apo- or anaphylatoxins" or "taraxins" are not important,
the distinctive characters of shock as well as of crises of
longer duration and other delayed reactions of a different
nature are defined as much by the pathogenicity as by the
symptoms.

To define a phenomenon, it is not sufficient to indicate
the process by which it is produced: We ought to know of
what it consists; in other words, its symptoms, the methods
by which these symptoms are produced and particularly the
properties of the elements which combine to produce them.

But if we do not know all the properties of all the anti-
gens and of all the antibodies as of all their compounds, we
can know with certainty that the anaphylactic state can be
produced only by antigens which form with their antibodies
insoluble compounds. We have seen that there is no ana-
phylaxis for toxins which form with their antitoxins soluble
compounds, and that there is always anaphylaxis for albu-
mins, bacteria and their broth cultures which provoke the
formation of precipitates.

The most convenient theory which could best explain the
total of actually known facts would show that the anaphy-
lactic crisis is a brisk reaction of coagulation caused by the
union in the organism of a certain dose of antigen with a

ANAPHYLAXIS 91

certain dose of antibody, no matter whether the antibody
preexisted normally in the organism or whether it was formed
as si result of special treatment. In the case of tr,ue antigens
these latter are coagulated or precipitated by the antibodies
of the organism. In the case of non-antigenic substances
such as iodoform, antipyrin, peptones, etc., it is the injected
substance which causes the coagulation of some substance
of the organism ; in either case the nature of the reaction will
be always the same, and although the last case does not
come within the limits of this study, it is not without
interest to note it in order to avoid confusions and possible
misunderstandings.

The effects of these coagulating reactions will be differ-
ent according as the precipitate is formed exclusively in the
blood or both in the blood and in a certain number of cells
or even exclusively in the cells. If formed in the cells, the
effects will depend upon the importance of the intracellular
antibody in the life of the cell as well as the importance of
the role of the cell in the life of the organism.

It would be superfluous to dwell here upon the symptoma-
tology of anaphylaxis in its different degrees or its different
localizations as this is found today in all the text-books of
pathology; but it is important to note that the total of
symptoms which characterizes anaphylactic shock includes:

1. The action of the recently formed poison— a word in
incorrect but current use (Richet, Vaughan, Wheeler, Fried-
berger and others).

2. A chemical reaction (combination of antigen with
antibody).

3. A physical or absorption reaction (Mutermilch) .

4. A mechanical action of the precipitate: embolism,
infarcts.

5. The function of time or the duration of reaction
(Besredka) .

6. The intervention of leukocytes in the transformation
and transportation of precipitates to the hemopoietic organs.

7. Finally dominating the mechanism as well as the effects
of all these reactions the influence of the central nervous
system.

92 IMMUNITY AND ANAPHYLAXIS

According to the point of view of the experimenter it is
now one, now another of these agents which predominates
in his mind and determines his preferences for this or that
interpretation of the effect. Each of these theories contains
a part of the truth but not the whole truth, and it is there-
fore necessary that the apparent effects of the reaction should
be considered separately without attempting to understand
their basis and their intricate mechanism.

But we have seen that only antigens can give rise to the
anaphylactic state in the organism. We have seen that all
antigens are colloids; that only colloids are antigens, that in
consequence, the nature of the formation of antibody should
be sought in the colloidal state of antigens, or in other words,
by seeking to understand the physicochemical and the bio-
logic properties of colloids and b}^ studying the transforma-
tion which heterologous and homologous colloids undergo
in the interior of the organism, that we will learn to know:

1. Why colloids cause the formation of antibodies.

2. Why and under what conditions colloids form with anti-
bodies soluble or insoluble compounds.

3. Why the compounds of antigens with their antibodies
are harmless when they are soluble and pathogenic when
they are insoluble and why this should necessarily be so.

COLLOIDS.

We know that colloids are substances which do not crys-
tallize and which therefore cannot be isolated from their
medium in pure state and we know that in attempting to
purify a colloid we generally cause it to cease to be a colloid.
According to the "happy simile of E. Duclaux, ''When we
try to analyze an albumin by chemical methods, we act as
if we were analyzing a watch enclosed in a case. We would
find iron, copper, silver, gold and the elements which com-
pose glass but we would never conclude from this analysis
that these elements arranged in a certain way and put in
motion in a certain state of equilibrium would constitute
a total which would enable us to measure time. One would
admit that after analyzing a watch in this way, by grind-

COLLOIDS 93

ing it in a mortar to facilitate the action of strong acids
or by melting it at a temperature of about 1000°, one would
destroy not only the instrument which tells time but also
those landmarks which might permit us to identify the
individual role of each of them in the function of the whole;
that is, in the movement of the hands."

But since then we have learned to do better.' By sub-
mitting an albumin to an action less brutal than that, for
example, of gastro-intestinal digestion, we may break it
down little by little without destroying the entire complexes
— "the wheels"— which compose it, and by continuing in
this way through a series of successive disintegrations, we
would find that every albumin which is a colloid is at last
split to amino-acids which are crystalloids. We know that
the molecules of a salt in solution coalesce one with another to
form crystals when there is not enough solvent to keep them
a certain distance apart, but we do not know how and why
amines, which can exist as free molecules, and which then
obey the laws of salt solutions may congregate into such
complex elements as colloids.

It would be especially interesting to know by what physi-
cal or chemical agent (electricity, magnetism, affinity) these
molecules of amino-acids are bound and held together. We
will know this certainly some time. At the moment we
must confine our study to the biologic and physicochemical
properties of the albumin as we find it in its complex medium
and to the substances which result from its successive dis-
integrations. Although incomplete, this study already gives
us a series of interesting reflections which are sufficiently
exact for our purpose; to learn how and why an organism can
become diseased, and perhaps also how it can recover under
the best conditions.

We have then determined that of all the products of the
disintegration of an albumin, those only are antigens which
are still in the colloidal state.

Free amino-acids are no longer antigens. There is here a
confirmation of the fact which we have noted above, that
only colloids can be antigens and it is possible to conclude
from this that foreign albumins taken as a food which gastro-

94 IMMUNITY AND ANAPHYLAXIS

intestinal digestion is incapable of splitting, that is to say,
of transforming into amino-acids and which may pass into
the interior of the organism as colloids will provoke the
formation of antibodies and in consequence the anaphylactic
state. These are the causes of the habitual or accidental
anaphylactic intolerance for certain foods, as well as for
infections by mouth, individual or specific, in typhoid,
cholera, tuberculosis, etc.

The organism can nourish itself on foreign albumins only
in cases it can assimilate them, that is to say, can transform
them into albumins of its own species; and we know that
to do this it can absorb them only in the completely dis-
integrated state of the amino-acid. This disintegration is
the role of gastro-intestinal digestion. What then becomes
of the incompletely digested albumins which have penetrated
into the interior of the organism in the colloidal state?
They can neither be assimilated nor eliminated in the
colloidal state.

Two hypotheses are possible: Either they would accu-
mulate in some part to which would be brought every other
unassimilable foreign body where they would be surrounded
by leukocytes; or else the interior of the organism would
finish the incomplete gastro-intestinal digestion and would
render them assimilable or eliminable as amino-acids. It
is this last hypothesis which happens in all the known cases.
It is true that up to the present we have never been able to
prove this parenteral digestion, but if we have no direct
experimental proof of it, we know with certainty by numer-
ous experiments (Hamburger and Moro and others) that
when we inject a rabbit with horse serum, we can recover
this serum in the rabbit's blood some time after the injection
but that finally this serum will disappear at a given moment
and that this disappearance, often quite sudden, will always
coincide with the appearance in the rabbit's blood of specific
antibodies. From the point of view of the reaction which
follows, it is of little importance by what route (intestinal,
subcutaneous, intravenous) the colloidal antigen penetrates
into the organism.

The transformation in the organism of a colloid into a

COLLOIDS 95

salt can be followed at the present time with some precision
only for a colloid obtained by synthesis which quite recent
researches permit us to consider as an antigen. This syn-
thetic colloid is disodo-dioxy-diamino-arsenobenzene-anti-
monious-silver-bromide (or product 102).

Judging by the experiments and analyses of Mile. Mitchel
this product injected into the blood of rabbits as a colloid
is entirely eliminated by the kidneys and the intestines as
a salt. We, therefore, say that the colloid has undergone in
the organism a transformation commonly called digestion
and since this colloid possesses all the biologic and physico-
chemical properties common to an antigen, since it gives
in the organism the same series of reactions under the same
conditions, we may assume by comparison, that all other
antigens undergo in the organism transformations of the
same nature; that introduced as colloids they will be digested,
and transformed into salts and as such either assimilated
or eliminated.

In consequence by taking a purely biologic point of view,
and by using all the experimental material known, we must
admit that the injection into the interior of the organism of
a colloid antigen which is digestible will always produce a
reaction of digestion on the part of the organism quite as
the introduction of an albumin into the digestive apparatus.
And we may add with some certainty that the formation of
antibody in excess which appears in the blood at the end of
the incubation period can be only the result of the normal
reaction common to every living cell which will always try
as long as it lives to reproduce and multiply a substance of
which it has need or which it loses by a neutralizing com-
bination with a foreign substance.

We may thus represent the steps of this process in the
following simple way:

Every organism possesses for every normally digestible
albumin a certain normal affinity (and this is not surpris-
ing since every albumin is constructed on the same plan
and belongs to the same chemical family) or, in other words,
a certain dose of normal affinity for a certain dose of foreign
albumin.

96 IMMUNITY AND ANAPHYLAXIS

If the dose of albumin injected is strictly equivalent or
less than the dose of normal affinity every antigen injected
will be fixed by normal antibody, digested, assimilated or
eliminated and the organism will reproduce and multiply
this normal affinity-antibody which then will become the
antibody in excess. If the injected dose of albumin is
greater than the dose of normal affinity the antigen will fix
itself to the normal antibody en surcharge and the organism
will suffer or rather the antigen in excess will circulate in
the blood up to the time when the organism can produce a
quantity of antibody sufficient to fix and digest this excess
of antigen. It is only after a total disappearance of antigen
that the antibody in excess will appear.

In this way is explained quite easily a fact which until
now has seemed inexplicable. We know that if a small
injection of antigen causes an excess of antibody and the
anaphylactic state to appear in ten to fifteen days, the injec-
tion of a large quantity of the same antigen into an animal
of the same species will produce the same effect only after
an incubation period of some weeks or even months simply
because the existence of an excess of antigen in the circula-
tion excludes the possibility of the simultaneous existence
of an excess of antibody in the organism.

More recently, however, Longcope and Rackemann^ have
been able to demonstrate that in the serum disease, which as
originally shown by Von Pirquet and Schick^ often follows
the injection of antitoxic or antibacterial serum in man,
there may be a coexistence of antigen and antibody in the
circulation.

Working with cases of pneumonia, which had been treated
with antipneumococcus serum obtained from horses, they
found that the horse serum persisted unchanged in the blood
for several days, and that in a few cases circulating antibody
could be demonstrated in the same specimen of patient's
blood serum in which horse serum could also be demon-

. 1 The Relation of Circulating Antibodies to Serum Disease, Jour.
Exp. Med., 1918, xxvii, 341.

2 Die Serumkrankheit, Leipsic and Vienna, 1915.

COLLOIDS 97

strated. They found that "the rapid diminution of antigen
follows the rapid rise of precipitin and is coincident with
recovery from serum disease"; so that although the two
reagents can coexist, they cannot both be "in excess."

Under what conditions then is an organism sensitive to
anaphylaxis? There will be a surcharge of antibodies.
That is, all the cells which possess a special affinity for the
injected antigen will have multiplied a substance which
fixes the antigen, holding a certain quantity en surcharge
and allowing the remainder to pass into the blood. There
will thus be an excess of antibody in the cells and in the
blood. If at this time we inject a sufficient quantity of the
same antigen there will be produced a reaction of the same
nature as the first time but the effects of this reaction on
the organism will be different, because the quantities and
the proportions of the two products will be no longer the
same and because the reaction will take place not only in
the cells but also in the blood.

We have seen above that the compounds of the antigen
with their antibodies may be soluble and under these condi-
tions they are neutral for the organism (diphtheria, tetanus)
or else they form coagula or precipitates, and are pathogenic.
Whenever there are antibodies in excess both in the blood
and in the cells, there will be pathogenic reactions intra-
vascular and intracellular.

The reactions will be pathogenic not because there is
formed on the second injection a toxic body different from
that which is formed at the first injection, but only because
this new body will form much more rapidly and in much
larger quantities than the first time. Precipitates formed
in the blood will result in emboli, infarcts, etc., from which
apoplectic attacks, syncope, abdominal congestion, pulmon-
ary and cutaneous edema accompanied by fall of tempera-
ture and intracellular lesions will be expressed by a variety
of symptoms, all the more severe as the cells in question play
a more important role in the general economy. These last
reactions, especially when they concern the nervous cells
to a greater or less degree, are accompanied by fever. Let
us note in passing that intravascular reactions when they
7

98 IMMUNITY AND ANAPHYLAXIS

are not rapidly fatal will always be less dangerous than
intracellular reactions.

We may thus affirvi that the basis for the production of anti-
body in excess is the obligation to digest colloids under which
the organism finds itself in order to assimilate or eliminate
these colloids. We know that this digestion will produce
pathologic manifestations when the compound of antigen
with antibody causes a precipitate: but on the contrary
when this compound is soluble, this digestion is completely
harmless.

This difference in the intimate mechanism of the reactions
which together result, on the one hand, in the formation of
a coagulum or of a precipitate and, on the other hand, of a
product which is soluble remains to be explained.

For this explanation only a very limited amount of experi-
mental material is at hand. The basis of the reply is the
physicochemical constitution of colloids which is still little
understood. Let us also see what we know and what con-
clusion we can draw from the point of view which is presented
to us.

From the physical point of mew a colloid can be represented
as formed by granules or * 'micelles" ^ composed of a variable
number of molecules of a single or of several different sub-
stances. The structure of these "micelles" is unknown,
but we may assume that when they are in suspension in a
liquid, they have, because of surface tension, a spherical or
ovoid form. The volume of the granules of the simplest
and most homogeneous and antigenic colloid which we know,
arsenobenzene, is variable not only because the "micelles"
may contain a larger or smaller number of molecules but
because several "micelles" may be combined into a single
granule. Experiments show, moreover, that in every liquid
containing a colloid in suspension there is also a certain
number of free molecules. Thus, when we allow a solution
of luargol (1 to 400) in 0.5 to 0.7 per cent, salt solution, to

^ The word "micelle" is used to define the units of albuminoid matter
of every colloid in the same sense that the word "molecule" expresses the
unit of chemical compounds. The word "particle" is used by many
American authors in the same sense.

COLLOIDS 99

stand, we find at the end of twenty-four hours that there is
formed in the liquid which was first uniformly colored and
uniformly fluid, four layers distinctly superimposed one
above the other. At the top is a layer of clear, highly
colored fluid; below this, two layers darker and more turbid
and at the bottom a translucent flocculent precipitate. At
the end of two or three days there will be in the tube only
a sediment and a perfectly transparent slightly colored
liquid. This liquid will, even when saturated with salt, be
no longer turbid and will traverse dialyzing membranes.
There is thus no more colloid and the hianner in which the
precipitate is formed and digested in the remainder of the
original fluid shows that there were in this fluid granules
of different sizes.

In a solution exactly disodic there will be at the end of
twenty-four hours about 50 per cent, of the product in the
precipitate and respectively 25, 20 and 5 per cent, in the
layers above it.

The proportions of amino-acids as free molecules or
grouped into more or less voluminous granules may be
different for different colloids and for the same colloids
according to the conditions of the medium in which they
occur. But if we judge by the total of reactions between
colloids and cells and by the results obtained in submitting
colloids to dialysis, we can see that in serum as in egg-white
or in a bacterial albumin, or in a toxin, that these fluids con-
tain granules of very different volumes as well as amino-
acid existing as free molecules, quite as has been established
for the arsenobenzenes.

Thus in recognizing that there are very distinct differences
between the formation of a crystal in which the molecules
of salt are mechanically deposited one on the other and a
colloidal granule in which the molecules are very probably
bound together by a single affinity we must note that there
are no clear-cut distinctions between the two sorts of sub-
stances when considered from the point of view of their
physical property of crossing dialyzing membranes.

There is no membrane which cannot be traversed by the
smallest granules of > every .cpUojd ^ijd^it;is very important

100 IMMUNITY AND ANAPHYLAXIS

to appreciate this because it is the smallest granules of
antigens, which, by traversing the membranes of cells,
provoke the condition of congestion and dilatation of the
cellular membrane which then becomes permeable for more
voluminous granules.

From the chemical point of view, we know that each mole-
cule of the chlorhydrate of dioxydiamino-arsenobenzene may
theoretically combine with two molecules of silver chloride
but when a dilute solution of silver chloride in potassium
cyanide is added drop by drop to a dilute solution (1 to 500)
of arsenobenzene, we find that each drop of silver chloride is
precipitated en masse without forming a globule and is then
redissolved. If the liquid is carefully shaken, the dissolu-
tion of each drop which follows becomes more difficult.
When we reach the proportion of almost one molecule of
silver chloride to one molecule of arsenobenzene, dissolution
no longer takes place.

An insoluble precipitate is also obtained by adding quickly
one molecule of a concentrated solution of silver cyanide to
twenty molecules of arsenobenzene, although there is still
in the liquid enough of the latter to fix and hold in solution
nineteen other molecules of silver cyanide. The difference
in these two cases may be explained by assuming that in the
first case by adding slowly into dilute media and by shaking
the mixture th^ silver chloride is more or less uniformly
distributed among all the molecules of arsenobenzene while
in the latter case each molecule of arsenobenzene which
comes into contact with silver chloride fixes two molecules
of it and there is thus formed an insoluble compound.

The granule of arsenobenzene may thus fix a salt for which
it has a certain affinity in quantity equal to the sums of
the affinities of the molecules which compose it, but it is
evident that it can also fix less of them and it is thus that
we can explain the "phenomenon of surcharge'^ and the
"phenomenon of least saturation" already described, in
studying the properties of mixtures with their antibodies
in vitro and in vivo.

For the arsenobenzenes we know exactly the chemical
equivalents; ^pr b^ojogic antigeas we do;nct; kiiow them but

COLLOIDS 101

the similarity, and even the identity of all the reactions of
arsenobenzenes with those of all the other antigens, allows
us to assume that the physicochemical constitutions are
also identical. This phenomenon of least saturation will
explain the formation of toxons, toxoids, epitoxons, epi-
toxoids in mixtures of toxins and antitoxins (Ehrlich).

For phenomena of absorption and hydrolysis, the precipi-
tant action of neutral salts and the dissolving action of
acid or alkaline media which characterize every colloid
permit us to consider each colloidal granule as a sort of cell
which can be hydrated and inflated, dehydrated and
retracted, which can absorb, retain and secrete all sorts of
salts by the purely physical phenomenon of osmosis with-
out regard to chemical combinations which can affect its
amino groups and other molecules by their special affinities.

The nature of the reactions between colloids or between
colloids and salts as well as the quantity of the substances
which can be combined or absorbed are determined espe-
cially by the physical characteristics of the colloid. These
include the form and volume of the granules which compose
the colloid as well as the proportion of the different sized
granules. So long as "the choice" of substances with which
a colloid may combine and the nature of the compounds thus
formed, depends eventually on chemical affinities of the
molecules which enter into the composition of the granules,
it is very possible to imagine, that in a granule composed,
for example of one hundred molecules, ten or twenty or sixty
of these molecules will form new combinations while the
others will remain intact. According to the proportion
of different granules the physicochemical properties as well
as biologic effects of the colloid will be different.

Arsenobenzene is the simplest colloid-antigen which we
know; its granules are of different and variable size but all
are composed of molecules of the same amine. Biologic
antigens in general have a much more complex composition;
casein, for example, is composed of a dozen different amino-
acids (alanin, leucin, serin, glutamic acid, aspartic acid,
arginin, lysin, hystidin, cystin, tyrosin, phenylalanin,
tryptophan) and it is certain that between casein and

102 IMMUNITY AND ANAPHYLAXIS

arsenobenzene we can find all intermediary substances. It
would thus be very interesting to know whether all the
different amino-acids which are found in casein, in serum,
or in bacterial antigens are united in different proportions
in each granule or whether each of them forms different
granules. Biologic chemistry will probably undertake some
day to solve these problems which we cannoL take up now.
What appears certain is that all the colloids of egg-white or
of serum or of bacterial bodies when introduced into the
interior of the organism do not become antigenic, nor do
all the colloidal granules of heterologous origin take part
in the same degree in the formation of specific antibodies.
Levaditi and Mutermilch^ have shown by their studies on
the production of anti-nagana antibodies in the guinea-pig,
rabbit and rat on the one hand and in the hen on the other
hand, that antibodies produced by the same antigens in
animals of different species are not identical.

Different antibodies can be produced only by different
antigens, which means that in the particular case brought
forward by Levaditi and Mutermilch, products of bacterio-
lysis of the trypanosome do not form a uniform antigen
but these products contain a mixture of colloidal granules
whose composition and affinities are different. In con-
sequence the colloidal granules w^hich are antigenic for the
organism of the rabbit, guinea-pig and rat on the one hand
and of the hen on the other hand are not compounds of the
same amino-acids or at least are not grouped in the same
way. We have also seen that in the case of Bacillus typhi
murium the substance virulent for mice is not the same
which gives this bacteria its virulence for rats. These two
examples allow us to conclude that in complex colloids formed
of every sort of amino-acid these latter are not uniformly
distributed among all the granules but constitute groups of
granules of different chemical compositions.

And if this is so, we should necessarily conclude that every
colloidal granule of an albumin or of a complex colloid which
is not antigenic ought to be immediately digested and trans-

1 Antibody and Animal Species, Ann. de I'lnst. Pasteur, 1913, xxvii, 924.

COLLOIDS 103

formed to crystalloids in a way different from antigenic
colloids. This allows us to approach the question of the
digestion of homologous albumin, which with the exception
or crystallin (the substance of the lens) can be assimilated
without producing the formation of an antibody and without
ever giving rise to a state of anaphylactic intolerance.

But how can we represent this assimilation of homologous
albumin? It is impossible to imagine an unbroken albumin
penetrating into a cell. Consequently a homologous albu-
min must be transformed into free amino-acids just like a
heterologous albumin; only this transformation must operate
in another way.

By studying this, after what we know, it seems as if a
homologous albumin was directly transformed into free
amino-acids in the blood and fluids in the organism without
passing through the stage of coagulation or, in other words,
as if there were in each organism a substance capable of
destroying or of binding the ties by which amino-acids are
united in granules and of thus freeing them and making them
assimilable. The example of the transformation of a col-
loidal arsenobenzene into " novo-arsenobenzene" which is a
salt by the fixation of formaldehyde sulphoxalate of sodium
to the amino group of dioxydiamino-arsenobenzene permits
us to assume that this is the case.

It is thus very probable that the colloids of foreign albu-
mins which are not antigens are transformed to crystalloids
in the same way as homologous albumins. This is not sur-
prising when we think, as already indicated, of the original
unity of every animal species and of the similarity of the
elementary composition of all albumins, which differ among
themselves much more by the proportions than by the
qualities of the chemical parts which compose them. What
should differ especially are the ties by which the molecules
are bound together into colloidal granules. Whatever are
the differences of detail between different albumins and the
colloids which compose them, the total of our knowledge
of the digestion of non-antigenic and antigenic colloids in
the interior of the organism permits us to visualize the
mechanism of these two sorts of processes in the following

104 IMMUNITY AND ANAPHYLAXIS

way: Every organism possesses in its fluids certain sub-
stances (normal antibodies) in a sufficient quantity to
rapidly transform by a single operation any quantity of
non-antigenic colloids into crystalloid solutions which can
be assimilated or eliminated and by the same procedure
which permits it to digest these in its own tissues.

Every organism can produce, as a result of a suitable
preparation, a specific antibody by which every antigenic
colloid can be transformed into a crystalloid but here the
process of this transformation may take place in one of
two different ways, either as a single reaction in the case of
non-antigenic colloids (toxins, antitoxins) or by two suc-
cessive reactions, of which the first consists of the formation
of a coagulum and the second of the dissolution of this
coagulum (all the other albumins and colloidal foreign
antigens) .

From what we know of the transformation of the arseno-
benzenes, we may assume that in the case of non-antigenic
colloids as in the case of toxins, the antibody, whether normal
or in excess, acts especially upon the ties which bind the
amines into colloidal granules to neutralize these ties. In
the case of antigenic colloids the antibody in excess forms
first new combinations with the molecules of these antigens
by rearranging the granules among themselves and thus
causing the formation of precipitates or coagula which ren-
der the subsequent liberation of molecules slower and more
difficult.

ANTIBODY.

It remains for us to investigate the physicochemical
nature of antibodies and we must recognize that this is the
least known element of the problem. We know that the
production of antibody in excess is the result of a vital
reaction of the cell because even if a dead cell or a dead tissue
could fix a certain quantity of antigen in the same way and
by the same affinity as living tissue it would be impossible
for it to reproduce and multiply this fixation substance
which in the living organism becomes the antibody in excess.
This explains why the production of antibody is necessarily

ANTIBODY 105

always inversely proportional to the pathogenic action of
antigens.

We know that the substance to which the role of normal
antibody belongs can fulfil different functions which are
more or less important in the normal life of the cell. This
"substance" may be in an organ of sense or a function of
nutrition or of reproduction or finally a substance of reserve
and in each the immunizing excitation or the lesion will
be manifested by its different effects on the function of
the particular tissue and on the general economy. We know,
further, that it is not always the same cells of an organism
which are sensitive to the action of an antigen. Where, for
example, it is the cells of the central nervous system which
are exclusively or more particularly sensitive to the action
of an antigen, the production of antibody is very precarious
if not absent, probably because the nerve cells do not recup-
erate and because the excitation even of this tissue, however
slight, always results in profound disturbances of the general
economy. We may conclude that the less important the
role of the particular tissue, the easier and less harmful will
be the process of immunization. This is almost all that
we can say as to the biologic origin of antibodies.

As to their physicochemical nature, we know that anti-
bodies are one of those components of "antiserum" which it
has been quite impossible to isolate by dialysis. We assume,
at least tentatively, that they are colloids, but we cannot
prove it directly. The example of the transformation of
coagulated arsenobenzene when one adds to the molecules
an acid or base which holds the colloidal granules in suspen-
sion in water; the redissolution of the coagulum as well as
the dislocation of the colloidal granules by a sort of sulpho-
nation will serve to prove that antibodies may be something
much more simple than a colloid, but if this is possible for
arsenobenzene it seems today too simple for antibodies and
all the other antigens. Let us be content for the moment
to remember the essential simplicity of the reactions which
determine the transformations of arsenobenzenes and to
hope that later researches will help us to recognize the
nature and the mechanism of biologic antigens.

106 IMMUNITY AND ANAPHYLAXIS

Summary.— 1. Salts introduced into the interior of an
organism may be assimilated or eliminated without under-
going any transformation because they can cross dialyzing
membranes.

2. Colloids cannot be assimilated or eliminated under the
same conditions because they cannot cross dialyzing mem-
branes.

3. Gastro-intestinal digestion results in the transforma-
tion of specific-colloid-albumins into salts (amino-acids)
which are no longer specific and with which the organism
reconstructs the albumins of its species.

4. When, as a result of incomplete intestinal digestion
an albumin penetrates into the interior of the organism it is
this interior which must achieve digestion and this doctrine
applies to all albumins or colloids introduced into the interior
either subcutaneously, intravascularly or through the
intestines.

5. Cells, tissues and organs of the interior of the organism
are adapted only in a certain measure to this function of
digestion and in a given time can transform only a certain
quantity of albumin or of foreign colloids. Each time that
a cell fixes a quantity of a substance to be digested in excess
of what it can easily digest (phenomenon of surcharge),
there will be intracellular indigestion which disturbs the
vital functions and the physiologic state of the cell for the
reason that there is no method for the evacuation of the
undigested surplus. This is the case for toxins, ricin, abrin,
venins and certain sera which are directly toxic for some
tissues.

6. Intracellular digestion can be explained only by an
attraction and fixation of the substance to be digested by a
substance of a cell; or by a chemical affinity between these
two substances, which results in the formation of a new
compound. When this operation is not pathogenic for the
cell the cell reproduces and multiples what it has lost in
the combination; in this way we may represent the forma-
tion of antibody in excess.

7. The presence in the organism of antibody in excess in
the cells and in the blood, which can of itself produce certain

ANTIBODY

107

functional disturbances (tuberculosis), increases the diges-
tive capacity of the organism for the corresp>onding antigen,
but at the time renders the digestion more rapid and more
tumultuous and one of two different processes may then
take place:

In the first, digestion takes place at one time and the
antigen, transformed to an assimilable or eliminable product,
becomes completely neutral to the organism. The antibody-
antigen compound produces no disturbances at all: diph-
theria, tetanus, non-antigenic colloids.

In the second, digestion takes place in two successive
phases: first, coagulation and second, dissolution of the
coagulum. Here the sudden formation of the coagulum will
produce immediate or delayed pathologic manifestations
whenever the quantity of antigen is greater than the capacity
for the rapid dissolution of the coagulum: septicemia and
heterologous albumins.

8. All the pathologic symptoms caused by an antigen which
are manifested in the organism at the time when it contains
corresponding antibody in excess are anaphylactic in nature.
A crisis of anaphylaxis is nothing but a crisis of indigestion.
The disturbances are produced by a sudden rupture of the
normal equilibrium between the state of gel and the state of
sol of those colloids which enter into the composition of cells
and blood.

The severity of the disturbance produced by these reactions
is determined by :

(a) The quantities and relative proportions of the reacting
substances.

(b) The concentration of these substances and in conse-
quence the duration of the reaction.

(c) The intracellular and intravascular localization of
lesions.

(d) The secondary and often delayed effect of these lesions
on the general economy.

In the spontaneous infectious diseases, intravascular reac-
tions are always less dangerous than intracellular reactions
because these latter often result in the destruction of cells and
consequently in lesions of the tissues which are severe and

108 IMMUNITY AND ANAPHYLAXIS

persistent. In contrast with intracellular reactions, intra-
vascular reactions may be considered as therapeutic.

9. The necessity or the production of antibody in excess
results from the obligation under which the organism finds
itself to transform antigenic colloids, which have penetrated
by any way whatever into its blood and tissues, into salts.

10. The mechanism of this digestion is still unknown but
we may suppose following the example of the transformations
of arsenobenzenes, that in certain cases (toxins) the antibody
is a substance which binds the ties which unite the amines
in colloidal granules and thus transforms the colloid into a salt
neutral for the organism; and that in every case there is first
fixation by th^ molecules of a colloidal granule of a substance
which unites the granules to each other to form a coagulum
or a precipitate and finally there is another substance which
dissolves the precipitate and destroys the ties of the molecules.

We may note in passing that the same substance may
coagulate or dissolve according to the proportions of the
reacting substances. Thus in two words:

The pathologic state in infectious diseases is due to
anaphylaxis.

Anaphylaxis is an indigestion which may be intracellular
or intravascular or both.

This indigestion consists in the inability of the organ to
rapidly transform colloidal antigens into salts.

When it is intravascular, the disturbance will be rapid and
immediate: anaphylactic shock; when it is intracellular the
disturbance and the lesions which result may be more or less
delayed and will last for hours, days or dozens of years (tuber-
culosis, leprosy, syphilis) : chronic anaphylaxis.

From the point of view of the evolution of infectious diseases,
anaphylaxis ought to be considered as a pathologic reaction of
the process of immunity.

CHAPTER VI.

THE INFLUENCE OF THE CENTRAL NERVOUS

SYSTEM ON IMMUNIZING REACTIONS

AND ON ANAPHYLAXIS.

The influence of the central nervous system on the pro-
cesses of immunity and anaphylaxis is not at the present
time understood, at least from the biochemical point of view.
It is indisputable that the cells of an organism, even the
leukocytes, have no individual independent life, concur in
all their functions to make a perfectly coordinated whole.
In other words, that the specific functions of each tissue,
organ, gland and cell are strictly dependent, not only on
the physicochemical affinities of the substances which com-
pose them, but also and especially on the action and condition
of the central and sympathetic nervous system, and on its
conscious and subconscious reactions.

Syncopies, respiratory and gastro-intestinal disturbances
produced by emotions, whether spiritual or psychic, real or
suggested, which simulate so accurately the syndrome of
anaphylactic shock in total or in part, the chronic disturb-
ances of general nutrition produced by grief; the activation
of salivary or gastric secretion by the sight of certain foods—
all prove that the nervous system can produce in the cells
all manner of reactions without the direct intervention of
any foreign product whatever.

Moreover in a diarrhea caused by a violent emotion or
in an urticaria of hysterical origin it is certainly not the
direct action of the peripheral nerves which can in a few
moments liquefy the intestinal contents or produce edemas
in different areas of the skin. These reactions in the last
analysis can be the result only of physicochemical modifi-
cations which are produced in the interior of particular

no INFLUENCE OF CENTRAL NERVOUS SYSTEM

cells. We know, moreover, nothing of the exact mechanism
of these reactions nor of the substances which enter into
them but we may assume that there is a disturbance of
that metabolism which regulates intracellular nutrition and
causes the capillary dilatation.

What is certain, and what is important to remember, is
that excitations of a purely psychic order which involve
those highest nerve cells which determine conscious states
may result in functional disturbances of certain tissues or
organs, that is to say, in purely physicochemical reactions.

We do not know with any certainty whether the inverse
is often true, whether, for example, it is possible to ward
off a contagion or its effects by a particular state of mind
but we do know that it is possible to mitigate anaphylactic
shock by certain narcotics as shown by the experiments of
Besredka inspired by E. Roux. Besredka noticed that the
surest method of producing anaphylactic shock in the
guinea-pig is to inject the antigen into the brain. At that
time E. Roux suggested to him the idea of anesthetizing
the animal before the second injection. The result was
as hoped for; animals narcotized by alcohol, ether, ethyl
chloride, urethane or chloroform, especially by the first two,
were rendered insusceptible to anaphylactic shock while
controls succumbed almost alwaj^s in a few seconds or in
a few minutes. The first was found vaccinated against a
later injection (anti-anaphylaxis) . This experiment leads
us to a combination of very complex phenomena which it is
almost impossible to interpret.

The effect produced by an antigen on a hypersensitive
organism depends to a certain degree, as we have seen
above, quite as much on the dose of the antigen injected
as on the rapidity with which the reactions take place.
For each condition of hypersensitiveness a dose of antigen
can be determined which will produce no apparent trouble,
a dose which will vaccinate and a dose which will kill.
However, no dose is always constant in its effect. A dose
which will produce violent death in an animal when quickly
injected within a few seconds, will become protective if
the injection is allowed to last a few minutes. The effect

INFLUENCE OF CENTRAL NERVOUS SYSTEM 111

thus depends upon the time during which the intracellular
reactions are allowed to take place and anesthesia has no
other role than to prolong the duration of the reactions.
By anesthetizing the nerve cells the transmission of the
excitation to the nerve centers and to the particular tissues
is impeded.

The combination between antigen and antibody in excess
takes place in spite of narcosis, because the animal is vac-
cinated by the dose, but the pathologic effect of the reaction
between the two substances is lessened either because the
duration of the reaction is longer, or better, because the
hypersensitiveness of important nerve cells has prevented
organs of tissues from reacting pathologically. We can
explain this better by a somewhat exaggerated comparison:

When a stone engages in a gall-duct or in the urethra the
walls of the canal contract as if they were trying to hinder
the passage of the foreign body. Local or general anesthesia
will prevent the contraction (and the pain at the same time)
so that if the dimensions of the stone do not exceed the
capacity for expansion of the canal, the stone will continue
on its way without pathologic manifestations.

Experiences have shown that certain nervous excitations
may produce pathologic manifestations, analogous to those
which characterize anaphylactic shock, and that anesthesia
of the nerve centers may hinder these manifestations by
moderating the resulting reactions and especially by hinder-
ing the secondary reaction of the organism.'

We know only two sorts of nervous influences but it is
very probable that there are many others and that their
effects may be different, either good or bad for the organism.
We suspect, for example, that when in an infectious disease
(typhoid fever, pneumonia, tuberculosis, etc.) nervous symp-
toms are predominant, the process of immunization does
not take place or takes place incompletely and the prognosis
is, therefore, always grave. We also know that in antitoxic
immunization, the production of antibodies is all the more
rapid and abundant when the nervous sensibility of the
treated animal is better protected against intoxication.

Thus, the guinea-pig is much more easily immunized against

112 INFLUENCE OF CENTRAL NERVOUS SYSTEM

diphtheria toxin than the rabbit because in the guinea-pig
the non-fatal dose of this toxin is completely fixed and
retained by the cellular tissue and never produces nervous
crises; in the rabbit the same toxin is not retained by cellu-
lar tissue and always paralyzes. But in attempting to
immunize these two animals against tetanus toxin the
reactions and results are exactly reversed. It is thus very
probable that in these two cases the production of anti-
bodies is, in a certain measure, modified by the influence of
the central nervous system.

We may quote here the experiences of KendalP on the
action in vitro of suprarenal cortex on ammonium carbo-
nate. This action is very different according to whether
the operation for the removal of the cortex is done in an
animal normally sluggish without having undergone any
nervous excitement or whether in an animal recently and
violently frightened. In the first case the ammonium car-
bonate undergoes no modification; in the second, it is trans-
formed into a poorly defined substance which Kendall has
called pre-urea because when excreted in urine it is trans-
formed into urea.

The researches of Cannon^ demonstrate beautifully the
actual physiological changes brought about by the central
nervous system. Cannon showed that after any violent
emotion, such as fear or rage, there is a marked liberation
of "epinephrin" from the suprarenal cortex and a liberation
of glycogen from the liver. This sudden liberation of epi-
nephrin, which takes place in a matter of seconds, causes
in turn the production of many and varied disturbances in
the organism such as stimulation of the sympathetic nerves,
increase in the blood coagulability and in the relative pro-
portion of red blood cells.

Psychic excitations can thus produce a proved modifica-
tion in metabolism and resulting from this a change not
only in the substances contained in the suprarenal cortex
but in the quantities of substances secreted.

1 Experimental Hyperthyroidism, Jour. Am. Med. Assn., 1917, Ixix, 610.

2 Am. Jour. Physiol., 1915-16, vols, xl-xlii.

INFLUENCE OF CENTRAL NERVOUS SYSTEM 113

Summary.— If the facts actually known hardly permit
us to understand the nature and the mechanism of the
influences which different varieties of excitations of nerve
centers exert on the reactions between antigens and anti-
bodies we may assume that these reactions are probably
never purely local, that they are always influenced by
nervous states, conscious or subconscious, direct or reflex.
The suggestion which we may draw from this is to investi-
gate the action of different anesthetics, hypnotics and
narcotics or infections, especially in the severe cases with
nervous disturbances.

CHAPTER VII.
THERAPEUTIC MEASURES.

In the evolution of pathologic states caused by actually
known antigens it is necessary to distinguish between a latent
state of anaphylaxis and an actual state of anaphylaxis.

By latent anaphylaxis we mean that the organism is
surcharged with antibodies in excess as a result of the pre-
vious injections or ingestion of the antigen or as a result of
the periods of remission of those diseases with relapses and
with long and slow evolution such as tuberculosis, syphilis,
trypanosomiasis and malaria. Each time that a sufficient
quantity of antigen in fresh doses is joined with these anti-
bodies in excess more or less violent crises will occur.

By actual anaphylaxis, we mean that the organism shows
symptoms of disease in which a state of anaphylactic crisis
is maintained on the one hand by the presence of new quan-
tities of antigens due to the multiplication of bacteria and
on the other hand by the continued formation of antibodies
on the part of the organism so that antibodies will always
be in excess. The formation of momentarily insoluble com-
pounds of antigens and antibody constitutes the pathologic
state of chronic anaphylactic crises.

We know that we can abort a crisis or an anaphylactic
shock by anti-anaphylactic vaccination. According to
Besredka and Steinhardt and according to Al. Wright, cases
of definite anaphylaxis can often be treated successfully by
an identical method— bacteriotherapy, that is to say, by
injections of small doses of antigen— the cause of the disease.

From the work of Besredka we know that preventive
vaccination is rigorously specific and for bacteriotherapy we
seek likewise to obtain curative preparations made with a
culture of the bacterial species which is the cause of the
infection or with the actual germs in the infection, "auto"
vaccines.

THERAPEUTIC MEASURES 115

In both instances, the preventive and curative action can
be explained by a progressive neutraUzation of the antibody
in excess which results in making the organism return to the
normal state following a new injection of the same antigen
and in the two cases "prophylaxis" or therapy confers very
rapidly on the organism a temporary anti-anaphylactic
immunity, but a new dose of the antibody will establish the
preceding anaphylactic condition even more acutely.

The anti-anaphylactic vaccination of Besredka as well as
the bacteriotherapy of Wright are discoveries due to one of
those happy chances in the course of experiments which have
revealed to the experimenters facts which they did not seek
but which, from the practical point of view, have shown them-
selves to be more important than those which they did seek.

And it is interesting to realize that this principle of anti-
anaphjdactic vaccination should arise from the false idea
that antitoxic vaccination should lead to an anti-anaphy-
lactic analogous to antitoxin (Roseneau, Anderson, Otto)
quite in the same way as bacteriotherapy (or vaccine
therapy) arose in the mind of Wright from anti-infectious
vaccination (anti-anthrax vaccination, and the treatment of
rabies: Pasteur, Roux, Chamberland) . Nobody has sought
to establish any relation whatever between those two phe-
nomena.

Besredka was far from doubting when an anaphylactic
shock was aborted by his successive injections, that he
obtained the same results by reactions identical to those of
Wright with his vaccine therapy, but if Besredka reached
little by little an exact conception or at least the only prob-
able conception of the mechanism of anti-anaphylactic
vaccination, the explanation of the facts of bacteriotherapy
is still and w^ill always be an "article of faith," or a "religion"
for all those who pretend to see in the pathologic manifesta-
tions of an infectious disease the effects of a poison and
nothing else and in the recovery an "antitoxic virtue" of a
drug or serum.

Moreover close inspection will reveal that the mechanism
of vaccination and of the treatment of anaphylaxis is simple
and easy of explanation only when previous vaccinating or

116 THERAPEUTIC MEASURES

curative antigens are specific or homologous (autogenous
vaccines). The mechanism is singularly complicated when
it is attempted to associate the identical results obtained by
non-specific antigens especially by the skeptophylaxis of
Ancel and Bouin or by the tachyphylaxis of Gley and
Champy, with lymphotherapy from the preventive point
of view or with chemotherapy from the curative point of
view. In skepto- or tachyphylaxis, whose discovery in 1880^
may be considered chronologically, as the origin of all the
researches on anaphylaxis and bacteriotherapy, the crises
»of anaphylaxis can be aborted by a vaccination injection of
any antigen whatever (Roger and Josue Lambert, Ancel and
Bouin).

In proteosotherapy, Rumpf used injections of sterilized
cultures of pyocyaneus with success in typhoid fever (1893);
Hallopeau and Roger cultures of streptococci and of prodi-
giosus in tuberculous lupus (1896) and quite recently Ch.
Nicolle, James W. Jobling and his numerous collaborators.
Bull, Dunklin, Eggstein, Manier, Peterson, and others,
have obtained undoubted results in treating acute and
chronic rheumatoid arthritis of unknown origin by different
proteoses, peptones or bacterial bodies.

In lymphoserotherapy (Baillon, Artaud, de Vevey, etc.)
as well as in chemotherapy, it is quite impossible to imagine
the direct action of the particular antigen on the antibody in
excess as in proteosotherapy.

From this is the conclusion that either the mechanism of
anti-anaphylactic vaccination and that of specific bacterio-
therapy are different from those of tachyphylaxis, of proteoso-
and of chemotherapy; or else the explanation which we have
just given is inexact or more or less incomplete.

The experimental material at our actual disposal does not
permit us to answer this question in a sufficiently exact way.
What we can say with certainty is that if the effects obtained

1 A. Schmidt Mulheim has shown that a non-pathogenic dose of peptone
rendered an animal insusceptible to a pathogenic dose injected shortly after
the first (Beitrage zur Kentniss des Peptons, etc., Arch. f. Physiol., 1880).

About the same time, Woolbridge established the same result by paren-
teral injections of organ extracts and Martin (Australia) by parenteral
injections of certain venins.

THERAPEUTIC MEASURES 117

by vaccination as, for example, in treatment by homolo-
gous and by heterologous antigens are in certain cases
undoubted, we cannot place these two methods in the same
category. Statistics and clinical observations as an index of
successful treatment must be relied on with caution since
the degrees of disease vary so widely. We know that an
elevation of temperature of 3 or 4° can help the organism to
rid itself of certain bacteria (gonococci) by aiding the disso-
lution of certain precipitates and we know that the intro-
duction of any antigen whatever, in immunizing doses, pro-
duces certain abnormal reactions or stimulates those which
are already begun. (Action of pilocarpine in the production
of antitoxins (Madsen and Salomonsen) .)

It is always the specific agents which exercise the most
obvious action and if the neutralization of antibody in excess
plays an important role in the cure of anaphylactic crises,
this role is only concomitant with other reactions of a nature
and mechanism little understood. We do not know whether
in skepto- or tachyphylaxis and in proteosotherapy all the
antigens are distinctly interchangeable or whether in anti-
anaphylactic vaccination, the vaccinating antigens are or
should always be as rigorously and exclusively specific as in
experiments with egg-white.

Friedberger and others have said that after a pathogenic
injection of anaphylatoxin the serum of the treated animal
contains less "complement" than it contained before the
injection and that at the same time the blood becomes inco-
agulable as in tachyphylaxis. It is then very probable that
in certain cases, if not in all, that the neutralization of the
excess of complement may be equivalent to the neutraliza-
tion of the excess of antibody rendered inactive.

A vast field is here open for experiments which will not
fail to influence the therapy of the future. By these re-
searches medicine aAd its methods will be sooner rendered
more exact and comprehensive. The problems to be solved
will always be infinitely simplified if it is borne in mind that
all the phenomena described under the names of skepto-
or tachyphylaxis, anaphylaxis, anaphylactic crisis, anti-
anaphylaxis, bacterio-, proteoso-, lympho-, and chemo-

118 THERAPEUTIC MEASURES

therapy and even under serum therapy whose discovery has
arisen in different ways and in which researches have devel-
oped parallel to the others, but without touching, are all
provoked by reactions of the same nature.

In fact, the products which provoke skepto- or tachy-
phylaxis are no other than the anaphylatoxins so that skepto-
phylaxis is synonymous with anti-anaphylatoxic vaccination.
An anaphylactic crisis is produced by reactions identical to
those produced by anaphylatoxin and in these two phe-
nomena there is this single difference that in the first, the
organism furnishes the reactive substance (antibody in
excess) while in the second, the antigen furnishes it. A
series of injections of a disodic arsenobenzene will render the
organism anaphylactic to a later or second injection of the
same product. The serum of the treated organism will
become more precipitating than normal serum: Mono-
sodium arsenbenzene is an anaphylatoxin because this
product on injection is more easily precipitable than the
disodic compound.

Finally latent anaphylactic crisis is made to abort exactly
by the same method as an outspoken anaphylactic crisis is
cured. The confusion of facts is caused only by a lack of
understanding of the background on which each develops
and to coordinate these it is only necessary to find in the
experimental material at hand suggestions useful for thera-
peutics.

CHEMOTHERAPY.

Chemotherapy may w^ell profit by all the experiments dis-
cussed above. We know (Dalimier) that the injection of a
small dose of a disodic arsenobenzene can protect the organ-
ism from the pathologic eft'ects of a larger dose and that the
pathologic state already existing and caused by a large dose
may lead to recovery or rapid improvement by a mechanism
identical to that of bacteriotherapy. It would be interesting
to see whether it were possible to cure and especially to
prevent anaphylactic or anaphylatoxic accidents caused by
arsenobenzenes by using other antigens— for example, pep-
tone, sera, or bacterial bodies. If this were possible, it would

CHEMOTHERAPY 119

be easy to increase the actual dose of arsenobenzene. On
account of individual intolerance which is always possible
and difficult to foretell, it is not safe to inject at once a strong
dose of arsenobenzene, but by proceeding with a series of
small injections the risk of habituating a parasite as well as
the organism to the drug would be diminished. There is
therefore every inducement to attempt to find whether by
the injection of vaccinating doses of other antigens, the
tolerance of the organism for arsenobenzene can be increased
so that a more surely curative dose of this drug can be injected
safely. As to the curative or parasiticidal action of chenaical
compounds, we can say with certainty that since they kill
infecting bacteria directly, all these products prevent the
anaphylactic state caused by bacteria much more than they
themselves cause them.

The disappearance from the lesions and from the blood of
treponema, spirilla or trypanosomes following an injection
of arsenobenzene by no means proves that the product has
directly poisoned them. Quite frequently the same result is
obtained by bacteriotherapy. Cases of typhoid fever have
been cured by bacteriotherapy in twenty-four hours (Widal)
or forty-eight hours (Fournier) and here it is impossible to
conceive of a direct destruction of living bacteria by the
injection of dead bacteria.

But at the same time we know :

1 . That to cure a case of recurrent fever or to make trepo-
nema disappear from chancres in twenty-four hours requires
the following drug doses :

Novoarsenobenzene 0.45 gin.

Arsenobenzene 0.25-0.30 "

Luargol 0.10-0.15 "

"Product No. 219" 0.0^-0.05 "

(This last is a product of luargol in which the silver bromide
is partially replaced by copper bromide).

Intramine (of MacDonagh) 1.00 gm.

2. That in the different experimental trypanosomiases
luargol and ''product No. 219" are much more active than

120 THERAPEUTIC MEASURES

606 and galyl for Trypanosoma gambiense, Rhodesiense and
Surra but they are less active for nagana. The product
No. 219 is the only one with which up to the present time it
is possible to destroy the trypanosome dimorphon in the
blood of mice. The principle is probably similar to that of an
antitrypanosome serum which causes agglutination of the
parasites.

3. In infectious lymphangitis, galyl (of Mouneyrat) is
much more active than 606 or luargol.

4. In bacterial septicemias (acute and chronic) all these
products are of equally little efficacy. The injection of 606
may prevent the development of anthrax when injected at
the same time or very shortly after the virus, but luargol in
which the bromide is replaced by the iodide of silver is much
more actiye than 606, probably on account of the specific
action of the iodine. A prolonged treatment with the product
219 has brought about the fairly rapid recovery (two to three
months) of several severe cases of generalized glandular
tuberculosis.

The conclusions which these facts suggest are:

1. Although the action of every arsenobenzene is equally
anti-anaphylactic, that is to say, causes in the organism
reactions of the same sort, the substances of the organism
and the substance of the infecting parasites which react with
the drug are not the same for each drug. By multiplying the
different affinities of the product the fixation and neutraliza-
tion of a much larger nmnber of different substances of the
parasite is brought about and thus the field of action of the
product is extended to a greater number of parasites.

For example, if 606 acts only by the free aflSnities of its
arsenic, 219 may act by its own affinities of arsenic and in
addition by those of antimony, bromine, silver and copper.

2. It is probably not necessary to complicate the composi-
tion of therapeutic products by elements with great anti-
toxic or antiseptic power as these might in the long run
become themselves dangerous for the tissues.

It is true that certain organic compounds (toxins, venins,
sera) are more pathogenic than the most toxic metallic salts
but since it is a question of obtaining anaphylactic effects

BACTERIOTHERAPY AND SERUM THERAPY 121

and since it is possible to attain these effects without using
in the composition of drugs any toxic metals, the idea of
MacDonagh of replacing the arsenic of arsenobenzene by a
sulphate or iron salt deserves to be given serious consideration.

BACTERIOTHERAPY AND SERUM THERAPY.

As long as it is possible to produce antigens and antibodies
by synthesis, bacterio- and serum therapy will be the methods
of choice in the treatment of infectious diseases. In bacterio-
therapy the uncertainty in the dose is most often the cause
of partial failure or of severe accidents which have made
chnicians hesitate to adopt this method and to apply it to all
cases where practically possible.

But experiments in anti-anaphylaxis and in skepto- and
tachyphylaxis permit us at the present to make this method
more sure and efficacious. We may assume that, other
things being equal, specific or autogenous bacteriotherapy
will always give us the best and most constant results; but
it is necessary to find the best curative preparation; the best
method of its administration (whether by mouth, by rectum,
subcutaneously or intravenously) and finally the best dosage.

Curative preparations may be either:

1. A culture on a gelatin emulsion in saline or distilled
water killed by heat (58° to 100° C.) and as fresh as possible.

2. The same cultures prepared in the same way but more
or less autolized.

3. The same culture killed by antiseptics.

4. A living culture of attenuated virulence.

5. A living culture of attenuated virulence and then
sensitized.

The best method of administering curative preparations is
always by intravenous injection. It will always give the
quickest results and will not aggravate the condition of the
patient. When the quantity of antigen is predetermined (by
determining the quantity of antibody in excess), vaccines
can be injected without danger.

The least dangerous method is to give the vaccme by
mouth but it is evident that this method can be applied with

122 THEHAPEUTIC MEASURES

success only in case gastro-intestinal digestion is incapable of
transforming the bacterial albumins into their amino-acids
(typhoid, cholera, f urunculosis) .

The dose should be regulated according to the quantity
of antibody in excess contained in the blood of the patient.
Too large a dose may produce a rapidly fatal anaphylactic
crisis: too small a dose will give a slight or inappreciate
result. As it is often difficult to rapidly determine the exact
quantity of antibody in the blood of the patient one may
replace a single injection by a series of injections made under
the following conditions :

Supposing, for example, that the total quantity of bacteria
to be injected is five hundred million, there would be given by
vein:

First, a primary injection of 500,000 bacteria; a second
injection, ten minutes later 5,000,000 bacteria; a third injec-
tion, five minutes later 50,000,000 bacteria; a fourth injection,
three to five minutes later 450,000,000 bacteria; by exhaust-
ing little by little the antibodies in excess, one could more
easily reach the dose of antigen necessary to neutralize all
the antibody without provoking a pathologic reaction.

SERUM THERAPY.

It is evident that an injection of antibacterial serum, that
is to say, of an antibody, into an organism containing already
an excess of this antibody can have no curative effect where
the disease is due to a chronic anaphylactic state. In fact
we know that the injection of such a serum always causes a
passive anaphylactic state and we know that in a certain
number of diseases, tuberculosis, plague, typhoid, strepto-
coccus, antisera have given up to the present time no appre-
ciable result. There are, moreover, septicemic diseases such
as erysipelas, anthrax, pneumonia, cerebrospinal meningitis,
in which the action of specific sera is indisputable. Either
the bacteria of these infections secrete in the organism toxins
analogous to those of diphtheria and tetanus and the serum
acts in*this case by its antitoxic properties; or else the action
of the serum is analogous to that of a proteose or of a non-

SeHum therapy 123

specific protein. The two actions may furthermore take
place simultaneously.

Diphtheria and erysipelas are very instructive in this way.
Most, if not all, horses yield in the normal state antidiph-
theritic and antistreptococcus serum of very appreciable
potency (up to 50 antitoxic units per c.c. for diphtheria) and
although it is unlikely that horses which are naturally refrac-
tory for these two diseases could acquire this spontaneous
immunity, it is possible that the serum of normal horses acts
like a non-specific antigen and this is not surprising since we
know that carmin will neutralize tetanus toxin. In other
words, a biologically neutral and non-specific substance can
produce a reaction of the same nature as a specific antitoxin.
The differences are only in proportions and degrees.

It would not be difficult to elaborate a program of studies
which would enable us to exactly diff'erentiate the cases of
intoxication, due to the direct action of toxins, from cases of
anaphylaxis caused by bacterial albumins, or in other words,
the cases amenable to treatment by antisera from those in
which such a serum could do only harm.

chapter viii.

principles of the classification of
Infectious diseases.

In every infectious disease, the pathologic manifestations
are produced by the action of antigens on tissues and organs
and the differences in the evolution of symptoms of these
different diseases are determined by:

1 . The physicochemical composition and the physiological
properties of antigens and antibodies.

2. The nature of the compounds formed by antigens with
their normal antibodies, whether soluble or insoluble, neutral
or active.

3. The elective affinities of antigens for certain tissues.

4. The physiological role of the antibodies in the life of
those cells which fix the antigen.

5. The role of the fixing cells in the life of the organism.

6. The adaptation of the infecting bacteria to life in the
infected organism.

7. The nature of the complications which may result from
the lesions produced.

The similarities and the differences in the physicochemical
properties of antigen, in the biologic action of the reacting
substances, in the nature and effects of the reactions; all
serve as a basis for a natural classification of infectious dis-
eases; but it is evident that such a classification will only
be of purely theoretical interest.

Every therapeutic intervention ought to be based on the
knowledge of the facts which we have just reviewed, because
they are facts which determine successive stages in the
evolution of each disease caused by an antigen. A classifica-
tion permits us at the same time to group in a rational
manner therapeutic methods and to foretell the results

CLASSIFICATION OF INFECTIOUS DISEASES 125

which a certain preventive or curative method should be
capable of yielding in each particular case. By proceeding
in this way, we ought little by little to make therapeutics an
exact science.

Thus, for example, the fact that in diphtheria the antigen
in excess forms with the normal antibody a pathogenic com-
pound while the antigen with antibody in excess forms a
compound which is neutral for the organism, permits us to
conclude that preventive or curative treatment by antitoxic
serum is the most efficacious method. And we should con-
clude that in all other cases when reactions between anti-
bodies and antigens are of the same nature the same treat-
ment will yield analogous results. On the other hand where
the antibody in excess forms with the antigen an insoluble
compound and where it is precisely this excess of antibody
which is the cause of the pathologic manifestations (ana-
phylactic state) (as in typhoid fever) the disease cannot be
treated by injections of antibody, which already exist in
excess but, on the contrary, must be treated by anti-anaphyl-
actic methods— that is, by injections of antigen which will
neutralize this excess of antibody.

There are diseases in which the antibody in excess neutral-
izes the antigen without producing appreciable disturbances
and there are others in which the antibody in excess, while
neutralizing the antigen, produces by its combination with
the latter a pathologic reaction. This difference between the
properties of the compounds of antigens with their antibodies
in excess allows us to divide the known diseases into two
great groups. Our knowledge of the properties of antibodies
and of antigens as well as of the compounds formed by these
two substances is altogether too incomplete in most cases
for us to assign at the present their exact place in each dis-
ease. Judging from what we actually know, we can group
together on the one hand, diphtheria, tetanus, certain pneu-
monias, perhaps anthrax fever, erysipelas, and certain cere-
brospinal meningitides in which the antigen acts directly and
rapidly on tissues and is neutralized by the antibody in
excess without anaphylaxis and, on the other hand, all the
other septicemias in which the incubation period is more

126 CLASSIFICATION OF INFECTIOUS DISEASES

or less long and in which the pathologic manifestations are
anaphylactic in nature.

The characters of the subgroups and species will be deter-
mined by the affinities of antigens for different tissues as
well as by the nature and properties of antibodies and the
role of these latter in the life of the sensitive cells. Thus, for
example, tuberculosis, glanders and leprosy on the one hand;
syphilis, trypanosomiasis, relapsing fever and malaria on the
other hand form two closely allied groups of diseases. As
common characteristics they have the physicochemical
properties of their antigens and the nature of their anti-
bodies. In both groups immunity and anaphylaxis persist
only as long as the infection itself. The quantity of antibody
produced in excess is relatively very small and the sensitive
cells cease to produce it immediately after the disappearance
of the infecting bacteria. On the other hand the bacteria
seem to adapt themselves very easily to the medium of the
infecting organism and may live in it for years or even dozens
of years. This facility of adaptation on the one hand,
determines the more or less regular cyclic evolution of these
diseases whose mechanism has been the object of the very
interesting study of nagana in the guinea-pig by Levaditi
and Mutermilch.

Typhoid and paratyphoid fever, plague, eruptive fevers,
yellow fevers, the hemorrhagic septicemia in animals, bovine
plague, the horse sickness of South Africa form another
group of diseases which are related to the preceding group
by the physicochemical properties of their antigens as well
as by the pathogenic properties of the compounds of these
antigens with antibodies in excess. This second group
differs from the first by the nature and origin of the anti-
bodies which sensitive cells produce in relatively large
quantities and reproduce for a long time after recovery from
the disease. In these cases acquired immunity-anaphylaxis
may persist for several years.

Gonorrhea, influenza, aphthous fever form still another
group which is related to the type of tuberculosis by the intra-
cellular origin of the antibodies which determines the short
duration of immunity-anaphylaxis but differs from^it by

CLASSIFICATION OF INFECTIOUS DISEASES 127

the nature and the localization of the sensitive cells and in
consequence by the lesions produced especially by the
rapidity of the evolution because the bacteria of these dis-
eases are less easily adapted to the infected medium than
those of tuberculosis or of syphilis.

Summary,— From the point of view of their evolution, all
infectious diseases have as a common characteristic the
formation of antibodies in excess under the action of antigens.

The common distinguishing characteristic between the
different diseases lies in the physicochemical nature and the
biologic properties of the compounds formed by the action
of the antibodies in excess with their antigens. These com-
pounds may be either soluble and neutral and here the
immunizing action of the antigens will confer on the organ-
ism immunity without anaphylaxis (diphtheria); or com-
pounds may be insoluble and pathogenic and here the immun-
izing action of the antigen confers on the organism immunity
and also anaphylaxis (almost all septicemias).

The two great families of infectious diseases can be sub-
divided according to the affinities of antigens, the relative
quantity of antibodies produced, and the duration after
recovery of the production of antibodies. This latter prob-
ably depends upon the nature and upon the role which the
mother substance of the antibody fulfills in the life of the
cell.

In the second great group three types can be distinguished :

1. Tuberculosis.

2. Typhoid fever.

3. Gonorrhea, aphthous fever, and a subtype; syphilis and
malaria.

The species in these groups may be differentiated and
characterized by the affinities of antigens for different
tissues, by the nature of lesions produced and by the adapta-
tion of bacteria to their host.

CHAPTER IX.
GENERAL CONCLUSIONS.

The collection of studies on the evolution and nature of
pathologic states which we have just analyzed, especially
the phenomena of surcharge or of least saturation which are
found in mixtures of antibodies and antigens; the recent
researches of physiology, more particularly those of Willcock
and Hopkins,^ and of Osborn and MendeP on the importance
of certain amino-acids (tryptophane and lysin) in the nutri-
tion, growth and reproduction of higher animals as well as
the quite recent work of Van Slyke.^ The present significance
of the amino-acids in physiology and pathology shows that
the amino-acids pass from the intestines into the blood with-
out undergoing any transformation and at least in part are
absorbed directly by the tissues.

These researches lead us to consider the organism from
the point of view of its physicochemical composition as a
total composed of colloidal "micelles," formed by the union of
a larger or smaller number of homo- or heterogeneous amino-
acids held together by certain chemical affinities. By reason
of surface tension, the molecules are more dense at the peri-
phery than at the center so that the peripheral layer acts
like a dialyzing membrane.

A "micelle" thus constituted can fix salts by chemical
affinities of its molecules and can absorb them by osmosis
and can exchange salts as well as water with the exterior. It
can also by the same affinities fix itself to other units and
form much larger voluminous granules. It is thus not the
molecule but the colloidal "micelle" which is the chemically

1 The importance of Individual Amino-acids in Metabolism, Jour, of
Physiol., December, 1896, p. 8.

2 The Role of Different Proteins in Nutrition and Growth.
» Arch. Int. Med., 1917, xix, 56.

GENERAL CONCLUSIONS 129

indivisable unit of living matter. The ''micelle" is the
organ of intracellular nutrition which by the stability of its
chemical composition and the resulting physical constitution
maintains the specificity of different tissues and of each
species and determines the cycle of evolution of each cell.
Separated into the salts, lipoids, and amino-acids which
compose it, the ''micelle" no longer possesses any specificity
nor any of those properties which characterize living matter.

What is the mechanism of the autoreconstruction of the
living "micelle?" The most recent researches mentioned
above oblige us to assume that animal "micelles" can assimi-
late untransf ormed amino-acids and they cease to live if they
have not certain preformed amino-acids (tryptophane) at
their disposal; which suggests that they are incapable of
constructing these substances from the simplest chemical
units. Van Slyke has shown that tissues absorb amino-acids:
the presence of amino-acids in the blood has been proved
by Delaunay and the works of Fischer, Kossel, and others on
the polypeptids permit us to conceive of the construction
of a biologic particle of a still more complex composition
and constitution.

Is there a ferment analogous to that which hydrolyzes
albumins, which causes the synthesis of albumins? That is
hardly probable. If we imagine that a "micelle" of a certain
composition can attract and assimilate by a total of its
physicochemical properties, the amino-acids of which it is
composed, as a crystal attracts and fixes by analogous
properties molecules identical to those of which it is formed,
we can readily understand the autoreconstruction of par-
ticles of the plasma with the materials which are found in
abundance in the medium in which they are constantly
bathed: and we do not need to consider a "ferment" whose
existence has at the present time never been proved.

When the "micelles" are free in a state of fluid, the colloid
is in the state of sol; when they are in unity in granules the
colloid is in the state of gel and in a living organism these
two states are always in unstable equilibrium; each "micelle"
is constantly in a state of change between gel and sol. Every
sudden stop, every rupture of equilibrium in this continuity
9

130 GENERAL CONCLUSIONS

of exchange and in the passage between sol and gel, every
stabilization of one or the other of these states results in
more or less severe disturbances of stabilization which in
turn, depend upon the dose and preparation of the stabilizing
agent.

The biochemical experience of Loewe, of which the true
significance has been brought to light by the studies of Ame
Pictet on the life and death of plasma, definitely confirm
these ideas and allow us to understand the probable chemical
mechanism. Loewe found that those substances which are
poisonous for living plasma and exercise no appreciable
action on dead albumin, act chemically by transforming
unstable linear compounds into relatively stable, cylic com-
pounds and Pictet drew from this work the conclusion con-
firmed by new and very ingenious experiments that it was
this chemical stabilization added to the durable stabilization
of a certain state of biologic equilibrium which might be the
cause of a pathologic state of the plasma of the cell and of its
death.

It may be that as, for example, in the case of mercury
salts and certain venins by acting not on the molecule but
on the "micelle," the same product produces the stabiliza-
tion of the colloid in various forms: gel, sol, etc., according to
the quantity or the proportion of the product which is fixed :
and that the rupture of equilibrium in certain "micelles"
will in a sense, necessarily result in a contrary reaction in
other "micelles."

All substances, salts as well as colloids, may disturb vital
functions, that is to say, the functions of nutrition of colloids,
and hence of the cells by virtue of their being in solution in
the interior of the organism and of possessing affinities for
the substances which compose the cells.

From the chemical point of view these substances can be
divided into two great groups— those which are nutritive and
those which are not. In the first category will belong all the
substances which normally enter into the composition of the
organism; in the second those of which analysis shows no
trace. The alimentary composition of all organisms is very
uniform but the relative proportions in which the different
elements are found differ infinitely.

GENERAL CONCLUSIONS 131

Specific differences are very probably determined by the
arrangement and by the proportions of different amino-
acids, the quantities of mineral substances, iron, arsenic,
potassium, sodium, magnesium, calcium, etc., which vary
widely from one species to another and by the ties which
bind amino-acids into "micelles."

Nutritive salts are fixed in definite proportions : the excess
being rapidly eliminated. Non-nutritive salts may be neutral
and then are rapidly eliminated but they are pathogenic
whenever their quantity disturbs the sol-gel equilibrium of
the colloids. Nutritive salts, like pathogenic salts, will not
produce the formation of specific antibodies because the
reactions between salts are innocuous and, furthermore,
because a salt produced in excess is rapidly eliminated.

Colloids may also be nutritive, neutral or pathogenic but
only after having undergone a complete digestion, that is to
say, a disintegration into free molecules. They will always
be pathogenic, when in the colloidal state they have pene-
trated by any way whatever into the interior of the organism
which must then digest them, without being specifically
adapted for this function. Certain colloids (toxins) composed
of very small "micelles" may be directly pathogenic, when
they are fixed "en surcharge" to certain cells. On the
other hand, other colloids with more voluminous, less pene-
trating "micelles" do not become pathogenic until after a
longer or shorter incubation period , when having entered the
cell and distended its membrane by the multiplication of
normal antibodies, they become able to penetrate to the
interior of the cells. In one case as in the other the cells not
fatally attacked will transform the colloid antigen into nutri-
tious or eliminable crystalloids and will multiply the trans-
forming substance which will then become antibody in excess.

This antibody in excess will be specific because the colloid
antigens are specific individually and the antibody will
accumulate in the cells and in the organism because as much
as we know of it, it is a colloid. The production of antibody
in excess is a vital reaction of the cells. Whenever the anti-
body in excess forms with its antigen an insoluble compound,
there results an increase in the degree of immunity and at

132 GENERAL CONCLUSIONS

the same time of the natural sensitiveness or anaphylaxis.
In every case, for salts as well as colloids, the differences and
the same contrasts in the reactions (nutritive, immunizing
or pathogenic) will be determined by the proportion of the
reacting substances.

A pathogenic bacterium will naturally obey the same
general biochemical law as any other cell in order to nourish
itself in the interior of the organism to which it has pene-
trated. If by its albumins or by its secretions, it is antigenic
for the cells of the organism the albumins or secretions of
these latter are antigenic for it and like the organism the
bacterium will produce antibodies intra- and extracellular
against these antigens. At the same time it will become
more immune and more sensitive and whenever the organism
produces its antibodies more rapidly than the infecting
bacterium, the bacterium will succumb to anaphylaxis. It
will be autolized or surcharged with antibody or antigen
(sensitized) and will become the easy prey of phagocytes on
account of the phenomenon of positive chemotaxis of Charles
Bordet and Massart. In this way the conditions of normal
or pathologic nutrition of a "micelle" and in consequence of
the cell may be understood.

In an organism composed of a combination of different
tissues, and of organs and glands with special functions,
reactions will obviously be much more complex. In these
cases a disturbance will never be strictly limited ; it will have
always multiple eft'ects. The intervention of the liver, spleen,
suprarenal capsule, thyroid and parathyroid glands, hypo-
physis and especially the central nervous system may greatly
modify the rate of each reaction, and may infinitely compli-
cate the study of its mechanism. But whatever these com-
plications may be, whether the objective symptoms are
caused by a purely local reaction or whether caused by a
reflex action, it is impossible to imagine that any modifica-
tion whatever in the normal state of the organism could be
produced by anything other than a disturbance of the nutri-
tion of the "micelle"; in other words, by a modification of
the physicochemical equilibrium of the " micelles."

. GENERAL CONCLUSIONS 133

Summary.— All the studies on physical ch(emistry and
normal and pathologic biology tend to prove that the ele-
mentary chemical composition of albumins and of living
beings is very uniform and that the specific differences are
caused only by differences in the proportions in which these
elements are united into "micelles." All albumins are con-
structed on the same plan. Their reactions are therefore all
of the same nature but the chemical, osmotic and physiological
equilibria determined by the different proportions of the
elements which constitute the "micelles," vary infinitely,
so that they can react differently to the same reacting
substance.

The chemical and physiological unit of the plasma is the
"micelle" which possesses for each animal or vegetable species
a particular and constant chemical and osmotic equilibrium.

A "micelle" can be nourished only by the crystalloids of
which it is composed, and can assimilate them without
trouble only in the proportions in which it normally contains
them. It may absorb them and fix them in different propor-
tions but then its equilibrium is changed and it is easy to
imagine that by absorbing a foreign substance (salt or
crystalloid) in progressively increasing quantity and over a
sufficiently long time in order that the new state of equilib-
rium may become hereditary, a "micelle," a plasma, or a
cell may acquire new properties which will constitute a new
race or even a new species.

A cell may absorb specifically different "micelles" but it
cannot incorporate them as such into its own plasma because
they possess a different nutritive equilibrium. It cannot
directly be nourished by them without first demolishing
them because the "micelles" cannot absorb other "micelles"
but only non-specific crystalloid compounds which come to
them.

Heterogeneous particles are thus necessarily dissociated
when they come into a medium foreign to themselves and
this process of intracellular dissociation is the origin of simple
immunity on the one hand or of immunity-anaphylaxis on
the other according to the rate of the reactions produced
and according as the formation of antibody in excess neutral-

134 GENERAL CONCLUSIONS

izes antigens outside of the cells, and prevents the direct and
too rapid transformation of one foreign species to another.

Thus in the last analysis, an organisni can be nourished
only by simple chemical compounds and can assimilate
them only in proportions identical to those in which th^y
are composed in its colloidal complexes. The absorption
by the interior of the organism of a complex of different
composition and constitution will always result in the creation
of a new and abnormal state of equilibrium.

This is a general biologic law applicable to all the mani-
festations of living matter without excepting the evolution
of conscience and the formation of states of mind. In fact
in analyzing the evolution of thought we find that a mind
can directly absorb only simple ideas and can assimilate
them without trouble only in proportions identical to those in
which its own complex of ideas is formed. Complexes of
ideas foreign to its understanding and which one may com-
pare to specifically different "micelles" can be assimilated
only on condition that they can be digested, that is to say,
can be analyzed or dissociated. If this is so, a state of simple
immunity or immunity-anaphylaxis, a new state of psychic
equilibrium will result by a process analogous to that which
induces modifications in the states of chemical and physio-
logical equilibrium of "micelles" and cells. A new theory,
a new religion, a new political or social system introduced too
suddenly or in too large a dose into subjects insufficiently or
badly prepared will always upset the normal equilibrium.
This is a pathologic state, quite as serious in the soul of
individuals and of societies as too large a dose of antigens
in the cell and in the organism.

PART II.

CHAPTER X.

EVOLUTION OF THEORIES CONCERNING

IMMUNITY, ANAPHYLAXIS AND

ANTI-ANAPHYLAXIS.

INTRODUCTION.

Since the origin of infectious diseases has been recognized,
we have tried to treat or prevent them by methods based
on the reactions produced in the infected organism by patho-
genic bacteria or by bacterial products (toxins). In this
research, only immediate results were considered: active
immunity by preventive vaccination or by bacteriotherapy,
or passive immunity by serum therapy. In both cases, the
vaccinated or recovered organism was considered normal.
In addition to these diseases, correctly designated as infec-
tious, with acute evolution (typhoid fever, cholera, plague,
pneumonia, etc.) or chronic (tuberculosis, syphilis, malaria,
etc.), there are a great number of chronic morbid states such
as gastro-intestinal troubles, asthma, various dermatoses,
rheumatisms and arthritides, neurasthenias, etc., of unknown
origin.

These diseases are not contagious; we cannot assign a
direct bacterial origin to them. Nevertheless they present
many analogies in their evolution and symptoms with true
infections or with the consequences of such infections (tuber-
culosis, syphilis, diphtheria, influenza, etc.).

Since the general use of vaccines, such as dead bacteria,
curative sera or certain drugs of complex composition, such
as the arsenobenzenes, quinine, antipyrin, chaulmoogra oil,
peptones; it has been found that reactions which are identical

136 THEORIES CONCERNING IMMUNITY

with those caused by bacteria or bacterial products may be
caused by inert substances : identical because they are directly
or indirectly antigenic. The introduction of these substances
into the organism causes in the organism the formation of
more or less specific antibodies, and it has been found that
mixtures prepared in vitro of antibodies with their correspond-
ing antigens are either neutral or toxic: neutral when they
remain clear (toxins and antitoxins); toxic when they pre-
cipitate (bacteria or sera and their antibodies) .

Similar results are obtained in mw— when an animal is
injected with an antigen which is precipitated by its serum.

The necessary conclusions are that :

1. In those diseases where an antibody is formed which
can precipitate its antigen, pathologic manifestations are
caused precisely by the very excess of this antibody.

2. The same pathologic manifestations can be caused by
inert antigenic substances.

3. In many cases the origin of a chronic disease is not the
direct action of a toxic substance itself, but a secondary
reaction between the organism and an antigen which may in
itself be innocuous— for example, a harmless bacterium,
normal serum, or egg-white.

4. Finally, in order to obtain an exact and complete idea
of the state of an immunized organism, it is not sufficient
to consider the accrued resistance to a definite pathogenic
agent; but one must also consider the results which this
state of immunity, that is to say, the excess of antibody
present in the blood and produced by the organs, may have
on the nutrition-equilibrium of the immunized organism.

But a mere statement does not suffice. To convince the
reader, it is necessary to produce the "proceedings of the
court," and to go over again the stages of the road traveled
by experimental biology since the time of Pasteur.

RESEARCHES BY PASTEUR, BY ROUX AND YERSIN AND
BY BEHRING AND KITASATO.

The researches by Pasteur and by his school have brought
out four fundamental biological rules or laws:

RESEARCHES BY PASTEUR 137

1. All contagious diseases are caused by living bacteria,
which multiply in the blood or in the tissues of the invaded
organism or, in other words: All bacteria able to multiply
and to live more or less steadily in the blood or in the tissues
of a superior organism, may cause infectious diseases which
are directly or indirectly contagious.

2. Bacteria are pathogenic because of the poisons which
they secrete or produce.

3. The virulence of pathogenic bacteria may be attenuated
or completely suppressed in certain cases by artificial cultures
and may be increased by passage through living organisms.

4. The introduction into an animal organism of a patho-
genic bacteria attenuated or sterilized, protects this organism
against later infection by the same bacteria when virulent.
The "vaccinated" animal thus acquires an active immunity,
and it is important to note that this immunity appears only
after an "incubation period," which varies in time for the
different infectious bacteria from eight to fourteen days, and
which lasts for several days at least.

Several years later, the researches of Roux and Yersin on
the "toxin" of diphtheria, led Behring and Kitasato to the
discovery of antitoxin; their researches showed that:

5. By the injection into an animal of a bacterial poison
in non-pathogenic or slightly pathogenic quantity, the animal
acquires at first a greater resistance to the same poison, and
later, when the treatment is continued, there is produced in
the blood of the animal a specific antidote, exclusively for this
poison. The injection of a toxin causes the production of an
antitoxin in the organism. The antitoxin neutralizes in
vitro and in vivo the pathogenic action of the toxin. The
product of a mixture of toxin with antitoxin, in suitable
proportions, is neutral.

These were the fundamental rules on which was based all
ulterior research concerning reactions between the infecting
bacteria and the infected organisms. It was then generally
thought that, on the basis of these rules, one would succeed
rapidly and without too many difficulties in cultivating or at
least in demonstrating the bacteria of all infectious diseases,
and in preparing preventive vaccines or curative sera for all

138 THEORIES CONCERNING IMMUNITY

these diseases. It was hoped that in the course of this
research it would become possible to explain at the same time
the mechanism of all these reactions— namely, why a bac-
terium is pathogenic or may become so, how and why an
infected organism may spontaneously recover or succumb
to the disease, whether all infectious diseases have the same
evolution— and also why the reactions caused by bacteria
or by their toxins differed from the reactions caused by most
toxic salts, inorganic or organic.

In reality these investigations have met with difficulties
as numerous as they were unforeseen. Even today, after
half a century of relentless labor, there are very contagious
diseases, such as measles, scarlatina, typhus, hydrophobia, of
which the germs are unknown; there are others such as leprosy
malaria, the trypanosomiases, of which the germs are known
but which cannot yet be cultivated on artificial media; there
are others for which we have not succeeded in preparing either
preventive vaccine or curative serum; lastly, there are others
(psoriasis, eczema, cancer, etc.) which are not contagious
and of which the germs are unknown, but which have many
characteristics in common with diseases of infectious origin.

It was therefore necessary to recognize that all these
problems could not be solved by frontal attacks; that if, in
certain cases, it was possible to arrive at practical solutions
by avoiding obstacles, and that if it was possible to discover
preventive vaccines or curative treatments without knowing
the causes of the disease— Jenner for small-pox and Pasteur
for hydrophobia— in many other cases it was necessary, in
order to arrive at the same results, to make a long detour
in the attempt to better understand the functions of the
organism, and the nature and mechanism of its normal and
pathologic reactions.

And thus it is that nearly all the exact and biological
sciences, chemistry and physics, general biology together
with medicine and bacteriology, have been drawn upon to
attack the immunity problem from several angles at the
same time. What often happens in the exploration of
unknown lands has occurred here: In following different
trails, the explorers lose sight of each other at times, their

TRANSFUSION OF BLOOD 139

discoveries lead to results which are apparently irreconcilable,
and contrary to the general ideas which inspired their
departure; yet in the end all these routes lead to a clearing
from which one can survey easily all the roads, and where
everything can be explained and mutually understood.

During the study of immunity such phenomena have been
discovered that it seemed impossible to find common bonds,
or to reconcile them with the laws which logically followed
the discoveries of Pasteur; we shall see that it has become
possible today to assemble all these phenomena into one
harmonious whole which, far from contradicting, confirms
Pasteur's ideas and completes them by new laws.

TRANSFUSION OF BLOOD AND INJECTION OF HETER-
OLOGOUS AND HOMOLOGOUS SERA AND
OTHER PROTEINS.

For a long time (since the old Egyptians) it was known
that it was possible to ''transfuse" blood from one animal
to another, and that transfusion between animals of the
same kind was less dangerous than transfusion between
animals of different kinds; but it was to Landois, and espe-
cially to Hayem^ (1885-1890) that we owe the first precise
experimental studies of this question. Among other experi-
ments Hayem injected blood from cattle into the veins of
dogs, and determined that while a first injection of about
50 c.c. is endured without noticeable reaction, a second
injection, of a dose half as strong, into the same animal twelve
days after the first injection, is followed several minutes
later by a violent crisis generally ending in death.

"The blood of an animal so treated," writes Hayem, "con-
tains elements more or less changed, and sometimes hyaline
concretions which are very refracting and extremely viscous.
The blood in a tied vessel, kept from the previous day,
remained liquid; there was a formation of clots like a sedi-
ment. It is these small masses of albuminoid matter (forma-
tion of a precipitate) which are the origin of the emboli.

^ On Blood and its Anatomical Alterations, Paris, 1889, pp. 240 et seq.

140 THEORIES CONCERNING IMMUNITY

When they are very numerous and able to obstruct the cir-
culation more or less completely, the animal soon succumbs;
but it is conceivable that in certain cases, they may deter-
mine local lesions of small size and the animals may survive."

Other similar experiments convinced this savant that the
injection of blood from cattle into dogs represents only one
special case of this kind of "coagulating injection," so that
one may generalize this fact and say:

The second injection of blood or of a heterologous albumi-
noid substance (from an animal of a different kind) into the
veins of an animal several days after the first injection, is
much more dangerous than the first.

The first injection of a strong dose is usually well endured,
the second and lesser dose is usually fatal.

The second dose is pathogenic because it causes the forma-
tion of a precipitate which obstructs the capillaries.

Hayem pointed out this phenomenon without endeavoring
to explain it, so that his discovery did not awaken at that
time the interest which it deserved.

It was only several years later (1894-1900) that all its
importance was realized through the works of Pfeiffer,
Metchnikoff, J. Bordet, Kraus, Belfanti and Carbone, and
others, on the reciprocal reactions between the sera of
immunized animals, on the one hand, and bacilli, the broth
cultures, sera, blood elements, or other injected cells, on the
other. Thus Pfeiffer determined that cholera vibrios injected
into the peritoneal cavity of a guinea-pig, previously immun-
ized against these bacilli, were agglutinated and partially
destroyed in the peritoneal fluid, without direct intervention
of phagocytes.

Soon after, Metchnikoff, followed by J. Bordet, showed
that the same phenomena could be reproduced in vitro by
mixing in a test-tube a culture of cholera vibrios with a small
amount of serum from an immunized animal.

Kraus obtained the same result, not only for cholera,
typhoid and plague bacteria, but also for the filtrated broth
cultures of these microbes. In mixing these broth cultures
with a little serum from immunized animals, he saw the
formation of a precipitate.

TRANSFUSION OF BLOOD 141

Soon afterward, Belfanti and Carbone (July, 1898) dis-
covered the very important fact that the injection of rabbit
serum into a horse made the serum of this horse toxic for all
rabbits; and Bordet completed this experiment by showing
that the serum of any animal injected with the blood of an
animal of different kind, acquires the property of agglutinat-
ing and dissolving the red corpuscles and of forming a pre-
cipitate with the serum of the animal which furnished the
injected blood, on mixing both liquids in a test-tube.

The reactions observed in vitro therefore allow us to per-
ceive what goes on in the organism, and to explain the
nature if not the fundamental mechanism of a series of
pathological reactions that might from this time on have led
us to regard immunity and the pathogenicity of certain
infectious diseases in a new light.

The results of the experiments of Hayem, Behring and
Kitasato, Pfeiffer, Metchnikoft', J. Bordet, Kraus, Belfanti
and Carbone, and others, has been to emphasize the follow-
ing biological rules:

1. The injection of a heterologous albumin (bacterial
bodies, blood, serum, casein, etc.) or of a non-albuminoid
bacterial product causes, in the injected organism, the forma-
tion of a substance in excess which possesses a specific
affinity for the injected substance.

The name of "antibody" has been given to all the substances
thus formed, and of ''antigen" to all those substances causing
such a formation.

2. The antibodies neutralize in vitro and in vivo the specific
pathogenic action of the antigen toxin and of the infectious
antigen bacilli; but whereas the mixtures of antigen toxins
(non-albuminoid) with their antitoxins give a product which
is soluble "in vitro'' and neutral in the organism— the mix-
tures of the infectious antigen bacilli with their antibodies
give a product which forms a precipitate. This precipitate
is neutral from an infectious point of view in the case of
pathogenic bacilli, and from a toxic point of view for toxal-
bumins, but in itself it is endowed with a special toxicity.

This special toxicity becomes evident when one eliminates
from the mixture the actual "toxin" or "infection" as for

142 THEORIES CONCERNING IMMUNITY

example by mixing with their respective antibodies harmless
albumin-antigens (like serum, casein, white of egg, etc.)
which are not toxic in themselves. For in such cases, the
two substances, each of them inoffensive, form a product— a
precipitate— which is toxic.

The pathologic manifestations caused by these toxic mix-
tures are always the same, regardless of the nature of the
antigen-albumin (pathogenic bacillus, toxalbumin or ordi-
nary food albumin) .

It follows by deduction that :

The reactions caused by the toxic products of mixtures
in vitro or in vivo of antibodies with their antigens, always
affect the same organs and are always of the same nature.

What is the nature of this reaction, and what justifies it?

It may be assumed, with Metchnikoff and his school, that
the heterologous albumins like bacteria, undergo intracellular
digestion in the blood and in certain organs. Anti-infectious
immunity through phagocytosis would be only a particular
case of this intracellular digestion, or quoting Bordet, "a
fortunate and efficient application, for the defense of the
organism, of a primordial function which would exist to the
same extent even if there were no pathogenic germs on the
surface of the earth." This theory, however, does not explain
the pathological manifestations which result from this
function. It does not explain and does not try to explain,
which substances, innocuous when first injected, become
pathogenic at the second injection, whereas true toxins, on
the contrary, become innocuous under the same conditions.

These discoveries were registered without connection with
any general biological phenomena, and these questions had
to remain unanswered for a long time.

ANAPHYLAXIS.

It is evident that for minds that were neither prejudiced
nor governed by the theories of the time which inspired all
the foregoing experiments, the general rules which we have
just formulated, contained already at this time (1897-1898)
all the elements which compose the phenomenon of anaphy-

ANAPHYLAXIS 143

laxis, and that they even gave a sufficiently clear explanation
of its mechanism.

In spite of all the foregoing experiments it was as a dis-
covery of a new phenomenon that most biologists regarded
anaphylaxis when introduced by Charles Richet and Portier
in 1902.

These scientists discovered that an albuminoid substance
called actino-congestion, extracted from the tentacles of
sea-anemones, when injected into the veins of dogs, was
toxic at certain doses, and innocuous at feebler doses. Con-
gestion should therefore have been regarded as a toxin, and
behave as such: The injection of a non-lethal dose into an
animal should have vaccinated it against a later injection
of a dose fatal for the control animals.

To their great surprise, the experimenters had to record
a result which was exactly the contrary.

''The characteristic experiment," writes Charles Richet,^
''the one which showed the phenomenon in all its indis-
putable clearness, was made on the dog Neptune. This was
an animal of exceptional strength and health. He first
received 0.1 c.c. glycerinated extract of sea-anemone ten-
tacles without becoming ill. Twenty-two days later, as he
was in excellent health, I injected the same dose of 0.1 c.c.
A few seconds after the injection, he became very ill; respira-
tion became painful and panting. He could hardly drag
himself along, lay down on his side, was seized with diarrhea
and bloody vomiting. Sensation disappeared and he died
in twenty-five minutes."

Having thus obtained a reaction contrary to vaccination or
prophylaxis, Richet called this phenomenon "anaphylaxis."

Neither Richet, nor all those who were interested in these
experiments, saw anything in common between anaphylaxis
and the phenomena described by Hayem, Krauss, Belfanti,
Bordet, and others, because it seemed hardly possible to
correlate the action of a poison (actinocongestin) with that
of blood or serum from animals of allied species which were
obviously considered as essentially alimentary substances.

On the other hand, it was already known that injections

1 Anaphylaxis, S. F. Alcan, p. 3.

144 THEORIES CONCERNING IMMUNITY

of diphtheria or tetanus toxins could be repeated at will
on the same animal without ever causing an anaphylactic
crisis, and that, on the contrary, the result of these injections
had been the formation in the blood of the injected animal
of an antitoxin which neutralized the noxious action of these
toxins.

Richet was therefore perfectly justified in considering
anaphylaxis as a new and peculiar phenomenon. He speci-
fies the conditions of its evolution by insisting on the neces-
sity of an "incubation period" (as in immunity), during
which the organism prepares its anaphylactic state and he
explains it by the formation of a "prepoison" (toxogenin),
which becomes a poison when in contact with a new quan-
tity of antigen. Interpreted in this wlay, Richet's discovery
contributed a new complication to the explanation of the
immunity process.

How and why is toxogenin formed, through what mechan-
ism does it become apotoxin when it combines with the
antigen? These were further questions that had to remain
unanswered at the time.

However, in spite of ignorance as to explanation and
classification, these phenomena created much interest,
exactly because they were in formal contradiction to the
fundamental principle on which was founded not only pre-
ventive vaccination but also the preparation of antitoxic
sera.

These were questions which closely affected the most
important, the most stirring problems of general biology.
It was impossible to leave them in suspense, or to be con-
tented with provisional, incomplete and often contradictory
explanations; and in order to arrive at more satisfactory
answers it was necessary to penetrate still further into the
mechanism of these reactions. And so research into the
properties and the action of heterologous albumins became
the order of the day in every laboratory of experimental
biology.

Soon after the publication of Richet's work, which con-
cerned itself only with anaphylactic shock, Arthus discovered
local and chronic anaphylaxis by showing that successive
injections of horse serum into rabbits, no longer into the

ANTI-ANAPHYLAXIS OF ANIMALS 145

blood but under the skin, resulted in the formation of indur-
ated edemas at the point of inoculation. Arthus found at
the same time that animals sensitized by a serum also become
hypersensitive to peptone or to gelatin, though to a lesser
degree; in short that the anaphylactic reaction is not always
an exclusively specific one.

Marfan confirmed these experiments by the observation
of ''Serum Disease" in children repeatedly injected with
antidiphtheritic (horse) serum.

In a series of most interesting experiments. Hamburger
and Moro showed that a heterologous serum injected into
the veins of an animal continues to circulate in this animal's
blood up to the appearance of the specific antibody. It is at
this moment that the incubation period ends, and that the
animal becomes hypersensitive to a new injection of the same
substance.

Besredka determined that this incubation period was
longer as the quantity of heterologous serum injected was
greater, and Friedberger's researches completed this series of
experiments by showing that, if an animal be injected repeat-
edly with the same serum in non-pathogenic doses, the incu-
bation period becomes progressively shorter, which means
that the formation of the antibody takes place progressively
more rapidly.

These researches, therefore, allowed certain elements of the
problem to be defined, but at the same time, they brought
out others of a complicating nature.

These facts as well as the observations of the unfortunate
accidents in the preparation of antibacterial sera already
caused the prediction that the phenomenon of anaphylaxis,
its causes, nature and mechanism could be regarded, from a
different and broader point of view than that which inspired
Richet in his experiments and in the interpretation of their
results.

ANTI-ANAPHYLAXIS AND THE IMMUNIZATION OF
ANIMALS.

The discovery of antidiphtheritic serum naturally sug-
gested the idea of trying in the same way to obtain curative
10

146 THEORIES CONCERNING IMMUNITY

sera for all the infectious diseases of which the bacteria were
known and could be cultivated (cholera, plague, t^'phoid
fever, tuberculosis, anthrax, and others).

Horses and other animals were therefore injected, first
with sterilized cultures, then with attenuated and lastly
with virulent cultures of these bacilli, repeating these injec-
tions for weeks and months and increasing the doses. Rarely
was the desired result, that is, a really active serum, obtained.
The animals so treated became immune, it is true, never
suffered from plague or typhoid fever, but the subcutaneous
injections caused the formation of edemas, abscesses and
other lesions which complicated the treatment, while animals
into whose veins the injections were made often died on the
very instant or several minutes after the injection, They
fell as if knocked down, and died after a few convulsions.
It was, therefore, Arthus's local anaphylaxis or Richet's
anaphylactic shock which were in these instances caused
by bacterial injections, and which complicated the process
of immunization.

In this way it was confirmed that living or dead pathogenic
bacteria, and in certain cases, also the filtered broth cultures
were able to cause in the organism the same reactions as
alimentary or toxic albumins.

Rarely could this be observed in the practice of preventive
vaccinations because, in order to protect the organism
against spontaneous infection, in which the dose of infecting
bacilli is always very small, it was sufficient to inject one or
at the most two small vaccinating doses. The serum of an
animal so vaccinated had no curative power, and could not
cure actual disease; but it was reasonable to suppose that
by multiplying injections and by increasing the doses of the
vaccine, sera would be obtained similar in curative power to
antitoxic sera (diphtheria, tetanus).

It was also thought that the anaphylactic complications
were the very obstacles to the formation of large quantities of
antibacterial products, and thus endeavors were made to
find a new weapon or circuitous road to overcome this obstacle
or to avoid it. But this attempt would perhaps not have
been undertaken with so much alacrity, had not the accidents

ANTI-ANAPHYLAXIS OF ANIMALS 147

of " serum disease" in children to be fought or avoided. This
was a complication which, although rare and often very mild,
was nevertheless very troublesome in cases where the illness
required prolonged treatment; in relapses, or also when it
was necessary to apply serotherapy to the same patient,
successively in different diseases.

In this research, as in many other cases where the logical
deductions from a general and well established law offers no
guide, chance once more proved itself more ingenious than
the experimenters. Considering that the serum which causes
an anaphylactic crisis must contain a poison, Rosenau and
Anderson in America and Otto in Germany, had simul-
taneously the same idea of endeavoring to immunize guinea-
pigs against this poison by intraperitoneal injections of large
doses (5.0 c.c.) of horse serum, at regular intervals of from
five to six days. In this way they hoped to obtain a specific
antidote similar to antitoxin.

It will be conceded that this idea was rather peculiar:
they were trying to obtain an anti-anaphylactic product by a
process which, as was already well known, should lead
straight to anaphylaxis, which should cause a poison, not a
counter-poison to appear; and they did not obtain what they
were seeking.

But a well performed experiment is never completely
wasted. Rosenau and Anderson found that when injections
were made every twelve days, there were often anaphylactic
accidents at the time of the second injection, whereas when
the injections were made every five days, no apparent acci-
dent occurred at the third injection, that is twelve days
after the first one; that, therefore, the intermediary dose
protected the animal against the following injection. Soon
after this, Besredka and Steinhardt, who at first followed
the errors of their predecessors, finally discovered that, in
order to avoid an anaphylactic crisis in a duly anaphylactized
animal, it was sufficient to inject a very small dose of the
product a few minutes before the shocking dose.

The explanation of these phenomena is very simple. It
logically follows the results of the series of experiments
quoted above, beginning with those of Hayem.

148 THEORIES CONCERNING IMMUNITY

It is not the serum, the blood or other injected heterol-
ogous albumin which becomes the "poison" at the time of
the second injection since it is always the same substance
which is injected, without having undergone any kind of
change. If the animal becomes ill after the second injection
the necessary conclusion is that he, his blood, his fluid or his
tissues were modified by the first injection.

In what does this modification consist?

As already seen in the experiments of Pfeiflfer, of Krauss,
and of J. Bordet, there is formed in the blood of the injected
animal, a substance which precipitates when mixed in certain
proportions with the injected albumin. This substance was
called by Krauss "precipitin" or "precipitating antibody."

MECHANISM OF AN TI- ANAPHYLAXIS.

We have seen in the experiments of Hamburger and Moro
that the antibody appears only after a longer or shorter
period of incubation, and that this appearance coincides with
the disappearance of the antigen from the organism of the
treated animal, and with the moment when the treated
animal becomes hypersensitive.

We saw also, in Besredka's experiments, that the " period
of incubation" increases in length with the dose of injected
antigen, which means, as was seen in the previous experiment,
that the length of time taken by the antigen to disappear
increases with the quantity of the injection.

Therefore assuming that for a certain quantity of antigen
the incubation period is twelve days, if an equal dose of
antigen is injected six days after the first injection, the incu-
bation period will be prolonged, and the animal will endure
a third injection on the twelfth day without showing any
sign of trouble.

Therein lies the explanation of the phenomenon of Rosenau
and Anderson and of Otto.

A similar explanat on applies to the anti-anaphylaxis of
Besredka. In order to cause an anaphylactic shock, it is
necessary to inject into the prepared animal, who already
is in a state of anaphylaxis, a particular dose of antigen.

MECHANISM OF ANTI-ANAPHYLAXIS 149

With a decreased dose the shock does not take place, which
means that the combination of the antigen with the antibody
becomes a poison only if the two substances be mixed in
certain definite proportions. If the total pathogenic dose is
injected in non-pathogenic fractions, the successively formed
combinations never become a "poison," and it is found that
after one, or after a series of these preventive injections, the
blood of the animal so treated no longer contains precipitating
antibodies. It is, therefore, to use Besredka's expression,
" restored anew," or, to be more exact, it begins a new period
of incubation.

The reactions obtained by the "vaccinotherapy" of Al.
Wright should be classified in the same category. This
method which is based on the principles of Pasteur's preven-
tive vaccination, in reality owes its success to anti-anaphy-
lactic reactions. In acute infectious diseases, the appearance
of symptoms coincides with the appearance of antibodies in
excess, and the result of an injection of killed or attenuated
bacilli is to neutralize this excess antibod}^ At the same
time the symptoms of the disease disappear.

It follows of necessity that the pathological manifestations
of disease are anaphylactic in nature, and that the result of
the introduction into the organism of a' suitable dose of
antigen is not only to forestall an anaphylactic crisis, but
also to cure the crises as they develop.

Attention must be drawn to the fact, however, that this
distinction between the preventive and the curative anaphy-
lactic actions is far more apparent than real. The course of
an acute infectious disease (such as typhoid fever), is made
up in reality of a series of crises succeeding each other more
or less rapidly so that by interfering at a given time, one
probably does not affect the current crisis, but prevents the
birth of the crisis which would otherwise have followed.

Kichet's experiments were thus the origin of a series of
researches undertaken, in addition to those previously men-
tioned, by many scientists of all countries, von Pirquet,
Friedberger, Schick, Auer, Ascoli, Nicolle, Doerr, Russ,
Bidl, Eisenberg, Vaughan, Jobling, Wheeler, Novy, de
Kruif, Levaditi, Mutermilch, and others. ... It would
take much too long to give here even a short analysis.

150 THEORIES CONCERNING IMMUNITY

These researches may be said to have brought out the
following general principles:

1. Every organism capable of producing an antibody in
excess by the action of a given antigen, normally contains a
small quantity of this antibody.

2. For the same quantity of antigen, the amount of pre-
cipitate formed in mixtures of antibody with its antigen, in
vitro and in vivo, as well as the speed of this formation, is
directly proportional to the quantity of antibody (normal or
in excess) which exists in the blood or in the serum.

3. Every anaphylactized animal can be vaccinated in a
few minutes against a fatal anaphylactic shock, by the pre-
vious injection of a non-pathogenic dose of the same antigen;
in other words, a pathogenic anaphylactic reaction may be
prevented by a previous non-pathogenic reaction.

TACHYPHYLAXIS OR SKEPTOPHYLAXIS.

Long before the discovery of anti-anaphylaxis, a similar if
not identical phenomenon was known, which was discovered
and confirmed by a series of researches concerning the direct
toxic action of peptones and of certain albuminoid sub-
stances such as extracts of organs, eel serum, certain
poisons, etc.

It was thus observed that the injection into a vein of 10
to 20 eg. of a peptone solution killed a dog in a few minutes.
Beginning with tachycardia, the crisis followed with dyspnea,
sometimes diarrhea, and ended with convulsions. The blood
of an animal so treated could no longer coagulate. Schmidt-
Mulheim was the first to observe that if the animal survived
a first peptone injection, its blood also was for a certain time
incapable of coagulation, but that this animal would endure
a second dose of peptone, even stronger than the first, without
any modification in the ability of the blood to coagulate.

This phenomenon, confirmed by Fano (1882), Grosjean
(1892), for peptones was restudied more thoroughly by Roger
and Josue (1896) for intestinal extract. Delezenne demon-
strated this anticoagulating action for the extract from
crawfish, eel serum, etc. Delezenne and Bose (1896-1898)

TACHYPHYLAXIS OR SKEPTOPHYLAXIS 151

found that peptone protects animals against fatal injections
of colon bacilli and streptococci, in short that certain antigens
protect the animal against the pathogenic action of other
antigens (living bacilli or toxic extracts), and therefore that
these reactions are not exclusively specific. Gley and Le Bas
(1897) showed at the same time that a non-pathogenic dose
of peptone, insufficient to prevent the coagulation of the
injected animal's blood, protects this animal against an
ordinarily fatal dose, and that this immunity is very rapidly
acquired in a few minutes. Hence the name of tachyphylaxis
given to this phenomenon.

Schenk (1889) made the same observation for placental
extract, and Lambert, Ancel and Bouin later (1910) showed
that a first injection of a non-pathogenic dose of a large
number of extracts: testicle, thyroid, liver, brain, muscle,
kidney, etc., immunized in a few minutes (skeptophylaxis)
against the injection of a fatal dose. In this case the immun-
ity was not an exclusively specific one: the first injection of
the extract from one organ not only protected against a fatal
injection of the same extract, but also against the extract
from any other organ.

This category of phenomena should also include passive
anaphylaxis, first studied by M. Nicolle, Charles Richet
(1906-1907), and more recently (1910) by Novy and his
collaborators. This research showed that by injecting into a
normal animal first a small amount of serum from an anaphy-
lactized animal, and then, shortly afterward, some of the
original antigen, there resulted an anaphylactic crisis exactly
as with a prepared animal; and that it was possible to prevent
this crisis by a small injection of the same antigen.

An anaphylactic crisis is also caused by injecting into a
normal animal a mixture made in vitro of serum from an
anaphylactized animal with the antigen.

In this last case, the mixture therefore of serum with
antigen acts in exactly the same way as an organ extract, a
peptone, or as other directly toxic albuminoid products, so
that all these products can be grouped under the common
name of anaphylatoxins.

152 THEORIES CONCERNING IMMUNITY

The results of these experiments can be summarized as
follows :

1. Certain albuminoid products as such, or partially
digested (transformed into albumoses, propeptones, peptones)
which when injected in non-pathogenic doses cause the ana-
phylactic state (active sensitization), are able to cause at
first injection a crisis similar in every way to anaphylactic
shock, when a strong dose is injected into the veins.

2. The injection of a non-pathogenic dose of these prod-
ucts immunize in a few minutes against a fatal dose, exactly
as in the anti-anaphylaxis of Steinhardt and Besredka.

We can conclude therefore that :

The crises which follow the second injection of an antigen,
and the first injection of an anaphylatoxin are caused by
reactions of the same kind; or, in other words, the normal
organism is in the same state of sensitiveness to anaphyla-
toxins as a prepared organism is to a second dose of the
specific antigen.

PHYSIOLOGICAL AND PHYSICOCHEMICAL CAUSES OF

THE FORMATION OF ANTIBODIES IN EXCESS

BY ANTIGENIC ACTION.

We know now^ hoio and in what circumstances an animal
becomes anaphylactized; there remains to explain why
anaphylaxis exists, and in particular:

1. Why heterologous albumins and biologic colloids as
a class are antigens.

2. Why the process of immunization by albuminoid
antigens is complicated by pathologic manifestations.

3. Why diphtheria and tetanus toxins are exceptions to
this general rule.

4. Finally, why crystalloids are not antigens.

The result of our summary of the above researches as a
whole is that the process of immunization consists in the
production by the organism of an antibody which is found in
excess in the blood or in the tissues of immunized animals.

This antibody neutrahzes in all cases the actual patho-
genic principle of the infecting agent: an organism vaccinated

CAUSES OF FORMATION OF ANTIBODIES 153

against Eberth's bacillis becomes better able to resist typhoid
infection. Where the bacillus acts solely by its albumin
(cholera, typhoid fever), or simultaneously by its albumin
and its toxin (certain pneumonias, dysenteries, meningitides) ,
the neutralization of the albumin-antigen by the antibody in
excess causes a pathological reaction.

In such cases, the pathological manifestations which
characterize disease are caused not by the direct action of a
bacterial poison, but by a reaction resulting from the com-
bination of antigen with antibody.

It is easy today, by carefully analyzing these experimental
facts to understand the causes of the confusions, of the
apparent contradictions and of the errors in interpretation
of certain experiments: The process of immunity is never a
simple reaction, because biological antigens are never chemically
simple substances. The simplest of all, a diphtheria or
tetanus toxin, is a mixture of a large number of complex
compounds arising from the culture fluid on the one hand, and
from the bacillus on the other. The bacillus body is very
probably composed of several kinds of albumins and of sub-
stances derived from these albumins, which, when dissociated
in the infected organism, may each on its own account be
anaphylactic or " antigenic" and may cause different chemical,
physiological and pathological, direct or secondary, reactions.
Some produce antitoxins, others anaphylactic antibodies,
still others produce antibodies which are both antitoxic or
anti-infectious and anaphylactic.

With toxins or very virulent bacilli, certain directly patho-
genic principles are so predominant that the reactions caused
by the other antigens are practically negligible; in many
other cases (syphilis, malaria, trypanosomiasis, typhoid
fever, etc.), the contrary has been found: In the case of
albumins of only a slightly toxic nature the anaphylactic
reactions are predominant.

We can consider as the two extremes in this order of ideas :
on the one hand the filtered broth cultures of tetanus or
diphtheria (toxin) directly and nearly exclusively toxic with-
out anaphylaxis; on the other hand a heterologous serum or
white of egg exclusively anaphylactizing; and between these

154 THEORIES CONCERNING IMMUNITY

two extremes we shall find all the intermediaries, that is
immunity complicated by more or less anaphylaxis.

We now have sufficient basis to understand the cause of
the reactions from antibodies in normal quantity or in excess :

All antigens are heterologous colloids; colloids can neither
be assimilated nor eliminated without having first been
changed into salts or into crystalloids.^

A rabbit can readily absorb horse serum by mouth without
ever becoming ill. The reason for this is that the serum thus
absorbed penetrates into the blood only after having been
digested.

On the other hand we know (Hamburger and Moro) that
horse serum injected into the blood of a rabbit always finally
disappears and we know that it is not eliminated as serum.

The chemical study of these phenomena is far from com-
plete, but judging by what we do know, we can well assume
that serum injected into a vein undergoes the same trans-
formations in the interior of the organism as in the digestive
tract, in other words, that it is digested. This digestion
occurs in organs which normally are not adapted to this
function. They may be induced to so act by repeated injec-
tions of serum, and then produce antibodies in excess which
contribute toward this digestion, as characterized by the
precipitation of horse serum in vitro and in vivo.

The antibodies found in sera of immunized animals do
not digest their respective antigens in vitro, therefore, they
do not contain all the ferments necessary for complete
digestion.

Such antibodies as we have so far been able to obtain
in sera must be considered as substances which contribute
to this digestion, which prepare for it by fixing themselves
to the antigens, and which give in vitro only the first phase
of a series of reactions which, effected in the organism, ter-
minate by the total disintegration of the albumins.

* Certain crystalloids, such as antipyrin, quinine, some mercury salts,
become indirect antigens in the organism, either by forming colloidal com-
pounds with certain substances of the organism, or by transforming certain
substances of the organism, which then become antigens (indirect anaphylaxis
of Charles Richet).

CAUSES OF FORMATION OF ANTIBODIES 155

The causes of the differences in the reactions caused in
the organism by the different antigens— immunity without
anaphylactic shock, immunity accompanied by anaphy-
lactic shock, or anaphylaxis alone as well as the action of the
anaphylatoxins must be looked for, in the different stages
of albumin disintegration on the one hand, in the nature and
physicochemical or physiological properties of antibodies
on the other.

All that we know today is that the antigens which cause
the formation of precipitating antibodies and therefore pre-
dispose the organism to anaphylactic shock, have a total of
properties characteristic of the albumins (animal fluids and
formed elenients, vegetable albumins, bacterial bodies);
whereas antibodies produced by non-albuminous antigens
(toxins) do not precipitate antigens and do not predispose
to anaphylactic shock.

It has so far been impossible to obtain an antibody in a
pure state and to separate from it the albuminoid substances
of the serum which are not antibodies (and these always
exist, as can easily be recognized by analyzing the liquid
which floats above the precipitate formed in a mixture of a
serum-antibody with its antigen) ; nevertheless, since there
are albumin-antigens and peptone-antigens or polypeptides,
it can be assumed that the differences between antibodies are
of the same order as the differences between pepsin and
kinase or erepsin.

Pepsin transforms liquid albumin into peptones by first
precipitating them; kinase and erepsin transform peptones
into amino-acids without precipitation.

We may therefore conclude that :

1 . The cause of the production of antibodies in excess, and
at the same time, of the state of immunity-anaphylaxis, is
the obligation on the part of the organism to digest, by means
of its cells, the antigens which have penetrated to its interior.

2. The excess antibody found in the serum and in the
fluids is a substance which contributes to this digestion.

3. Salts and crystalloids are not antigens because they are
assimilated or eliminated directly without previous digestion
or disintegration.

156 THEORIES CONCERNING IMMUNITY

IMMEDIATE AND SECONDARY RESULTS OF THE
CONDITION OF IMMUNITY- ANAPHYLAXIS.

An organism which has been immunized or sensitized by an
antigen is no longer a normal organism, and it will remain
abnormal as long as it will produce antibodies in excess.

The principal object of research concerning active immun-
ity up to the present, was to obtain an immediate result: in
immunity an accrued resistance against spontaneous or
experimental infection; in anaphylaxis, a more or less severe
rapid crisis or vaccination against this crisis.

It was known that although in certain cases (tuberculosis,
syphilis) immunity and anaphylaxis ceased to exist during
the period of infection in the large majority of cases, immun-
ity and anaphylaxis are more or less lasting chronic states;
and we have seen above (Arthus' phenomenon) that experi-
mental intensive immunization of animals ends most often
in chronic morbid states.

When horse serum in very small doses (0.01 c.c. to 0.1
c.c.) is injected into the vein of a rabbit, and when this
injection is repeated daily, or even two or three times daily
for several weeks, no crisis of acute anaphylaxis is ever
observed, although the rabbit serum after the first fortnight
becomes a strong precipitant of horse serum. The immunity
of the rabbit against these injections is explained by the
action of the small doses which are vaccinating one for the
other.

If, after this series of injections w^hich occasioned no note-
worthy incident, the rabbits are kept at rest and under
observation, it is found two or three months later that, out
of a dozen animals so treated, one or two will show nerve
palsies, others dermatoses with alopecia, others rheumatism ;
and even if no accidental infectious disease interferes with
the experiment, at the end of a year only one or two animals
will remain alive. All the others will have been affected by
more or less well characterized chronic diseases, and will have
succumbed to cachexia.

Similar phenomena are observed with all horses that have
been intensively immunized for the production of antitoxic
or antibacterial sera.

RESULTS OF IMMUNITY-ANAPHYLAXIS 157

All these animals at first become less active and vigorous
and often succumb to internal hemorrhages caused by a
rupture of the liver. At autopsy in a certain number of
immune horses A. Petit and G. Loiseau^ found the following
lesions: "marked changes in the hemolymphatic organs,
which are the seat of definite hyperplasia (spleen and bone
marrow); the endocrin glands show evident signs of hyper-
secretion; the liver and especially kidney show quite definite
lesions."

The results of repeated injections of foreign proteins into
the tissues and organs of guinea-pigs have recently been
studied by W. T. Longcope^ and by T. Harris Boughton^ who
found degenerative lesions of the small arteries in nearly all
organs excepting the lungs: The lesion begins with edema
of the endothelium, followed by granular degeneration and
vacuolization of the cells with rupture of the intima. The
nuclei may disappear (be expelled). Then comes a stage of
regeneration with increase in the number of endothelial
nuclei. The edema reaches the internal elastic layer which
may rupture. This swelling and undermining may extend
to the whole of the middle coat. There is no connective-
tissue proliferation. The more serious lesions are found in
the liver in the animals killed by shock or which died during
the week following the last injection of protein. LongcopC
also has described very important and interesting lesions
consisting of round-cell infiltration, degeneration and finally
necrosis with scar formation especially in the heart, kidneys
and liver of rabbits repeatedly injected with egg-white.

In order to understand the nature and the pathogenicity
of the morbid manifestations which an organism so treated
may undergo, two phenomena must be taken into account:

1. The presence of the antibody in the blood and tissues.

2. The production of this antibody in excess by the cells
of certain organs.

1 Bull. Biolog. Soc, May 26, 1908, p. 869.

2 The Relationship of Chronic Protein Intoxication in Animals to Ana-
phylaxis, Jour. Exper. Med., 1915, xxii, 793.

^ Vascular Lesions in Chronic Intoxication by Proteins, Tr. Chicago
Pathol. Soc, April, 1917, x, 156-157.
* Loc. cit.

158 THEORIES CONCERNING IMMUNITY

The presence of an excess of antibody in the blood exposes
the organism to a more or less violent anaphylactic shock
whenever a new dose of antigen comes in contact with it.

Symptoms are explained by the formation of a precipitate
which obstructs the capillaries and causes, in consequence, a
sudden break in the nutritive equilibrium in the cells of
various tissues, and especially in the cells of the nervous
system.

The production of excess antibody results in hypertrophy
and in lesions of nearly all the organs the reactions of which
maintain the normal functions of the organism.

We saw above (A. Petit and G. Loiseau) that horses
immunized against toxins or bacterial cultures show radical
changes and lesions in liver, kidney, spleen, endocrin glands,
hemol>Tnphatic glands. Similar lesions are found in rabbits
injected with horse serum.

These lesions of necessity depress the functions of these
organs; and it is solely in these more or less pronounced
depressions that the direct or indirect causes of the lesions
of skin, digestive apparatus, joints, lungs (asthma, emphy-
sema), nervous troubles (neurasthenia, cachexia, etc.) are
to be found.

We are thus led quite naturally to assume that in all cases
of chronic disease of unknown origin, the primary cause of
the lesions and of the apparent symptoms must be looked for
in the anaphylactic state brought about by the antigen.

Might it be possible to attribute the lesions observed at
autopsy to a direct toxic action of culture fluid ?

This is hardly probable since immediately after the first
few small non-pathogenic injections, there is found in the
blood of animals so treated a much greater quantity of anti-
bodies than is needed to neutralize the injected doses of
bacterial poison. There is even less probability in the case
of rabbits injected with horse serum, which properly speak-
ing, is not a poison.

A harmful action is certainly present since the organism
sooner or later becomes ill. There is a breakdown of the
physicochemical and therefore vital equilibrium of the
affected cell; but this breakdown of equilibrium results not

ORIGIN OF CHRONIC NON-CONTAGIOUS DISEASES 159

from the direct combination of a foreign substance (poison)
with the contents of the cell, but ,from the overproduction
of a substance (antibody) which normally is produced by the
cell in small quantities only.

Briefly : The overburdening of the cells entrusted with the
production of antibodies causes the hypertrophy, the lesion
and the insufficient functioning of the organ; and, conse-
quently, the appearance of chronic disturbances.

ORIGIN OF CHRONIC NON-CONTAGIOUS DISEASES.

The lesions and the pathological states observed in animals
intensively immunized or sensitized are caused by conditions
which in nature occur only very rarely. They are sometimes
observed in chronic infectious diseases of slow and very long
evolution, particularly in tuberculosis, syphilis, malaria, the
trypanosomiases, and it is impossible in these cases not to
correlate the causes and results of the succession of crises,
alternating with more or less long abatements in the chronic
infections, on the one hand, with the rep>eated injections of
living or dead antigens, on the other.

Preventive vaccinations as practised on man and domestic
animals, usually do not lead to unpleasant consequences,
because the doses are small and the injections not numerous.
The immunity-anaphylaxis acquired by vaccinations is,
however, in most cases of short duration.

Acute infectious diseases usually leave the recovered
organism with a lasting immunity-anaphylaxis; but it has so
far been impossible to establish with accuracy the relations
which may exist, for instance, between an eruptive or typhoid
fever contracted during childhood, with a dermatosis or
arthralgia appearing in mature age. It is hardly possible to
acquire accurate knowledge in these cases by experiment,
because in order for the experiment to correspond exactly
to any particular question, it would be necessary to consider
entirely new and perfect organisms, which in all probability
do not exist. On account of heredity and of the conditions
of individual evolution each organism finds itself in a different

160 THEORIES CONCERNING IMMUNITY

state of immunity-anaphylaxis ; and even if these differences
are not usually sufficiently pronounced to interfere with
ordinary biological experiments, they do exert a decisive
influence on secondary and distant reactions.

To these differences of ''diathesis" must be attributed the
different pathologic manifestations observed in the case of
rabbits injected with horse serum. For the same reason
injections of arsenobenzene will cause gastro-intestinal dis-
turbances in certain individuals, dermatoses or arthritides
or nervous disturbances in still others or perhaps all these
symptoms at the same time; while in the majority of cases,
there will be no apparent reaction.

It is solely by the state of previously acquired immunity-
anaphylaxis that one can explain the idiosyncrasies, predis-
positions or hypersensitiveness of individuals to foreign
proteins of all kinds, to drugs, to certain smells, to changes
in temperature and to emotions. So that when one meets
these same morbid states manifesting themselves chronically
without any apparent immediate cause, the idea forces
itself of its own accord that these diseases can have but one
origin, a preexisting state of immunity-anaphylaxis.

In order, therefore, to find a biological method of treating
these diseases in conformity with the conception of the
specificity of ''sensitizing" and "shocking" antigens, it is
necessary, above all, to search for the antigen which is the
primary cause of the disease, and which may be different in
each particular case.

That a definite susceptibility to foreign proteins existing
in the form of dust and with which the patient comes in
contact through the respiratory tract, as well as in the form
of food which is ingested, jn&y be responsible for a certain
number of chronic states has recently been discovered.

The literature contains many reports of these cases and such
diseases as hay fever, asthma, urticaria and eczema should
always be studied with the possibility of such a foreign pro-
tein sensitiveness in mind. The studies of Goodale,^ Long-

^ Diagnosis and Management of Vasomotor Disturbances of the Upper
Air Passage, British Med. and Surg. Jour., 1916, clxxv, 181.

ORIGIN OF CHRONIC NON-CONTAGIOUS DISEASES 161

cope/ Walker,^ Schloss,^ Cooke^ and many others have
brought out the fact that this hypersensitiveness depends
upon an inherited tendency, the nature of which is unknown,
that it can be demonstrated by applying some of the protein
to a scratch in the patient's skin and observing the urticarial
wheal which occurs locally within ten minutes and finally
that this hypersensitiveness and the clinical conditions
depending on it can be relieved by treatment either by
removal of the offending protein or vaccination with an
extract of it. In some of these cases the hypersensitiveness
is to bacteria or their products.

The local reaction as well as the clinical conditions depend
upon an excess of antibodies in the cells which at once com-
bine with the foreign protein by virtue of their extraordinary
affinity for it and form a product which is insoluble and poi-
sonous for the cell and for the organism. Briefly, the method
of treatment in chronic diseases is "vaccinotherapy" which
has been so successfully studied and applied by Al. Wright
in the treatment of certain acute infectious diseases; and it
is in this direction that experiments were undertaken.

1 The Susceptibility of Man to Foreign Proteins, Am. Jour. Med. Sc,
1916, No. 5, clii, 625.

2 Studies in Asthma, Jour. Med. Research, 1917.

3 Allergy in Infants, Am. Jour. Dis. of Children, 1920, xix, 433.
^ Human Sensitization, Jour. Immunology, 1916, i, 3.

11

CHAPTER XL

PRINCIPLES OF THE ANTI-ANAPHYLACTIC

TREATMENT OF CHRONIC DISEASES

BY ENTERO-ANTIGENS.

From Metchnikoff's work on intestinal flora it could be
deduced that the digestive tract, and especially the large
intestine must be considered as the principal source of all
kinds of infections and of chronic intoxications. Metchnikoff
thought that these intoxications were due to the develop-
ment and to the secretions of certain bacilli, and that by
modifying the reaction of the medium in which they lived, it
would be possible to prevent their multiplication. He
endeavored to obtain this result by causing in the intestine
an acid reaction by means of the bacteria of curdled milk.

Allen,! S. Marbais,^ A. Berthelot and D. Bertrand^ and
others tried to obtain the same result, i. e., the destruction
of poisonous intestinal bacilli, by bacteriotherapy based on
the "vaccinotherapy" of Al. Wright.

Metchnikoff's idea of looking for the origin of gastro-
intestinal disturbances in the normal intestinal flora is prob-
ably very sound, and the treatment of such troubles by the
bacteria of curdled milk or by bacteriotherapy has often
given very good results; but it was found, however, at the
same time, that while the disease was cured, the intestinal
flora was not appreciably changed.

Treatments by Bacillus bulgaricus or by intestinal bacilli
were therefore efficient, although the mode of action was not
in accordance with the theory.

1 Vaccinotherapy, Levis, London.

2 Bull, de la Soc. de Biol., February 20, 1915, p. 66.

' Vaccinotherapy in Chronic Enteritis, La Presse med., 1917, Nos. 23
and 44,

ANTI-ANAPHYLACTIC TREATMENT OF DISEASES 163

Then again, we must not lose sight of the fact that the
intestinal contents are not solely composed of bacteria, that
they always contain more or less digested albuminous matter,
and that the congested intestinal mucous membrane may
allow this matter to pass into the blood.

We know that any heterologous albuminous substance
which, undigested or incompletely digested, that is, in the
form of albumose, peptone or polypeptid, has penetrated
into the blood, will behave as an antigen, and we know that
any ordinary occurrence, even a slight emotion, can make
the intestinal mucous membrane permeable to these antigens,
as well as to bacterial antigens.

An anaphylactic state, as well as the disturbances resulting
from it, can thus be caused just as well by incompletely
digested alimentary substances, as by intestinal bacteria or
their secretions; but as it is easy to determine and to prove
that the intestinal flora and the digestion of a normal man
do not differ from those of a man affected by psoriasis or
suffering from emphysema, the conclusion is necessary that
the causes of these diseases must be looked for, not in the
nature of the bacteria living in the intestine, nor in the nature
of the albuminoid substances on which the organism feeds,
but solely in the method by which it digests and assimilates
both bacteria and albumin.

It often happens that of several thousand individuals
living in the same surroundings and under the same condi-
tions, only a few became ill with typhoid fever or chdlera,
and one wonders why the remainder escape infection : Why
horses, rabbits, guinea-pigs, are not infected by the ingestion
of the bacilli of these diseases, which are pathogenic for
these animals, when injected into the peritoneum or into the
blood.

In the case of man, we may assume a previous spontaneous
immunization in certain cases, but in animals, this is very
improbable. The only plausible answer to these questions
is that the large majority of individuals who escape infection,
and all animals who are never spontaneously infected, are
refractory to these diseases.

And why are they refractory?

164 ANTI-ANAPHYLACTIC TREATMENT OF DISEASES

Simply because they either digest and completely destroy
these bacilli, or they attack them not at all, in short, because
these bacilli or their secretions do not penetrate into the
blood as incompletely digested albumins or colloids.

Pathogenic bacteria differ from those which are not patho-
genic principally because the first can live and multiply in
blood and living tissue, while the others are destroyed by
phagocytes or by proteolysis before having had the time to
multiply; yet both the first and the second will by their
albumins cause anaphylactic states.

Bacteria of the intestinal flora are thus not pathogenic,
properly speaking, because they cannot multiply in the
blood or in the tissues, but their albumins may penetrate into
the blood through a congestion of the intestinal mucosa and
cause an anaphylactic state in the same way as any other
heterologous albumin.

From the whole of these conjectures and of the precise
facts determined experimentally, one may therefore conclude
that :

1. Chronic disturbances of nutrition which manifest
themselves by different symptoms according to the affected
organs or tissues, have for their common cause a state of
anaphylaxis.

2. This state of anaphylaxis arises from the introduction
into the blood of bacterial or of alimentary albuminoid
substances.

3. The resulting illnesses may successfully be treated by
antigens taken from the normal intestinal flora. This treat-
ment is neither anti-infectious nor antibacterial but solely
anti-anaphylactic.

Inspired by these considerations we undertook at random
a series of attempts at anti-anaphylactic treatment, at first
of some dermatoses, and later of all kinds of other chronic
affections.

I. CASE REPORTS.

A. Deim&toses.— Observation L— Indeterminate Dermatitis.
— M. F. W., aged forty-five years. For four years oozing
red plaques varying in size from a pea to a fifty-cent piece

CASE REPORTS 165

all over the body, and particularly on the legs. Insufferable
itching. Sleepless nights, emaciation. General condition
bad, attributed , to insomnia. Transient gastro-intestinal
disturbances.

The patient has consulted several specialists, and has tried
several external treatments and changes in diet, without
lasting success.

Examination of the Intestinal Flora.— ^o account was
taken except of germs which grew in twenty-four hours'
incubation on ordinary gelatin slants (meat-broth, pep-
tone).

Found.— Colon bacilli 90 per cent., enterococci 5 per cent.,
indeterminate diplococci 3 to 4 per cent., very small strepto-
cocci 1 to 2 per cent.

Preparation to he Injected.— A\l the germs were mixed in
0.7 per cent, salt solution in the proportions in which they
grew on the gelatin. The mixture was distributed in sealed
ampoules, sterilized by heating to 70° C. for an hour.

Each ampoule contained about 1 c.c. of liquid with about
0.02 mg. of bacterial matter dried at 140° to constant
weight.

Treatment.— First Series of Injections.— First injection at
2 P.M., 1 c.c. into the muscular tissue of the arm. Slight chills
three or four hours after the injection. No itching at night,
good sleep. Next day, slight general fatigue, slight pain and
redness at the point of inoculation.

Second injection, twenty-four hours after the first, 0.5 c.c.
followed every day for a week by injections, increasing the
doses from 0.1 c.c. to the maximum of 1.0 c.c.

The patient no longer suffers from itching, the plaques
have faded and are not so moist.

No treatment for the next month.

At the end of the month, the plaques are clearly on the
road to recovery. There is no more itching, sleep is good,
general condition much improved.

New Examination of the Intestinal Flora.— The same germs
are found in the same proportions.

Serum Diagnosis.— The serum of the patient does not
agglutinate any of the germs in a 1 to 40 dilution.

166 ANTI-ANAPHYLACTIC TREATMENT OF DISEASES

Second series of injections under the same conditions as
the first, with this difference that at the beginning the dose
was very small, 0.1 c.c.

Results.— At the end of the second series of injections, the
plaques have completely disappeared.

For five years the patient has been in very good health,
from every point of view.

Observation 2.— Urticaria with Phlyctenules.— M.. L., aged
forty-two years. General condition fair. Declared "fit" for
active service at the beginning of the war. Discharged after
three months for incurable skin disease.

The patient has lived for fourteen years in central Africa,
where beginning with the first year of his residence there, he
contracted a skin disease characterized by the appearance
on the whole surface of the body, but especially on the back,
of small, red phlyctenules with a small yellowish center.
This center exuded a small amount of pinkish liquid which
dried, leaving a red crust. Insufferable itching after the least
fatigue together with sweating.

The patient has consulted many dermatologists, and has
followed without success all the treatments recommended,
among others, he has received several injections of his own
serum. One of the dermatologists he consulted told him
that his dermatosis was very similar to scabies.

The bacteriologic examination of the patient's stools gave
approximately the same results as in the preceding case, and
the same treatment was applied with exactly the same result.

The patient has never had a relapse, and has been in very
good health for four years.

The second examination of his intestinal flora showed the
same germs as the first.

These two observations taken at random among many
other similar ones suggest the following reflections :

While the supposition was that one of the germs living in
the large intestine and contained in the fecal matter of our
patients must be the cause of their illnesses, we could not
assimae a priori that all the germs seen by the microscope in
fresh or stained preparations of fecal matter, could share in
the cause to an equal degree. On the other hand, as we had

CASE REPORTS 167

no guide which could have suggested the choice of one germ
rather than of another, we chose, to begin with, the germs
whose cultivation was easiest and simplest: surface growths
on gelatin slants, therefore, the commonest aerobes.

In order to recognize their morphologic characters, their
biochemical and pathogenic properties, each germ was
isolated in a pure culture, then cultivated in different media,
and lastly injected, either mixed or separately, into mice.

It is to be noted here at once that the mice so treated never
contracted a fatally infectious disease in spite of the relatively
strong doses (0.1 c.c. of a twenty-four-hour broth culture) . .
We were thus handling only innocuous germs.

Another patient was treated with a heterogeneous prepara-
tion and encouraged by the result obtained we entrusted the
same material to Dr. Labonnette for the treatment of a
serious case of eczema.

Observation 4.^— This patient had a long history of gastro-
intestinal disturbances with abdominal and rheumatic pain
at various times. In April, 1919, a seborrheic eczema of the
trunk and scalp plus an oozing eczema of the perineum and
scrotum appeared. The patient was given dead heterogeneous
bacteria of which he took by mouth 2 mg. as an emulsion
daily. Disappearance of the pains and of the eczema was
almost instantaneous.

Observation 5.— Another patient was treated in a similar
manner except that the development of pustules indicated
additional treatment with a staphylococcic autovaccine
obtained by culture of these pustules which was given.

Observations 6 and 7.— Two cases of psoriasis were also
much relieved by the injection of entero-antigens. In one of
these, a second course of treatment was begun ten days after
the end of the first course but the local reactions were not
more severe than the first— the patient was therefore not
sensitized by the first course.

Case 7 received during his psoriasis and independently the
Pasteur treatment for rabies— as a sequel to which the skin
lesions healed.

1 Observation 3 omitted in English translation.

168 ANTI-ANAPHYLACTIC TREATMENT OF DISEASES

Two facts are important: 1. The nearly complete dis-
appearance of the cutaneous lesions in no case resulted in
other morbid manifestations, such as asthma or acute
articular rheumatism, which are quite frequent when one
tries to "stifle" the evolution of cutaneous psoriasis by
ointments.

We must therefore suppose that, in this case, the antigen
treatment acted not only on the apparent symptom, but on
the cause of the lesions as well.

2. Different antigens are not equally active. In one case
the addition of an anaerobic bacillus, although in very small
quantity to the vaccine, had a curative action which was
evidently greater than that of all the other bacteria pre-
viously injected.

We shall see further on what may be the nature of this
action. In this manner 25 cases of more or less serious
psoriasis were treated. The most interesting cases were
given us by Dr. Sabouraud whom I wish to thank here for his
kindly assistance.

In all these cases, the antigen treatment gave far better
results from the point of view of the disappearance of the
lesions, of its harmlessness, and of the duration of cure, than
all the other treatments previously advocated. One case
only, treated for two months by an autogenous preparation
taken by mouth (the patient refusing to be injected), showed
no apparent improvement.

Struck by the particular activity of the anaerobic bacillus
(Case 6), we wished to determine the importance of searching
in each particular case, for the most active antigen. Con-
vinced of the harmlessness of our preparations, we varied
their composition, and even tried non-bacterial antigens.

Thus, of 25 cases of psoriasis, 12 were treated by auto-
genous bacterial preparations, 9 by heterogeneous prepara-
tions, 3 by intravenous injections of luargol.^ The results
obtained in all cases were about identical, and we can add
that a psoriatic patient, bitten by a mad dog, was cured of
psoriasis by antirabies treatment.

1 Dr. Dalimier has treated 5 cases of psoriasis with luargol. Three were
completely cured; in the other two luargol produced no results.

CASE REPORTS 169

Observation 9.^— Recurrent Psoriasis Caused by Iodine.—
One of these eases was of special interest. Treated in 1915,
for the first time with an autogenous preparation, for psoriasis
in small plaques spread all over the body, and completely
relieved, the young woman returned in 1917 with the same
plaques, this time localized exclusively on the back of the
thorax. She stated that these plaques appeared some time
after painting this region with tincture of iodine.

Relieved anew, but this time by means of a heterogeneous
preparation containing a mixture of colon bacilli and of a
small non-motile bacillus, she returned in 1918 covered from
head to foot with a multitude of plaques which caused intoler-
able itching and which had appeared after the ingestion of
an iodized preparation "taken on the advice of a friend,"
which was supposed to cure her of a little general fatigue.
This time a series of ten injections of a mixture prepared
especially with heterogeneous diplo-, strepto- and entero-
cocci, conquered the eruption under the same conditions as
previously.

The observed persistence of hypersensibility to iodine in
this case, makes one believe that the treatment by the differ-
ent antigens was simply symptomatic, and that it had not
attacked the fundamental cause of the evil.

From all these observations it seems that, though the
treatment of psoriasis is practically very simple, the theo-
retical explanation of it appears to be rather complex.

The identity of the results obtained in the majority of
cases by autogenous and heterogeneous preparations, but of
very similar composition, would lead one to think that the
disappearance of psoriatic lesions results from a reaction
caused by the same antigens or by closely allied antigens.

Observation 6 indicates the predominating action of an
anaerobic germ which we did not use in any other case, while
Observation 7, as well as the results from the cases treated
with rabbit-marrow and luargol, seem to prove that the same
results may be obtained by any antigen.

One must, however, take into account the difference in

^ Observation 8 omitted in English translation.

170 ANTI-ANAPHYLACTIC TREATMENT OF DISEASES

doses of the different antigens which it was necessary to use
to obtain similar results.

The total quantity of bacterial bodies used in from twenty
to sixty injections, varied from 0.4 mg. to 2 mg., while the
total quantity of marrow injected in fifteen injections and
of luargol injected in ten injections can be estimated at from
1.5 to 2 gr., that is to say, a quantity a thousand times
greater than that of the bacteria.

The same can be said of the action of the anaerobic bacillus
(Observation 6) which seems to be at least 100 times as
pronounced as that of all other bacteria put together.

The antigenic action on psoriatic lesions could thus be
explained as follows :

1. Recovery is determined by reactions in the organism
caused by antigens.

2. These reactions are all of the same kind, or at least
very similar.

3. The same results can be obtained by different antigens
in very different doses, which can also be explained by saying
that antigens are mixtures in which the proportions of the
active substance, always causing the same reaction, are very
different.

The practical suggestion arising from the above would,
therefore, be that in order to obtain the maximum curative
result with the minimum harmful result, one must search
for the proper antigen.

B. Asthma,.— Observation 10.— M. M., aged forty-seven years,
has suffered for five years from dyspnea which grows worse
every year, and shows itself particularly in the evening after
sunset, and lasts all night until 10 a.m. or 11 a.m. Cold
and rainy days are usually much worse than good weather.
Dyspnea is then accompanied by coughing with very difficult
expectoration. During and since the war, this condition of
asthma has become sensibly aggravated on account of the
open air life of the patient who had to dig trenches.

The patient received in a total period of eighteen days
two series of eight hypodermic injections of an autogenous
bacterial preparation isolated from his own intestinal flora

CASE REPORTS 171

and sterilized by heat. This was a mixture of colon bacilli,
of Gram-positive diplococci and of Micrococcus tetragenus.

Several minutes after the first injection into the left arm,
the patient felt "like a trembling," followed by a tingling
and itching in the whole left side of the body and immediately
afterward his respiration became easier. '

Improvement continued during the course of the treatment.
The patient can now (eighteen months after) go out and work
in bad weather without suffering therefrom, sleep is normal,
cough has completely disappeared. The general state is
better than it has been for a long time, the patient feels
younger. The attacks of asthma have not recurred for the
last eighteen months. Gastro-intestinal functions, often dis-
turbed previously have at the same time become completely
normal.

Observation 11 ( Dr. Dalimier).— Hay Asthma.— Mi. J. L.,
navy engineer.

Family History.— Is/Lother died from cardiac rheumatism;
father died at seventy-nine from arteriosclerosis. Neither
parent suffered from asthma. Brother has slight and tem-
porary hay fever. Both maternal grandparents suffered
from hay asthma.

Personal History.— ScsLTlatina and whooping-cough. At
twelve years, first attack of hay asthma. Since then, every
year without exception, in the second fortnight of May, had
an attack.

The minutest contact of a particle of hay is sufficient to
bring on asthma. Wheat and barley have the same action,
as also grapevine, but to a lesser degree. Flowers of any kind
have no influence. Honey, however, it must be noted, some-
times produces some respiratory and gastro-intestinal dis-
turbances. Never any attack on the ocean.

The attack is characterized by a very pronounced oculo-
nasal catarrh, coryza and headache; then, after some days,
dyspnea appears, asthmatic in type, very troublesome,
especially at night. The attack lasts two to three months,
with alternate increases and decreases, and leaves behind it
an early morning dyspnea until the autumn.

Apart from this hay fever, this patient enjoys good health.

172 ANTI-ANAPHYLACTIC TREATMENT OF DISEASES

During the last twenty-five years, he has undergone all
known treatments. Locally he has had his adenoids removed,
he has taken nasal douches of hot air, and of various anti-
septic or analgesic liquids. He has undergone several thermal
cures: Luchon, La Bourboule, Le Mont-Dore, where he
spent several consecutive seasons. He has tried ozone, which
produced a notable and constant increase of the trouble:
carbonic acid, and pollantin, without any benefit. The only
measures causing relief have been arsenic by mouth, and
"Doctor Tucker" applied direct.

Physical examination, April 15, 1919, normal.

Bacteriologic examination of the feces shows colon bacilli,
diplococci.

Treatment.— k^ the patient, at this date (April 15, 1919)
showed no morbid symptom, treatment was given from a
preventive point of view. Autogenous entero-antigen, 8
subcutaneous injections, every fourth day. Very slight local
reactions.

Patient seen again June 6. Has been in frequent contact
with hay, in Paris and during his travels in England, begin-
ning about May 15. It was only in the first days of June
that oculonasal catarrh occurred to a very slight degree,
without coryza or headaches. There is no trace of asthma.
The patient, very pleased with his condition, states that this
is the first time in twenty-five years that he has been so well
at this time of the year, and he judges it useless to undergo
the slightest treatment for the slight cough which still
persists.

Observation 12 {Dr. Dalimier).—Emphysematic Asthma.—
M. F., aged forty-one years, printing compositor.

Family History.— Mother rheumatic; father died at
seventy-eight; no asthma.

Personal History. -ArticulsLT rheumatism in 1900, scarlatina
in 1902, appendectomy in 1903, bronchitis in 1911, slight
chronic lead poisoning. Two nervous crises during the last
ten years, corresponding to lead intoxications. No children.
His wife has had no miscarriages.

Permanent dyspnea since 1911, aggravated by attacks of
asthma. Difficulty in breathing becomes considerable every

CASE REPORTS 173

year from May to October, and the patient has found that it
is increased by the inhalation of dusts.

He has tried codein, bromide, caffein, and iodide, and the
only soothing liquid he now uses is "Doctor Tucker's Asthma
Cure."

Classed as unfit for active service on account of asthma
and emphysema.

Examination.— An obese man, heavy eater, evident signs
of very pronounced pulmonary emphysema. Heart normal,
blood-pressure 160/90. Urine: Neither sugar nor albumin.
Slight pupillary inequality. Dyspnea on exertion with
inspiratory spasm.

Diagnosis.— Chronic pulmonary emphysema, with inter-
current crises of asthma.

Fecal Examination.— BsicteTi8i\ flora: Colon bacilli, diplo-
cocci, enterococci.

Treatment.— Autogenous entero-antigen. Ten subcuta-
neous injections, one every fourth day. Violent reaction at
each injection consisting of local pain with inflammatory
halo the next day, definite, even painful exaggeration of the
respiration for twenty-four hours. After the end of this
reaction, the patient feels each time much improved. After
the termination of the series of injections, he has no more
dyspnea ; he gives as illustration of his improvement the fact
that "he can now climb the Sorbonne hill by the rue St.
Jacques without effort or trouble," whereas during the last
ten years he was unable to do so.

C. Other Cases.— Detailed case reports of 32 additional
cases comprising a wide variety of chronic morbid states
have been omitted in this English translation.

The reports picture the remarkable results following the
use of dead bacteria in the form of an emulsion (a vaccine)
and administered either by mouth or by subcutaneous injec-
tion. In most cases, improvement is immediate. Practically
complete relief of sxinptoms is experienced by the majority
of the patients after at most fifteen treatments at one- to
three-day intervals.

These cases include those with such diagnoses as the
following: Neurasthenia, scleroderma, dysmenorrhea, meno-

174 ANTI-ANAPHYLACTIC TREATMENT OF DISEASES

pause, a large number of gastro-intestinal disturbances
including several forms of enteritis and chronic diarrhea,
gastroptosis, neuro-arthritis, rheumatism and the gastro-
intestinal symptoms of tuberculosis.

SUMMARY OF OBSERVATIONS.

Two hundred and sixty cases of chronic disease, similar to
those quoted were treated in this manner (with the collabora-
tion of Drs. Cazin, Dalimier, Delettre, Dominici, Labonnette,
Raspali, Richard, Smiechowska, and others).

In analyzing these cases, one finds from the first that the
treatment by antigens prepared from the germs of intestinal
flora, showed itself efficient, not only in cases of digestive
disturbance and in urticaria, but also in many other cases,
which appear to have no direct relation with the functions of
the digestive apparatus. We must, therefore, conclude that,
even if the primary causes of these diseases differ, the reactions
determining the pathologic symptoms must always be of the
same nature.

On the other hand, the minuteness of the curative doses
(2 to 3 mg. by mouth and a few hundredths of a milligram in
hypodermic injections) and the rapidity of the reactions
caused by these doses, suggest that the bacterial antigens
contain a much greater proportion of the active substance
than peptone, animal proteins, milk or any serum which in
certain cases of urticaria, asthma (Widal, Nolf, Paignez and
Vallery-Radot Pasteur, and others), give similar curative
results in doses a hundred or a thousand times greater.

The action of the bacterial preparations which were used
in the cases quoted above were probably not "specific,"
in the sense of the antigens used in the vaccinotherapy of
Wright, but their actions are remarkably selective.

GENERAL AND LOCAL REACTIONS CAUSED IN THE
ORGANISM BY ENTERO- ANTIGENS.

Action on the Intestinal Flora.— We have already seen that
the injections or the ingestion of our preparations, at the

REACTIONS CAUSED IN THE ORGANISM 175

doses used, do not appreciably modify the intestinal flora of
the patients. A decrease of one bacterial species or another
is sometimes observed in the stools after a fortnight's or a
month's treatment; but the same changes are observed in
normal non-treated persons; so that these passing decreases
cannot be attributed to the action of the treatment.

We have never found a complete disappearance of any
bacterial species living normally in fecal matter; on the other
hand, we have found that certain pathogenic bacteria such
as the paratyphoids or certain strains of colon bacilli com-
pletely disappeared after treatment by injection or ingestion
of such dead bacteria.

We have never observed any marked agglutination reaction
with any species of injected bacteria in the serum of treated
patients fifteen, thirty or sixty days after the end of the
treatment. The conclusion is therefore that the treatment,
as applied, did not cause the formation of ''antibodies in
excess" in appreciable quantity.

General Reactions.— The first striking phenomenon after
the first, or the first few injections or ingestions of an auto-
genous or heterogeneous preparation, is the rapid change of
the patient's general condition. A direct action on the ner-
vous system is nearly always observed which is shown by
lassitude, a need for sleep, relaxation and rest, a general lull
which is in no wise disagreeable, which may last several hours,
rarely two or three days, and is usually followed by a long
period (several weeks or months) of surprising exhilaration.
The patient feels himself "being born again," he feels a sur-
prising need for physical and mental activity, and can under-
take without fatigue work, which a few days before would
have seemed beyond his strength. Sometimes the period of
lassitude is so short and slight, that the period of exhilaration
seems to appear all at once. In other, less frequent cases,
the first doses of the preparation are followed by headaches
which may last for several hours, by chills or by a slight rise
in temperature. Still more rarely, the symptoms of the dis-
ease are seen to increase slightly. Asthmatics may have a
more violent crisis, the itching in dermatoses increases,
psoriasis plaques become darker; but these aggravations

176 ANTI-ANAPHYLACTIC TREATMENT OF DISEASES

never last long, are not a contra-indication to further treat-
ment, and are always followed by appreciable and rapid
improvement. At the most, it may sometimes be necessary
to diminish the dose. If this is necessary only one-tenth or
even one-hundredth is given.

Local Reactions.— When the treatment is applied in the
form of injections, the reactions at the point of inoculation
vary considerably. Sometimes redness, and a more or less
painful zone may persist for one to three days: at other
times the injection leaves no other trace than the small
needle point.

If the treatment is by ingestion, one often notes, on the
first and second days a slight pain in the epigastrium. This
pain is only slight and manifests itself only on pressure in
the epigastrium.

Whether the treatment is applied by injection or by inges-
tion, palpation discloses a sensitiveness over the gall-bladder
and over the posterior part of the liver between the eleventh
and twelfth ribs, near the upper edge of the right kidney.

The kidney is never tender, but undergoes important
functional modifications. A phenomenon is observed similar
to that which often characterizes the terminal period of acute
infections (typhoid fever, influenza), namely, polyuria.

The reaction on the gastro-intestinal functions is quite
remarkable. No matter what the preparation, autogenous
or heterogeneous, or whether administered by injection or
by ingestion, it acts as a regulator of the digestion and of
evacuations.

In those cases where gastro-intestinal functions are normal,
for instance in psoriasis, the beginning of the treatment is
characterized by a tendency toward constipation, which
may last several days and recovers spontaneously without
medication.

The circulation is also influenced by the action of the
entero-antigens. In the cases of either increased or decreased
blood-pressure, one often sees hypertension diminish by 10,
20 or 30 mm. and hypotension increase by 10 or 20 mm.
after the treatment.

THEORY OF CURATIVE REACTIONS 177

THEORY OF CURATIVE REACTIONS. KENDALL'S
EXPERIMENT.

How then may we explain the nature as well as the
mechanism of these curative reactions?

In order to answer these questions we must remember
that:

1. Every normal or abnormal function of an organ, a
gland or a tissue depends on the central nervous system, so
that all the modifications of the physiological equilibrium of
a cell may be caused or arrested by the direct or reflex action
of the nervous centers.

2. Whatever be the cause of a lesion or of a functional
disturbance of an organism, the pathologic symptom will
be always caused by a nervous reaction.

3. Each functional disturbance of a cell can be but the
rupture of the nutritive and respiratory equilibrium of this
cell.

In this way, an emotion causes in certain people enteritis,
dermatosis or an attack of asthma. This means that certain
psychic centers have reacted on the trophic centers of the
bulb, that their excitation has interfered with the capillary
circulation of the intestinal or pulmonary mucosa or of the
skin.

It is therefore in the excitation of the nervous centers
that the initial cause of the disease must be looked for; it is
likewise the nervous centers which prepare the lesions and
which set off pathologic symptoms through the reflex action
of the lesions.

In many other more numerous cases, the initial cause of
the disease is an agent which is exterior to the organism: a
poison, an antigen or a traumatism. It is this agent which
disturbs the nutritive equilibrium of the cells and which
thus prepares the lesions; but the maintenance of these
lesions and the reactions causative of pathologic symptoms
are still governed by the nerve centers.

To make this argument more plain let us suppose the pres-
ence of a stone in the gall-duct. The stone manifests itself
by violent pains, because the walls of the canal contract
12

178 ANTI-ANAPHYLACTIC TREATMENT OF DISEASES

before and behind the stone and prevent it from passing.
Morphine or atropine will relieve these pains by relaxing the
walls of the canal so that the stone continues on its way
without causing the slightest harm. The primary cause of
the evil here is therefore the formation of the stone and its
entry into the canal. It is likewise the stone which prepares
the traumatic lesion of the walls of the canal, but it is the
reflex reaction of the nerve centers which maintains the lesion
and the pain. To abolish the sensitiveness of the nerve
centers is to end the contractions and the pain.

In the same order of ideas, an anaphylactic state is created
by preparatory injections of an antigen, and a fatal crisis
is precipitated by the second injection of the same antigen,
but this crisis can be avoided by the absorption of a suffi-
cient dose of alcohol or ether (Roux and Besredka), or also
by an injection of adrenalin (Milian). Here the primary,
initial cause of the pathologic state is .the preparatory injec-
tion of the antigen which causes the formation of the anti-
body by certain cells. The resulting lesion is localized in
these cells; there is no symptom. The anaphylactic crisis
is caused by the action on the nerve centers of the precipi-
tate which results from the combination in the blood of the
excess antibody with the antigen of the second injection,
suddenly disturbing the general nutritive equilibrium and
more especially that of the nerve centers. A sufficient dose
of alcohol or ether anesthetizes the nerve centers, while
adrenalin contracts the capillaries and prevents the precipi-
tate from reacting in them.

As in the case of stone, so in the case of the antigen, it is
through the nerve centers that the pathologic manifestations
may be relieved or prevented.

It is interesting to quote here, on this subject, an accurate
experiment of E. C. Kendall, inspired by the work of Crile
on the role of the suprarenal capsules in Barlow's disease.
This experiment as reviewed in the Presse Medicate^ deserves
to be quoted in toto:

"Operating on dogs, Kendall slowly injected intravenously

1 Kendall, Edward C: Experimental Hyperthyroidism, Jour. Am. Med.
Assn., lix, 612. From the Presse Midicale, 1917, No. 59, p. 612.

I

I

THEORY OF CURATIVE REACTIONS 179

amino-acids. The animals had been previously thyro-
parathyroidectomized, and into some of them there was
injected, before or during the introduction of amino-acids,
the active principle of the thyroid (Kendall).

"The observed results allow of the classification of the
animals into two groups: Some had abundant diuresis and
their temperature increased, sometimes reaching 113°.
Their respiration became accelerated, and deep; their pulse
became rapid. Nervous excitability was increased, and there
were rigors accompanied by spasms which suggested the
contractions of tetany.

"Other animals showed quite different manifestations:
urine was scarce, temperature remained normal, pulse was
small and regular, respiration feeble and superficial, nervous
system greatly depressed.

"Between these two types intermediate forms could be
observed, and sometimes tetanus was seen to develop after
a period of depression.

"Among the conditions intervening to modify these
symptom-complexes, the influence of food is important.
The depressive form is observed with digesting animals,
the tetanic form with those fasting for twenty-four or forty-
eight hours.

"The effects of thyroid extract are quite varied. If
thyroid extract is introduced before the injection of the
amino-acids, the depressive phenomena predominate.

"Since amino-acids determine under experimental condi-
tions, results diametrically opposed, one is led to suppose
that they undergo in the organism changes which modify
their properties. It has long been known that they are
transformed, at least in part, into ammonia and urea. It was
therefore interesting to determine the proportions of these
substances in the urine excreted by these experimental
animals.

"When the symptoms of nervous excitation predominate
the quantity of urine is often considerably increased. A dog
weighing twenty-four pounds, in one hour excreted 1760
c.c. of urine. Before the experiment, urea formed 80 per
cent, of the total nitrogen in the urine but during the experi-

180 ANTI-ANAPHYLACTIC TREATMENT OF DISEASES

merit, urea fell to 15 per cent. As the ammonia did not
increase, the conclusion is that the urine contains a new
substance. This new substance (X) deserves the name of
preurea, because if the urine stands for twentj-four hours,
the quantity of urea increases up to a double amount.

"In making the same analyses of the urine of these dogs
affected with depressive manifestations, an increase of
ammonia is observed, but no substance X is found. The
conclusion was therefore arrived at, that if the ammonia
from the amino-acids is transformed rapidly into X,
phenomena of excitation appear; if it is transformed only
slowly, depressive manifestations predominate.

"The substance X, which might be the cause of tetany,
is normally transformed into urea by the parathyroid glands,
and this fact explains perfectly the role of these glands in
the development of nervous manifestations. But in which
organ is the ammonia transformed into X (preurea)?
Kendall supposes that it is in the suprarenals, because the
removal of these glands results in depressive phenomena.

"To verify this hypothesis, he made the following experi-
ment: He removed the cortical layer of the suprarenal of
an etherized cat, and submitted it to digestion with ammo-
nium carbonate. This salt was transformed into a special
substance different from urea. In repeating the experiment
with suprarenals taken from cattle or from other cats, the
result was absolutely negative; the ammonium carbonate
remained intact.

"For a time Kendall was unable to understand the cause
of these contradictions. Suddenly he remembered that
before being etherized, the first cat had been for some time
in the presence of two dogs which had terrorized it. This
was a flash of light. The ferment which transforms the
ammonia into preurea must be produced by the influence of
nervous excitation. He resumed his experiments on cats
previously frightened, and found again in the cortex of the
suprarenal the ferment he was looking for. He also obtained
a positive result, not however constantly, by submitting the
suprarenals to the action of an electric current.

"Besides nervous influences, one must always consider

INFLUENCE OF THE NERVOUS SYSTEM 181

the action of hormones in the blood. As the suprarenal
cortex acts on ammonium carbonate and changes it to pre-
urea, it is probable that this salt stimulates the functions
of the gland, at least under certain conditions. It was
therefore of interest to resume the study of the effects pro-
duced by intravenous injections of the ammonium salt.

''As with amino-acids, both depression and excitation
are observed. In the first case the animal was feeble and its
respiration remained light and superficial; in the second, the
animal was strong, and its respiration became deep. A
process of oxidation must therefore take place to activate
the suprarenal cortex.

"These two reaction-types are accompanied by abso-
lutely characteristic urinary modifications. When the
depression phenomena predominate, the urine contains
ammonia; when the tetanus manifestations predominate,
the ammonia decreases. Thus by analyzing the urine, all the
unseen phases of the experiment are followed.

"These facts all demonstrate the role of the suprarenal
in the development of the nervous excitations attributed to
the thyroid, and, it must be added, also demonstrate, the
role of the nervous excitation on the functioning of the
suprarenals.

"The main thing to remember is that this experiment brings
out with accuracy the nature of the functional and chemical
reactions caused by emotion. It was fright that caused the
formation in the cortical layer of the cat's suprarenals of
the substance X, the preurea which is not normally formed
there, but which also appears after the injections of large
doses of amino-acids into the veins of parathyroidectomized
animals. Here the injection of amino-acids causes a big
nervous excitation which determines in the cortex the same
reaction as emotion: the formation of preiirea.^'

THE INFLUENCE OF THE NERVOUS SYSTEM.

We have seen above how all kinds of morbid states may
be cured by injections or ingestions of antigens, and we
have pointed out that it is difficult, in these cases, to admit

182 ANTI-ANAPHYLACTIC TREATMENT OF DISEASES

a direct action of the medicine on the intestinal germs or on
the lesions. We have definitely shown that, in general, the
pathologic manifestations of a lesion can be caused only by
nervous reactions, and we have also seen that, in preventing
the nerve centers from acting, it is possible to prevent or to
cure a hepatic or nephritic colic; we could therefore deduce
that our bacterial preparations were curative only on account
of their action on the nerve centers.

A confirmation of this hypothesis can be found in the
results sometimes obtained by a method applied in China
from time immemorial, chilled "cha-chin," from w^hich
" reflexotherapy " is derived, as practised during these last
years by several European doctors, and propagated in France
particularly by. Peter Bonnier.

We have not been able to obtain definite information
about "cha-chin." According to several European doctors,
who have sojourned in China, the "cha-chin" method con-
sists in pricking the patients with long needles at different
parts of the body, and particularly at the joints, which must
be pierced, right through. Chinese doctors obtain by this
method, and apparently often, rapid cures, even in serious
cases of acute infectious diseases, and more particularly in
cholera.

Peter Bonnier treated all kinds of infirmity and chronic
disease (deafness, nervous ticks, asthma, certain dermatoses,
gastro-intestinal disturbances) by touching certain points
of the nasal mucosa with a galvano-cautery. According to
his idea, by cauterizing the termination of the trigeminal
nerve, he caused a reaction in the bulbar centers, which then
acted to restore the peripheral cellular functions.

Whatever the explanation, there are cases of asthma and
of serous mucomembranous enteritis which have resisted all
other known treatments and have been undoubtedly and
radically cured by Bonnier. In several of these cases the
cure has lasted for over ten years.

Is it possible to attribute today the curative results of
reflexotherapy— it appears that this method has proved
itself of certain efficacy only in the ratio of 1 case in 10— to
reactions of a kind differing from nervous shock?

INFLUENCE OF THE NERVOUS SYSTEM 183

When we consider the infinitely small quantities of our
bacterial antigens which proved active in our trials (200 to
300 mg., and even less in Observation 6), we might assume
that the tissues destroyed by cauterization or by injections,
and later resorbed, act as antigens; but even then we would
still have to explain the nature of the reactions caused by
these antigens. The problem would be shifted, but not
solved.

We have seen above, in the section on anesthesia, in the
experiment of Roux and Besredka, in Kendall's experiment,
how predominating the role of the nerve centers is in all
preventive, curative or pathologic reactions.

In these cases, the action of the nerve centers on the
symptoms, and sometimes on the deeper causes of lesions is
indisputable, and as it must be admitted in comparing the
results obtained by bacterio- and reflexotherapy, that in
both methods the nature as well as the mechanism of the
curative reactions must be the same.

The injections of antigens, as well as the cauterization of
the terminations of the trigeminal, cause local curative
reactions by the excitation and the reflex action of certain
nerve centers.

In the cases treated in our laboratory and by our colla-
borators, nearly identical results have been obtained by
autogenous or heterogeneous preparations.

Diseases apparently as different as psoriasis, eczema,
enteritis, asthma, jaundice or chronic appendicitis have
been treated with equal success by the same heterogeneous
preparation.

From the point of view of the theories of immunity and
anaphylaxis, as well as from that of the therapeutic indica-
tion which may result, it is therefore very important to note
that in the diseases considered (and probably in many others) :
the curative reactions are not determined by the chemical
affinities which may exist between the curative substance,
the pathogenic agent and the diseased tissue or the antibody
produced, but by an elective action of the curative product
on the nerve centers.

If the anatomy and the physiology of the nerve cells were

184 ANTI^ANAPHYLACTIC TREATMENT OF DISEASES

known down to their intimate details, if we knew which
nerve termination had to be pricked, burned or excited in
order to affect a given nerve center and produce the desired
general or local reaction, it is certain that on this knowledge
one might base a method of treatment as efficient as it would
be easy to apply; but as long as our ideas on this subject are
as inexact as they are today, the results of this treatment
will depend much more on chance than on the knowledge of
the operator.

We are much better equipped today to fight chronic dis-
ease efficiently and intelligently by antigens.

The bacteriotherapy and the choice of the most efficient
curative antigen in each particular case are not dictated by a
chance discovery. This method is the result of logical deduc-
tions based on a long series of experimental researches, and
confirmed by other experiments which allow us all to appre-
ciate its value.

cha;pter XII.

GENERAL SUMMARY: THEORETICAL
DEDUCTIONS.

1. The work of Pasteur, of his pupils, and successors on
pure cultures and on the specificity of germs in infectious
diseases have led to the practice of specific preventive vaccina-
tion with bacterial cultures of attenuated virulence or with
sterilized bacterial bodies.

2. The work of Roux and Yersin and of Behring and
Kitasato (1889-93) on bacterial toxins and antitoxic sera
has resulted in the practice of specific serum therapy in ill-
nesses caused by toxins (diphtheria, tetanus, certain kinds
of pneumonias, of dysenteries, etc.).

3. The work of Hayem (1885-1890), Kraus (1897),
Belfanti and Carbone (1898), J. Bordet (1898), Ehrlich
(1899), and others, on the reactions caused in the animal
organism by repeated injections of blood serum, bacterial cul-
tures and of other heterogeneous albuminoid liquids, have
resulted in:

(a) The conception and application in medical practice
of Wright's specific vaccinotherapy in the treatment of acute
infectious diseases.

(6) The discovery of Charles Richet's anaphylaxis (1902)
and the practical application of the specific anaphylaxis of
Besredka and Steinhardt (1907).

4. At the same time the researches of Schmidt Mulheim
(1880) on peptones of Roger and Josue, Delezenne and Beso
(1893-1895), Gley and Le Bas, Ancel and Bouin (1897-1907),
and others on organ extracts have led to non-specific tachy-
phylaxis; the researches of Widal and his collaborators,
Abrami, Brissaud, Lermoyez, and others, on paroxysmal
hemoglobinuria; of Nolf, James W. Jobling, Pagnez and

186 THEORETICAL DEDUCTIONS

Vallery-Radot-Pasteur, and others (1910-1917), on the
curative properties of peptones, autogenous sera or heter-
ogeneous sera, of heterogeneous bacterial antigens in the
treatment of acute, chronic or infectious diseases, have
resulted in non-specific sero- or proteosotherapy.

5. Our researches (1912-1919) on the properties and the
action of the organism of the colloidal substances obtained
by synthesis, and particularly of arsenobenzenes proved to
us that all the phenomena of immunity anaphylaxis and
of tachyphylaxis, and the methods of preventive vaccina-
tion of vaccinotherapy, of anti-anaphylaxis, of serobacterio-
therapy and of proteosotherapy, specific or non-specific
derived from such phenomena are caused by reactions
which, in principle, are of the same kind.

6. Our researches in the etiology and nature of chronic
diseases, inspired by the whole of the preceding work, have
resulted in the application in practice of non-specific but
selective bacteriotherapy.

The application of this last method is based on the follow-
ing considerations :

1. Any congestion of the gastro-intestinal mucous mem-
brane may be the cause of the passage into the blood of
incompletely digested albumins (bacterial or alimentary)
which act as antigens.

2. Every antigen, heterogeneous to the organism, will
cause in this organism a state of immunity and of anaphy-
laxis; it will be therefore more or Jess harmful.

3. Every specific curative or preventive antigen (vaccino-
therapy, anti-anaphylaxis) will prevent or cure disease, but
will at the same time reinforce the specific condition of
immunity-anaphy laxis .

4. If a certain number of different antigens can give, in a
given disease, the same preventive or curative result; if, for
example, typhoid fever can be treated with equal success
by specific bacteriotherapy or by peptone (Nolf), an attack
of asthma or urticaria by the injection of a serum, by an
autogenous or heterogeneous bacterial preparation or by
peptone; syphilis or trypanosomiasis by atoxyl, arseno-
benzene or luargol; these results will be obtained by very

r

THEORETICAL DEDUCTIONS 187

different doses. Where several grams of serum or of peptone
will be needed, a few hundredths of a milligram of bacterial
bodies will suffice; several grams of atoxyl or of arseno-
phenylglycin will produce the same effect as a few decigrams
of luargol.

In order to cause a minimum of harmful result and at
the same time a maximum of curative result, we must there-
fore look for the most selective products for each particular
case, or rather groups of antigens for those groups of diseases
which present a group of characteristics in common.

It would thus be very important to prefer heterogeneous
curative antigens to specific antigens whenever possible on
condition that they be very selective, because in this way we
will avoid the reinforcement of the existing state of immunity-
anaphylaxis, and the small doses of heterogeneous antigen
will not cause the formation of a new immunity-anaphylaxis.

THEORETICAL DEDUCTIONS.

1. Disease, no matter what its nature and its manifesta-
tions is always the result of the breaking-down of the normal
nutritive equilibrium of certain cells. This breakdown of
equilibrium, resulting in characteristic lesions and symptoms
for each disease may have as origin:

(a) Either crystalloid chemical poisons which fix them-
selves directly on the cellular matter and modify its com-
position and its reactions.

(6) Or antigens which bring about the passage into the
blood of antibodies in excess and oblige certain cells to per-
form greater work to the detriment of their normal functions;

(c) A direct excitation of certain nerve centers by a poison,
an antigen or an emotion.

Pathologic manifestations will always result from the reflex
reactions of the nerve centers.

2. Most, if not all, non-contagious chronic diseases, as
well as idiosyncrasies, have as primary cause antigens of
intestinal origin; as determining cause, the anaphylactic
state of certain tissues; as "exciting" causes, the reflexes of
the nerve centers.

18$ THEORETICAL DEDUCTIONS

3. All and any medicines or methods of local or general
application which have shown themselves to be in any degree
efficacious in the treatment of these diseases, act fundamen-
tally through the nerve centers. The degree of their efficacy
depends on their greater or less selective action on a given
nerve center, or portion of nerve center.

THE THEORIES OF IMMUNITY, OF ANAPHYLAXIS AND
OF ANTI- ANAPHYLAXIS.

In order to understand the cause and the nature of the
reactions which an organism may or must undergo under
the influence of external agents, as well as the possible effect
of these reactions on its evolution, it is necessary to consider
the following:

1. The essential physicochemical properties of living
matter.

2. The structure of a living being.

3. The general rules determining the nutrition of the
organism and of its component cells, or, in other words,
the conditions under which an organism can assimilate the
substances which it needs in order to keep its tissues living
and multiplying and to furnish energy to perform its work.

Without going into too great detail our knowledge today
may be summarized as follows:

Living matter as found in the cells of all living beings, is
made of albuminoid substances of which the composition
and the physicochemical properties are very uniform.

Albumins are combinations of four elements (C, H, O, N)
in fairly constant proportions, and of a dozen other elements
in varying proportions. They form colloidal complexes, or
"micelles," of which the constitution and intimate structure
are unknown.

All that one does know at the present time on this point
is that living albuminous "micelles'' are complexes main-
taining themselves at a certain constant state of physico-
chemical equilibrium, by drawing from their surrounding
medium the substances of which they are composed and
which they assimilate; and by eliminating the useless waste

THEORIES OP IMMUNITY ISO

from these transformating reactions, and by utilizing other
substances the transformations of which furnish the energy
needed for the work so performed.

An albuminous "micelle" thus may be compared to a
moving engine, which, thanks to special affinities, draws
from the medium through which it passes the fuel necessary
to produce its working energy, and at the same time matter
identical to its own in order to keep its parts in good repair
and even to strengthen them.

Albuminous "micelles" are the nutritive units of living
matter, and all "micelles" of similar albumin have the same
physicochemical equilibrium. "Micelles" of different albu-
mins are distinguished among each other by differences in
physicochemical equilibrium and it has been determined
that the albumins of all beings belonging to the same plant or
animal species are the same.

The albumins of different species have a different physico-
chemical equilibrium. Thus the white of egg from a hen
has not the same properties as the white of egg from other
birds, the casein of cow's milk is different from that of goat's
milk; the blood, the muscular or nervous substances of the
horse are different from the same substances fi;om all other
animals; whereas the salts and the crystalloids entering into
the composition of the tissues of different plants and animals
and which are derived from the albumins are always identical.

The specific differences between the "micelles" and the
albumins which they form are therefore determined solely
by differences in the proportions of the component elements,
by the arrangement of these elements and by the different
physicochemical equilibria resulting.

We do not know of any living being that might be con-
stituted by a single free albuminous "micelle."

The biological unit of living matter is a cell, and a cell is
an arrangement of a certain number of albuminous "micelles"
of different structures, physicochemical equilibria and there-
fore functions which form a harmonious structural and
functional whole.

At least three kinds of "micelles" can be distinguished in
a cell : those forming the plasma, the nucleus and the external

190 THEORETICAL DEDUCTIONS

membrane. All these particles form more or less dense
agglomerations, are immersed in a clear liquid composed of
salts and crystalloids. The cells themselves are immersed
in a liquid which is composed of the same salts and crystal-
loids, and which in addition contains colloidal particles
(plasma, lymph, etc.).

From the point of view of the nutrition of intracellular
particles, we distinguish in the organism three zones or media
through which nutritive substances must pass.

These zones or media are separated from each other by
dialysing membranes which function by virtue of their
density, and by virtue of the differences in tonicity of the
liquids on either side of the membrane, and especially by
virtue of the chemical affinities between the components of
the membrane and of these liquids.

The organism as a whole begins by making a first choice
of the substances needed for its nutrition from the first
external medium. A second choice is made by the mem-
branes of the digestive tract which allow to pass into the
blood only certain selected substances which have been
transformed into simple compounds. A third choice is made
by the cell-membranes which absorb certain substances
and allow the remainder to be eliminated by the kidneys
and the intestines.

In this way, the alimentary substances absorbed by the
mouth undergo a series of successive fragmentations and
selective passages through the membranes before they, in a
crystalloid state, reach the intracellular "micelles," that
is the nutrition units.

A cell may allow certain colloids made up of small "micelles"
to penetrate into its interior. If these "micelles" are homo-
geneous, that is to say, have the same physico-chemical equili-
brium as those which compose the plasma of the cell, the
cell may assimilate a certain number without undergoing
appreciable change in its own gejneral nutritive equilibrium;
but in the case of "micelles" having physico-chemical equili-
bria differing from those of the cell "micelles," the nutrition
equilibrium of the invaded cell and of the new "micelles"
will be disturbed to a greater or less extent.

THEORIES OF IMMUNITY 191

All albuminous micelle, considered as a unit of specific
function can no more assimilate entire ''micelles," whether
homogeneous or specifically different than a house or a
machine could be constructed from other complete houses
or machines.

In either case, the first step must be to demolish, isolate
and separate the individual materials, which will then possess
no specificity and with which new units can be reconstructed
according to the plans and specifications.

The differentiated superior organism is guided in its choice
of food by its organs of sensation and by its intelligence;
the second and third degree units are guided by positive
or negative chemotaxis which is but the non-differentiated
combination of feeling and intelligence; and it is likewise
affinities or chemotaxis which determine the formation of
antibodies as well as the action of these latter on their
antigens.

In order to well understand the mechanism of the results
which these reactions may have for the entire organism, we
must always remember that:

1. The work of demolition or of digestion for each nutritive
unit must take place outside of its interior. The particle,
the cell, and the entire organism, expel from their interior
beyond their protecting membranes, the substances (anti-
bodies) or, more generally speaking the energy which is
needed for the digestion or transformation of foreign sub-
stances (antigens). This is done by that chemotaxis which
by sensation, intelligence and memory can act at a distance.
Thus it is that the sight of food causes the sensation of appe-
tite and the secretion of gastric juice, and that the sight or
odor of individuals of opposite yex causes amorous feelings
and corresponding reactions of the reproductive organs.

2. In differentiated organisms each functional unit, while
its reactions obey its own chemotaxis, must also conform
to the chemotaxis of the whole. The "micelle" is influenced
by the chemotaxis of the whole cell, the cell by the chemo-
taxis of the organism, the organism by the surroundings and
the society in which it lives, and so on; and the history of
the greatest organization of units, the society of nations is

192 THEORETICAL DEDUCTIONS

reechoed inversely by the same routes back again to the
"micelles."

In order to understand in its entirety, the mechanism by
which the animal organism can live normally, become ill and
recover, we must also take into account the fact that the
individual reactions of "micelles" and of cells, determined
by specific chemotaxis are influenced also by the reactions
of the central nervous system which dominates the functions
of all the units of the organism, and can by itself disturb or
readjust the nutritive equilibrium of these units.

It is always the central nervous system which, in the last
resort, reestablishes normal equilibrium ; or, more accurately,
which establishes a neiv general equilihrimn in an organism
which has been influenced more or less seriously by a hetero-
geneous substance; and the influence of the central nervous
system will be all the greater, as it will have attained a higher
degree of development.

All these considerations lead us to conclude therefore that
an organism is absolutely incapable of assimilating colloid
particles wHich are specifically dift'erent from its own without
digesting them. This results not from a defensive biological
law, but simply from the physicochemical properties of its
structural and functional units.

This having been stated, the theory of immunity and of
anaphylaxis may be formulated as follows :

Every bacterium, every substance which penetrates in a
colloid state, into the blood or the tissues, or in other words,
into the interior of an animal organism must be transformed
into salts and crystalloids, that is, must be digested in order
to be assimilated or eliminated.

Every organism, by its cells, glands or organs normally
produces a certain quantity of the substance, or more exactly
of a series of substances which carry on this digestion.

When an organism has once been obliged to perform this
operation, it continues to produce digestive substances in
quantity greater than normal. It is then immunized and
anaphylactized.

All the substances which the organism is obliged to digest
in its interior are antigens.

THEORIES OF IMMUNITY 193

The digestive substances normally produced by the organ-
ism are normal antibodies.

The excess antibody found in the blood and in the fluids
of an immunized anaphylactized organism, is the excess of
one of the digestive substances of which the whole constitutes
the normal antibody. The excess antibody found in the
serum of immunized animals is a substance which contributes
to the digestion of the corresponding antigen, without being
able in itself to finish this operation.

Reactions between antibodies and antigens are specific,
but are not always exclusively so.

Thanks to the antibodies in excess, the organism will
digest more easily and more rapidly antigens which have
determined the excess of these antibodies and the results
will be :

1. A certain degree of anti-infectious or antitoxic immunity
in those cases where the antigen is a germ which is patho-
genic by its albumin or by its toxin.

2. A certain chronic morbid state determined by the
functional insufficiency of the organs assigned to the pro-
duction of the excess antibodies, and lasting as long as the
overproduction of the antibodies.

3. Anaphylactic crises more or less acute and serious,
whenever a new and sufficient dose of antigen will suddenly
combine with the excess antibody and form a precipitate.

Thus acquired anti-infectious immunity consists in the
ability to digest a certain dose of infectious germs before
these germs have had time to multiply so as to become patho-
genic; and the organism acquires this property by producing
a series of intracellular and extracellular digestive ferments.
One of these ferments is the excess antibody.

The first phase of this digestion, that is, the combination
between the antigen and the excess antibody, occurs there-
fore outside the cells, in the fluids of the organism. If the
quantity as well as the quality of the antigen is such as to
form an abundant precipitate with the antibody, the defen-
sive act of the organism, the neutralization of the infectious
agent, will be accompanied by pathologic manifestations
which constitute the anaphylactic crisis.

194 THEORETICAL DEDUCTIONS

The mechanism of anti- or tachyphylaxis must therefore
be considered and explained in two different ways:

1. As a specific neutralization of the antigen by the excess
antibody.

2. As a reflex reaction of the nervous centers on the intra-
cellular metabolism caused by the selective action of certain
antigens on the nerve centers regulating cellular nutrition.
In this case, the reciprocal specificity of antigens and anti-
bodies does not come into play, or plays only a secondary
role.

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