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MODERN THEORIES OF BACTERIAL

IMMUNITY

MODERN THEORIES OF BACTERIAL

IMMUNITY

HAROLD C. ERNST, M.D.

BOSTON

PUBLICATION OFFICE OF

THE JOURNAL OF MEDICAL RESEARCH

688 Boylston Street

1903

Copyright, 1903,
By Harold C. Ernst, M.D.

32 ff

INTRODUCTION.

The following pages are an abstract of a short
series of lectures delivered by request to the
class of 1905 in the Harvard Medical School,
in January, 1903. The method of illustrating
Ehrlich's theories is given in an attempt to
make this obscure subject somewhat more clear,
and the glossary of terms, may prove useful to
beginners.

Modern Theories of Bacterial
Immunity.

I.

Immunity in the bacterial infectious processes
is divided into:

Natural Immunity. — By this term is meant
the ability to resist the invasion of infectious
agencies, which is often found under natural
conditions, e.g., the resistance of many races of
animals to infection with typhoid fever, or the
resistance of the human race to hog cholera;
and

Acquired Immunity. — This form of immu-
nity is said to occur when the condition of re-
sistance appears, following an attack of and
recovery from an infectious agent. It is mani-
fest in persons or animals that have recovered
from many forms of such invasion, or it may
appear as the result of measures purposely
taken in order to favor its development. In

THtORIES OF IMMUNITY.

this case it may be spoken of as an artificial
immunity, and such artificial immunity has been
obtained in a number of different ways.

Acquired immunity, as seen following- the
action of bacterial infectious agents, is again
divided into the forms of Active and Passive
Immunity, and the distinction between these
two is of great importance in understanding
many of the problems arising in connection
with the study of immunity in general.

Active acquired immunity occurs in the course
of recovery from an infection, or may be pro-
duced artificially. In the latter case it is the
result of the injection of gradually increasing
doses (amounts) of the toxic products of micro-
organisms, beginning with quantities much less
than the minimal lethal dose, and increasing until
there is reached a condition of resistance without
reaction to many times such minimal lethal dose.
Such a condition may be obtained by the injec-
tion of the bodies of bacteria killed by the appli-
cation of heat; of the bodies of bacteria in the
living condition, but whose virulence has been
diminished in various ways; or by the use of

THEORIES OF IMMUNITY.

filtered culture fluids in which bacteria have
grown and produced soluble poisonous products.
Examples of the first method are the proced-
ures in securing immunity against typhoid fever,
cholera, and plague; of the second, the first and
second " vaccines " of anthrax ; of the third, the
use of the soluble toxines of tetanus and diph-
theria.

Passive acquired immunity. — It has been
found that in certain cases of active immunity
produced as above, there appears coincidently
with the complete resistance to the injection of
the toxic material a substance, existing in the
blood-serum of the animals so treated, that has
an antagonistic action to the toxic material, both
in the test-tube and in the living animal tissues.
This substance is spoken of as " antitoxine," and
with the serum containing it is used for the pro-
tection of tissues invaded by the toxine-producing
bacteria; as in the therapeutic use of diphtheria
antitoxine.

Such antitoxines occur in the blood-serum of
animals attacked by, or immunized with the toxic
products of tetanus and diphtheria — the cause

THEORIES OF IMMUNITY.

of both of these diseases being bacteria that pro-
duce extra-cellular or soluble toxines.

They do not occur, or only to a very limited
extent, in animals attacked by or immunized
with the toxic products (bacteria) of typhoid
fever, cholera, or plague ; the cause of these dis-
eases being bacteria that produce intracellular
or non-soluble toxines.

When they do occur and are used for pro-
tective purposes, the condition following their
use is spoken of as Passive Immunity.

The differences between these two forms of
immunity are very marked.

Active immunity is slow in appearing, is more
or less dangerous to secure, is always attended
with at least some discomfort, but is very lasting
when once attained. A horse brought to a high
degree of immunity to diphtheria toxine will
show a marked degree of such immunity for a
very long time — extending over months and
even years.

Passive immunity, on the other hand, is very
rapid in its appearance, is attended with no

THEORIES OF IMMUNITY.

danger and practically no discomfort, but is
limited in duration and disappears very rapidly.
An animal protected against a dose of diphtheria
toxine by the injection of antitoxine (of diph-
theria) is protected only against that dose of
toxine, and is susceptible to a second dose in a
very short time.

Attempts to produce a condition of artificial
immunity to infections of various kinds have been
made for a very long time, and there exist ac-
counts of such attempts among savage tribes —
the beginning appears to have been in the
direction of protection against the bites of ven-
omous serpents.

The most well-known efforts to secure arti-
ficial immunity, and before the present knowl-
edge of the bacteria was developed, were the
inoculations against small-pox — a knowledge of
the beneficial effects of which existed in Asia
certainly for generations before its introduction
into England by Lady Montague. These inocu-
lations consisted in the use of contents of the
pustules in mild cases of small-pox, which were
introduced through scarifications of the skin or

THEORIES OF IMMUNITY.

mucous membranes of well persons, in the hope of
producing' a mild case, and thus protecting the
individual from an attack of a more malignant
form of the disease.

Jenner's application of his observation in
Gloucestershire, where he was born, that dairy-
maids handling cows sick with cow-pox ap-
peared to be protected against small-pox was
the beginning of the stamping out of this great
plague in all parts of the civilized world.

The discovery of the possibility of the attenu-
ation of the virulence of a culture on the one
hand, and of the possibility of securing an arti-
ficial immunity with such attenuated cultures on
the other, were more or less the result of chance.
Pasteur, with Chamberland and Roux, had been
studying the bacillus of chicken-cholera, and
interrupted their work during the vacation sea-
son of 1879. Upon attempting to resume it
they found that their cultures, kept over during
the summer, still retained their vitality, but had
lost their virulence, either wholly or in great
part. (Valery-Radot. La vie de Pasteur, p.
427.) Testing the effects of such cultures led

THEORIES OF IMMUNITY.

Pasteur to the steps resulting in the practical
application of the laboratory results in such pro-
cedures as the protective inoculations against
anthrax and rabies. (See C. Renclus de
l'Academie des Sciences, 1880, T. XC, pp. 936,
952, 1030; T. XCL, pp. 571, 673.)

The statement of the general principles was at
first met with much opposition and incredulity,
but was so overwhelmingly confirmed by other
observers that such incredulity soon disappeared.

The first theory that was advanced to explain
the phenomena seen was that of Pasteur himself,
and was known as The Exhaustion Theory. In
accordance with this, the condition of immunity
following the injection of attenuated cultures of
a bacterium may be supposed to be due to the
exhaustion of certain elements in the tissues used
by the bacteria during their growth. These ele-
ments are not resupplied for some time by the
tissues, and during that time fresh bacteria en-
tering the tissues, finding the absence of some-
thing necessary for their growth, cannot grow,
and therefore no infection can take place. Such
a condition of things apparently exists in the test

7

THEORIES OF IMMUNITY.

tube; for if a fluid in which a micro-organism
has grown be filtered and planted with a fresh
culture, no growth will occur. This certainly
might be due to the exhaustion of the nutrient
medium, and that it is so seems to be shown by
the fact that an addition of a very small amount
of fresh medium is followed by a profuse growth
of the bacterium in question. The same thing
was supposed to occur in the living tissues.

Such a theory, however, would not account for
the facts seen in Natural Immunity, in which no
previous growth of the bacteria could be sup-
posed to occur. Nor would it explain the results
seen in Algerian sheep. These animals are not
susceptible to inoculation with anthrax bacilli
sufficient to kill ordinary French sheep, but will
succumb to very large doses of such bacilli. If,
then, the first resistance was due to the absence
of nutrition for a comparatively small number
of bacilli, how could a much larger number find
enough to live upon?

In view of such objections as these, Chauveau
brought forward his Retention Theory to explain
the phenomena seen. In accordance with this,

THEORIES OF IMMUNITY.

the bacteria may be supposed to elaborate a ma-
terial that is hurtful to themselves, and this sub-
stance is retained in the tissue cells or fluids for
some varying length of time, during which time
a fresh invasion of bacteria would be followed by
no results. To explain such cases as those of
the Algerian sheep by this theory — in which
the sheep are not susceptible to attack by small
doses of anthrax bacilli, but are susceptible to
overwhelming doses — it would be necessary to
suppose the existence of a fixed amount of the
opposing substance which would be more than
neutralized by the excessive doses of the anthrax
bacilli, after which infection occurred. Although
Chauveau objected to the exhaustion theory, that
it did not explain natural immunity, his own
supposition did not do so any better. ]STor did
it serve to explain more than a very small part of
the experimental facts observed. Pasteur him-
self furnished one instance — that of chickens
that are not susceptible to anthrax at their
normal temperature, but become so when this
temperature is lowered. His comment upon
this fact and its bearing upon Chauveau's
theory was that it could not be supposed that a

9

THEORIES OF IMMUNITY.

preventive substance existed that would dis-
appear under the influence of cold.

Buchner brought forward a theory to explain
the fact of obtaining immunity in the infectious
processes. It was based upon the then ac-
cepted belief (1877-1883) that a bacterium pro-
duced its effects in a localized fashion (that the
pneumococcus, for example, could produce effects
only in the lung), and also that the inflammatory
reaction occurring at the site of growth of
the bacteria represented a reenforcement of the
local tissues, by the general system. So soon
as evidence accumulated that the action of very
few bacteria is limited in the way suggested, it
became clear that this theory was not sufficient
to explain even a small part of the facts observed.

Various other partial explanations were
offered, each lasting only so long as the rapidly
growing results of experimentation needed to
show their limitations.

The only ones that have withstood the test of
time are those of Metchnikoff, representing the
cellular theory, and of Ehrlich, representing the
humoral theory.

10

THEORIES OF IMMUNITY.

II.

MetchnikofTs work is of the most remarkable
kind; painstaking and laborious to an extreme
degree, he has for more than twenty years put
forth a series of papers that are unsurpassed
for the closeness of reasoning and fertility of
device used to demonstrate his points. No ac-
count can be so satisfactory as his own, and the
present summary of his theory of the phagocytic
action of the tissue cells in securing immunity
is largely paraphrased from his own words.
(Metchnikoff. L'Immunite. Paris, 1901, pp.
541 et seq.)

He began his studies on the germinative lay-
ers, and was able to explain satisfactorily to
himself the part played by the ectoderm and
the entoderm. While working in this direction
his attention was attracted to the intracellular
digestion occurring in many of the lower ani-
mals, and he was led to consider this property
as one common to the stock from which are

derived all present known types of the animal

li

THEORIES OF IMMUNITY.

kingdom (except protozoa). Considering the
ectoderm as the source of the covering of all
primitive polycellular animals, and the entoderm
as the source of the organs of digestion, the
part of the mesoderm remained a mystery until
certain of his studies on sponges led him to
think that perhaps this layer might have acted
in the hypothetical primitive animals as a mass
of digestive cells, in every respect like those of
the entoderm. Such a theory necessarily at-
tracted his attention to the property that these
mesodermic cells have of seizing upon foreign
bodies.

The fact had been known for a long time, both
in respect to the power of the white corpuscles
of the vertebrates to seize upon foreign bodies
and of the ameboid cells to seize upon particles
of coloring matter. But no one had looked
upon this property as one of digestion, and it
had even been considered as simply a passive
action. Metchnikoff's studies upon sponges and
some of the simpler forms of sea animalculse
convinced him that the presence of foreign
bodies in the ameboid cells of the mesoderm
should be interpreted as an active englobement,

12

THEORIES OF IMMUNITY.

and that in all its aspects it resembled very
closely the phenomena of intracellular digestion
going on in the epithelial cells lining the digest-
ive tract of very many of the inferior animals.
At Messina, in 1882-1883, he set himself to
secure definite evidence of this fact, and did so
by proving that these cells (of the mesoderm)
seize upon foreign bodies of very varying nature
by their living prolongations, and that some of
these foreign substances undergo a true diges-
tion in the interior of these ameboid cells.

Then the idea suggested itself to him that this
digestive function, evidently fixed in the meso-
dermic cells, might also play a part in many of
the vital processes of the animal. Working
from this point of view, he was able to demon-
strate that during the complicated metamorpho-
sis of echinoderms, such as the synaptera, the
mesodermic ameboid cells played a part in the
atrophy of many embryonic organs.

He had never studied medicine, but he was
struck at one time by an exposition by Cohnheim
of the facts of the latter's theory of inflammation.
The facts as presented impressed him strongly,

13

THEORIES OF IMMUNITY.

especially that of the emigration of the leuco-
cytes, but the theory made to fit the facts did
not appeal to him, and he saw at once that study
of inflammation among lower animals of the
simplest type and organization would certainly
throw light on this process in the vertebrates,
as well as in the frog — the animal upon which
Cohnheim's experiments had been made.

Since, in the atrophy of the larval organs of
the synaptera, the essential part is played by
the ameboid cells of the mesoderm which col-
lects in masses there, possiblj the inflammatory
exudates manifest some especially important
function by their richness in white corpuscles.
So that it suggested itself to him to introduce
splinters through wounds under the skin of
transparent marine animals; if the supposition
was correct there should appear a collection of
ameboid cells at the point of irritation. Choos-
ing " bipinnaires," — the large embryonic forms
of star-fish, — he stuck rose thorns in them, and
these were seen to be at once surrounded by
masses of ameboid cells, exactly as in man after
the introduction of a splinter or other irritant
substance. In other words, the first point was

14

THEORIES OF IMMUNITY.

determined, that an inflammatory exudate must
be considered as a reaction against all sorts of
lesions, and that exudation is a primitive phe-
nomenon, older than the nervous system or the
blood-vessels.

At the time these researches were going on
(1882), the general theory in regard to inflam-
mation was that it was, at least in most part if
not wholly, the result of bacterial action. As a
result of this belief, the conclusion was reached
that diapedesis and the gathering of the white
corpuscles in inflammatory disease was to be
looked upon as a means of defence of the tissues
against the bacteria, and that the leucocytes
served to englobe and destroy them. Upon
such a hypothesis, the explanation of inflamma-
tion becomes at once most clear and simple, and
it was such an explanation that Metchnikoff set
himself to prove, if possible.

The general belief of the pathologists at
that time was that the bacteria found a
favorable location in the leucocytes and were
carried about by them instead of being de-
stroyed. So that to secure recognition for his
theories he was obliged to overcome the then

15

THEORIES OF IMMUNITY.

belief of all but a few of the specialists in that
branch of medicine.

His effort was to develop) the idea that cel-
lular digestion in unicellular organisms had
been transmitted by heredity to the superior
animals, and is preserved in the mesodermic
ameboid cells. These cells being able to en-
globe and digest all sorts of histological ele-
ments may well be able to apply the same
power to the digestion of the bacteria — and
that they are able to do this he demonstrated
in many cases by introducing bacteria into
lower animals and watching their englobing
and destruction by the ameboid elements. It
was evident that the simple demonstration of
this occurrence was not sufficient for the devel-
opment of the general theory, and he went on
to find diseases in the lower animals that were
illustrative of the same thing. This he suc-
ceeded in doing in the case of the daphnia, —
small Crustacea common in fresh water, — and in
them followed out and watched an actual
struggle between their leucocytes and the sj)ores
of a blastomycete ; on the one hand it often
happened that the cells were successful in

16

THEORIES OF IMMUNITY.

protecting the body against the attacks of the
spores, and on the other the spores overcame
the action of the leucocytes and overwhelmed
the tissues. (Yirch. Arch., 1884, T. XCYL, p.
177.) Some time after this he published his
work on anthrax (Ibid., 1884, T. XCVL, p.
502), in which he demonstrated in the case of
the vertebrates, also, that the bacteria penetrated
the cells and set up a definite reaction between
themselves and these cells.

As a result of these investigations, Metch-
nikoff elaborated his theory of phagocytosis
against bacterial invasion — based upon the
power of the ameboid cells to seize upon and de-
stroy bacterial cells, thus preventing them from
developing and injuring the tissues.

He goes on to say (I. c.) that he had sup-
posed that the facts of absorption and in regard
to the leucocytes already accumulated would
lead the pathologists to look favorably upon the
theory that these leucocytes were active de-
fenders of the system against the attacks of the
bacteria. This, however, was far from being the

17

THEORIES OF IMMUNITY.

case, and the most active opponents of the
theory were those he had supposed would find
reason to support it.

Baumgarten was the first of these and perhaps
the most important, his most forcible theoretical
objection being that just when the danger is the
greatest the leucocytes are conspicuous by their
absence, and that this is a fatal objection to any
assumption that they can play an active oppos-
ing part to the growth of bacteria in the tissues.
Metchnikoff devoted several years (Yirch.
Arch., 1888, T. CXIY., p. 465; Ann. de l'ln-
stitut Pasteur, 1890, IV., p. 35) to taking up,
point by point, the objections raised by Baum-
garten and his students, and according to his
thought succeeded in answering them. In the
latter communication he makes the remark (p.
84) that he has often been accused of claiming
for phagocytosis the entire influence in the pro-
duction of immunity, denying any other as as-
sisting the organism to disembarrass itself of the
bacteria. He repeats again that the part of the
phagocytes is a very important one in the pro-
duction of immunity in general (and of anthrax
in pigeons especially), but this does not in any

18

THEORIES OF IMMUNITY.

wise prove that some other influence will not
some day be found assisting the phagocytes in
their action — an influence that has as yet
escaped our observation.

Ziegler also, from whose text-book Metchni-
koff had received his first stimulation, took up
a strong position against the theory, considering
that the intervention of these cells was purely
fortuitous, and that the part played by them in
infectious diseases was entirely accidental as
against the action of the bacteria. His students
and assistants after experimenting upon the
subject reached the specific conclusion that
phagocytosis had nothing to do with the phe-
nomena of immunity to be found in anthrax and
symptomatic anthrax, as supposed by Metchni-
koif ; but this work was also carefully reviewed
by independent observers (Lubarsch, Ruffer,
Leclainche, and Yallais) and by Metchnikotf
himself, and the correctness of the observations
was again demonstrated, by which the assertions
were supported that phagocytosis was an active
force in these diseases.

Other pathologists — notably Yirchow (Yirch.
Arch., 1885, T. CI., p. 12), Ribbert (Deut. Med.

19

THEORIES OF IMMUNITY.

Woch., 1890, no. 31, p. 690), and Hess (Yirch.
Arch., 1887, T. CIX., p. '665) were more inclined
to favor the theory, and Bibbert noted especially
that in the reactions produced by the staphylo-
cocci there was a modification of the phagocytic
action manifested by the collection of the leuco-
cytes about the bacteria — this collection acting
as a hurtful surrounding to the bacterium;
although Metchnikoff considers this preliminary
gathering as simply a first stage to the following
englobing and digestion of the bacterial cells by
the leucocytes.

Some theories in opposition to the suggestions
of Metchnikoff were offered by the bacteriologists
interested in the subject, and according to
Metchnikoff the starting point of these theories
was the observation made by Fodor (Deut. Med.
Woch., 1886, p. 617; Arch. f. Hyg., 1886, T. IV.,
p. 129) that the defibrinated blood of the rabbit
was able to destroy a large number of anthrax
bacilli. This was the first announcement of the
bactericidal property of the blood, and it was at
once concluded from it that the body-fluids con-
tained a substance capable of destroying bacteria,
and that this property was quite sufficiently

20

THEORIES OF IMMUNITY.

powerful to explain the facts seen in the occur-
rence of immunity. Nuttall's work (Zeit. f.
Hyg., 1888, T. IV., p. 353, in which he refers to
Fodor's work as full of errors) was in the same
direction and of the first importance. It was
based upon observations on the warm stage with
the defibrinated blood of various animals, in
which it was shown that this same bactericidal
property was present — existing, of course, out-
side of the leucocytes, and that it could be de-
stroyed by subjecting it to fifty-five degrees
Centigrade.

Such observations as these formed the first
foundation for the humoral theory of immunity,
and served as the starting point for innumerable
experiments, all of which were intended to show
that the theory of phagocytosis had absolutely
no foundation in fact.

Behring was one of the first to take up the
bactericidal property of the blood as explaining
immunity. He (Cent. f. klin. Med,, 1888, No.
39) had discovered the remarkable power of the
blood of the white rat to destroy anthrax bacilli

21

THEORIES OF IMMUNITY.

with great rapidity — and did not hesitate to
conclude that this bactericidal property was re-
sponsible for the immunity of the animal to the
disease.

To generalize this fact, Behring and Nissen
(Zeit. f. Hyg., 1890, T. Yin., p. 41) undertook
a long series of experiments. They showed that
in animals well immunized against certain bac-
teria (notably "V". Metchnikovii) the blood serum
acquired a strong specific bactericidal property,
but they also showed at the same time that the
blood of animals, even well immunized in other
diseases, was very frequently incapable of de-
stroying the bacteria. Therefore, the bactericidal
property did not appear to be a general charac-
teristic and was of limited importance ; and such
facts led Behring to abandon the idea that the
bactericidal property was an active factor of a
general nature, and essential in the production
of immunity.

Buchner confirmed Nuttall's assertion that
the bactericidal property disappeared at 55° C. ;
demonstrated the part that the salts play in
the exercise of the bactericidal action; and

22

THEORIES OF IMMUNITY.

especially insisted upon the fact that this prop-
erty depended upon the presence of special sub-
stances of an albuminoid nature to which he
gave the name of alexines. He also demon-
strated the very important fact that the red
blood globules of one species of animal intro-
duced into the blood of another would undergo
destruction (a globulicidal action) similar in
nature to the bactericidal action already demon-
strated.

In France, Bouchard especially adopted the
humoral theory as explaining immunity (Les
Microbes Pathogenes, Paris, 1892), and was
strongly supported by Charrin and Roger, his
students. Most of their work was done with
the bacillus pyocyaneus and their results con-
firmed them in the belief that the condition of
immunity was due to the action of the body
fluids, and not in any case to the action of the
cells. They attributed both natural and ac-
quired immunity to a special property of the
body fluids, and considered that the part of the
phagocytes was secondary, that they were con-
cerned simply in carrying off the bodies of the

23

THEORIES OF IMMUNITY.

bacteria, either dead or rendered inoffensive by
the previous action of the body fluids.

: The humoral theory made many converts in
all parts of the world, and was and is very
generally accepted. It has, however, been
queried by a few observers whether the phe-
nomena seen to take place in the test-tube
really are the same as those that occur in the
living* body tissues, and it has been shown that
similarity of action does not uniformly exist.
It has been shown many times that the blood of
animals susceptible to infection is bactericidal
to the specific bacteria of that infection; while
on the other hand, the blood of animals not
susceptible to such infection has absolutely no
bactericidal properties towards the specific bac-
terium. Such parodoxes as this are not at all
uncommon in the case of infections already
investigated, and are so common as to form an
almost insurmountable obstacle to a belief in
the general action of the body fluids in the pro-
duction of immunity." (Metchnikoff, I. c.)

In reference to what has just been said, as
long ago as 1889 (Cent. f. Bakt., 1889, T. VI.,
pp. 481, 529) Lubarsch carried on a long series

24

THEORIES OF IMMUNITY.

of experiments, in which he showed that animals
may be very susceptible to a very small number
of bacteria, whose blood-serum is exceedingly
bactericidal to a much larger number of the
same bacteria in the test-tube. For example,
the defibrinated blood and the blood serum of
the rabbit destroys numbers of the anthrax
bacilli, whilst the animals themselves succumb
also very promptly to the injection of a small
number of the bacteria in the blood vessels.
The assertion is made that such a contradiction
in results is only to be explained by the fact
that the blood itself undergoes a profound
change after its removal from the body.

In 1891 the discovery by Behring and Kit-
asato of the existence of the antitoxines had not
made much impression so far as being con-
sidered a factor in the production of immunity
was concerned. It had been demonstrated as
occurring in the two diseases of diphtheria and
tetanus, and by Ehrlich for the vegetable alka-
loids— ricine, robine, and abrine; but it was
thought of as a special phenomenon peculiar to
these few diseases rather than as a general prin-
ciple capable of wide application. It was after

25

THEORIES OF IMMUNITY.

the International Congress of that year that Behr-
ing attempted to argue that antitoxine forma-
tion occurred in all forms of acquired immunity,
and that bacteria introduced into the bodies of
animals containing this principle were incapable
of producing any hurtful results.

Taking up this point, Metchnikoff undertook
to investigate the acquired immunity occurring
in pneumo-enteritis of hogs (hog-cholera?).
He demonstrated (Ann. de l'lnst. Pasteur, 1892,
T. "VI., p. 289 ) that the resistance of the animal
to the bacterium in this case does not depend
upon the formation of an antitoxine — which is
entirely wanting in this form of acquired im-
munity. (He demonstrated this in the paper
spoken of, as follows : he first tested the serum of
animals immunized to pneumo-enteritis, and
found that it made a favorable medium for the
cultivation of the bacillus; there was, therefore,
no bactericidal action in the serum. He injected
mixtures of the serum of animals dead of pneu-
mo-enteritis (hog-cholera?) with the serum of
immune animals and with the serum of non-
immune animals, and in both cases found that

26

THEORIES OF IMMUNITY.

these mixtures produced just as fatal results as
when the serum of animals dead of the disease
was used alone; there was therefore no antitox-
ine present.) In this same article he also estab-
lished the fact that the serum of immune rabbits
possessed a very active preventive power against
infection with the bacillus of pneumo-enteritis
(hog-cholera?), which he lays stress upon as
being the first time that an anti-infectious prop-
erty had been demonstrated, in addition to the
bactericidal and antitoxic properties of the serum,
this anti-infectious property being, in accord-
ance with his explanation, a stimulation of the
phagocytes in their struggles against the bac-
teria. The same sort of reaction has since been
shown to occur in typhoid fever and cholera.
Kichet and Hericourt (C. Rend, de l'Acad. des
Sciences, 1888, T. CVIL, pp. 690, 748) had
demonstrated before this an immunizing action in
the serum of animals resisting inoculation with
the staphylococci, and when Behring and Kita-
sato discovered the presence of the antitoxine
in diphtheria and tetanus, it was supposed that
this staphylococcus immunity was also antitoxic
in nature. It was shown to be of the same kind

27

THEORIES OF IMMUNITY.

as that in pnenmo-enteritis, however — of the
anti-infectious nature, and that the serum of the
immune animals did not contain an antitoxine.
As just stated and referred to by Metchnikoff,
the same thing was shown to occur in the arti-
ficial disease produced by the injection of the
cholera spirilla; in Pfeiffer's results (Zeit. f.
Hyg., 1894, T. XVI., p. 268) in cholera he ob-
tained a serum from highly immunized animals
with no antitoxic power, but with very active
anti-infectious properties.

Such instances as these, together with many
others that may be found admirably summarized
in Metchnikoff 's book upon Immunity (chapter
VI.), together with the demonstration of a
marked excitation of the phagocytic reaction,
served at that time to turn the scale of judg-
ment in favor of the cellular theory of immunity,
but the discovery of " Pfeiifer's phenomenon "
seemed at the time to upset it entirely just as it
was about to be " at least admitted into court."
Buchner in the meantime had attempted to
reconcile the two theories by supposing that his
w alexines " originated in the phagocytes, but
that they were present in the body fluids and

28

THEORIES OF IMMUNITY.

performed their functions there, while the en-
globing and digestive action of the phagocytes
was a secondary process.

PfeifFer's phenomenon seemed to show, how-
ever, that there was no cell action whatever
necessary in the production of immunity, for it
took place in a fluid apparently entirely free from
cells. It consisted (Zeit. f. Hyg., 1894, T. XYIL,
pp. 1, 355) in the following: In working to
secure immunity in guinea-pigs against experi-
mental cholera he found that living and virulent
cholera spirilla injected into the peritoneal cav-
ity of a fresh gninea-pig together with a small
amount of the serum of an immunized guinea-
pig, and then examined at short intervals, became
bunched together, granular, and finally disap-
peared entirely. This destruction he claimed to
depend entirely upon the action of the body fluids,
and to be the result of the action of a substance
wholly different from the alexines of Buchner;
the immune serum in an inactive state did not
contain it by itself, but as soon as it was intro-
duced into the tissues of a fresh animal, the bac-
tericidal substance undergoes some change as a

29

THEORIES OF IMMUNITY.

result of " the activity of the endothelial cells,"
changes to an active condition, and becomes
capable of destroying great numbers of the
spirilla. This activity of the endothelial cells
was developed into a "new fundamental law" of
immunity (Deut. Med. Woch., 1896, pp. 97, 119),
and the discovery renewed the vitality of the
" humoral theory."

As Metchnikoff (I. c.) himself goes on to say,
it may be easily supposed that he undertook
the investigation of this phenomenon of extra-
cellular destruction of the bacteria as soon as
possible, with a view of determining its real im-
portance in the question of immunity. He was
soon able to show that Pfeiffer's phenomenon
takes place in special circumstances only; previ-
ously existing phagocytes must undergo much
damage before the spirilla can become trans-
formed into granules; such " phagolysis " is in-
dispensable in order that Pfeiffer's phenomenon
may occur in the peritoneal fluids. If it be sup-
pressed by preparing the phagocytes beforehand
— by the injection of various liquids — an in-
stantaneous phagocytosis is produced instead of

30

THEORIES OF IMMUNITY.

Pfeiffer's phenomenon; in places where there are
no or almost no preexisting leucocytes, Pfeiffer's
phenomenon does not occur at all. The same
with the cholera vibrio, — the extra-cellular de-
struction does not exist except under special con-
ditions, and the vast majority of other bacteria do
not show this phenomenon at all under the con-
ditions in which the cholera vibrio manifest it.

Metchnikoff interprets the facts as indicating
that this destruction of the bacteria takes place
in the tissues as the result of the action of the
soluble ferments of the phagocytic" digestion.
These ferments are normally found in the inte-
rior of the phagocytes, and not outside except as
the result of the destruction or temporary injury
of these cells.

Such a conclusion was in direct contradiction
to Pfeiffer's belief, who laid especial stress upon
an action of the endothelial secretions. So that,
to prove that these latter had nothing to do with
it, the reaction should occur outside of the body.
This Metchnikoff easily did by adding a little
lymph, full of leucocytes, to an inactive anti-in-

31

THEORIES OF IMMUNITY.

fectious serum — when the transformation of the
cholera spirilla into granules promptly made its
appearance.

This result was what led Bordet (Ann. de
Flnst. Pasteur, 1895, T. IX, p. 462, and 1896,
T. X., p. 760) to study the intimate nature of
the reaction. He was successful in producing
it, not only by adding a little of the peritoneal
fluid to the specific serum, but also by adding a
little of the fresh blood from the same animal
(from which the peritoneal fluid had come).
These and other results of his work brought him
(Bordet) to the generalization that the destruc-
tion of the bacteria in immunized animals re-
sults from the action of two substances, — one of
these is the alexine of Buchner, which under
normal conditions is to be found in the leu-
cocytes. It produces bacteriolysis properly so-
called when it exists normally within the cells,
and also when it has escaped from them as
the result of phagolysis. There must, however,
be present a second substance in addition to the
alexine, and this is the " substance sensibilisa-
trice " of Bordet, which circulates in the plasma

32

THEORIES OF IMMUNITY.

and carries the :<r specific " property that is not
possessed by the alexine at all.

Bordet continued his most important studies
(Ann. de l'Inst. Past., 1898, T. XII., p. 688; 1899,
T. XIII., p. 273) by attempting to determine the
fate of the red blood corpuscles in the animal
body as the result of hemolysis. He established
the exceedingly narrow line between the devel-
opment of the bacteriolytic and the hemolytic
properties of the serum of animals, prepared by
repeated injections of bacteria and of blood, and
his results were soon confirmed by Ehrlich and
Morgenroth (Bed. Klin. Woch., 1899, p. 6), who
added the important conception that the sensi-
tizing substance of Bordet (the intermediary
body of Ehrlich and Morgenroth) has the prop-
erty of fixing itself in the red corpuscles. The
work of these three observers during the last
few years has rendered it possible to get some
conception of the mechanism of the action of
the two substances on the bacteria and the cells
of the animal tissues, as will be more clearly
stated below.

33

THEORIES OF IMMUNITY.

Metchnikoff (I. c.) summarizes the present
status of affairs in substance, as follows: The
theory of Ehrlich is not in opposition to the
theory of phagocytosis. Ehrlich considers that
the bacteriolytic ferments as well as the cyto-
toxic-alexines or complements (called cytases by
Metchnikoff) exist in a soluble condition in the
circulating blood plasma, whilst Metchnikoff
believes that they are normally present in the
interior of the phagocytes. This has nothing
to do with the Ehrlich theory in regard to the
receptors or lateral chains, which considers the
antitoxines and certain other anti-bodies (inter-
mediary substances) as products detached from
the cells and having an affinity for the toxines
and bacterial products.

The theory of phagocytosis seeks to establish
the part played by the cells in the destruction
of the bacteria. It premises that the vital phe-
nomena of the phagocytes, such as motility,
sensitiveness (chemiotaxis), and voracity are
essential conditions for relieving the tissues from
the bacteria, for the true bacterial ferment is
contained within the phagocytes except when
phagolysis has occurred. The destruction of

34

THEORIES OF IMMUNITY.

bacteria follows the laws of the destruction of
formed elements in general, and this resorption
is, in the last analysis, the work of two soluble
digestive ferments, of which one (fixateur,
immune body) is easily excreted by the phago-
cyte into the plasma of the blood and exuda-
tions, and the other may exist there at all times.

The theory of the phagocytes attempts to es-
tablish these principles in as exact a fashion as
possible, but it has not attempted to penetrate
the depths of the phenomena of intracellular di-
gestion, which is mixed up with the action of
soluble ferments in general, and this problem is
still far from being solved.

In spite of the numerous objections, the theory
of phagocytosis within the limits indicated has
not only not been overthrown, but appears to
have slowly and gradually gained strength, as is
shown by the marked disappearance of opposi-
tion that is very noticeable of recent years.
Such changes are shown by the instance given
(Metchnikoff, I. c.) of Buchner's change of atti-
tude toward the theory (Muench. Med. "Woch.,
1900, p. 1133). At the International Medical
Congress in Paris he maintained his theory of

35

THEORIES OF IMMUNITY.

the leucoeytic secretion of the alexines, but
he went a step further than had before been the
case; he admitted that phagocytic activity has a
decisive importance in many cases in overcom-
ing the infectious processes, particularly in those
in which the alexines secreted have been unable
to produce more than a passing diminution in
the vitality of the bacteria. In such conditions
the bacteria have been so modified that their
chemical functions have been transformed into
a latent condition from which they would be
able to revive in full vital energy if the phago-
cytes were not present to prevent them from
doing so. In any case, as Metchnikoff says, this
conception is far from Buchner's original theory,
according to which the phagocytes are to be
considered only as capable of englobing dead or
harmless bacteria. He further speaks of other
marked changes in opinion which have occurred,
and sums up the present condition of things as
follows: the theory of phagocytosis has been
strengthened by the demonstration of the follow-
ing facts, that the phagocytes, in cases of immu-
nity, engj.obe and destroy living and virulent
bacteria, without these having been previously

36

THEORIES OF IMMUNITY.

deprived of their toxines; that the phagocytes
contain the bactericidal cytases and produce the
fixatives; that the phagocytes absorb the toxic
substances. The great contradiction between the
occurrence of the bactericidal property and the
non-occurrence of immunity is to be explained by
the fact that the bactericidal substances in the
living tissues remain in the leucocytes and do not
escape except when the cells have received some
injury. The fact brought out by Gengou, that
the blood plasma has no bactericidal property,
has given the " coup de grace " to the bacteri-
cidal theory of the body fluids.

This work of Gengou (Ann. de l'Inst. Past.,
1901, T. XV., p. 231) is one of the strongest
supports of Metchnikoff's theory. In it he at-
tempted to determine whether the properties of
the shed blood are actually the same as those of
the blood in the body. The general results
were of great importance in showing that in
blood received under conditions preventing the
appearance of coagulation there would appear
no, or almost no, bactericidal properties, while

37

THEORIES OF IMMUNITY.

in the same blood after coagulation there would
appear marked bactericidal powers.

If further experiments serve to support these,
and to show that under ordinary circumstances
there is no bactericidal property in the circu-
lating blood, it can easily be seen how impor-
tant this would be for Metchnikoff 's theory of
the formation of such a property in the cells as
the result of vital action.

Metchnikoff goes on, in his summing up, to
say that; There is only one constant element in
immunity, — either natural or acquired, — and
that is the property of phagocytosis. The ex-
tent and importance of this factor cannot be
denied. It has been fully shown that the phago-
cytes are sensitive cells that react against mor-
bific agents whether they are organized or not.
These cells englobe the bacteria and absorb the
soluble substances. They seize upon bacteria
that are living and able to exercise their hurtful
properties, and subject them to the action of
their cellular contents which are able to kill and
digest the bacteria, or at least prevent their

38

THEORIES OF IMMUNITY.

pathogenic action. The phagocytes act by
virtue of their vital properties and the power of
exerting a fermentative action on the morbific
agents. . . .

*

This is a brief statement of the position of
Metchnikoff's theory of Immunity, by which the
facts seen are supposed to be due in large part
to the vital activity of the mesodermic cells,
which have retained their power of englobing
and digesting foreign substances. The full
details can of course only be obtained by a
study of his book upon Immunity, in which may
be found a most complete summary of the work
done, with the interpretation of the results from
his point of view.

39

THEORIES OF IMMUNITY.

III.

We come now to a discussion of Ehrlich's
theories in explanation of the same phenomena,
which are based upon the idea that the reactions
seen are primarily chemical in nature, although,
as will appear, it is impossible to neglect the
vital factor even in these theories.

Dr. James Ritchie (Review of current theories
regarding immunity. The Journal of Hygiene,
1902, Yol. II., nos. 2, 3, 4) has published a
very elaborate and painstaking discussion of
these theories, the best and most complete that
has yet appeared in English. It is, however,
useful only for those who already have some
familiarity with the subject.

It has been attempted, therefore, in what fol-
lows to condense the material gathered, to the
end that confusing details may not enter, and
that merely the main facts may be brought out.
The method adopted for illustrating the reac-
tions supposed to occur is entirely original, and

40

THEORIES OF IMMUNITY.

is evidently capable of indefinite expansion, as
well as of being applied to all the reactions at
present known to occur.

Ehrlich first conceived his theory, or at least
the beginning of it, to explain the occurrences
in passive immunity; specifically, those seen in
the application of the antitoxine treatment of
diphtheria.

For the proper understanding of the case the
two types of bacterial action must be borne in
mind. The first, of which diphtheria is an
example, is that in which the results seen follow
the action of soluble poisons; which are de-
veloped during the growth of the bacteria;
which pass away from the site in which the
development of the bacteria may be going on;
and which produce their results at a distance
from that site. Diphtheria and tetanus are both
examples of this form of bacterial action; in both
of these diseases the bacteria producing them
grow mainly in one place in the body, and pro-
duce poisonous substances that act at a dis-
tance from this place. In the cases mentioned,
the poisonous substances also act upon special

41

THEORIES OF IMMUNITY.

groups of cells. Therefore it happens that the
toxic substances are brought into existence out-
side of the cells, or at any rate can be separated
from the bacterial cells with ease, and may go
on producing their results after the bacteria
themselves have disappeared. In cultures, also,
the filtrates are found to contain the poisonous
products, whose action can be studied in such
filtrates, whilst the residue, consisting of the
bodies of the bacteria, is found to have very
little or no poisonous action whatever. The
actual constitution of these poisonous products
is not known, in spite of all the work done upon
them, but they are examples of extra-cellular
toxines, and they have the common property of
being precipitated by agents that also precipitate
the intermediate products of ordinary digestion —
the albumoses, — a fact that is of interest, for it
is possible that these toxic bodies may not be
far removed in composition from those that under
normal conditions form the food of certain of
the tissue cells.

Bacteria which grow in this way more or less
locally and produce their effects most promi-

42

THEORIES OF IMMUNITY.

nently by means of " soluble " toxines are mem-
bers of the first group.

The second group of bacterial diseases, how-
ever, is a most important one, and in it there is
seen no such production of separate and soluble
toxines. In the bacteria concerned, the filtrates
of bouillon cultures have little — or absolutely no
— poisonous properties, and the effects in the
diseases produced by them are more or less di-
rectly connected with the bacterial cell itself.
These diseases are the result of the growth of
bacteria, which if they act by the production of
toxines at all do so by what are called " intra-
cellular toxines." These substances are inti-
mately connected with the bacterial protoplasm
and cannot be separated from it, or if they are,
only with very great difficulty. Pneumonia, the
septicemias, typhoid fever, cholera, plague, and
tuberculosis (as a chronic disease) are examples of
this form of bacterial action. The general char-
acteristics of all diseases of this type are fever as
a general manifestation, and of inflammation as a
sign of the local presence of the bacteria. In
the bacteria producing results of this general

43

THEORIES OF IMMUNITY.

character, bouillon cultures, filtered, show in the
filtrate very slight toxic power, and the bodies
of the bacteria left behind often give evidence
of containing much more powerful substances.

An illustration of the conditions resulting
from such properties is furnished by the many
curious facts developed in attempting to secure
protection against cholera and typhoid. In
both cases it is possible to immunize an animal
by the use of small and gradually increasing
doses of a virulent culture of the typhoid ba-
cillus, or cholera spirillum, but the serum of an
animal so immunized is found to have no power
of protecting another animal against injections
of the toxines, but only against injections of
the bacterium itself — representing, of course,
MetchnikofF's "anti-infectious" condition. The
same thing is true in regard to plague.

The two groups of diseases outlined above

should be carefully distinguished from each

other, for there is a marked difference in the

practical results that can be obtained in each —

in the degree (at present), in the method, and in

the explanations offered, in accordance with

u

THEORIES OF IMMUNITY.

Ehrlich's theories, of the reactions by which
they are obtained.

In the first group — those in which soluble
poisons are formed — the results are secured by
successful efforts to protect the tissues against
the soluble toxines, without reference to the
presence or absence of the bacilli themselves.
In the second the actual bacterial cells them-
selves must be considered as well as the toxic
substances that are very intimately connected
with them and only to be separated with diffi-
culty.

Ehrlich's theories were first elaborated to
explain the conditions seen in the protection of
the tissues against the antitoxine of diphtheria
(passive immunity) , and were based upon the fun-
damental supposition that the action of the anti-
toxine upon the toxinewas of a chemical nature;
and this opinion was supported, among other
facts, by the demonstration that the two can be
titrated against each other " like an acid and an
alkali, and that it takes place more readily with
concentrated solutions than with weak.'' The

45

THEORIES OF IMMUNITY.

experiments with porcelain filters coated with
gelatine were also brought forward to show
that the reaction is an actual chemical combina-
tion. In them it was found that at first, in mix-
tures of toxine and antitoxine, the latter would
not pass through, but the former would; later,
however, a neutral fluid would appear, which was
interpreted as showing that an actual chemical
combination had taken place.

Subsequent observations showed that a simple
chemical reaction was not .sufficient to explain
all the conditions. It was found that toxines
lost a considerable degree, if not all of their
power, if allowed to stand for some time, an ob-
servation that had been made by many observers ;
but Ehrlich also found that this weakened toxine
— to which he gave the name " toxoid " — re-
quired the same amount of antitoxine to neutral-
ize it as when fresh. In other words, the toxic
power of the toxine had diminished, whilst its
combining power remained the same. This being
true, the reaction could not be considered the
same as a simple chemical neutralization.

46

THEORIES OF IMMUNITY.

The explanation offered by Ehrlich of this loss
of toxic power with no loss of combining power
is this: he supposes that in the ultimate toxine
molecule there exist two chemical affinities (sets
of atom-groups), one of which has the power to
bind the molecule to a corresponding affinity in
the antitoxine molecule, and to which he gives
the name of 'haptophorous'1 affinity; but he
supposes that there also exists another set of
atom-groups, which exert the toxic power of the
toxine molecule when the haptophorous group
has bound the molecule to another, and this he
calls the " toxophorous " affinity or atom-group.
In the case of the loss of toxicity observed in
toxine that has been kept for some time, he sup-
poses that it is this toxophorous group that has
been altered, whilst the haptophorous group has
remained unchanged. This supposition, if cor-
rect, would account for the condition seen — the
loss of toxic property, and the retention of the
combining property in as high a degree as it
existed at first.

Applying this supposition to actual facts ob-
served, the action of the toxines in diphtheria

47

THEORIES OF IMMUNITY.

and tetanus may be explained in this way; the
evidence in favor of a chemical union between
the toxine and antitoxine already exists, and in
the same way there may be supposed to exist a
similar affinity between the toxine and the cells
of the tissues upon which it exerts its action. If
these affinities be satisfied — if the toxine is
bound to the tissue cell by the haptophorous
atom-group — the condition called susceptibility
appears, and the specific results of the toxic
action make their appearance; this of course
being the interference with -the normal metabol-
ism of the cell by having the cell molecule dis-
turbed and perhaps destroyed.

So, also, an explanation of the production of
the anti-toxine may be built up on this supposi-
tion. "It is impossible to conceive that the
affinities in the brain cell to which, for example,
the tetanus toxine becomes attached, are ordi-
narily of no use in the cellular metabolism. They
must bear a part in the latter, or else they would
be examples of absolutely useless mechanism in
the body. Now the process of immunization
consists in its initial stages in the administration

48

THEORIES OF IMMUNITY.

of small non-fatal closes of the pathogenic agent.
Looking at the action of the first of these, we
see that the cells must be robbed of affinities
needed in the ordinary metabolism, by the fact
of the attachment of toxine molecules to these
affinities or :<r side-chains." (Ritchie, I. c.) The
use of the term " side-chain " is unfortunate, for
in chemistry it can only be employed in relation
to molecules of which the exact composition is
known, and this is not the case with any of the
toxines; furthermore, it should be employed only
in connection with molecules in which the K ben-
zine ring " appears, and of course there is no
thought of its presence in these toxine molecules.

Xow, in accordance with general biological
law, that protoplasm tends to repair injuries if
not too great, — and furthermore, that this re-
pair, if it occurs, occurs in excess, — it may
be supposed that, when the interference with the
cell metabolism is not too great, the tendency
is to repair the loss of the haptophorous cell-
groups, — which if not replaced would result in
the death of the cell; that this replacing goes on
to excess, — and that when this occurs the ex-

49

THEORIES OF IMMUNITY.

cess of haptophorous groups are cast off from
the cell molecule, and exist free in the blood
stream as the antitoxine, ready to combine with
such molecules of toxine as may come in its way.
When such combination occurs, the haptopho-
rous group of the toxine is taken up by the
similar atom-group in the antitoxine. This being
so, of course the toxine cannot combine with
anything else; if it cannot so combine, its tox-
ophorous atom-group can exert no deleterious
influence, and no result is produced; in other
words, immunity exists.

Ehrlich has demonstrated the reactions illus-
trating his theory by the use of figures which
are familiar to most persons interested in this
subject, but they have been found to be confus-
ing to the beginner. Being figures, and having
something the appearance of cells with pseudo-
podia extending out from their periphery, it has
been shown by experience that many students
have difficulty in separating the idea of a vital
action from the reaction which they are intended
to illustrate. It has, therefore, seemed best to
adopt some other method for illustrating the

50

THEORIES OF IMMUNITY.

reaction just spoken of, and this has been found
as follows :

Let H represent the haptophorous atom-group,
T represent the toxophorous atom-group,
and X represent the remainder of the atom-
groups in the molecule.

Then the toxine molecule =H+T+X,
and the antitoxine molecule =H+X.

When two such molecules come together, the
haptophorus groups will combine by reason of
the affinity they have for each other, and the
result is the inability of the toxine to effect
further or different combination, so that its tox-
ophorous groups will be unable to exert any
hurtful influence : the combination would appear
thus : /H+T+X

\H+X

The production of the antitoxine may be
illustrated in very much the same way, except
that here the reaction lies between the toxine
molecules and those having the same haptopho-
rous groups in the tissue cells.

51

THEORIES OF IMMUNITY.

In this case, the toxine molecule is to be rep-
resented as before :

The toxine molecule =H+T+X,
The cell molecule =H-KN"+X,

in which the X may be supposed to represent
the atom-group concerned in nutrition, and X
other atom-groups not necessary in the expres-
sion of this reaction.

Then the H groups in the two molecules com-
bine (the combination appearing thus:

/H+T+X

\H+N+X)

and a double action may be supposed to take
place; on the one hand the T group will exert a
more or less irritant action on the cell molecule,
and on the other hand the H group of the tox-
ine molecule will take up the H. group in the cell
molecule. Xow, under ordinary conditions this
H group of the cell molecule is necessary for
the proper growth and metabolism of the cell, —
if it be taken up for something else, the cell
molecule will die or else its II group must be
replaced. This replacement occurs in the case
we are supposing, and takes place in excess;

THEORIES OF IMMUNITY.

the excess of atom-groups is thrown out from

the cell and exists free in the blood stream as

H+X, which is the antitoxine.

This is not only the simplest way for illus-
trating what goes on in passive immunity (the
use of diphtheria and tetanus antitoxine), but
this passive immunity and the production of the
antitoxine is the simplest form of immunity that
workers in the subject are called upon to ex-
plain. In giving the formulas thus far shown,
it is of course to be understood that only the
simplest forms are used, and that the X dis-
played must be supposed to contain all the other
atom-groups that are useful in other reactions,
but not in the particular one under discussion.

The believers in the physiological explana-
tion of the condition of immunity are not under
the necessity for supposing any such reaction
as that just illustrated; they believe that the
antitoxine excites the cells to resist the toxine,
and the evidence for this rests upon the series
of experiments (Buchner, Calmette with snake
venom, Wassermann) in which it was appar-

53

THEORIES OF IMMUNITY.

ently shown that a mixture of antitoxine and
toxine neutral to one species of animal was not
neutral to another; if this was so, there could have
been no chemical union between the two. These
experiments are discredited, however, by the sup-
porters of the chemical theory of union, on the
ground that the mixture was not exactly neutral
in the first place.

Apparently the strongest support of the
theory of chemical union are the experiments
of Martin and Cherry (Proc. Royal Soc. of
London — quoted by Ritchie, I.e.), mentioned
above, in which they tested the behavior of
mixtures of toxine and antitoxine when passed
through a porcelain filter whose pores had been
filled with gelatine. The non-appearance of the
toxine after a time they interpret as an indica-
tion that a complete chemical union had taken
place — although the opponents of the theory
of chemical action say that the results may be
equally dependent upon an actual degeneration
of the toxine due to the amount of time elaps-
ing, such as is constantly seen when toxine is
allowed to stand by itself.

54

THEORIES OF IMMUNITY.

Another point in favor of the chemical nature
of the reaction is brought forward by Ehrlich in
the case of the action of the red corpuscles and
the alkaloid (?) ricine. By injections of the latter
he was able to secure a resistance to it by the
red corpuscles of the animal injected, an anti-
ricine is formed, apparently of the same nature as
the antitoxine in diphtheria, and this serves to
protect the red corpuscles against a further
action of the ricine. j^ow, he says, if the union
is not of the nature of a chemical reaction, a
new physiological function must be ascribed to
the red-blood corpuscles, which are not usually
looked upon as anything but acting as carriers
of oxygen. This supposition, however, goes on
the ground that there never will be any new
function ascribed to them, which is of course
inadmissible.

A great deal of experimental work has been
brought forward in support of Ehrlich's theory
of a purely chemical relationship between the
substances active in the various reactions, and
much also that has been interpreted as support-

55

THEORIES OF IMMUNITY.

ing his views, but that is certainly open to other
constructions.

The most important seems to be that of
Madsen upon tetanus. His experiments were
carried on in the test-tube, avowedly to avoid
any chance of physiological action, and were
of extreme interest and importance. He found
that in certain cultures of the tetanus bacillus
he was able to demonstrate a substance which
he called " tetano-lysin," and which was capable
of destroying the red-blood corpuscles, and that
this might exist side by side with the ordinary
w tetano-spasmin." He further showed, by special
methods, that an anti-tetano-spasmin could be
produced which would act in a manner precisely
similar to that of diphtheria antitoxine.

A most important matter for the support of
Ehrlich's theory is the determination of the
place where the antitoxine is formed, for if it
be supposed that the antitoxine is produced by
a specific chemical reaction in the cells, it must
also be supposed that this reaction takes place
in certain tissue cells and no others. It must
be formed in at least some of the fixed cells,

56

THEORIES OF IMMUNITY.

otherwise the experiments of Hey mans (quoted
by Ehrlieh himself) would upset the theory
entirely. In these he injected a minimal lethal
dose of tetanus toxine and immediately removed
all the blood of the animal, at the same time
replacing it by the blood of a fresh animal, yet
death occurred from tetanus just the same.
These experiments as well as many others show
that the toxine must act within the fixed cells as
well as in the free cells of the blood or body
fluids, but just where this reaction takes place
has not been definitely proven. The suggestion
that the antitoxine may be the result of the
splitting up of the toxine molecule, while con-
ceivable, is negatived by the facts thus far
observed that seem to show that the toxine
molecule is smaller than that of the antitoxine.

Antitoxine is formed in the body somewhere,
there can be no doubt of that in the minds of
any one who has ever had to do with the im-
munizing of horses with diphtheria toxine. In
these animals, after bleeding and the removal of
a considerable proportion of the antitoxine pres-
ent, there is a return of antitoxic strength in the

57

THEORIES OF IMMUNITY.

blood after a short time, even if no more toxine
be injected to induce its return. This has also
been shown by Roux and Yaillard in the case of
a rabbit immunized against tetanus, in which
practically the whole of the blood was removed
during a series of days, with no sensible lessen-
ing of the antitoxic power; whilst a similar
thing was demonstrated by Salomonson in goats
immunized against diphtheria. (Ann. de l'Inst.
Past., 1893, VIL, p. 65; and Ibid., 1898, XII.,
p. 763.)

All of these instances would seem to indicate
that the production of antitoxine is in the nature
of a hypertrophy of function, and how great this
may be is illustrated in not an extreme degree
by Ritchie (I. c, p. 236), in which he demon-
strates that an antitoxic serum may be produced
one hundred times stronger than the toxine
originally introduced; i.e., if tetanus toxine be
acted upon by hydrochloric acid until its tox-
icity be destroyed, it still retains the capacity of
giving rise to immunity. By acting for the
same time on different portions of the toxine
there is no doubt that on each occasion the

58

THEORIES OF IMMUNITY.

state of the modified toxine would be the same.
Guinea-pigs were immunized by this modified
toxine, and instead of gradually increasing
doses, the amount used was always kept the
same. One set of animals received four doses
of the modified toxine, and another set eight
such doses. Of the serum of the first series of
animals 0.5 gram was required to protect against
a minimal lethal dose of the toxine — whilst of
the serum of the second series .005 gram was
sufficient to exert the same amount of protection.
In other words, twice the amount of toxine
gave rise to a serum of one hundred times the
strength.

Of course many objections have been raised
against Ehrlich's theory, and after all is said
there are many points that are still obscure.
These objections are nowheres brought together
as in the papers by Ritchie (I. c), and the first
is this : How is it that after an animal has been
brought to a very high degree of immunity,
consisting according to Ehrlich's theory in the
presence of a large number of antitoxine units
in the blood, free and ready for combination,

59

THEORIES OF IMMUNITY.

that the toxine is not neutralized by these free
antitoxine units before it gets a chance to reach
the cells where its function will be to excite the
production of more antitoxine units? Even after
it gets to the cells, why is it not taken out of
them by the stronger affinities of the haptopho-
rous groups existing in the blood-stream, as is
known to be the case in ordinary diphtheria
immunity ? As a matter of fact the toxine is not
destroyed in this way, and upon injection it
does go on increasing the activity of the cells
in throwing off fresh haptophorous atom-groups,
and this is a difficulty that is not easy to explain
away. This objection does not arise from the
physiological point of view, for the first irritation
of the cells is a continuous one and does not
require the supposition of the existence of free
antitoxine molecules in the blood stream.

The only possible explanation in accordance
with Ehrlich's theory is that the affinities in the
tissue cell are a little stronger for the toxine
than are the affinities in the antitoxine; so that
when the combination of toxine and antitoxine
reaches the tissue cell, as it must in circulating

60

THEORIES OF IMMUNITY.

through the blood, the II group of the tissue
cells overcomes the attraction of the H group
in the antitoxine, and binds the toxine to itself,
so that the irritant action of the toxine may
occur. This, however, is no explanation, for it
supposes exactly the opposite of what was sup-
posed in the previous clause: in the present
instance, that the H groups of the tissue cells
have a stronger affinity for the H groups in the
toxine than have the H groups of the antitoxine,
while in the preceding paragraph the opposite
supposition is made to explain what is seen in
diphtheria immunity.

Another very perplexing question is brought
forward in the same place : What is it that pro-
duces the safety of the animal in the very early
days of the process of immunity against a toxine?
Active immunity? In experiments quoted by
Ritchie (I. c), and upon tetanus toxine, it was
shown that 0.5 gram of antitoxic serum was
sufficient to neutralize one minimal lethal dose
of the tetanus toxine; as a matter of fact, the
animals resisted in the series spoken of an
average of one hundred and ten minimal lethal

61

THEORIES OF IMMUNITY.

doses (if the same proportion of serum contain-
ing antitoxine were required as just stated this
would need fifty-five cubic centimeters of serum,
and an average guinea-pig does not hold so
much blood); but where is it possible for the
extra antitoxine units to come from? The con-
clusion is forced upon us that resistance to a
toxine is not necessarily related to the possession
of antitoxic power in the serum, but if we are
forced to this conclusion, what becomes of the
whole theory? In the experiments spoken of
above (Ritchie, I. c), the animals could certainly
resist sixty-six minimal lethal doses without the
slightest symptoms of tetanus, and no part of
Ehrlich's theory is as yet capable of giving an
explanation of how the toxophorous groups of
this amount of toxine are prevented from acting.

Further, in the later stages of Active Immu-
nity — to secure a " strong antitoxine " — thou-
sands of minimal lethal doses are injected. In
accordance with Ehrlich's theory, the toxine
must combine with the tissue cell in order to
stimulate the cell to the production of fresh atom
groups (H groups, which shall exist in the

62

THEORIES OF IMMUNITY.

blood as antitoxine). If this process goes on,
the T groups may produce their effects, but why
do not the thousands of extra T groups produce
some result, when it is known that in the begin-
ning one minimal lethal dose will do so?

Many other objections and difficulties are
brought forward against the theory, which of
course cannot be expected to explain all the
phenomena in such obscure reactions as these of
which we are speaking, but perhaps the one that,
whether valid or not, requires more accurate
terminology in those speaking upon the subject,
is brought out by the use of the formulae above
displayed. The expression is constantly heard
that these atom-groups (receptors, side chains,
radicals) are produced in the cell in excess, and
thrown off to exist free in the blood as the anti-
toxine or other antibody, as the case may be.
If the chemical reaction can be expressed at all
by such a formula as employed above, what is
thrown off is a radical — an incomplete sub-
stance — and cannot exist free in the blood as
would be supposed from the expressions used
in regard to it. It is therefore necessary to

63

THEORIES OF IMMUNITY.

suppose that the radical combines at once with
something else — which I have represented by
X — so that the unfortunate conclusion may not
be forced upon us, that a skilled chemist has put
forth the supposition of the existence of some-
thing in violation of the laws of all known
chemistry.

In considering difficulties like these one is re-
minded of the remark of Metchnikoff, — spoken
of earlier, — that he does not seek to penetrate
the laws governing intra-cellular digestion, which
has to do with processes as yet absolutely un-
familiar to us.

A way out of the difficulties presented has
been found by the suggestion that there is an
essential difference between the two forms of
immunity — active and passive; that the first
(active) has to do with the cell, and should be
called Isopathic, and that the second has to do
with the fluids (principally the blood) and is the
ordinary antitoxic immunity.

It was said in beginning to speak of the sub-
ject of Immunity in the case of those diseases in
which the results are due to the production of

64

THEORIES OF IMMUNITY.

soluble toxines, that it was the simplest part of
the problem. It will, however, by this time
appear that the term "simple" is of relative
significance only.

The second group of diseases produced by
bacteria attracted attention very soon after the
facts in regard to the production of passive im-
munity in diphtheria and tetanus were known.

It was at first supposed that similar antitox-
ines could be secured in these diseases also, —
such as typhoid fever, cholera, and plague, — but
it was quickly demonstrated that this was not the
case, except to the very slightest extent. In
these diseases, and others in which the bacteria
do not produce soluble poisons, the actual pres-
ence of the bacteria is necessary for the results
to appear, and it soon became evident that the
production of immunity in such processes must
be dependent to a great degree upon the de-
struction of the bacteria themselves rather than
to a neutralization of any poisons that they
might elaborate.

65

THEORIES OF IMMUNITY.

Both active and passive immunity can be
secured in such diseases, but the latter only to a
very slight degree.

The active immunity secured is obtained by
the injection of non-fatal or attenuated cultures
of the bacteria — or by the use of virulent cul-
tures that have been killed by heat (as in the
procedure of Wright and Semple against t}7phoid
fever).

The passive immunity is of the slightest de-
gree, and the curious fact is developed that
in both typhoid and cholera the serum of
animals treated with dead cultures of the bacteria
of these diseases is bacteriolytic to the living and
virulent bacilli, but not antitoxic to the toxine.

Bordet's publication of his results in the study
of hemolysis, and the light they threw upon
Pfeiffer's phenomenon, were the first steps tow-
ards the explanation of the phenomena seen in
the second group of bacterial infectious processes.
Pfeiffer's phenomenon is one of a purely bac-
teriolytic nature (of course bactericidal also,
although a bactericidal serum need not be bac-
teriolytic), and one of the ways in which it can

GG

THEORIES OF IMMUNITY.

be secured is by adding the serum of an animal
immunized to the cholera vibrio, and that has also
been subjected to a temperature of 55° Centi-
grade for half an hour, to a culture of active and
virulent cholera vibrios, and injecting the mix-
ture into the peritoneal cavity of a fresh animal.
The bacteria are soon seen to become gathered
together, granular, and gradually to disappear.
The action is specific and limited to animals
immunized to the disease produced by the bac-
terium employed — in the case cited, of course,
the cholera vibrio. It was at first supposed that
a similar reaction could be demonstrated for
other bacteria, and that such a reaction could be
utilized for differentiating species and races of
bacteria from each other.

The significance of this reaction was not under-
stood until the publication of Bordet's results in
hemolysis above referred to. In these he found
that upon injecting the blood corpuscles of one
species of animal into the blood stream of an-
other, there resulted in this blood stream the
appearance of a substance that was able to de-
stroy the blood corpuscles of the first species of

67

THEORIES OF IMMUNITY.

animal — a hemolytic or globulicidal property
was developed. A specific example is that of
using the blood corpuscles of a rabbit for injec-
tion into a goat; in a short time there appears in
the goat's blood an antibody to the rabbit's corpus-
cles, which will destroy those corpuscles whenever
it is brought in contact with them. This hemo-
lytic property, it was also found, would disappear
upon heating the serum containing it for one-
half an hour to fifty-five degrees Centigrade.
The very remarkable fact was, however, brought
out that it would reappear upon the addition to
the heated serum of a little fresh serum, although
this fresh serum itself possessed no hemolytic
property.

These are similar to the occurrences going on
in Pfeiffer's phenomenon (of bacteriolysis), and
with others formed the basis of an extension of
Ehrlich's theory to explain what is seen to occur
in immunity against infection.

In explanation of the facts seen in hemolysis,
Bordet, and Ehrlich as well, suppose that there
must be two bodies present to permit the com-
pletion of the reaction. One of these exists in

68

THEORIES OF IMMUNITY.

normal serum, and may be destroyed by heating
to 55° C. for half an hour; its presence is
demonstrated by such an occurrence as that
above mentioned, in which the hemolytic power
returns after the addition of a little fresh serum,
not of itself possessing the lytic property. This
substance (in the fresh serum) is called " com-
plement " by Ehrlich (also " addiment "), and is
the alexine of Bordet, Metchnikoif, and other
writers; it is probably also the same as the
" alexine " of Buchner, although there seem to be
some minor differences in the thought in regard
to their identity.

The second substance exists in the serum of
an animal subjected to the process of immun-
ization, and can be destroyed by being subjected
to heat at 75° C, for one-half hour. To this
substance Ehrlich has given the name " immune
body." It corresponds as nearly as may be
to the " substance sensibilisatrice " of French
writers and supporters of the cellular theory of
immunity.

In order to develop his theory of chemical
action in explanation of the condition of immu-

G9

THEORIES OF IMMUNITY.

nity in this group of diseases, Ehrlich supposed
that in this immune body there exist two hapto-
phorous atom-groups of affinities — not one as
before — and that one of them was concerned
in satisfying a similar haptophorous atom-group
(receptor) in the blood corpuscle (of the same
nature as the receptor in the tissue cells in anti-
toxine immunity) ; and the second haptophorous
atom-group of affinities (receptor) is satisfied by
a similar group in the complement, which, as has
been seen, exists in the serum (blood stream?)
of fresh animals.

In the complement there is supposed to exist
a group of affinities analogous to the toxophor-
ous group of the toxines — except that now it is
supposed to exist normally in the blood stream
(or cells of the body, according to Metchnikoff ),
and this atom-group acts as the hemolytic or
bacteriolytic, or, in general, the cytolytic sub-
stance.

The experimental evidence upon which this
theory rests is as follows: If a goat be treated
with repeated doses of sheep's blood, there devel-
ops in its serum the capacity of dissolving

70

THEORIES OF IMMUNITY.

sheep's red-blood corpuscles. (It may be said that
a great number of similar hemolytic sera can be
obtained by treating one species of animal with
the blood of another species.) Ehrlich took four
cubic centimeters of five per cent defibrinated
sheep's blood in .75 per cent salt solution,
added one cubic centimeter of immune goat's
serum which had been heated half an hour to
55° C. (and which thus contained only immune
body), and placed the mixture for fifteen minutes
at 40° C. The question of where the immune
body was, he now investigated in the following
way: the mixture was centrifngalized until all
the corpuscles were deposited at the bottom of
the tube; the supernatant clear fluid was de-
canted, and there was added to it .2 cubic cen-
timeter of ordinary sheep's blood (containing,
therefore, susceptible red-blood corpuscles) and
.8 cubic centimeter of " fresh " goat's serum
(containing, therefore, goat's complement) ;
the mixture was placed at 37° C. for two hours
without any trace of hemolysis occurring. Now,
if the immune body had been left in the fluid
after centrifugalizing, the complement from the
fresh goat's serum ought by it to have been

71

THEORIES OF IMMUNITY.

linked to the sheep's corpuscles, and hemolysis
of the latter ought to have occurred. The im-
mune body therefore was not here. The sheep's
corpuscles of the original mixture were, of
course, in the deposit separated by the centrif-
ugalization. This was now taken, stirred up
with four cubic centimeters of .75 per cent salt
solution and there was added .8 c. c. of fresh
goat's serum (containing of course complement).
The mixture was placed at 37° C. for two
hours, and at the end of this time there was
found to have occurred hemolysis of the cor-
puscles. During the fifteen minutes that the
original mixture was kept at 40°, therefore, the
immune body in the immune goat's serum had
united itself to the sheep's red corpuscles, as was
evidenced by the fact that when the latter were
exposed to fresh complement, hemolysis occurred.
As remarked above, complement cannot cause
hemolysis by itself. The method of the experi-
ment is that three factors are necessary to the
occurrence of a given hemolysis: the red-blood
cells to be acted on; a body resistant to heat,
occurring in the serum of the immune animal
(immune body) ; and a body susceptible to

THEORIES OF IMMUNITY.

heat, occurring in the serum of an unimmunized
animal (complement). When the presence of
any one of these substances is suspected, it can
be traced by adding the other two, and observ-
ing whether hemolysis takes place. In the in-
vestigation, sheep's blood was taken next, fresh
goat's serum was added, the mixture centrifugal-
ized, and the fluid on the one hand and the de-
posit on the other investigated for complement.
JSTone was found in the deposit, but it was found
in the clear fluid, so that no combination had
taken place between it and the blood corpuscles.
Next it was found that there was a greater affin-
ity between the immune body and the blood
corpuscles than there was between it and the
complement. The proof was as follows: It
was observed that in a mixture of five cubic
centimeters of five per cent sheep's blood, one to
one and one-third cubic centimeters of heated
immune goat's serum, and one-half cubic centi-
meter of fresh goat's serum, there was just
enough of all the constituents to satisfy all the
affinities and leave none over. If all these sub-
stances were mixed at 0° C, and the mixture
centrifugalized as before, it was found that the

73

THEORIES OF IMMUNITY.

complement present was still free in the super-
natant fluid. Therefore the affinity of the im-
mune body for the corpuscles was greater than
its affinity for the complement. This last ex-
periment also shows that at 0° C. the immune
body and the complement must have existed
free, side by side. (Ritchie, I. c, p. 245.)

The reactions that are supposed to take place
may be expressed by the following formulae:
Hemolysis requires for its appearance

1. The blood cell.

2. The immune body (in the serum of
the immune animal).

3. The complement (in the serum of the
fresh animal).

These may be represented as follows :

1. The blood cell molecule=H+]N"+X

2. The immune body " =H+i7+X

3. Complement " =i7+L+X

The H group of the complement binds the
molecule to the immune body by one of its H
groups, and the second H group in the immune

74

THEORIES OF IMMUNITY.

body binds the two to the blood cells — thus al-
lowing the L atom group of the complement to
exert its destructive (lytic) action.

For the production of the hemolytic property
(blood immunity it may be called), there are
required :

1. The blood cells that are injected.

2. The body cells in the animal into which
the above are injected.

3. Complement (present in fresh serum.)
The molecules of each of these and their re-
action upon each other may be shown thus :

1. The blood cell molecule=H+N+X

2. The body cell " ^H-f-^T+N+X

3. Complement, =//+L+X

As in the preceding case, the H group of the
complement is bound to the body cell by the cor-
responding H group, the blood cell by another.
The H groups of the body cell are needed for its
ordinary metabolism, but are taken up in this
way ; if the cell is to live they must be repro-
duced ; as the cell does live they are reproduced,
and as is usual, this reproduction goes on to ex-

75

THEORIES OF IMMUNITY.

cess; then the H groups not needed are thrown
off into the blood stream and exist as

H+iJ+X, or the immune body.

The reactions in hemolysis having been made
more clear by the investigations of Ehrlich
spoken of above, it became evident that the
reaction in bacteriolysis (of which Pfeiffers
phenomenon was the first example) could be ex-
plained in the same way — and it can also be
shown by a formula similar to that used in the
demonstration of hemolysis, as follows:

The bacteriolytic reaction requires for its
completion

1. The bacterial cell, molecule=H+T+X

2. The immune body, " =H.+H+X

3. The complement, " =iJ+L+X

Then, as before, the complement and the im-
mune body are bound together by one set of
haptophorous atom groups ; these two are bound
to the bacterial cell by another similar set of
atom groups, and when this has occurred, the
lysin atom group (L) can set up its action and
the bacterial cell may be destroyed.

76

THEORIES OF IMMUNITY.

So, also, the production of this bacteriolytic
property may be represented as follows :
Its production requires

1. The bacterial cell (which is

injected) . . . molecule^HH-T+X

2. The tissue cells (from which

the immune body is pro-
duced) . . . molecule=H+.HH-iN'+X

3. The complement (present in

fresh blood) . . molecule=i/-t-LH-X

In this reaction the H groups of the body cell
molecule are satisfied by the combination with
the similar sets of atom groups in the bacterial
cell and in the complement ; they are, however,
required for the ordinary metabolism of the body
cell molecule ; they must, therefore, be repro-
duced or the body cell molecule will die ; being
reproduced, they are in excess of the require-
ments of the cell — are thrown off and exist in
the blood stream as " immune body," ready to
combine with fresh bacterial cells as they are in-
troduced, i.e., as

H+i7+X.

77

THEORIES OF IMMUNITY.

The facts in hemolysis and bacteriolysis have
led to the investigation of the action of other
kinds of cells when introduced into fresh ani-
mals. A very large number of different kinds
of action of this nature have been studied, and
it is demonstrated that it is possible to secure
sera of many sorts which have a specific action
upon the cells originally used for the production
of the cytolytic power. Thus, for example, the
study of the results following the injection of
living spermatozoa has been the demonstration
of the production, in the serum of the animal in
which they are injected, of ii property that has
the power of immobilizing fresh spermatozoa, if
not of absolutely dissolving them ; the same
thing holds true of other cells. Liver cells in-
jected in the same way will produce a serum
capable of inducing fatty degeneration of the
liver cells of a fresh animal. Of course the pos-
sible results that may come from such cytolytic
action as this are of the most important nature.

The reactions are explained by Ehrlich in the
same way as the phenomena of hemolysis and

78

THEORIES OF IMMUNITY.

bacteriolysis, and they may be illustrated by
formulae similar to those already explained.

Thus — cytolysis requires

1. The cell to be acted upon, molecule=H-hX-|-X

2. The immune body (produced by

the previous injection of the

above) moleeule=H-r-i?-fX

3. The complement . . " =H+Ij+X

And when the H groups have produced the
necessary combinations, the L atom group of
the complement may exert its lytic action.

The production of the cytolytic property may,
of course, also be illustrated in the same way as
follows :

Its production requires

1. The foreign cell to be in-

jected .... molecule=H+]^+X

2. The tissue cells in which the

injection is made, molecule=H+i/-f\X+X

3. The complement . molecule=^T+LH-X.

The same combinations are supposed to occur
in this as in preceding cases : the H atom-groups
combine together, so that those needed for proper

79

THEORIES OF IMMUNITY.

metabolism of the tissue cells in which the injec-
tion is made are used for another purpose —
these are reproduced in excess, and cast off into
the blood stream, where they exist as substances
capable of aiding in the cytolytic action.

Both sides, that which supports the "humoral"
and that supporting the " cellular " theory, agree
in supposing that two bodies are necessary for
the production of these reactions, but there
are two special points of dispute — first as to
whether the complement exists in the cells or out
of them; and second, whether it is single and
specific for the race of animals in which it occurs,
or whether it is multiple and specific only for
the reaction in which it appears active.

There is no dispute as to the complexity or
rather multiplicity of the immune bodies, which
are generally acknowledged to be very numerous
and capable of action only in special directions
— on the particular bacteria or tissue cells, as the
case may be.

As to the multiplicity of complement, it has
been shown that it is possible to reactivate a
serum by the addition of a little fresh serum

80

THEORIES OF IMMUNITY.

from an animal of a different species. Such a
fact tends to show that complement is the same
in all species of animals, although there are other
experiments that indicate that this conclusion
may not be absolutely warranted.

Still another fact that is of importance is the
conclusion warranted by the evidence that com-
plement and immune body are not produced in
the same quantity, which would be expected
from the circumstances of the case. An illus-
tration is furnished by the possibility of demon-
strating that a given quantity of a cytolytic serum
may destroy a given quantity of cells. . If, how-
ever, fresh serum be added, the same quantity of
the cytolytic serum will be found capable of
dissolving; manv times the number of cells it
could act upon in the first place.

The main point of controversy is upon the
multiplicity of complement, but not enough evi-
dence is yet before us to enable us to form a
definite opinion upon the matter. MetchnikofF
takes very strong ground in the matter, and de-
clares that the complement exists only in the
cells of the body, from whence it passes into the

81

THEORIES OF IMMUNITY.

blood stream only after some destructive action
on the cells, and furthermore that it may take
part in the completion of the immunity occurring
in many infectious processes as well as in many
cell reactions. On the other hand, Ehrlich
argues forcibly for the multiplicity of comple-
ment, claiming that this substance is multiple
and specific for each reaction, as is the case with
immune body.

Walker (Journal of Hygiene, 1902, Vol. II.,
p. 85) furnishes the specific evidence of the
identical nature of complement coming from dif-
ferent animals as follows: .he found that the
anti-typhoid serum from a horse that has been
inactivated by the application of heat — thus de-
stroying its complement — may be reactivated
by the addition of serum from the rabbit, ox, and
the pig (thus adding fresh complement). This
may be represented graphically as follows :

Anti-typhoid serum contains

Complement, molecule =H+L+X
Immune body, molecule=H+iZ4-X

Other constituents, molecule=P(roteids)+S

(alts)+X.

82

THEORIES OF IMMUNITY.

If this be heated to 55° C, for one-half hour,
the complement is destroyed, and the comple-
ment molecule (H+L+X) no longer exists.
The serum therefore is incapable of exercising
its bacteriolytic property. If now the fresh
serum of an ox, rabbit, or pig (containing of
course fresh complement (H+L+X)) be added,
the same constituents as at first would exist in
the anti-typhoid serum, and the bacteriolytic
power would be restored.

The various facts brought forward show that
one of the difficulties that may arise in the treat-
ment of diseases of the second order (like ty-
phoid fever, cholera, and plague) is in the fact
that much more immune body may be formed
than there is complement to help make active,
and it is possible that this may be the explana-
tion of the poor results obtained with antitoxic
sera in the diseases just spoken of. Just how
this difficulty is to be met has not been shown,
but it is true that the apparently simple thing
to do, the addition of fresh sera (containing more
complement) does not fulfil the requirements,
at least so far as experiments have yet gone.

83

THEORIES OF IMMUNITY.

The following summary of this part of the
subject is exceedingly good (Ritchie, I. c, p.
261) : It is to be observed that the methods by
which bacteria are dealt with in the body are
similar to those which obtain when many kinds
of foreign cells gain an entrance into the latter.
The development of artificial immunity against
such bacteria depends on the latter being intro-
duced either in a form not strong enough to
cause death, or, if virulent, not in sufficient
numbers to cause death. In either case, the
affected animal probably resists infection be-
cause it can develop in its body, or already
possesses a substance — immune body — which
attaches itself to the bacterial protoplasm, and in
virtue of this attachment permits another body,
the complement, which exists normally in the
animal's body, to act on the bacteria, with a
fatal result to the latter. In the case of a further
infection with bacteria, such as might occur
naturally, or as occurs during the process of
immunization, then no illness may result, but a
fresh formation of immune body may occur.
Whether a fresh formation of complement may
occur to any extent is a question for further

84

THEORIES OF IMMUNITY.

investigation, but in an immune serum the com-
plement is always present to a less degree than
the immune body. What the nature of these
bodies is is unknown, but the complements are
less resistant to heat than the immune bodies.
Further, the nature of the reaction which takes
place between bacteria, immune body, and com-
plement is disputed, and lastly, while the multi-
plicity of immune body is undoubted it is still
open to question whether there is a great number
of complements in each animal's body, or whether
there is, for each species at least, only one com-
plement which is capable of acting in conjunc-
tion with a great variety of immune bodies, so as
to produce a solvent effect on many different
kinds of bacteria.

One of the greatest difficulties standing in the
way of the supporters of Ehrlich's theories is
the existence of the bactericidal property in the
blood serum of animals that have not been
treated in any way, and at the same time are
susceptible to the action of the bacterium that
their blood serum will destroy. The well-known
fact that the blood serum of the rabbit has a

85

THEORIES OF IMMUNITY.

marked bactericidal action upon the anthrax
bacillus, whilst the animal itself succumbs very
promptly to an infection by these bacilli, is an
illustration in point, and is not by any means the
only one that can be brought forward.

Whether or not this bacteriolytic action is the
same as that seen after the condition of immu-
nity has been produced has not been shown; if
it is the same, its production must be accounted
for, and the reactions may be explained in the
same way as has been adopted for the illustra-
tion of the other parts of Ehrlich's theory; if,
however, it is not the same, and its presence
seems to show that a bactericidal property of
the serum does not of necessity indicate a con-
dition of immunity, then the explanation of its
appearance and the method by which it acts has
not yet been furnished.

Somewhat the same position must be taken in
regard to the phenomenon of agglutination.
The relation of this phenomenon to immunity
does not appear to be any more intimate than
that of the possession of a bacteriolytic property
on the part of the blood serum. Agglutination,

86

THEORIES OF IMMUNITY.

moreover, seems to be even less connected with
any action of a " specific " nature than the
bactericidal property spoken of just now. In
this connection it may be of interest to repeat
some conclusions reached in an investigation
upon this matter some time ago: 1, That the
agglutinating property does not lie in and is
in no way connected with the flagella of the bac-
teria concerned. 2, That agglutination is not
to be accepted as a specific property connected
with a condition of immunity, although this is a
difficult idea to give up. 3, That the homolo-
gous nature of agglutination cannot be con-
sidered a positive characteristic, for how then
explain the clumping of typhoid bacilli by diph-
theria antitoxine? 4, Finally that no universally
applicable theory of agglutination has yet been
offered. That of Bordet (Ann. de lTnst. Past., T.
XIII. , p. 224, 1889) seems to us the most rational
yet suggested — that there is an agglutinating
agent ("agglutinine ") acting upon an agglutina-
ble substance (" substance agglutinee," the nature
of which is not yet determined), and that this
reaction occurs not only with bacteria, but with
many other elements — globules, casein, and

87

THEORIES OF IMMUNITY.

precipitates of various kinds. (Ernst and Robey.
Trans. Triennial Congress of Physicians and
Surgeons, Vol. V., p. 28, 1900.)

If one favors the idea that phagocytosis is the
active factor in disposing of bacteria in the oc-
currence of immunity from infection, the phe-
nomenon of chemiotaxis must be accounted for,
both positive and negative. Metchnikotf does
this by the supposition that there exist sub-
stances in the immune serum which stimulate the
chemiotactic power of the phagocytes toward
the invading bacteria. These " stimulines " are
supposed by Metchnikotf to" exist along with the
" cytases," or else to be these bodies themselves,
possessing the stimulating property along with
the others that have been ascribed to them.

Xot enough attention has been paid to the
condition of phagocytosis in the phagocyte pro-
ducing tissues, after the acute stage has passed
away, and on this point there is much to be
said. Recently the condition of these tissues
has been studied by Roger (Les Maladies Tnfec-
tieuses, Paris, 1902, p. 680 et seq.), and Muir
(Journal of Pathology, Vol. VII., p. 161, quoted

88

THEORIES OF IMMUNITY.

and summarized by Ritchie, I. c, p. 283 et seq.).
"The fact has long been known that in many in-
fectious conditions the number of leucocytes in
the circulating blood is increased, but these
observers were the ones to demonstrate the
pronounced genninative activity which occurs in
any infection, in the precursors of these cells.
With regard to the leucocytic phagocytosis,
Muir has shown both experimentally on animals
and by observations on man, that in infections
where there is a polymorphonuclear leucocytosis,
not only is there evidence of an active division of
the parent cell in the bone marrow, but so active
is this process that the red marrow increases in
amount and encroaches on the yellow. In a
case of pneumonia, for instance, a few days after
the commencement of the disease the red mar-
row may have increased so as to occupy a
seventh part of the whole medullary cavity of
the femur. Not only, however, does prolifera-
tion occur in the site of formation of such an
important class of cells as the polymorphonu-
clear leucocytes, but Muir has also shown that
proliferation occurs during some infections in
such fixed cells as those lining the sinuses of

89

THEORIES OE IMMUNITY.

lymphatic glands and also in the hyaline cells
lying free in the lymph sinuses, which later may
be connected with some at least of the large
mononucleate hyaline cells of the blood. He
further points out that similar hyaline cells — en-
dothelial cells, connective cells — proliferate dur-
ing infection, as can be shown by mitotic figures
beinix found. It is no doubt the case that in
different infections different groups of cells thus
proliferate : in typhoid fever, for instance, there
is no polymorphonuclear reaction, but here the
proliferation of endothelial cells and hyaline
cells in lymphatic glands -has been observed.
Thus while Metchnikoff has insisted with justice
on the importance of the local reaction and of
the wandering cells of the body in infections,
and has noted the occurrence of phagocytosis
in other cells (his fixed ameboid cells), he has
missed the fact of the great proliferative changes
in various parts of the body which may be de-
scribed as the reaction of the body generally
against infection. It must be insisted upon that
there are not only local chemiotactic effects, but
in the case of the wandering cells there is the
sreneral chemiotactic effect which draws the

90

THEORIES OF IMMUNITY.

polymorphonuclear leucocytes from the marrow,
and in all cases of severe infection there is the
further stimulative effect which leads cells in
various parts to divide. Either this stimulation
is part of a reparative process, or it is to be
looked on as the result of injury due, say, to cir-
culating poisons. The fact that in relation to
one aspect of the process, namely, the poly mo r-
phonucleate reaction, the effect is often to in-
crease at a given point the available number of
cells capable of playing the part of phagocytes
leads one to think that all these tissue changes
may be of the nature of an exaggeration of nor-
mal functions, the general effect of which ex-
aggeration is to have a beneficial effect. It is to

So

be noted as a very important point in this pro-
cess that most of the distant effects must be due,
even in the case of bacteria which in vitro do
not produce soluble poisons, to the circulation of
soluble toxines, unless — which is possible — we
consider bacteria capable of exerting purely
physical influences. Connected with these is
the other very important fact that embryonic
activity may be dissociated from any actual
phagocytosis on the part of the proliferating

91

THEORIES OF IMMUNITY.

cells, and this taken along with such facts as
the proliferation in certain infections of the non-
phagocytic eosinophilic leucocytes raises anew
the question of the possible secretion of chemical
substances into the serum which may be con-
cerned in the complicated process by which bac-
teria are destroyed in the animal body. It may
also be noted here that Muir has observed an
increase in the size and distinctness of the gran-
ules in the young polymorphs which occur in the
marrow during a severe infection. This might
indicate the preparation of material to be secreted.
So that from what has just been said it is thus
possible that on the fixed cells of the body and
the fixed precursors of the wandering cells are
impressed qualities which perpetuate immunity
in an animal which has survived an infection."
(Ritchie, I. c, p. 283.)

Such a conclusion as that just drawn is at
least in part in direct accord with Metchnikoff's
assertion that there is an inheritance of a ten-
dency towards phagocytosis by the descendants
of cells upon which the property has been
impressed.

92

THEORIES OF IMMUNITY.

In concluding his review, Ritchie brings for-
ward (p. 452, et seq.) the further considerations
that follow, and says in regard to them, in
substance, that in the first place it is difficult
to see how, granted that two substances are
necessary for the production of immunity (the
immune body and the complement), these sub-
stances are to meet the bacterial cell in the first
instance except in the body cell. Unless all
immune bodies are existent in the serum as w go-
betweens" (amboceptors) — substances of an
identical nature except that they are utilized for
the normal metabolism of the cell until needed
for the reactions occurring in immunity — how
can the bacterium when it first enters the body
come in contact with the immune body for which
it has an affinity? The receptor is in the cell
(as represented in the formula used to illustrate
the reaction) and the bacterial cell receptor must
also get into the tissue cell — except it be sup-
posed that they exist under normal conditions
in the blood stream. It is undoubtedly possible
that the immune body may exist in the blood
stream as the result of normal metabolism, but
this is the only supposition which would explain

93

THEORIES OF IMMUNITY.

how it gets there; if it does not so exist, then
the bacterium must be conceded to enter the
tissue cell at the first in order to start the exci-
tation resulting in the production of the immune
bodies; if this be the explanation, then Metch-
nikoff's contention that phagocytosis — at least
cellular action — takes place in the very first
instance must be adopted.

In the second place the query arises as to
why, if the bacteria must meet both complement
and immune body in the cell, why is the latter
produced so much in excess and not the former?
On the basis of the supposition that the comple-
ment exists normally, and that the immune
body is the result of an excess of cell activity
set in motion by the taking up of the hapto-
phorous atom-groups needed in the ordinary
metabolism by the bacterial atom-groups of the
same nature, this is easily understood, because
this new vital activity goes on in excess and may
be supposed to result in the production of a
great excess of the atom-groups representing the
immune body.

It is most probably the case that the reactions

94

THEORIES OF IMMUNITY.

occurring in the production of immunity are
closely related to those that go on under the
ordinary conditions of tissue metabolism, and the
only way in which this can be settled is by the
determination, in the first place, of what the nor-
mal functions of the cells are ; and in the
second, whether substances similar to the anti-
bodies exist under normal conditions in the body.

Inquiry in the first direction has as yet left
much obscurity to be cleared away, and the exact
functions of the leucocytes, or of the cells from
which they are derived, are not clearly understood.
As to the second point, so many investigations
have seemed to show the facts that it can hardly
be doubted that substances closely allied to if not
identical with both complement and immune body
do exist in the sera of normal animals — it is,
however, disputed as to whether they exist free
in the normal blood stream.

If they do so exist they must have some
normal function, for it is not to be supposed
that they exist for the sole purpose of taking
part in the specific reactions of immunity when
such necessity may arise. They must take some
part in normal tissue metabolism; and in attempt-

95

THEORIES OF IMMUNITY.

ing to determine what these functions were
Bordet first called attention to the occurrence of
the so-called " precipitines." (Ann. de V Inst.
Past., 1899, T. XIIL, p. 225.) He found that in
treating rabbits with chicken's blood, a hemolytic
serum could be obtained; but also, that when
this hemolytic rabbit's serum was added to
chicken's blood a precipitate made its appear-
ance.

Many such precipitates have been obtained
with many kinds of blood, and also with many
kinds of bacteria as well. Their nature is not
well understood, but the reactions seem to be
specific and most exact, and these reactions are
of great medico-legal value in the determination
of the presence of human blood in suspected
stains.

The general reaction may be shown by the
same formulas as were used for the purpose of
illustrating the forms of immunity as follows :

The production of the precipitate requires :

1. The blood globule, molecule^H+X+X

2. The immune body, " = H+iJ+X

3. The complement, " = ZT+P+X

9G

THEORIES OF IMMUNITY,

The complement and the immune body are
boimd to the blood corpuscle molecule, and the
P atom-group acts in such a way as to produce
the precipitate.

The production of the precipitine power re-
quires :

1. Blood serum, molecule^H-f-XH-X

2. The body cell, molecule=H+J7-HN"+X

3. The complement, molecule=iZ+P+X

The complement and the blood serum mole-
cule are bound to the tissue cell by the H atom-
groups; these latter in the tissue cell molecule
are reproduced in excess and are thrown off
after this reproduction occurs and exist free as
H+J3-hX=the immune body, ready for the pro-
duction of the precipitine reaction when the need
arises.

Any specific reaction — as that resulting from
the addition of rabbit's blood to the goat — may
be represented by the addition of the sub-letters
desired.

The belief that the affinities existing in the
body cells are very numerous is forced upon the

97

THEORIES OF IMMUNITY.

supporters of Ehrlich's explanation of the reac-
tions that occur, and this is especially emphasized
by the formulae presented in illustration. It is
to be supposed that these affinities are con-
cerned under normal circumstances in helping
on the normal food metabolism of the tissue
cells, and possibly other reactions. Ehrlich has
given the name of "haptine': to the whole
group, and that the number is great may be
seen by those already known — lysins, aggluti-
nines, precipitines, complements, ferments, anti-
complements, ferments, etc.

The production of an anti-complement, for ex-
ample, may be represented as follows : it may
be obtained by injecting serum containing com-
plement from one animal {e.g., a guinea-pig)
into another (e.g., rabbit) :

The injected serum, molecule^H+L+X
The receiving blood cell, molecule=H+(H+H

+H+H+H)+X+X

The two are bound together, the special H
group is reproduced in excess, is thrown off, and
exists as H-fX=the anti-complement.

98

THEORIES OF IMMUNITY.

The action of this anti-complement may be
very simply represented :

The anti-complement molecule=H+X
The complement molecule =II-hL+X

Bnt the two are bound together, and therefore
the L atom-group cannot be bound to anything
else, and therefore cannot do any harm or assist
in the ordinary action of the complement with
the immune body.

99

THEORIES OF IMMUNITY.

IV.

SUMMARY.

A study of the present position of the two
main theories explanatory of immunity shows
that they are not so far apart as is generally
supposed.

Both sides agree that the phenomena seen in
active immunity require two substances (immune
body or substance sensibilisatrice, and comple-
ment or alexine).

One side, however, insists that these sub-
stances remain in the cells (phagocytes). The
other maintains that they exist in the blood
stream (although, as has been seen, cell activity
is necessary for the production of the immune
body, at least). This latter fact of itself pro-
hibits the belief in a purely humoral explanation
of immunity.

Both sides agree that ;r immune body " (sub-
stance sensibilisatrice) varies, is multiple and

100

THEORIES OF IMMUNITY.

specific for each reaction in which it occurs; one
for typhoid, one for diphtheria, and so on.

They do not yet agree, however, that T com-
plement" (alexine) is multiple. One side main-
tains that it is the same for all reactions, the
other that it differs and is specific for each.

The point that has been insisted upon by
Metchnikoff from the beginning is maintained:
that in all reactions the cell activity must inter-
vene at some stage of its production.

101

THEORIES OF IMMUNITY.

V.

SUMMARY OF METHOD OF ILLUSTRATING
REACTION.

Let H represent the haptophorous atom-group

in the molecule.
T represent the toxophorous atom-group

in the molecule.
X represent the nutrient atom-group in

the molecule.
L represent the lysin atom-group in the

molecule.
X represent the remainder of the molecule.

It is not necessary to separate the X atom-
group; it is done, however, to make clearer the
fact that there is some vital action going on.

Then to represent the interaction of toxine
and antitoxine the following may be used:

Toxine molecule contains . . . H+T-j-X

Antitoxine molecule contains . . H+X

102

THEORIES OF IMMUNITY.

The two H groups are bound together, thus:

/II+T+X

\h+x

therefore the T group in the toxine cannot be
bound to anything else, and the substance exists
as a harmless material in the blood stream.

The production of the antitoxine by the injec-
tion of the toxine maybe represented as follows:
Tissue cell molecule contains . . H+X+X
Toxine cell molecule contains . . H+T+X
The H groups bind the two together; but
the H group of the tissue cell molecule is nec-
essary for the metabolism of the cell ; it must be
reproduced if the cell is to live; being so repro-
duced the reproduction occurs in excess, and
then the H groups are thrown off and exist free
in the blood stream as

H+X, which is the antitoxine.

Bordet's work on Hemolysis, and Ehrlich's
later work, showed that two substances were
necessary for other reactions, and necessitated
the supposition of the existence of two hapto-
phorous atom-groups. In accordance with this

103

THEORIES OF IMMUNITY.

idea the reaction in hemolysis may be shown
thus :

It requires the cell to be destroyed, the im-
mune body, and the complement.
The cell molecule contains .... H+X+X
The immune body molecule con-
tains H+27-HX

The complement molecule con-
tains J7+L+X

The complement is bound to the immune body
by one H group, the two to the blood cell by
the other II group in the immune body, and
then the L group in the complement may act.
In cases where two H groups occur, the different
affinities are indicated by capital and italics.

The production of the immune body requires
blood cells injected, the cells of the body in
which the injection is made, and the complement.
The reaction is shown' thus:

The blood cell molecule con-
tains H+N+X

The body cell molecule con-
tains H+iJ+X+X

104

THEORIES OF IMMUNITY.

The complement molecule con-
tains jy+L+x

The two H groups in the tissue cell molecule
are used up, but must be reproduced; being re-
produced, this occurs in excess; they are thrown
off and exist free in the blood stream as

H-h ZZH-X, which is the immune body.

So with Bacteriolysis: the formulas are the
same, except in this instance the cell to be acted
upon is the bacterial cell, and not the blood cell:

The bacterial cell, molecule con-
tains II+T+X

The immune body, molecule con-
tains ...... H+//+X

The complement, molecule con-
tains ...... -ZZ-hL+X

As before the // groups in the complement
and the immune body combine, and then these
two are joined to the bacterial cell molecule by
the remaining H groups, and thus the L group
in the complement may exert its destructive
action upon the bacterium.

105

THEORIES OF IMMUNITY.

The production of the bacteriolytic power re-
quires the bacterial cell to be injected, the tissue
cell from which the immune body is to be
produced, and the complement existing in the
fresh blood stream. The reaction is as follows:
The bacterial cell molecule con-
tains H+T+X

The tissue cell molecule contains H+JfZ-HN'-t-X
The complement molecule con-
tains ..... .ZZ-hL+X

The H atom-groups in the tissue cell molecule
being taken up, are reproduced, cast off, and
exist free in the blood stream as

H+iZH-X, the immune body.

Cytolytic action may also be shown:
The cell molecule to be acted upon

contains ..... H+N+X
The immune body molecule contains H-hfl-r-X
The complement molecule contains . J7-KL+X

The H groups are joined together, and the L
group of the complement may then act.

The production of the cytolytic property is
secured thus:

106

THEORIES OF IMMUNITY.

The foreign cell molecule in-
jected contains . . . H+JSH-X

The tissue cell molecule, in the
body in which injection is
made, contains . . . H+.ff-HN'+X

The complement molecule con-
tains ..... i/H-L+X

The H groups in the tissue cells are repro-
duced in excess, and exist free as
H+.ff-f-X the immune body active in cytolysis.

Precipitine reactions may also be shown :
The blood globulin molecule contains H+N+X
The immune body molecule contains H+.ZZ4-X
The complement molecule contains . iT+P+X

The H groups being bound together, the L
atom-group may act, in this instance producing
the precipitate, and therefore it may be more
clearly represented as P.

The production of the precipitine power occurs

as in all the others:

Blood injected, the molecule con-
tains H-HN"-fX

107

THEORIES OF IMMUNITY.

The cell (of the body in which the
injection is made) the molecule
contains . . . . . H+^T+K"-|-X

The complement (molecule con-
tains) ..... iZH-P+X

The H groups are reproduced in excess as
before, and exist free as

H+.//+X, the immune body necessary for this
reaction.

Anti-complement reaction is shown :
The complement molecule contains . H+L+X
The anti-complement molecule con-
tains ...... H+L

The two H groups combine, and the comple-
ment is rendered harmless by this combination.

The production of the anti-complement is
shown thus:
The injected serum (containing complement)

molecule contains H+N+X
The receiving blood molecule contains H+(II

-hH+H+H+etc.)+X+X.

The two H atom-groups combine, the one in

108

THEORIES OF IMMUNITY.

the receiving- blood is renewed in excess, is
thrown off and exists free as

H+X, the anti-complement.

It is of course to be understood that the let-
ters and formulae given above are representative
of the general reaction only, in each case. If it
be desired to express a specific reaction — as for
instance that of the diphtheria antitoxine — it
may be done by placing a sub-letter " d " in each
place where its need is felt; for example, HD+X,
with the snb-letter at II, represents the special
reaction used for illustration in diphtheria; any
other reaction may be shown in its specific nature
by the same means.

The molecule must also be supposed to con-
tain, in the letter X, all the other atom-groups
not needed for the expression of the special reac-
tion under consideration.

[Note. — The use of H and II to indicate the binding of the com-
plement and tlie immune body, and of these two to the cell, was sug-
gested almost simultaneously by Prof. Neisser, of Frankfurt, and Dr.
Griinbaum, of Liverpool, and had been adopted when their letters
came.]

10(J

THEORIES OF IMMUNITY.

VI.

GLOSSARY.

Active immunity: more or less permanent im-
munity, the result of the use of gradually
increasing doses of the toxines of a bac-
terium.

Addiment : another term, used by Ehrlich, for
complement.

Agglutinin's : substances found in the blood (and
possibly elsewhere) during and after the
progress of an infectious disease, capable of
clumping the bacteria producing the infec-
tions; non-specific; not dependent upon a
condition of immunity.

Alexines : substances existing in the serum of
both immune and non-immune animals (per-
haps of different nature in each) possessing
bactericidal properties. May be free in the
blood stream, or always, except by accident,

in the leucocytes.

no

THEORIES OF IMMUNITY.

Alexines : (Bordet) bodies recognized by Bordet
as existing* in the cells and possessed of bac-
tericidal properties; because of the fact
that they may be destroyed by heat (55°
C), and thus resembling Buchner's bodies of
the same name, Bordet called them alexines;
probably the same as the complement of
others.

Amboceptors: receptors of the third group,
capable of becoming normal factors in meta-
bolism; (Zwischen-korper, go-betweens;)
immune bodies.

Anti-complement : a substance produced in the
blood of an animal, injected with serum
containing only complement (no immune
body) ; it acts against the complement, and
prevents the latter from acting with the
immune body.

Anti-immune body: a substance that may be
supposed to exist in the blood of an animal
treated with immune serum in which only
" immune body ' exists — the complement
having been destroyed.

Anti-infectious: term used by Metchnikoff to

111

THEORIES OF IMMUNITY.

denote the condition of resistance to further
injections of the infectious agent.

Anti-sera : the sera of animals which have been
treated in such a way as to produce in them
substances antagonistic to various bodies ;
e.g., bacteria, toxines, blood-corpuscles, etc.
Most commonly used to denote antitoxic
sera.

Antitoxic immunity : passive immunity.

Antitoxine unit: the amount of immune serum
necessary to exactly neutralize one hundred
minimal lethal doses of toxine, after being
mixed one-half hour.

Atom-groups : atoms of the molecule supposed
to have special affinities ; become recep-
tors.

Autolysin: a substance in serum capable of dis-
solving the animal's own blood ; existence
not demonstrated.

Bacteriolysis ; the breaking up of bacteria by
substances present in certain sera ; differ-
ing from proteolysis in that the bacteria
may not be dead.

112

THEORIES OF IMMUNITY.

Chemiotaxls: the property of certain cells of
being attracted towards (positive) or re-
pelled from (negative) foreign bodies, such
as bacteria, or irritant substances.

Complement : first conceived by Ehrlich, in an
extension of his antitoxine theory, to ac-
count for the facts in immunity against
infection. Exists normally in serum and is
destroyed after an exposure of one-half
hour to 55° C. Must act with the immune
body to produce hemolysis, bacteriolysis,
etc. Contains two atom-groups of affini-
ties, one binding it to the immune body,
the other exerting the active lysin action
(hemolysis, bacteriolysis, etc.) ; this cor-
responds to the toxophorous atom-group in
the toxines. Perhaps the same as alexines
of Bordet.

Cytase : Metchnikoff's term for the substance
existing in the phagocytes, which acting
through, or with the immune body, destroys
the bacteria. It is single of its kind ; cor-
responds to the complement of Ehrlich,
except that the latter is said to be of many
kinds and to exist in the blood stream.

113

THEORIES OF IMMUNITY.

Enzymes: non-organized ferments, capable of
causing- splitting or decomposition of other
substances without entering into combina-
tion with them or their products.

Fermentation : the process in which a body may
originate changes in other bodies, whilst
remaining unchanged itself.

Fresh animal : fresh sera, etc. ; not treated in
any way to produce any form of immunity.

Globulins : albuminous bodies, insoluble in
water, but soluble in dilute neutral salt
solutions ; possibly the active principle of
the antitoxines.

Go-betweens : see Zwisehen-korper.

Haptines : Ehrlich's name for all the groups of

receptors.
Hafptopliorous (binding) : applied to groups of

affinities in body and bacterial cells, as well

as in toxines and immune bodies in general ;

satisfied by corresponding affinities in other

bodies; receptors.

114

THEORIES OF IMMUNITY.

Hemolysis : breaking up of red corpuscles, see
lysins. Three factors are necessary for the
production of the phenomenon: 1, red-blood
corpuscles to be acted upon ; 2, a body oc-
curring in the serum of immune animals
and resisting heat up to (35° C, i.e., the im-
mune body ; 3, a body not resisting heat
above 55° C, and occurring in the blood
of a fresh animal, i.e., the complement.

K Horror autotoxicus"' : Ehrlich's expression for
the fact that the tissues seldom, if ever, pro-
duce antibodies to receptors already exist-
ing in them.

Immune body : exists in the serum of an immu-
nized animal; resists one-half hour at 75°
C; has two haptophorous atom-groups, one
satisfied by a receptor in the cell binding
tli em together, the other satisfied by a
receptor in the complement binding these
two together.

Immunity: Natural, exists in many animals to
many infections diseases.
Acquired, may be the result of an
attack of a disease, or the result

115

THEORIES OF IMMUNITY.

of artificial procedures. If the
latter, it may be
Active: the result of the use of

toxines, or
Passive: the result of the use of
autitoxiues.
Immunity unit : see antitoxine unit.
Inactivated: used especially to denote the de-
struction of the complement in an immune
serum by exposure to heat (55° C), thus
making the immune body inactive.
Infection: often applied to the action of the bac-
teria, as distinct from that of their toxines.
Intermediary body : see Immune body.
Intoxication : applied to the results of the action
of bacterial poisons as distinguished from
that of the bacteria themselves.
Isolysin: a substance produced artificially in
serum, capable of destroying the blood cor-
puscles of animals of the same species.
Isopathic immunity : term suggested by Behring
to indicate the immunity of the individual
cell (the condition he thinks probably ob-
tains in active immunity) ; immunity secured
by the use of toxines.

116

THEORIES OF IMMUNITY.

Leucojyenia : absence or disappearance from a
part of all phagocytes or wandering cells;
occurs temporarily in intraperitoneal injec-
tions. (Metchnikoff.)

Lysins : see Spermatolysin.

Macrocytase : cytase derived from the macropha-
gocytes, and active in the destruction of
blood corpuscles (hemolysis). (Metchni-
koff.)

Macrophagocytes : large mononuclear leucocytes
of the blood and of the endothelium, and
also, according to Metchnikoff, from the
large cells lining the sinuses of the lymph
glands and the sinuses of the spleen.

Microcytase : cytase derived from the micropha-
gocytes, and concerned in the destruction of
bacteria. (Metchnikoff. )

Microphagocytes : polymorphonuclear leucocytes.

Minimal lethal dose (M.L.D.): the amount of
any toxine necessary to kill a two hundred
and fifty gram guinea-pig in four days, after
subcutaneous injection.

Passive immunity : more or less temporary im-
munity, the result of the use of the serum of

117

THEORIES OF IMMUNITY.

an animal already subjected to active immu-
nity (antitoxine immunity).

Peritoneum : the French conception is " of a great
opened-out gland (un ganglion lymphatic
etale), whose cells have proliferative and
protective powers, and whose removal
renders an animal more susceptible to bac-
terial infection than usual." (Ritchie.)

Pfeijfers reaction (or Phenomenon) : the disinte-
gration of bacteria resulting when these,
together with immune serum, are injected
into the peritoneal cavity of a fresh animal.
The starting point of all the recent work on
bacteriolysis, hemolysis, etc.

Phagocytosis : the property possessed by certain
fixed and free ameboid cells of englobing
and digesting bacteria and other bodies.
Supposed by Metchnikoff to be derived from
the cells of the mesoderm.

Phagolysis : partial or complete destruction of
phagocytes, used especially in connection
with intraperitoneal injections in Pfeifier's
phenomenon. (Metchnikoff.)

Precipitines : substances found in the blood of

an animal, after injection with blood of an-
us

THEORIES OF IMMUNITY.

other species of animal, capable of producing
a precipitate in the blood of the same species
of animal from which the injections were
made. The precipitate found is soluble (in
some cases at least) in two per cent solu-
tion of sodium chloride, and is therefore not
a coagulation.
Proteolysis : the breaking up of proteid bodies
as seen in ordinary digestion in connection
with the intestinal glands; takes place in
dead material.

Reactivated : used to denote the supplying of
fresh complement to an immune serum, pre-
viously made inactive by heat (55° C), thus
making the immune body active. (See Inac-
tivated.)

Receptors: chemical affinities conceived by
Ehrlich as existing in the blood corpuscles,
other tissue cells, etc.; satisfied by corre-
sponding affinities in other substances (im-
mune bodies, toxines, etc.).

Receptors of the first order : affinities in the cell
concerned with fixing relatively simple ma-

119

THEORIES OF IMMUNITY.

terials, i.e., toxines, ferments and other cell-
ular secretions.

Receptors of the second order : affinities in the
cell, fixing the molecule by one arm and
breaking it up with another of a ferment-
like capacity; more complicated and for ab-
sorbing molecules of large size.

Receptors of the third order : affinities fixed in
the cell, and also containing two hapto-
phorous atom-groups, one fixing the food
particles, the other fixing the ferment-like
body (complement), whose action is neces-
sary for breaking up the. particle fixed; the
most important of the three groups.

Sensitizing substance (substance sensibilisatrice) :
see Immune body; it is the same, except
that it is supposed to exist in the cell rather
than in the blood stream.

Side-chains : see Receptors. The term 'r? side-
chains " should be used only of a molecule
whose composition is known.

Spermatotysin (and other lysins) : refer to ex-
periments made with certain cells, after in-
jecting which sera can be obtained contain-

120

THEORIES OF IMMUNITY.

ing substances capable of destroying' these
cells.
Stimulines : Metchnikoff ' s term to denote bodies
existing in immune sera, which stimulate
the phagocytes to move in a special direc-
tion, englobe, and digest invading bac-
teria.

Tetanus sine tetano : used by Donitz to describe
the condition of a rabbit dying after injec-
tions of tetanus toxine and antitoxine not
quite balanced; death from marasmus, but
no tetanus.

Tetano-lysin : a substance existing in some
bouillon cultures of the tetanus bacillus,
capable of destroying red-blood corpuscles
of certain animals; destroyed by heat at
50° C. (Madsen.)

Teta?io-spasmin : what is usually considered the
tetanus toxine; with no hemolytic power;
very slightly affected by twenty minutes at
50° C. (Madsen.)

Toxine immunity : active immunity.

Toxophorous (poison carrier} : the group of

chemical affinities in the toxine molecule

121

THEORIES OF IMMUNITY.

(and in the bacterial cell molecule in certain
cases) that exerts the poisonous action on
the cell, or is neutralized by the antitoxine.

Toxines : the powerful poisonous substances
elaborated during- the growth of many bac-
teria; the soluble toxines are those remain-
ing in the filtrate of fluid cultures of some
bacteria.

Toxoids: the less poisonous substances remain-
ing in a filtered culture when this has been
kept for some time, and after the soluble
toxines have disappeared.

Toxones : supposed by Ehrlich.to exist along with
toxines and toxoids and possessing hapto-
phorous atom-groups having a less strong
affinity for similar groups in antitoxine
or cell than toxine: capable, however, of
combining with antitoxine, and of pro-
ducing very slow poisonous results (e.g.,
diphtheria paralyses).

Vital nucleus: Ehrlich's term for his conception
of a centre of vital activity existing in the
protoplasm of the cell, with which are asso-
ciated the special cell capacities.

122

THEORIES OE IMMUNITY.

Zwischen-Jcorper : bodies in normal sera capable
of linking the hemolysin (or other lysina)
to the cell; corresponding to the immune
bodies in immune sera.

[Note. — This glossary contains terms found in general reading, as
well as those in the text.]

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