Ch XVII

SUMMARY

Means of defence of the animal against infective agents.—Absorption of micro-organisms.—Phagocytes, and their function in inflammation.—The action of phagocytes in the absorption of micro-organisms.—The cytases, phagocytic ferments.—The cytases are closely bound up with the phagocytes.—The fixatives and their function in acquired immunity.—The fixatives are excreted by the phagocytes and pass readily into the fluids of the body.—Essential mechanism of the action of the fixatives.—Adaptation of phagocytes to destroy micro-organisms in acquired immunity.—Difference between the fixatives and the agglutinins.—Antitoxins and their analogy with the fixatives.—Hypotheses as to the origin of antitoxins.—Cellular immunity is a fact of general import.—Susceptibility and its rôle in immunity.—Applications of the theory of immunity to medical practice.

[Sidenote: [568]]

When an animal remains unharmed in spite of the penetration of infective agents it is said to be immune to the diseases usually set up by these agents. This idea embraces a very great number of phenomena which cannot always be sharply separated from allied phenomena. On the one hand, immunity is closely connected with the process of cure, on the other, it is related to the disease. An animal may be regarded as unharmed if the penetration of a very dangerous virus sets up merely an insignificant discomfort. Nevertheless, this discomfort is accompanied by morbid symptoms, though they may be very slight. It is useless and impossible to set up any precise limits between immunity and allied states.

Immunity presents great variability. Sometimes it is very stable and durable; in other cases it is very feeble and transient. Immunity may be individual or it may be generic. It may be the privilege of a race, of a species.

Immunity is often innate, as is the case of the immunity which is called natural. But it may also be acquired. This last category of immunity may be developed either by natural means, after an attack of an infective disease, or as a result of human intervention. The principal means of obtaining artificial acquired immunity consists in the inoculation of viruses and of vaccines.

[Sidenote: [569]]

Immunity is a phenomenon which has existed on this globe from time immemorial. Immunity must be of as ancient date as is disease. The most simple and the most primitive organisms have constantly to struggle for their existence; they give chase to living organisms in order to obtain food, and they defend themselves against other organisms in order that they may not become their prey. When the aggressor in this struggle is much smaller than its adversary the result is that the former introduces itself into the body of the latter and destroys it by means of infection. In this case it takes up its abode in its adversary in order to absorb the contents of its host and to produce within it one or more generations. The natural history of unicellular organisms, both vegetable and animal, often presents to us these examples of primitive infection.

But infection also has its counter. The attacked organism defends itself against the little aggressor. It protects itself by interposing a resistant membrane, or it uses all the means at its disposal to destroy the invader. As a very large number of organisms, in order to obtain nourishment, are obliged to submit their food to digestion by various chemical substances, they utilise these substances in the struggle against the infective agents. They digest them whenever they are able to do so.

One of the most primitive of organisms, the plasmodium of the Myxomycetes, which is composed of formless protoplasmic masses intermediate between lower animals and plants, ingests foreign bodies of various kinds. It often happens that it incorporates numerous bacteria which are growing alongside it on rotten wood or elsewhere. The plasmodium allows them to live for some time within its digestive vacuoles. But in the end it digests them by means of its soluble ferments, substances intermediate between pepsin and trypsin. Owing to this digestive power the plasmodia are not attacked by bacterial infections.

[Sidenote: [570]]

This example, taken from amongst the most simple organisms, may serve as a prototype for the phenomena of immunity in general. At the commencement of the study of this remarkable property of so many living organisms it was thought that the pathogenic micro-organisms encountered, within the refractory organism, a medium which did not allow them to live, either because of the absence of certain nutritive substances indispensable for their existence or because it contained some substance injurious to micro-organisms. Very numerous and detailed researches have demonstrated the incorrectness of these hypotheses. There are, of course, certain pathogenic micro-organisms which are very exacting as regards the medium in which they will grow. Some will develop only in the presence of particular substances, whilst others are extremely sensitive to the slightest traces of poisons. These, however, are quite the exception. The great majority of pathogenic micro-organisms belonging to the group of bacteria readily adapt themselves to all kinds of culture media, and most of them live and develop freely in the blood or other fluids of refractory organisms. This, therefore, is not the cause of the immunity in such organisms. The cause must be sought for amongst factors more closely connected with life.

Wishing to penetrate more deeply into these phenomena the hypothesis was put forward that the unharmed organism got rid of the infective micro-organisms by expelling them to the outside along with the excreta. It was maintained for a considerable time that the animal organism possessed the means of causing pathogenic bacteria to pass into the kidneys, whence they were eliminated by the urine. It had to be acknowledged, however, that this elimination never takes place in cases of immunity, and only comes into operation when the animal is ill and the integrity of the renal filter is impaired.

The infective micro-organisms, after they have entered into the unharmed organism, remain there for a longer or shorter period, and perish without being expelled. This disappearance of the micro-organisms takes place by the same mechanism that rids the plasmodium of those bacteria which it has managed to ingest during its slow peregrinations over dead leaves or rotten wood. The micro-organisms are absorbed into the refractory organisms as the result of a true act of digestion. It is very remarkable that the gastro-intestinal ingestion, so well provided with means of rendering the most varied aliments soluble, is generally incapable of digesting pathogenic or other micro-organisms. It is very rare to meet with soluble ferments of the intestinal canal which are capable of digesting microscopic organisms, especially bacteria. Consequently this organ, so rich in digestive diastases, is generally inhabited by a large number of bacteria and other micro-organisms.

[Sidenote: [571]]

Even in animals whose food contains large numbers of microorganisms, _e.g._ the larvae of flies, the digestive juices are powerless to destroy them. Nevertheless, there are organisms which feed exclusively, or almost exclusively, on bacteria and which are quite capable of digesting them. These are the Protozoa, such as the _Amoebae_ and certain Infusoria, which, without any trace of a digestive tube, easily bring about this result. _Amoebae_ can be grown on the surface of agar by taking care to sow along with them bacteria for their nourishment. It is only necessary to give them a single species of micro-organism, and this may be selected from the pathogenic forms, such as the cholera vibrio or the _Bacillus coli_. The _Amoebae_ ingest a number of these bacteria in the living state. They then kill them and digest them in their digestive vacuoles which contain, along with a little acid, a ferment belonging to the trypsin group, the amoebodiastase.

The bodies of lower and higher animals, alike, are very rich in elements which closely resemble the _Amoebae_. Sometimes these are to be found in the epithelial cells of the digestive canal which put out protoplasmic processes for the purpose of seizing food and transferring it to their interior, where it is submitted to the action of digestive ferments. Sometimes they are the cells disposed between the body wall and that of the intestinal canal, which float freely in the fluids of the body or are more or less fixed in the interstitial tissue. The animal kingdom presents a great variety of these amoeboid elements, known under the general name of phagocytes (cells capable of devouring solid bodies). One of the most primitive arrangements of phagocytes is met with in _Ascaris_ and its allies belonging to the group of the Nematoda. All the organisation that these round worms possess consists merely of four, or a few more, enormous cells attached to the body wall. These are phagocytes which push out processes of enormous length, capable of exploring the whole of the internal cavity of the body.

[Sidenote: [572]]

The majority of phagocytes circulate in the lymph and blood and pass into the exudations. These white corpuscles have a comparatively uniform structure in the Invertebrata and present themselves as small cells with a nucleus and a protoplasm capable of amoeboid movements. In the Vertebrata we meet with two great categories of white corpuscles, of which one group resembles those of the Invertebrata in that they also possess a single large nucleus and an amoeboid protoplasm. These are the macrophages of the blood and of the lymph, and are intimately connected with the macrophages of such organs as the spleen, lymphatic glands, and bone marrow. Another group of white corpuscles in the Vertebrata is made up of small amoeboid cells which are distinguished by having a nucleus which, although single, is divided into several lobes. These are the microphages whose chief peculiarity, the multi-lobed form of the nucleus, must be regarded as an adaptation for the purpose of passing as rapidly as possible through the walls of capillaries and small veins.

The diapedesis of the white corpuscles, their migration through the vessel wall into the cavities and tissues, is one of the principal means of defence possessed by an animal. As soon as the infective agents have penetrated into the body, a whole army of white corpuscles proceed towards the menaced spot, there entering into a struggle with the micro-organisms. Aided by the special form of their nucleus the microphages are the first to pass through the walls of the vessels. Each of the several small lobes, into which the nucleus and its protoplasm is divided, passes readily through the minute orifices between the endothelial cells of the vessels. The macrophages follow the microphages and become mixed in greater or less numbers with the exudations. But it is not micro-organisms only which set up this inflammatory reaction accompanied by the emigration and the accumulation of leucocytes. The introduction of inert bodies and of aseptic fluids brings about the same result. The phagocytes are, as a matter of fact, endowed with a special susceptibility, which enables them to perceive exceedingly small changes in the chemical or physical composition of the medium that surrounds them.

The leucocytes, having arrived at the spot where the intruders are found, seize them after the manner of the _Amoebae_ and within their bodies subject them to intracellular digestion. This digestion takes place in the vacuoles in which usually is a weakly acid fluid which contains digestive ferments; of these a very considerable number are now recognised.

Just as the _Amoebae_ and the Infusoria make a choice from amongst the small organisms that surround them, so the leucocytes choose bodies which are best suited to their use. The macrophages seize by preference animal cells such as the blood corpuscles, the spermatozoa, and other elements which are derived from animals. Among the infective micro-organisms the macrophages have a predilection for those that set up chronic diseases such as leprosy, tuberculosis, and actinomycosis and also for those which are of animal nature. Into this last category come the amoeboid parasites of malaria, Texas fever and the _Trypanosomata_. The macrophages can also ingest the bacteria of acute diseases, but, save in exceptional cases, their intervention is of little moment.

[Sidenote: [573]]

The microphages, on the other hand, appear to play their part specially in acute infections. Their intervention against animal cells is _nil_, or almost so. Thus they rarely seize the red corpuscles of the same or of a foreign species of animal. They also appear to be repelled by parasites of animal origin and by certain bacteria which set up chronic diseases. Whilst the macrophages seize the bacilli of leprosy with great avidity, the microphages ingest them only exceptionally.

The morphological and physiological differences between the two great categories of mobile phagocytes (leucocytes), correspond to differences in the composition of their soluble ferments. Just as the _Amoebae_ digest their prey by means of their amoebodiastase, a soluble ferment of the group of trypsins, so the white corpuscles submit the foreign bodies ingested by them to the action of what are now known as cytases. These cytases (alexins or complements of other writers) are soluble ferments which also belong to the trypsin group. They act in a medium which is feebly acid, neutral, or feebly alkaline, and, like the amoebodiastase, they are distinguished by a great sensitiveness to heat. When the cytases are contained in fluids, a temperature of 55°–56° C. destroys them rapidly and completely. When they are found in organs reduced to the state of an emulsion, their sensitiveness diminishes and it is necessary to raise the temperature to 58°–62° C. in order to destroy their activity.

[Sidenote: [574]]

Bordet maintains that the cytases are very different in the various species of animals, but that in the same species only one cytase exists. Ehrlich and Morgenroth, on the other hand, hold that the same serum contains several, sometimes many, different cytases. This question is too difficult to be definitely solved at present. It appears to me very probable that there exist, in the same species of animal, two different cytases. One of these, the macrocytase which is found in the lymphoid organs and in the serum of the blood, acts more particularly on animal cells. Thanks to this substance an extract or maceration of the spleen, omentum or lymphatic glands dissolves the red blood corpuscles more or less readily; these extracts and macerations, however, are incapable of destroying bacteria. When the macrophages seize the nucleated blood corpuscles they digest them completely, not sparing even the nucleus, so resistant to attack, but when the same phagocytes ingest such micro-organisms as are most easily digested, such as the cholera vibrio, their action is feeble. The vibrios, without any transformation into granules, remain alive for some time and are destroyed and digested with very great difficulty. The cytase of the microphages, or microcytase, is distinguished by other properties. It destroys and digests easily many micro-organisms, but has little or no action upon the red blood corpuscles and other animal cells. The exudations which are rich in macrophages, such as those of the lymphoid organs, are not at all or only slightly bactericidal, but exhibit a solvent action on red blood corpuscles. On the other hand, the exudations, which are composed in great part of microphages, leave red blood corpuscles intact, but readily destroy micro-organisms. Similar properties distinguish the bone marrow, extracts and suspensions of which do not dissolve red corpuscles, but attack micro-organisms. Now, we know that the bone marrow is the principal seat of origin of the microphages.

Even after the addition of some of the specific fixative to the microphagic exudations no solution of the red corpuscles is produced, which demonstrates most clearly that the microcytase is really incapable of attacking these animal cells.

We are, therefore, compelled to accept the existence of two different cytases, of which one (the macrocytase) acts specially upon elements of animal origin, and the other (the microcytase) acts principally on micro-organisms. The indication of any more detailed differentiations is impossible in the present state of our knowledge.

[Sidenote: [575]]

There are certain ferments which, during the life of the cells which produce them, pass readily into the surrounding fluids. For instance, sucrase can be recovered without difficulty from the culture fluid of moulds and yeasts. The ferments of the intestinal digestion also pass with great facility into the secreted fluids. Other soluble ferments, on the other hand, remain very closely bound up with the cells which manufacture them. Thus the zymase of the yeasts can only be freed from the cells of these fungi with great difficulty, under the influence of great pressure and under conditions which profoundly alter the cell. The proteolytic ferment of the yeast is also very adherent to the cells of these organisms. The fibrin-ferment, or plasmase of the white corpuscles, is not secreted by these cells so long as they are quite intact. But it is sufficient to subject them to unfavourable conditions of existence to cause them to throw it out from their bodies. The leucocytes, when removed from the animal, undergo a deterioration which soon leads to the deposition around them of filaments of fibrin.

The cytases must also be grouped with the soluble ferments which are not thrown off by the phagocytes so long as these remain intact. Immediately these cells are injured, however, they allow a part of their cytases to escape. In the blood, withdrawn from the animal, the white corpuscles allow the plasmase to pass into the fluid, where it sets up the coagulation of the fibrin and the formation of a clot. At the same time these cells give up some of their cytases which communicate to the serum its haemolytic and bactericidal properties. This fact is of the highest importance in connection with the question of immunity. The best demonstration of this has been furnished by a comparison of the bactericidal power in the different parts of the body and in the body fluids extracted from the animal.

When micro-organisms are introduced into those situations in the refractory animal which contain pre-existent leucocytes, the leucocytes, under the influence of the shock, undergo serious lesions, accompanied by the throwing out of the cytases. Under these conditions the least resistant micro-organisms (such as the cholera vibrio) exhibit undeniable signs of deterioration: they become transformed into granules and may even die in greater or less numbers. When, however, the leucocytes are well protected and withstand the injection of the micro-organisms without being profoundly altered, the extracellular destruction of the micro-organisms does not take place. On the contrary, a very rapid phagocytosis is produced which brings about the death and intracellular digestion of these micro-organisms. Under these conditions vibrios are also transformed into granules and perish, but only within the leucocytes. The phenomena I have just mentioned are brought about in the peritoneal cavity and in the blood vessels of refractory animals, that is to say, in situations rich in leucocytes.

[Sidenote: [576]]

In the subcutaneous tissue, in the fluids of oedemas and in the anterior chamber of the eye of these same refractory animals, the phenomena are very different. As in these situations there are no pre-existing leucocytes or their number is insignificant, the micro-organisms introduced do not suffer serious injury; they continue to live up to the moment when the leucocytes, having come up as the result of the inflammatory reaction, seize them alive, kill them, and digest them within their substance. Just as it is easy, in situations populated by pre-existing leucocytes, to suppress the extracellular destruction of the micro-organisms by preserving the phagocytes against injury or phagolysis, so this same extracellular destruction is easily set up in situations where leucocytes are absent. When, after exudations rich in leucocytes have been injected into the subcutaneous tissue, we introduce micro-organisms which are not very resistant, such as the cholera vibrio, it is observed that these vibrios are destroyed outside the cells, having first been transformed into granules.

There can be no doubt as to the conclusion to be drawn from these various experiments. The microcytase is the substance which transforms the vibrios into granules. It is within the microphages, when they remain intact, that the vibrios undergo transformation. When, on the other hand, the microphages are injured and allow the microcytase to escape, the transformation of the vibrios into granules and their partial destruction take place in the plasmas outside the phagocytes.

This conclusion is supported by comparative researches on the bactericidal power of the serum and of the blood plasma outside the animal. It is true that it is impossible to prepare a fluid which shall in all respects be comparable to the plasma of the circulating blood. There is, however, always a means of obtaining outside the animal a fluid which approaches much more closely to blood plasma than does serum. Gengou succeeded in preparing in tubes coated internally with paraffin a fluid which coagulates very tardily, and which contains very little fibrin-ferment. This fluid is found to be much less bactericidal than is the blood serum of the same animal. It is, indeed, often found to be entirely without bactericidal power, whilst the corresponding serum is capable of destroying a large number of micro-organisms.

[Sidenote: [577]]

In the phenomena of the absorption of cells also a great number of facts are met with which demonstrate that the macrocytase escapes from the macrophages at the moment of their phagolysis only. For example, the extracellular solution of the red corpuscles takes place easily in the peritoneal fluid of animals prepared by a previous injection of the same corpuscles. When the leucocytes of the peritoneal cavity are abandoned to their fate, a marked phagolysis is produced and consequently a solution of the red corpuscles in the fluid itself. When, on the other hand, phagolysis is prevented, the macrophages remaining intact do not allow their macrocytase to escape and the solution of the red corpuscles takes place almost exclusively inside the phagocytes.

In certain animals the blood serum arrests the movements of their own spermatozoa at once, whilst these remain quite motile in the animal itself. This is due to the fact that the immobilising macrocytase is contained within the macrophages and does not escape from them so long as these cells remain intact. When, in such animals, their own spermatozoa are introduced into the subcutaneous tissue, they remain motile for a long time; when, on the contrary, the spermatozoa are injected into the peritoneal cavity, where the leucocytes have not been prepared, phagolysis is produced at once and the spermatozoa become motionless immediately.

As all these data agree in demonstrating that the uninjured phagocytes retain the cytases—which remain within them, and are not found in the surrounding fluids,—we can readily understand the reason for the differences between the phenomena of immunity and the bactericidal power of the body fluids. The rat’s serum is capable of destroying a large number of anthrax bacilli, although these rodents are certainly susceptible to anthrax. The reason for this is that in the serum of the rat the bacilli are destroyed by the microcytase which is set at liberty, whilst in the body of the animal it remains enclosed within the bodies of the living microphages. So long as these cells exhibit a negative chemiotaxis against the anthrax bacillus, the micro-organism remains in the plasma, where it is not interfered with. Thanks to this, multiplication of the bacilli goes on in the body of the animal, the micro-organism killing it after becoming generalised in the blood and in the organs. The susceptibility of the leucocytes is, then, the cause of the death of the rats from anthrax, the organism of these rodents being unable to take advantage of its richness in bactericidal microcytase.

Another paradoxical fact is met with in guinea-pigs immunised against Gamaleia’s vibrio (_Vibrio metchnikovi_). As demonstrated by von Behring and Nissen, the blood serum of these guinea-pigs is very bactericidal for the vibrio in question. A contact of less than an hour is quite sufficient to destroy large numbers of the micro-organisms. Nevertheless, when a small dose of a culture is injected subcutaneously into these hypervaccinated guinea-pigs, the vibrios remain alive for several days, up—indeed, to the moment when they are ingested and destroyed by the leucocytes which come up in large numbers to the menaced spot. This apparent contradiction is easily explained by the fact that it is in the serum only that the vibrios encounter the microcytase, which has escaped from the microphages at the time of the formation of the clot and the separation of the serum.

[Sidenote: [578]]

Alongside those cases in which the serum of susceptible animals is found to be very bactericidal, examples are not wanting where the blood and the serum of refractory animals are entirely without this power. For instance, the pigeon is refractory to Pfeiffer’s influenza bacillus, but the blood of the pigeon forms the best culture medium for this micro-organism. The dog is refractory to the anthrax bacillus, against which the blood serum of the same animal is not at all bactericidal. The cause of this absence of parallelism between immunity and the bactericidal power of the serums must be sought in the difficulty with which the cytases escape from the leucocytes, and also in the modifications which they may undergo, once they are distributed in the fluids.

[Sidenote: [579]]

In cases of natural immunity, the cytases rid the animal of the micro-organisms without the slightest observable co-operation on the part of other soluble ferments. It is impossible to settle definitely even the question whether, in animals which enjoy this innate immunity, there exists, alongside the microcytase, any ferments which come to its aid. The conditions are quite otherwise in a very large number of cases of acquired immunity. Here it is found, as a fairly general rule, that in addition to the microcytases there exist other substances whose rôle in the defensive action offered by the animal against micro-organisms is very important. These substances are fixatives which co-operate in a remarkable fashion with the bactericidal action of the cytases; but whilst these latter injure the bacterial cell directly, the fixatives do not interfere with its life. The bacteria, permeated by fixatives, may even continue to reproduce themselves and, under certain conditions, to invade the animal. The fixatives, then, are not bactericidal, but by fixing themselves upon the micro-organisms they render them much more susceptible to the bactericidal action of the microcytases. These latter are further distinguished, in several other respects, from the cytases. The fixatives must also be classed with the group of soluble ferments, but they resist much higher temperatures than those which destroy the cytases. Whilst the latter are quite destroyed at 55° C., the fixatives, to be completely altered, must be heated to beyond 60° C. and even 65° C. On the other hand, the fixatives are distinguished by a high specificity which is never observed in the cytases. The majority of the fixatives are incapable of fixing themselves upon more than a single species of bacteria or upon a single class of animal cells, and only certain of them can fix themselves upon allied species or cells, such as the red corpuscles of several species of animals. In these cases, too, there exists a sharp quantitative difference between the fixation on the different formed elements. The same microcytases are, on the other hand, able to attack all kinds of micro-organisms, and the same macrocytases attack all kinds of animal cells.

We have seen that the cytases correspond to the zymase and to the proteolytic diastase of the yeasts in the sense that all these soluble ferments adhere with tenacity to the cells which produce them and contain them. The fixatives, in this respect, approach sucrase (invertin): these various soluble ferments pass readily into the fluids which bathe the cells that produce them. The fixatives are found not only in the blood serums, prepared outside the body, but also in the blood plasma, whence they pass into the fluids of the exudations and transudations. Whilst no cytases are found in the subcutaneous tissue, or in the clear fluids of oedemas containing no, or almost no, cells, fixatives are not absent from these various situations just indicated. For this reason, when micro-organisms are introduced subcutaneously, they are not found to be altered by the cytases, but it is easily seen that they are permeated with fixatives. The same rule applies to the fixatives of the animal cells. In the example we have cited, the spermatozoa, in an animal whose serum renders these cells motionless, remain quite motile in the epididymis and below the skin. From this fact it may be concluded that these situations contain no free macrocytase. It is sufficient, however, to add to these motile spermatozoa a drop of normal serum containing macrocytase to stop their movements at once, the fixative being well distributed in the plasma of the living animal. The spermatozoa, then, were sensibilised by the fixative which was found in both the epididymis and in the subcutaneous tissue.

[Sidenote: [580]]

The cytases are soluble ferments which are essentially intracellular: the fixatives are, on the other hand, soluble ferments which are humoral. These fixatives, however, although circulating in the plasmas, are undoubtedly of cellular origin. This fact was first demonstrated by Pfeiffer and Marx, who found the specific fixative of cholera vibrios in the “haematopoietic organs,” that is to say, in the spleen, lymphatic glands, and bone marrow, at a period when there was, as yet, none in the blood. This fact has been extended to other examples of fixatives of micro-organisms, and it cannot be questioned that the phagocytes produce these soluble ferments. Under the influence of the introduction of micro-organisms into the body, a phagocytic reaction is produced which has, as a consequence, the digestion of these micro-organisms and the production of corresponding fixatives. There is every reason to believe that, in these cases, it is the microphages which, seizing and digesting the micro-organisms, produce the fixatives.

But the macrophages are also capable of producing these adjuvant ferments. Even in normal animals the macrophagic organs, such as the spleen, and especially the mesenteric glands, contain fixatives which help in the solution of the red blood corpuscles. Into this group of facts we must also place the production by the mesenteric glands, as well as by certain other lymphoid organs, and the leucocytes of exudations and the blood, of enterokynase,—the soluble ferment which aids the digestive action of trypsin. This enterokynase is also a species of fixative; it permeates the flakes of fibrin and renders them much more accessible to the influence of the trypsins.

The fact that the enterokynase of the intestinal digestion corresponds in so many respects to the fixatives which act in the absorption of formed elements in general and of micro-organisms in particular, furnishes a further proof that the destruction of micro-organisms in the animal is an act similar to true digestion.

[Sidenote: [581]]

Phagocytes, those elements which accomplish the absorption of micro-organisms and of animal cells, those holders of digestive cytases, are also the manufacturers of fixatives. Having brought about this absorption, the phagocytes set to work to elaborate large quantities of fixatives, although they are unable to increase the amount of cytases in any marked degree. The fixatives, produced in abundance, can be excreted outside the phagocytes and pass into the blood plasma, and, with it, into the fluids of exudations and transudations. But this excretion is not an indispensable act for the functioning of the fixatives. As these ferments prepare the way for the digestive action of the cytases, it is necessary only that they should be able to fix themselves on the formed elements before the latter. It is, therefore, easy to explain cases of acquired immunity in which no fixatives are found in the body fluids. Such examples are not rare, and are characterised by the absence of any protective action on the part of the blood serum. In these cases, the fixatives, whose existence is very probable, remain lodged within the phagocytes, just as are the cytases. Within these digestive cells the fixatives may quite well fulfil their preparatory rôle, this being followed immediately by the action of the cytase. The same rule may apply also to the cases of absorption in the unprepared animal, where fixatives are not found in the blood serum, but where they are able to act within phagocytes.

The excretion of fixatives into the plasmas, which constitutes the rule in cases of acquired immunity, presents an analogy with the excretion of pepsin into the blood. This soluble ferment can and does pass habitually from the stomach into the blood and thence into the urine, where it is often met with. As the pepsin, which only acts in an acid medium, cannot be utilised in the alkaline blood plasma, it is evident that its excretion is only the consequence of a too abundant over-production.

In recent years great attention has been paid to the essential mechanism of the action of fixatives on the formed elements on the one hand, and on the cytases on the other. According to Ehrlich, the fixatives are bodies intermediate between the two. In possession of two haptophore molecular groups, they are capable of entering into chemical combination with the micro-organisms or the animal cells on the one hand, and with the cytases on the other. It is for this reason that Ehrlich applies to them the name of “amboceptors” or “intermediary substances.” Based on analogous examples in organic chemistry, Ehrlich thinks that the fixatives serve to introduce the cytases into the cells upon which they have to act. Bordet does not share this view and maintains that the action of the fixatives is not a chemical action in the proper sense of the word, but is a kind of mordanting which sensibilises the formed elements to the fermentative action of the cytases. According to him, the fixatives have no affinity for the cytases and in no way serve them as intermediaries, for which reason he gives to them the name of sensibilising substances. The question is still under discussion, but we may hope that it will soon enter into its final phase.

[Sidenote: [582]]

According to Ehrlich’s theory, the fixatives contain no product coming from the micro-organisms or from the animal cells upon which they are fixed. The fixatives are, according to him, side-chains or receptors, produced in excess and expelled into the blood plasma by the cells which produce them. Ehrlich does not tell us to what category these cells belong; he maintains only that these cells must be in possession of receptors endowed with a specific affinity for certain molecular groups of micro-organisms and of animal cells. As soon as the receptors are saturated by these molecular groups, the cells which make use of the former for their nutrition produce them in superabundant quantity. The cells of animals, treated with micro-organisms and their soluble products, or with red blood corpuscles or any other kind of element of animal origin, acquire the property of elaborating more and more of the corresponding receptors, a large proportion of which are expelled into the blood plasma.

The common point between Ehrlich’s theory and the view maintained in this work consists in the admission of a cellular property which develops more and more in proportion to the treatment of the animal by formed elements of all kinds. As, in acquired immunity against micro-organisms, the fixatives are most frequently found in the body fluids, it must be concluded that, in all these cases, the cells which produce them have become adapted by a kind of education to manufacture increasing quantities of fixatives. But even in those examples of acquired immunity where fixatives are not found in the plasmas, we must accept a modification of the cells which resist the invasion of micro-organisms. These changes in the cellular properties constitute, therefore, the most general, and consequently the most important, element in acquired immunity against micro-organisms.

As already mentioned Ehrlich does not assign any position to the cells which exhibit these modifications. It must, however, be accepted that they belong to the category of phagocytes. Indeed, the phagocytes put themselves into most intimate contact with the micro-organisms and foreign animal cells, and it is in the phagocytic organs that the fixatives are found before they are met with in the blood plasma. It may then be concluded that, in acquired immunity against micro-organisms, the phagocytes become adapted to elaborate the fixatives in large quantities, of which a portion is excreted into the body fluids, as has been shown in many examples of such immunity.

[Sidenote: [583]]

The progressive adaptation of the phagocytes in intracellular digestion can be demonstrated by the fact that in an immunised animal the fixatives are found more especially in the phagocytic organs. The leucocytes which digest gelatine exhibit in an even more distinct fashion the modification of these cells in animals which have received several injections of gelatine. The leucocytes of exudations, when the fluid is removed, become much more fitted to digest the gelatine than they were at first.

A similar adaptation is also observed in intestinal digestion, which may serve as a fresh point of comparison between the intracellular digestion of the phagocytes and the extracellular digestion in the intestines. The pancreas, in order to secrete its soluble ferments, adapts itself to the nature of the food which passes into the digestive canal.

The fixatives are not the only soluble ferments which appear in large quantities in the fluids of the immunised animal. Very often there are found along with them substances which agglutinate the micro-organisms in animals which have received several injections of micro-organisms of the same or an allied species. The same fact is observed in animals treated with animal cells. Thus the fluids of animals injected with blood corpuscles become agglutinative for these corpuscles.

[Sidenote: [584]]

The analogy between the agglutinins and the fixatives is so great that for some time several observers assumed them to be one and the same substance. This can no longer be upheld, for it is clearly demonstrated that the property of the body fluids to agglutinate micro-organisms and animal cells is different from that which brings about their permeation by fixatives. The agglutinins resist the same temperatures as the fixatives; both are specific to the same degree and pass equally from the cells which produce them into the plasmas of the blood, lymph, exudations, and transudations. The agglutinins capable of clumping the formed elements into masses may, under certain conditions, render their ingestion by the phagocytes more easy. In general, however, the part played by the agglutinins in acquired immunity must be regarded as of little importance, and for that reason we abstain from basing any theory of this immunity on the agglutinative property of the body fluids. Besides fixatives and agglutinins, the fluids of an animal which has acquired immunity very probably possess other properties which must have a greater or less function in acquired immunity. Thus, we are often struck by the stimulating action of these fluids on the normal animal into which they are introduced. This stimulation is especially manifested against the phagocytic reaction.

As, in the majority of cases of acquired immunity, the blood serum contains fixatives in considerable proportion, and as these fixatives aid the action of the cytases in a remarkable fashion, we can readily understand that the introduction of such a blood serum into a normal animal, unprepared by any vaccination, may bring about a great resistance against the corresponding pathogenic micro-organisms. The fixatives, injected with the serum, fix themselves with avidity upon the micro-organisms. These organisms may become a more ready prey to the phagocytes and be destroyed very rapidly. In particular cases, where the injection of microbial cultures sets up a phagolysis, enough cytases are thrown out to affect the microbes already sensibilised by the fixative. This is followed by a refractory condition of the animal proportionate, in general, to the amount of fixative serum that is injected. This kind of acquired immunity, conferred by serums or certain other body fluids rich in fixative substances, has often received the name of passive immunity. This term is only justified in those rare cases where the introduced serum itself contains a sufficient amount of cytases to destroy all the micro-organisms. Most often it is the normal animal which has to furnish this bacteriolytic ferment. Now, as in phagolysis the quantity given off is too small, it is to the co-operation of the holders of cytases, that is to say, to the phagocytes, that the animal must have recourse. The phagocytes, being susceptible cells, their co-operation can only be counted upon in cases where they exhibit a sufficient activity. When these elements are weakened by narcotics or by any other cause, they become incapable of intervening with efficacy and the animal falls a victim to the pathogenic micro-organisms, in spite of the more than sufficient amount of fixatives that was introduced.

[Sidenote: [585]]

In natural or acquired immunity, it is the resistance of the animal against the micro-organisms which plays the principal part. The introduction of toxins ready prepared is only done under artificial conditions, as in laboratory experiments. Hence we see that, under natural conditions, it is against the penetration of the micro-organisms that the animal must be protected. So soon as these producers of poisons can no longer maintain themselves in the immunised animal their toxic secretions do not come into play. It is for this reason that animals vaccinated against pathogenic micro-organisms do not suffer from intoxication, although they are by no means insusceptible to the microbial poisons. It is a fact of the highest importance from the point of view of immunity in general, that the resistance offered to micro-organisms in no way implies insusceptibility to their poisons. The view has frequently been expressed that, in acquired immunity at least, the animal must first acquire immunity against the microbial toxins, after which the micro-organisms, deprived of their principal weapon, descend to the rank of inoffensive saprophytes. Such cases may be found, but it is none the less true that immunity against micro-organisms may be acquired independently of that against the toxins, and that this constitutes the general rule.

Immunity is much more readily acquired against micro-organisms than against their toxins. Hence, antimicrobial vaccination was accomplished by science before that against their toxins. In the early researches on this subject antitoxic immunity appeared to be very difficult of attainment, and it was only after the discovery made by von Behring, who inaugurated a new path in microbiology, that better results were obtained. Von Behring not only succeeded in immunising animals against some of the principal microbial toxins, he demonstrated the existence of specific antitoxins in their body fluids.

This very unexpected conception of antitoxins at once took root in science, for it has been possible, thanks especially to the remarkable works of Ehrlich, to extend it to toxins of non-microbial origin. We are already acquainted with a certain number of antitoxins which, however, are not comparable in number to the other antibodies. Amongst these, the fixatives have many points of analogy with the antitoxins. Like them, they are resistant to heat: they exhibit also a fairly marked specificity, and, like the fixatives, they are distributed in the plasmas.

[Sidenote: [586]]

In the presence of so many points of similarity with the fixatives, one is tempted to attribute to the two categories of antibodies the same origin. The elaboration of antitoxins by the phagocytic elements, accumulated in the blood and disseminated in the organs, appears, in fact, to be very probable. Certain facts bearing on the absorption of various toxins by the leucocytes, as well as the distribution of antitoxins in the animal body, speak in favour of this view. On the other hand, the impossibility of attributing the elaboration of antitoxins to cells attacked by the corresponding toxins is quite in harmony with the same hypothesis. This hypothesis is especially supported by the numerous facts which prove the readiness with which the leucocytes react against all kinds of poisons, microbial or other toxins, as well as against organic and mineral poisons, such as the alkaloids and the arsenical combinations. However, in spite of so many data which speak in favour of the phagocytic origin of antitoxins, it has been impossible to support this view by rigorous facts easy of interpretation, such as those which science possesses in support of the phagocytic origin of fixatives.

The antitoxins have acquired a very great importance in the artificial cure of toxo-infective diseases, the aim in these cases being to paralyse the action of the toxins already produced by the micro-organisms and absorbed by the diseased animal. But their function is less in the protection against diseases where the object to be obtained is a reaction against the micro-organisms before these are able to inundate the animal with their toxic secretions. It is for this reason that the immunity against toxins must, in the study of immunity, occupy a less preponderant place than does the immunity against micro-organisms.

As the micro-organisms placed in the refractory animal ultimately undergo a digestion by chemical substances elaborated by the phagocytes, so also the toxins undergo a chemical modification due to the presence of substances in the production of which the living elements of the animal play a large part. The direct action of antitoxins on the toxins, so well demonstrated, especially by Ehrlich’s investigations, does not, however, exclude the intervention of living cells, which, though sometimes not very manifest, is in other cases very marked.

[Sidenote: [587]]

The reaction of the living elements against the microbial toxins and their allies leads to the production, and even the over-production of antitoxins. According to Ehrlich, these elements are the receptors, or side-chains, which, to a certain extent, pre-exist in the cells which are capable of elaborating the antitoxins. On entering into combination with the toxin molecules, the side-chains, which are indispensable for the nutrition of the cells, are reproduced in very large numbers. After having saturated, so to speak, the productive elements of the antitoxin, the superfluous side-chains escape from the cell and pass into the plasmas of the body fluids. This theory may be brought into harmony with the other theory, which maintains that certain elements of the animal, capable of acting on the complex molecules of microbial toxins and their allies, produce special soluble ferments, which digest the toxins whose introduction frequently excites the hypersecretion of the ferments. Here we have something similar to the hypersecretion, by the glands of the stomach, of pepsin, a part of which passes into the blood in order to escape with the urine.

According to Ehrlich’s theory, the antitoxins are only capable of neutralising the injurious action of toxins when the former are found dissolved in the body fluids. The same receptors which fix the toxins in the plasmas and thus prevent them from reaching the susceptible elements, bring about an opposite result when they are found inside the cells. In this latter case, the receptors, owing to their great affinity for the toxins, attract them and allow them to pass into the cells, in this way aiding the dangerous function of the toxophore group.

This is an ingenious idea, conceived to bring into harmony a certain number of observed facts. In the present state of our knowledge it cannot be subjected to rigorous experimental test. Many well-established facts, however, are not in complete accord with this hypothesis. According to it the antitoxic immunity resides exclusively in the body fluids; the living cells, instead of acquiring immunity, become more and more susceptible. Under these conditions it is difficult to conceive of an immunity against poisons of the simplest organisms; nevertheless, this certainly exists. A plasmodium, which becomes adapted to all kinds of toxic substances, acquires an immunity against them, and this is due to changes taking place in the living elements; it is not the result of modifications in the toxic fluids which bathe them. This biological adaptation is observed in the case of physical factors which may interfere with the life of these primitive organisms.

On the other hand, it must be accepted that the living cells of a complicated and higher organism may also acquire immunity against toxins. The first example of this kind was shown in relation to the red blood corpuscles of mammals vaccinated against the toxic serum of the eel. Whilst the body fluids of immunised rabbits become antitoxic, their red blood corpuscles, when completely freed from the serum, in certain cases resist the action of the eel’s serum. It must be admitted that in this example we have an acquired immunity of the cells similar to that met with in lower organisms.

[Sidenote: [588]]

A second example of the immunity of the red corpuscles was observed by Ehrlich and Morgenroth in goats prepared by injections of the blood of other individuals of the same species. In this case, according to these writers, no co-operation by antitoxin is met with. The body fluids of the goats do not become capable of neutralising the toxin of the haemolytic serum, whilst the red corpuscles themselves acquire an immunity against this toxin, an immunity entirely cellular. Ehrlich attempted to penetrate into the essential mechanism of the resistance of the red blood corpuscles on the supposition that these corpuscles, instead of reproducing their receptors, as when there is production of antitoxin, get rid of them entirely. Deprived of receptors, they can no longer be affected by the haemolytic cytase which, as Ehrlich maintains, only penetrates into the red corpuscles owing to the affinity of the intermediate substance (fixative) for the receptor. This hypothesis of the mechanism of acquired cellular immunity scarcely accords with the hypothesis of the special function attributed to the receptors in the nutrition of the living elements.

Cellular immunity can be most easily demonstrated in relation to the red corpuscles of the blood, as these elements are very numerous and are capable of being isolated and freed from the fluid in which they are bathed. For this reason, science does not as yet possess sufficiently exact data on the immunity of other cells in higher animals. Many facts, however, indicate that such immunity does exist. There are, indeed, living elements which only acquire immunity with great difficulty and very slowly. Such are the nerve cells, elements which are specially susceptible. Von Behring has strongly insisted on the fact that in animals subjected to repeated injections of bacterial toxins, the nerve centres not only do not become accustomed to their injurious action, but even acquire a hypersusceptibility which is often very great. The observation is perfectly accurate, but it is none the less true that this period of exaggerated susceptibility is followed by another, during which the susceptibility becomes less marked and ends by giving place to a true adaptation. We are, therefore, compelled to accept the fact that even the nerve cells are no exception to the general rule, but are able to acquire a diminished susceptibility to a poison.

[Sidenote: [589]]

Several facts of another series confirm this conclusion. In the study of the action of the nervous system one frequently has occasion to observe instances of adaptation. I will cite as an example the adaptation of animals to spinal concussion studied by Lépine[922]. By percussing the lumbar region of rabbits and guinea-pigs we may induce in them an immediate paraplegia. This is transitory, and lasts at most for a few hours. The phenomenon may be reproduced several times in the same animal. “But,” remarks Lépine, “when these experiments are continued for several days or several weeks, striking always at the same level, we soon observe that the resistance of the animals to the blows increases very rapidly, and that excitations which, in normal animals, produce paraplegias of several hours’ duration, produce no effect upon those which have been under experiment for several days.” We have in this example a real adaptation of the spinal region when subjected to concussion.

Similar facts are known to everyone as an experience of daily life. We can become habituated more or less easily to all kinds of violent sensations. Light and very intense noises which, at first, excite exaggerated reflex actions are ultimately perceived without setting up the least movement. Even in the psychical sphere habit dulls painful feelings, and it is very probable that a whole gamut of adaptation, starting from unicellular organisms which accustom themselves to live in an unsuitable medium, up to cultured human beings who habituate themselves to a disbelief in human justice, will be found to rest upon one and the same fundamental property of living matter.

[Sidenote: [590]]

Regarded from this point of view, immunity becomes a very general phenomenon, passing far beyond the resistance offered by the animal to infective diseases. After all is said and done, it invariably reduces itself to that cellular susceptibility [irritability] which governs so many of the vital phenomena in plants and in animals. It is this susceptibility which impels the branch towards the light and the root towards the ground, and which guides the spermatozoon towards the ovum. From the very commencement of embryonic life the cells derived from the segmentation of the egg exhibit a marked susceptibility. Wilhelm Roux[923] observed that the earliest cells of the frog embryo, if they are separated by artificial intervention, guided by their positive chemiotaxis again come together. In the formation of the tissues cellular susceptibility plays an important undoubted rôle. The prolongations of the nerve cells direct themselves towards the organs of sense or towards the muscular fibres, according to their specific susceptibility[924]. The mother-cells of the capillary vessels are also guided by susceptibility, when they go towards a new-formed tissue, or when they approach one another and come together in order to form a vascular loop.

The phenomena of the organism which bear the sharpest impress of their physical and chemical nature, also come under the influence of cellular “sensations.” Thus, in gastro-intestinal digestion, the secretion of the active juice is subordinated to the control of the nerve centres and even of the psychic centres. The sight of various kinds of food stimulates, unconsciously, by reflex action the activity of different digestive glands. In the same way the contraction of the contents of the cells of a plant subjected to plasmolysis, brings about the secretion of acid in order to augment the osmotic pressure.

Susceptibility, whose part is so great in the phenomena of immunity, taken as a whole, is a general property of living beings, regulated by a common law. Thus, in the chemiotaxis of the lowest unicellular organisms, as in the movements and the osmotic reaction of plants, there is manifested the same psycho-physical law of Weber-Fechner which regulates our own sensations.

[Sidenote: [591]]

All cells are able, by modifying their function under the direction of susceptibility, to adapt themselves to changes in the surrounding conditions. All living elements are able, therefore, to acquire a certain degree of immunity. But, amongst all the cells of the animal body, the elements which have retained most independence—the phagocytes—most easily and first acquire immunity to infective diseases. These are the cells which betake themselves to situations where micro-organisms and their poisons make their appearance, and which manifest a reaction against them. The phagocytes of the immune organism ingest and destroy micro-organisms and absorb toxins and other poisons. The final act of the reaction of the phagocytes is constituted by the chemical or chemico-physical processes concerned in the digestion of the micro-organisms, with the help of cytases, assisted by the fixatives; in the defence offered against poisons the phagocytes must also exert a chemical action. Before these phenomena come into play, however, the phagocytes manifest phenomena which are purely biological, such as the perception of chemiotactic and other sensations, the migration towards menaced situations, the ingestion of micro-organisms and the absorption of toxins, and finally the secretion of substances to be utilised in intracellular digestion.

The immunity in infective diseases presents itself, therefore, as a section of cellular physiology, and especially as a phenomenon concerned in the absorption of micro-organisms. This absorption being carried out by an act of intracellular digestion, the study of immunity comes into the chapter on digestion regarded from the general point of view.

As in the struggle of the body of the animal against infective agents the phagocytes play the principal part, it happens that in certain diseases the micro-organisms in order to manifest their morbific effect must be protected from the attacks of these defensive cells. It is for this reason that the cholera vibrio, which is not very injurious when introduced below the skin of the human subject, becomes very formidable when it succeeds in gaining access to the digestive canal. Incapable of maintaining a struggle against the phagocytes, the vibrio is able to overcome in the stomach and in the intestines without difficulty the obstacles which it here meets with. It is for this reason that the channel of entrance of the micro-organisms at times plays such a prominent rôle in immunity against infective diseases.

The question is often asked whether a theoretical study of immunity is capable of rendering service in the search for means of conferring immunity on the animal. It must not be forgotten that theory and practice frequently march side by side, but that sometimes they advance without very much regard for each other. Thus the first preventive inoculations against snake-bite, small-pox, and pleuropneumonia, attempted by laymen were evidently made independently of any theoretical ideas of any kind, but were guided by the purest empiricism. On the other hand, the theoretical researches on the nature and origin of ferments led to the discovery of vaccinations by means of micro-organisms and microbic products which have rendered immense services to practical medicine.

[Sidenote: [592]]

[Sidenote: [593]]

The discovery of antitoxins, so rich in practical applications, was influenced by theoretical researches on the mechanism of immunity. Von Behring began his important series of investigations on this subject with the study of the immunity of rats against the anthrax bacillus. It did not suggest itself to anyone to suppose that this question could have the slightest immediate practical interest; nevertheless, starting from this investigation, von Behring, after giving up the theory of the bactericidal property of the body fluids as a cause of immunity, advanced, step by step, to the discovery of the antitoxic power of the serums. When a study of the properties of the blood of animals treated with the red corpuscles of another species was commenced, no one would have suspected that these researches would end in the discovery of new methods for the recognition of human blood in medico-legal researches, or in the interests of hygiene for the determination of the source of a milk. The cellular theory of immunity is, as yet, of too recent date for us to claim the right to expect it to have amongst its assets methods for purely practical application. Nevertheless, it has already been found to be of service in the investigation of problems very closely affecting medical practice. Lord Lister, the greatest surgeon of the nineteenth century[925], asked himself how it was that wounds could heal “by first intention under circumstances before incomprehensible. Complete primary union was sometimes seen to take place in wounds treated with water-dressing, that is to say, a piece of wet lint covered with a layer of oiled silk to keep it moist. This, though cleanly when applied, was invariably putrid within twenty-four hours. The layer of blood between the cut surfaces was thus exposed at the outlet of the wound to a most potent septic focus. How was it prevented from putrefying as it would have done under such influence if, instead of being between divided living tissues, it had been between plates of glass or other indifferent material?” “How were the bacteria of putrefaction kept from propagating in the decomposable film? Metchnikoff’s phagocytosis supplied the answer. The blood between the lips of the wound became rapidly peopled with phagocytes which kept guard against the putrefactive microbes and seized them as they endeavoured to enter. If phagocytosis was ever able to cope with septic microbes in so concentrated and intense a form, it could hardly fail to deal effectually with them in the very mitigated condition in which they are present in the air. We are thus strongly confirmed in our conclusion that the atmospheric dust may safely be disregarded in our operations; and Metchnikoff’s researches, while they have illumined the whole pathology of infective diseases, have beautifully completed the theory of antiseptic treatment in surgery.” (_Rep. Brit. Ass._, p. 27.)

We may even attempt to increase phagocytosis in surgical operations, especially in those on the peritoneal cavity, by there setting up an artificial aseptic inflammation, by means of various substances, innocuous in themselves, which attract a large number of leucocytes. In laboratory practice this method is in daily use for the purpose of increasing the resistance of an animal against intraperitoneal injections of various micro-organisms, and Durham has suggested the extension of the same method to human medicine. Certain surgeons have already made attempts in this direction.

The application of the cellular theory of immunity to researches on new micro-organisms of infective diseases has already been crowned with success. Nocard and Roux have attempted to cultivate in the animal body the virus of the pleuropneumonia of cattle. They selected the rabbit, an animal naturally refractory against this infection. On the supposition that, in this immunity, the phagocytes must play an important part as destroyers of the presumed micro-organisms, the idea suggested itself to them to withhold the virus from their voracity. With this object they filled sacs of collodion or of reed pith with pleuropneumonia virus, and introduced these sacs into the peritoneal cavity of rabbits. Some time after this operation these investigators were able to demonstrate in the contents of the sacs impregnated by the blood fluid of rabbits, immune animals, the development of specific micro-organisms, the smallest discovered up to the present. By means of cultivations of this micro-organism, obtained in suitable media, they worked out a method of vaccinating animals which, as mentioned in Chapter xv., has already begun to give good results in veterinary practice. This method has thus contributed to the prevention of diseases, a branch of knowledge which has made such great advances since medicine became an exact science under the inspiration of the discoveries and ideas of Pasteur.

[Sidenote: [594]]

Within a very short period immunity has been placed in possession not only of a host of medical ideas of the highest importance, but also of effective means of combating a whole series of maladies of the most formidable nature in man and the domestic animals. Science is far from having said its last word, but the advances already made are amply sufficient to dispel pessimism in so far as this has been suggested by the fear of diseases, and the feeling that we are powerless to struggle against them.

LIST OF AUTHORITIES QUOTED.

Abel, 443, 444, 445, 536

Abel. _See_ Loeffler

Achalme, 96

Achard and Bensaude, 264, 451

Adil Bey. _See_ Nicolle

Almquist, 178

Arloing, 264, 452

Arloing, Cornevin and Thomas, 471

Arnold, 411

Arthus, 95

Babes, 75, 348

Bach, 408, 410

Bail, 151, 185, 359

Balbiani, 13, 23, 133

Bardach, 150

Barthels, 507

Bary (de), 31, 32

Batzaroff, 411

Baumgarten, 138, 193, 521, 522, 524

Bayeux. _See_ Roger

Behring, 20, 152, 153, 205, 242, 290, 334, 335, 348, 350, 352, 367, 369, 374, 375, 378, 417, 526, 540, 561, 564, 567

Behring and Kitasato, 266, 344, 347, 354, 357, 493, 495

Behring and Kitashima, 42, 290, 368, 370, 373

Behring and Knorr, 355

Behring and Nissen, 211, 226, 526, 531

Bensaude, 439

Bensaude. _See_ Achard

Bernard, 59

Bernheim, 408

Bertrand. _See_ Phisalix

Besredka, 111, 191, 231, 263, 273, 318, 353, 390, 396

Besson, 170

Beumer and Peiper, 230

Biedl and Kraus, 44

Birch-Hirschfeld, 514

Bitter, 525

Bizzozero, 48, 177, 418, 428

Bjelooussoff, 55

Blagovestchensky, 323

Bolton, 205

Bordet, 22, 68, 79, 87, 90, 94, 95, 105, 107, 111, 112, 115, 123, 166, 179, 185, 193, 194, 196, 199, 215, 217, 223, 244, 251, 256, 257, 258, 282, 298, 302, 313, 320, 321, 535, 537

Bordet. _See_ Gengou

Bordet and Danysz, 467

Borrel, 478

Borrel. _See_ Roux, Yersin

Bouchard, 184, 232, 286, 323, 343, 427, 529

Bouchard and Charrin, 42, 528

Bourne, 327

Braun, 12

Brieger, 369

Brieger and Fränkel, 344

Briot, 109

Brücke, 66

Brunner, 45

Buchner, 87, 95, 184, 185, 188, 193, 255, 357, 362, 377, 412, 512, 527, 528, 530, 539, 540

Cahanescu, 430

Calmette, 334, 339, 345, 346, 347, 348, 358, 365, 386, 389, 395, 425, 489

Calmette. _See_ Yersin

Calmette and Deléarde, 365

Calmette and Salimbeni, 491

Camus and Gley, 110, 121, 360

Cantacuzène, 224, 225, 306

Castle. _See_ Davenport

Cattani, 446

Cayley, 484

Celakovsky, 30

Celli, 278

Centanni, 446

Chamberland, 470

Chamberland. _See_ Pasteur, Roux

Chantemesse, 259

Chantemesse and Widal, 230, 267, 319, 437

Chapeaux, 55, 56

Charrin, 232, 286, 287, 427, 428, 541

Charrin. _See_ Bouchard

Charrin and Gamaleia, 290, 343

Charrin and Gley, 446

Charrin and Lefèvre, 419

Charrin and Magnin, 427

Charrin and Roger, 232, 256

Chatenay, 393

Chauveau, 289, 446, 455, 511, 512

Chépowalnikoff, 59

Cherry. _See_ Martin

Cienkowski, 446

Cobbett, 205

Cohn, 23

Colombot. _See_ Sabrazès

Cornevin, 452

Cornevin. _See_ Arloing

Couch, 53

Courmont, 400

Courmont. _See_ Nicolas

Courmont and Doyon, 330, 386, 394

Curtis, 172

Czaplewski, 146, 147

Dallinger, 26

Danysz, 21, 25

Danysz. _See_ Bordet

Daremberg, 87

Darwin, 8

Davenport and Castle, 27

Davenport and Neal, 24

Decroly and Rousse, 396

Deléarde. _See_ Calmette

Delezenne, 61, 96, 98, 107, 116

Delezenne and Froin, 66

Delius and Kolle, 277

Dembinski, 147

Denys, 533

Denys and Havet, 151, 185

Denys and Kaisin, 151

Denys and Leclef, 243, 246, 283, 312

Denys and Marchand, 313

Denys and van de Velde, 359

Deutsch, 107, 293, 294, 537

Dienert, 26

Dieudonné, 139, 143, 147

Dinkelspiel. _See_ Nuttall

Doederlein, 429

Dönitz, 391

Dominici, 78

Dominici. _See_ Gilbert

Doyon. _See_ Courmont

Dreyer, 350

Duclaux, 26

Dujardin-Beaumetz, 478

Dungern (von), 91, 109, 123, 324

Durham, 256, 261, 569

Dzierzgowsky, 448, 449

Effront, 26

Ehrlich, 114, 115, 344, 346, 349, 356, 360, 361, 365, 378, 391, 392, 420, 449, 562, 563

Ehrlich and Hübener, 446, 452

Ehrlich and Lazarus, 76

Ehrlich and Morgenroth, 88, 89, 92, 95, 104, 114, 116, 124, 193, 194, 199, 268, 537, 538, 563

Ehrlich, Kossel and Wassermann, 496

Ehrlich and Wassermann, 356

Elmassian. _See_ Morax

Emden (van), 264

Emmerich, 237, 322, 527

Emmerich and di Mattei, 236, 527

Emmerich and Löw, 254

Emmerich and Mastbaum, 475

Ermengem, 420, 491

Errera, 39

Escherich. _See_ Klemensiewicz

Faber (Knud), 344

Fahrenholtz, 138

Fehleisen, 434

Fermi and Pernossi, 109

Ferran, 480

Fischer, 193, 213, 253

Fischl and Wunschheim, 445

Fleck, 413

Flügge, 43, 184, 525, 540

Fodor, 184, 525

Foerster, 380

Fontana, 333

Forssmann, 565

Frank, 35, 154, 542

Fränkel, 344, 347, 499, 534

Fränkel. _See_ Brieger

Fränkel and Sobernheim, 268

Frantzius, 425

Fraser, 345, 425

Frédéricq, 55, 57

Freudenreich, 323

Freund, Grosz and Jelinek, 365

Froin. _See_ Delezenne

Funck, 267, 319, 320, 456

Galeotti. _See_ Lustig

Gamaleia, 419

Gamaleia. _See_ Charrin

Garnier, 220, 304

Gaule, 515

Gautier, 400

Gengou, 19, 20, 146, 151, 157, 185, 190, 203, 242, 252, 255, 260, 264, 308, 543

Gengou and Bordet, 190

Geret. _See_ Hahn

Gheorghiewsky, 210, 234, 236, 261, 269, 301, 307, 359

Gibier, 137

Giessler, 37

Gilbert and Dominici, 424

Gilkinet, 172

Gley. _See_ Camus, Charrin

Glogner, 434

Goldschmidt, 411

Gottstein, 499

Gramatschikoff, 412

Grancher. _See_ Pasteur

Grawitz, 513, 515

Griffon. _See_ Landouzy

Grosz. _See_ Freund

Gruber, 224, 256, 262, 542

Gscheidlen. _See_ Traube

Guarnieri, 455

Guinon. _See_ Voisin

Günther, 541

Haeckel, 517

Haffkine, 480, 486–488

Hafkine, 17

Hahn, 188, 190

Hahn and Geret, 197

Hankin, 156, 187

Hardy. _See_ Kanthack

Harnack, 337

Häser, 507

Havet. _See_ Denys

Hayem, 47, 514

Hegeler, 196

Herbst, 565

Héricourt. _See_ Richet

Herzen, 62

Hess, 144, 149, 524

Hewlett. _See_ Thomson

Heymans. _See_ Lang

Heymans and Masoin, 396

Hildebrandt, 109, 119, 412

Himmel, 182

Hippocrates, 342

Hirsch and Mehring, 64

Hoffmann and Recklinghausen, 46

Horvath, 337

Hübener. _See_ Ehrlich

Hudalo, 436

Hueppe, 254

Hugenschmidt, 415

Issaeff, 219, 262, 287, 318, 320, 441

Issaeff. _See_ Pfeiffer

Jakowski, 42

Jeanselme, 411

Jelinek. _See_ Freund

Jenner, 507

Jetter, 193

Jona, 172

Joubert. _See_ Pasteur

Kaisin. _See_ Denys

Kanthack, 360, 542

Kanthack and Hardy, 185

Karlinsky, 134, 260

Kempner and Schepilewsky, 387

Kempner. _See_ Rabinowitsch

Kilborne. _See_ Smith

Kitasato. _See_ Behring

Kitashima. _See_ Behring

Klebs, 514

Klecki (von), 44

Klein, 324

Klemensiewicz and Escherich, 443

Klemperer, 271, 356, 411, 441, 449

Klipstein, 170

Knorr, 361, 362, 370, 375, 378, 383, 392, 443

Knorr. _See_ Behring

Koch, 137, 247, 278, 279, 283, 419, 425, 434, 436, 466, 514, 529

Kolle and Turner, 466, 467

Kolle. _See_ Delius, Pfeiffer

Kondratieff, 365

Kossel, 110, 121, 183

Kossel. _See_ Ehrlich

Kossiakoff, 25

Kovalevsky, 41, 133, 134, 209

Krafft-Ebing, 436

Krajouchkine, 465

Kraus and Seng, 258

Kraus. _See_ Biedl

Kretz, 371

Krikliwy, 46

Krompecher, 83

Krönig. _See_ Menge

Krukenberg, 30, 49, 55

Kübler, 458

Kupffer, 75

Kuprianow, 204, 340

Kurt, 499

Laehr, 413

Landouzy and Griffon, 451

Landsteiner, 100

Lang, Heymans and Masoin, 363

Langhans, 73, 84

Laschtschenko, 188

Laurent, 33, 35, 86

Laveran and Mesnil, 173, 248, 316

Lazarus, 272, 441

Lazarus. _See_ Ehrlich

Leber, 79, 96

Leclainche, 475, 476

Leclainche. _See_ Nocard

Leclainche and Vallée, 107, 171, 472, 523

Leclef. _See_ Denys

Le Dantec, 13

Lefèvre. _See_ Charrin

Leishman. _See_ Wright

Leo and Senator, 66

Lépine, 564

Lermoyez. _See_ Wurtz

Lesage, 47

Le Sourd. _See_ Widal

Leube, 67

Levaditi, 223

Levin, 159

Lewes, 53

Lewin, 337, 338

Lignières, 247, 279

Lindemann, 68

Lingelsheim, 193, 244, 312

Lister, 521, 530, 568

Loeffler, 7, 283, 513

Loeffler and Abel, 267

Löhr, 500

Lombard, 396

London, 94

Lorenz, 475

Löw. _See_ Emmerich

Lubarsch, 141, 151, 184, 529

Lustig and Galeotti, 490

Madsen, 349, 350

Madsen. _See_ Salomonsen

Magnin. _See_ Charrin

Maksutow. _See_ Pawlowsky

Malm, 149

Manfredi, 428

Mankowski. _See_ Podwyssozki

Marchand, 167

Marchand. _See_ Denys

Marchoux, 240, 276, 309, 311

Marie, 331, 382, 465

Marinesco, 75

Marmorek, 243, 312

Martel, 150, 159

Martin and Cherry, 361

Marx, 465, 476, 497

Marx. _See_ Pfeiffer

Masoin. _See_ Heymans, Lang

Massart, 34, 38, 39, 79, 281

Mastbaum. _See_ Emmerich

Mattei (di). _See_ Emmerich

Maupas, 16

Mehring. _See_ Hirsch

Melkich. _See_ Sawtchenko

Mendez, 470

Menge and Krönig, 429, 430

Mesnil, 55, 75, 78, 135, 139, 141, 143, 188, 209, 221, 238, 262, 270, 305, 307, 527

Mesnil. _See_ Laveran

Metchnikoff, 31, 55, 69, 70, 73, 100, 101, 116, 131, 137, 138, 146, 149, 151, 153, 154, 156, 160, 163, 180, 181, 185, 214, 221, 227, 237, 239, 241, 256, 259, 266, 271, 275, 286, 287, 290, 302, 304, 311, 377, 382, 385, 393, 396, 405, 426, 441, 520, 521, 522, 531, 532, 534

Metchnikoff (Mme), 20, 159, 193

Métin, 44

Miller, 414, 415, 418

Mitchell, 423

Morax and Elmassian, 409

Morgenroth, 109, 119, 331

Morgenroth. _See_ Ehrlich

Morishima, 390

Morse, 412

Mouton, 15

Moxter, 101, 185, 199

Müller, 17, 89, 114, 233

Myers, 68, 107

Myers. _See_ Stephens

Neal. _See_ Davenport

Néfédieff, 68

Neisser, 194, 196

Neisser and Wechsberg, 205, 298, 349, 359

Nencki, 419, 424, 427

Nencki and Sieber, 109, 355

Nencki, Sieber and Wyznikiewicz, 468

Netter, 503

Nicolas and Courmont, 353

Nicolas, Courmont and Prat, 353

Nicolle and Adil Bey, 279, 468

Nikanoroff, 348

Nissen. _See_ Behring

Nittis (de), 277, 288

Nocard, 148, 279, 494

Nocard and Leclainche, 461

Nocard and Roux, 130, 466, 478, 479, 569

Nolf, 94, 96

Nowakowski, 12

Nuttall, 107, 138, 150, 184, 192, 525, 527

Nuttall and Dinkelspiel, 107

Oken, 337

Opitz, 43, 44

Oppel, 231

Orlowski, 443, 444

Pagel, 507

Panum, 514

Pasteur, 2, 181, 208, 288, 322, 477, 508, 510, 511, 569

Pasteur, Chamberland and Roux, 469

Pasteur and Joubert, 144

Pasteur, Roux and Grancher, 208

Pasteur and Thuillier, 283, 473

Patella, 97

Pawloff, 59, 62, 65, 427

Pawlowsky, 44, 323

Pawlowsky and Maksutow, 348

Peiper. _See_ Beumer

Péré, 26

Pernossi. _See_ Fermi

Petruschky, 138

Pfaundler, 259

Pfeffer, 27, 38, 79

Pfeiffer, 130, 165, 185, 219, 221, 267, 269, 271, 277, 290, 301, 303, 320, 365, 438, 455, 532, 533, 534

Pfeiffer and Issaeff, 212, 533

Pfeiffer and Kolle, 230, 267, 274, 302, 319, 481

Pfeiffer and Marx, 185, 264, 291, 442

Pfeiffer and Proskauer, 253

Phisalix, 387, 425

Phisalix and Bertrand, 333, 337, 338, 345, 347

Pierallini, 218, 219

Plato, 181

Podwyssozki, 77

Podwyssozki and Mankowski, 456

Pollender, 11

Ponfick, 46

Portier, 96

Prat. _See_ Nicolas

Preobrajensky, 431

Prevôt, 374

Proskauer. _See_ Pfeiffer

Rabinowitsch and Kempner, 248, 316

Ransom, 351, 379, 382, 389

Ranvier, 409

Rauchfuss, 501

Recklinghausen (von), 514

Recklinghausen. _See_ Hoffmann

Remlinger, 447, 450

Répin, 420

Rhumbler, 15

Ribbert, 413, 428, 524

Richet and Héricourt, 266, 532

Rindfleisch, 514

Rochebrune (de), 506

Röden, 109

Roger, 243, 257, 287

Roger. _See_ Charrin

Roger and Bayeux, 414

Rogers, 468

Römer, 401

Roncali, 170

Roser, 515, 516

Ross, 129

Rossbach, 95

Rouget. _See_ Vaillard

Rousse. _See_ Decroly

Roux, 156, 347, 358, 497, 498, 530

Roux. _See_ Nocard, Pasteur

Roux (W.), 565

Roux and Borrel, 340, 383, 386, 391

Roux and Chamberland, 530

Roux and Vaillard, 347, 355, 356, 357, 367, 379, 432, 493

Roux and Yersin, 343

Ruffer, 427, 428, 523

Rysselberghe (van), 37, 39

Sabouraud, 406

Sabrazès and Colombot, 135

Sakharoff, 160, 177

Salimbeni, 222, 245, 261, 478

Salimbeni. _See_ Calmette

Salmon, 455

Salomon, 418

Salomonsen, 19

Salomonsen and Madsen, 346, 356, 370, 379, 380

Saltykoff, 272

Samoïloff, 63

Sanarelli, 262, 287, 415

Sanchez-Toledo, 170

Sarassewitch, 195

Sawtchenko, 21, 99, 156, 162, 227, 240, 260, 270

Sawtchenko and Melkich, 162, 227

Schattenfroh, 172, 188, 196

Schepilewsky. _See_ Kempner

Schiff, 62

Schimmelbusch, 42

Schoumow-Simanowski. _See_ Sieber

Schumacher, 451

Schütz, 283, 422

Schütz. _See_ Voges

Schütze, 107, 114

Schütze. _See_ Wassermann

Sclavo, 276, 310

Selander, 290

Senator. _See_ Leo

Seng. _See_ Kraus

Serpa Pinto, 506

Shaffer, 42

Sicard. _See_ Widal

Sieber. _See_ Nencki

Sieber and Schoumow-Simanowski, 419, 424

Skchiwan, 172

Slateano, 277

Slawyk, 501

Smith, 259

Smith and Kilborne, 247, 279

Sobernheim, 242, 276, 310, 441

Sobernheim. _See_ Fränkel

Soudakewitch, 75

Soulié, 460

Stadelmann, 97

Stahl, 30, 31

Stein, 12

Stephens and Myers, 360

Stern, 419, 542

Sticker, 411

Stöhr, 428

Stoudensky, 388, 394

Strassman, 499

Straus and Wurz, 417, 418

Stroganoff, 429

Takaki. _See_ Wassermann

Talma, 424

Tarassewitch, 86, 87, 98, 99

Tchistovitch, 68, 75, 106, 110, 120, 121, 122, 283, 413

Thiltges, 145, 147

Thomas, 452

Thomas. _See_ Arloing

Thomson and Hewlett, 410

Thuillier. _See_ Pasteur

Tizzoni, 357, 446

Tooth, 484

Torday, 498

Toussaint, 509

Trapeznikoff, 139, 145

Traube and Gscheidlen, 184

Trommsdorff, 23, 189

Trumpp, 261

Turner. _See_ Kolle

Uhlenhuth, 68, 107

Vaillard, 204, 335, 347, 356, 372, 447

Vaillard. _See_ Roux

Vaillard and Rouget, 169, 170

Vaillard and Vincent, 169, 394

Vallée, 289, 425

Vallée. _See_ Leclainche

Velde (van de). _See_ Denys

Viala, 465

Vincent. _See_ Vaillard

Vincenzi, 443

Virchow, 48, 519, 524

Voges, 238, 272

Voges and Schütz, 475

Voisin and Guinon, 502

Vries (de), 35

Wagner, 144

Waldeyer, 514

Wallgren, 168

Walter, 64

Walz, 193

Warlomont, 456

Washbourn, 485

Wassermann, 115, 191, 205, 231, 234, 273, 317, 318, 319, 322, 351, 358, 371, 441

Wassermann. _See_ Ehrlich

Wassermann and Schütze, 107

Wassermann and Takaki, 292, 382, 394

Wassilieff, 65

Watson-Cheyne, 323

Weber-Fechner, 27, 38, 566

Wechsberg. _See_ Neisser

Wecker, 502

Wehrmann, 417, 419, 424

Weichhardt, 118, 124

Weigert, 363, 379, 399, 424, 523

Werigo, 281

Wernicke, 276, 446, 447

Widal, 257

Widal. _See_ Chantemesse

Widal and Le Sourd, 439

Widal and Sicard, 260, 261, 264, 439, 440, 450

Wood. _See_ Woodhead

Woodhead and Wood, 323

Wright, 482

Wright and Leishman, 482

Wunschheim. _See_ Fischl

Wurtz and Lermoyez, 410

Wurz. _See_ Straus

Wyssokowitch, 43, 412, 485

Wyznikiewicz. _See_ Nencki

Yersin, 468

Yersin. _See_ Roux

Yersin, Borrel and Calmette, 487

Zabolotny, 95

Zeliony. _See_ Zilberberg

Ziegler, 519, 522

Zilberberg and Zeliony, 282

INDEX.

Abrin, 344, 345, 346, 401

Abrin intoxication, action of body fluids on, 365, 420; leucocytic reaction against, 393, 401

Absorption. _See_ Resorption

Acari, mechanical action of, 3

Acclimatisation. _See_ Adaptation

Acid reaction inside phagocytes, 83, 182

Acid, secretion of, in osmosis, 37, 566

Acidophile microbian flora of stomach, 418

Actinians, digestion in, 53, 82, 85

Actinodiastase, 57, 197

_Actinophrys_, 14, 18

Adaptation. _See also_ Immunity

Adaptation to toxic substances, 21–27, 30, 342, 390; to saline solutions, 23, 30, 515; to physical conditions, 26, 30–31; of plasmodia to arsenious acid, 31; of pancreatic secretion to kind of food, 64, 65; of phagocytes to destroy micro-organisms, 281, 558, 566; of animals to spinal concussion, etc., 564; of cells, 513

Addiment (syn. Complement), 95

Agglutination in natural immunity, 202, 206; and phagocytosis, 202, 242, 245; in the diagnosis of typhoid, 256, 257, 261, 439; its mechanism, 257; of red blood corpuscles by serums, 258; of red blood corpuscles by ricin, 360; does not prevent growth of micro-organisms, 262

Agglutinative power, transmission by heredity or suckling, 450; not developed parallel with bactericidal power, 483

Agglutinins in immunity, 242, 245, 256–265, 295, 542, 559; characters of, 255, 559; origin of, in immunised animal, 263–265, 294; difference between fixatives and, 255, 265, 559; not the same as protective substances, 268, 269, 294

Albuminoid substances, resorption of, 106–127

Alexins. _See also_ Cytases

Alexins, 87–95, 96, 98, 184, 193, 255, 528, 533, 535, 539

Alimentary canal. _See_ Intestine

Alizarin sulpho-acid, 13, 83, 183

Alligator, 77, 143, 332, 401

Amboceptors (syn. fixatives), 91, 93, 297, 557

_Ammocoetes_, 77, 78

_Amoeba_, 14, 18, 23, 547, 549

Amoebo-diastase, 16, 197, 549

Amoeboid cells. _See_ Leucocytes and Phagocytes

Amphibia. _See_ Frog, Axolotl

Amylase, 95; in the urine, 65

_Androctonus._ _See_ Scorpion

_Anopheles_ and malaria, 129

Antagonism between certain bacteria, 323

Anthrax, 11, 20, 21, 25, 41, 46, 180; immunity of dog against, 149–151, 242; acquired immunity of _Scolopendra_ against, 209; natural immunity of white rat against, 526; protective serums against, 20, 276, 309–311; phagolysis in acquired immunity against, 280; immunisation against, by means of other bacteria, 323; infection by inhalation, 412; by ingestion, 423; immunity against, transmitted to offspring, 445, 447; vaccinations against, 208, 241, 468–471; method, 470; statistics, 471; vaccination against, by heated anthrax blood, 507; vaccines against, 208, 470, 509; phagocytosis in, 521, 523

Anthrax bacillus, action on rabies, 150; bactericidal action of blood serums on, 20, 146, 150, 151, 156, 157, 240; increasing the virulence of, 150; attenuation of, 208, 288; eosinophile transformation in, 198; protective thickening of bacterial membrane in, 242; agglutination of, 203, 242, 260, 264; natural immunity against, 132–140, 143, 147, 149–159, 511, 512; acquired immunity against, 239–242, 276, 277; antagonism between, and certain bacteria, 323; fate of, in Algerian sheep, 512; destruction of, by defibrinated blood, 525

Anthrax, symptomatic: immunity against bacilli of, 171; heredity of immunity against, 452; vaccinations against, 471–473; phagocytosis in, 523

Antiabrin, 401

Anti-arsenic serum, 390

Anticytases, 112

Anticytase serum, 115, 371

Anticytotoxins, 110, 118, 122, 127, 360

Antidiastase, 109

Antidiastatic serums, 361

Anti-enzymes, 109

Antifixative, 112

Antihaemolysins, 111

Antihaemotoxins, 111, 119, 122

Anti-infective. _See_ Protective

Antileucocidin, 359

Antineurotoxin, 116

Antirennet, 109

Antiricin, 360

Antisepsis, Nature replaces by asepsis, 432

Antiseptics. _See also_ Toxins and Adaptation

Antiseptics and foods, 26

Antiseptic action of the gastric juice, 417

Antispermofixative, 124

Antispermotoxins, 116, 122–126

Antistreptococcic serum, 243–245

Antitetanin, nervous origin of, 390

Antitoxic. _See also_ Protective

Antitoxic unit of Ehrlich, 373, 496; action of non-specific and normal serums and of broth, 365; function of the saliva, 417; function of pepsin and other digestive ferments, 419, 424; action of intestinal flora, 427; property of the body fluids, 531 (_see_ Body fluids, Serums); power of the blood of new-born children, 445

Antitoxins, natural, in normal blood, 111, 204, 444; rarity in body fluids in natural immunity, 204, 532, 533; development of, during immunisation, 354; properties of, 354; present in various fluids of immunised animal, 355, 531; mode of action of, on toxins, 356–362, 371; conditions acting in mixtures of, with toxins, 362; immunity against toxins not in direct constant ratio to amount of, 367–376; effect of using serum from same species, 379; hypothesis as to nature and origin of, 377–402, 562; probable part played by phagocytes in production of, 400–402; rapid regeneration of, after bleeding, 379; augmentation in production of, by pilocarpin, 380; transmission of, by milk to offspring, 449; analogy of, with fixatives, 561; hypersecretion of, 563

Antivenomous property of blood of scorpion, 328; action of serums, 334, 338; serum, action of, 334, 338, 358, 360

Aqueous humour, bactericidal action of, 184, 192; in immunised animals contains no fixative, 217, 222; in immunised animals contains antitoxin, 355

Arsenic; adaptation to, 31, 343, 390; protective serum against, 390; leucocytic reaction against, 396–399; as a remedy against microbial disease, 513

Arsenic acid, action of, on anthrax bacillus, 25

Arsenious acid, adaptation of plasmodia to, 31

Arthropoda. _See_ Clothes-moth, Crayfish, Crustacea, _Daphnia_, _Scolopendra_, Scorpion, Spider, Tick

Arthrospores of Hueppe, 254

_Ascaris_, poor microbian flora in intestine of, 421; phagocytic organs of, 547

Asepsis is Nature’s method, 432

Aspergillosis, 2, 4. _See also_ Mycoses

Atrophic diseases, probably due to a parasite, 3

Atropin, reaction of rabbit and guinea-pig to, 395, 396

Attenuation. _See also_ Vaccination, Vaccines

Attenuation of micro-organisms and viruses, discovery and application of, 208, 247, 288, 508; of micro-organisms by the fluids of immunised animals, 286–289; of toxins, 344

Autodigestion in yeast, 197

Autospermotoxins, 101

Autotoxins, 104

Axolotl, susceptible to tetanus toxin, 330

Bacilli, anaerobic, natural immunity against, 169, 170

_Bacillus aërogenes_, agglutination in, 264

_Bacillus chauraei._ _See_ Anthrax symptomatic

_Bacillus coli_ attacks potato, 35; vaccination against, 267; transformation of, into granules, 198; modified growth on certain serums, 259

Bacillus of Doederlein, 429; of Kiel water, 408

_Bacillus pyocyaneus_, 42, 180, 254, 528; acquired immunity against, 210, 232–236, 301; Pfeiffer’s phenomenon in, 234, 307; special forms of growth in serums from vaccinated animals, 256; agglutination of, 261, 307; susceptibility to the toxins of, 290, 351; action of specific serum on, 307, 358; antagonistic to anthrax bacillus, 323; immunisation against toxin of, 351; a leucocidin from, 359; action of liver on toxin of, 427; heredity of immunity against toxin of, 446

_Bacillus ranicida_, 140

Bacteria. _See_ Micro-organisms

Bactericidal action of serum, influence of alkalinity or acidity on, 196; function of the tears, 408

Bactericidal property. _See also_ Body fluids, Humoral theory, Serums

Bactericidal property: in blood and other fluids, 20, 146, 150, 151, 156, 157, 184–193, 211, 226, 233, 238, 240, 241, 243, 244, 512, 525–531, 542, 554; of body fluids, theory of osmotic pressure, 193, 213; of extracts of glands and exudations, 195; of the saliva, 415; absence of, from the intestinal ferments, 424, 567; of serums, Wright’s method of testing, 483; does not develop parallel with agglutinative, 483; and immunity, absence of parallelism, 554

Bactericidal substance (alexin, complement, cytase): in blood and other fluids, 184–193, 534; source of, in body fluids, 185–193; theory of leucocytic secretions, 187–191; presence in body fluids due to phagolysis, 191; is of phagocytic origin, 185, 192; in body fluids, microphages source of, 187; not resistant to heat, 268; and so distinguished from protective substance, 268; Pfeiffer’s theory of, 534

Bacteriolysis. _See_ Micro-organisms, destruction of

Bacteriolysis, analogy between haemolysis and, 537

Bat, immunity against tetanus of hibernating, 339

Baumès-Colles’ law in syphilis, 436

Behring’s “normal serum,” 496

Bile, function of, 60; salts protective against snake venom, 388; protective function of, 424

_Bipinnaria_, 70, 518

Blastomycetes. _See also_ Yeast-cells

Blastomycetes, resistance of _Daphnia_ to, 131, 404, 520; fa

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