For centuries the question of immunity has occupied the human mind because the prevention of disease has ever been one of the greatest preoccupations of Man. Savages had already observed that man can become refractory to the venom of serpents, either through a slight bite or by the application of certain preparations of that venom on scarified skin. It was also a popular and very ancient notion that the contact of a slightly scratched hand with the pustules of cow-pox conferred immunity against human small-pox. It was on this observation that Jenner founded his method of antivariolic vaccination. The latter, in its turn, suggested to Pasteur the idea of attempting antimicrobian vaccinations. Having ascertained that old cultures of chicken cholera, previously very virulent, had become harmless, he wondered whether they had become a vaccine and proved by experiment that they had. That led him to the principle of the attenuation of viruses and to that of vaccination by attenuated microbes. Thus the problem of the mechanism of immunity was stated.

The first theories propounded on the subject concerned the humors. Pasteur supposed that immunity was due to the absorption, by the vaccinating microbes, of certain nutritive substances in the humors, which, not being renewed for some time, were missed by the microbes afterwards introduced into the organism, which therefore could not develop completely. Chauveau, on the other hand, thought that, in cases of immunity, the humors contained substances which were unfavourable to microbes. Those theories explained particular facts, but were not applicable to the generality of cases.

Other theories,[21] whilst attributing an active part to the organism itself, failed to account for the mechanism of immunity in general. This was due to the fact that knowledge at that time lacked the two essential elements, i.e. the modifications suffered by the organism which was becoming immunised, and the fate of the microbes in the refractory organism.

The disappearance of the microbes in the cured or refractory animal had indeed been observed;[22] the inflammatory reaction of the organism in the course of immunisation had been noted;[23] microbes had long ago been observed inside the white globules of pus;[24] but, either an erroneous interpretation was given to the facts observed, or, rather, the links of causality between those factors failed to be established because they were observed solely in the complicated organism of superior beings. Humoral theories, less easy to test, preserved an appearance of generality and were easily admitted.

Such was the state of the question when Metchnikoff approached it from a naturalist’s point of view. He knew the life of unicellular beings and that of the lower multicellular organisms in their complete simplicity; he knew their mode of defence by ingestion and intracellular digestion. Having become familiar with these phenomena, visible in the single cell, he was better able to see his way in the complicated milieu of higher beings. He was therefore able to discover the connection between the divers factors which other scientists had observed singly. He was able to prove that it is the combination of these factors, i.e. inflammation, the ingestion of living and virulent microbes, and their disappearance by means of intracellular digestion which makes immunity possible. He demonstrated that “there is but one permanent element in natural or acquired immunity, and that is phagocytosis.”

The extension and importance of this factor, applicable to the whole animal kingdom, proved the truth and general scope of the phagocyte doctrine of immunity.

In 1900, Metchnikoff presented to the International Congress in Paris a complete tabulation of his researches and fought his contradictors for the last time, after which, convinced that his deductions were solid, he began to write a work on Immunity in Infectious Diseases. In it he epitomised, as in a great harmonious chord, the results of his researches, reaching over a period of nearly twenty years; he affirmed and gave final expression to his doctrine of immunity, based on the comparative study of the mechanism of that phenomenon and of its evolution along the whole scale of living beings; he related his controversies, analysed the objections to his doctrine, expounded the theories of other scientists concerning immunity, and gave a general view of the present state of the question. This book is a living picture of a long and important part of Metchnikoff’s scientific achievements.

The question of immunity is of such great importance, the mechanism of this phenomenon and the physiology of intracellular digestion are so complicated, that I have thought it useful to epitomise here the exposition given of it by Metchnikoff in his book. Readers who do not care to go further into the subject can pass over the next few pages without hindering their comprehension of the following chapters.

Diseases affect all living beings, and the greater number of plants and animals would cease to exist without innate or acquired immunity.

Unicellular beings are generally immune against infectious diseases, which are rarely observed in them. Their body being almost entirely made up of digestive protoplasm, the microbes which they absorb are directly introduced into a noxious medium and are destroyed therein like any other food. If the microbes are indigestible, they are immediately rejected; hence, in the majority of cases, they cannot become harmful.

This resistance of unicellular beings to many microbes and microbian toxins is due not only to the intense digestive power of the cell but also to the extreme sensitiveness which rules over the choice of food. Owing to this protoplasmic sensitiveness (chimiotaxis) protozoa are attracted towards certain microbes or substances (positive chimiotaxis) and repelled by others (negative chimiotaxis). Thus, many ciliate infusoria choose bacteria only for their food; they are sharply repelled by dead infusoria, etc.

Therefore, in the natural immunity of unicellular beings, two fundamental elements may already be observed: sensitiveness and intracellular digestion. No researches have yet been made on the possibility of conferring on protozoa an artificial immunity against certain pathogenic microbes and their poisons. But unicellular beings, insensible to microbian poisons, are the reverse to many chemical substances which, in their normal life, they have no opportunity of ingesting.

It has been proved by experiment that, against many of those chemical substances, an artificial immunity may be given to the protozoa by accustoming them gradually. Very diluted solutions are added at first to the medium in which they live and, by gradually concentrating those solutions, an artificial immunity is conferred; the negative chimiotaxis becomes positive, allowing the protozoa to absorb and digest the poison, now become a food.

Habit is therefore the fundamental condition of artificial immunity; it must be that also of immunity naturally acquired. Having accidentally digested enfeebled microbes or having suffered an attack of disease, the unicellular being becomes accustomed to a stronger virus and becomes immune against it. The fact that so many unicellular beings have become thus accustomed is therefore connected with their sensitiveness and their digestion. Accordingly, sensitiveness, habit, and digestion are the fundamental factors of the mechanism of immunity in protozoa; this immunity thus indisputably belongs to the category of purely cellular phenomena.

Having arrived at this conclusion, Metchnikoff thought that the same mechanism of immunity must be found in other primitive and analogous cells, such as the phagocytes of multicellular beings. This was proved by a whole series of observations and by the fact that the immunity of higher animals is connected with an intense phagocytosis. In fact, as he ascended the scale of beings and studied their natural and artificial immunity, he ascertained that, in all of them, the essence of immunity, masked by the complexity of the organism, reduced itself to the phagocytes becoming accustomed to noxious agents. The mechanism of immunity in protozoa could therefore really be compared with that of immunity in multicellular beings.

Becoming accustomed and becoming immune are phenomena of a general order, for they can be manifested not only by animals, but also by plants. They, too, have to defend themselves against numerous diseases. Lower vegetables, such as myxomycetes (beings which stand on the limit between the animal and vegetable kingdoms), have an amoeboid phase, in which they are but a simple heap of formless protoplasm. During that stage of their life, myxomycete behave towards noxious agents exactly in the same way as unicellular beings and, like them, acquire immunity by becoming gradually accustomed.

In higher vegetables, the mechanism is different because of their structure. The cells of nearly all plants are immobilised by rigid membranes; therefore they cannot surround their prey, but protect themselves by the production of tough membranes (cicatrisation) and by the secretion of various juices. Certain of these juices (gums and resins) become solid when exposed to the air and constitute a sort of natural (dressing); others (essences) are antiseptic. The secretion of these cellular juices in plants is therefore a powerful means of defence. This defence is due to the extreme sensitiveness of the protoplasma of vegetable cells: they react against irritation by a defensive secretion. Vegetables, as well as unicellular beings, can accustom themselves or become artificially accustomed to noxious influences and acquire immunity.

As to animals, Metchnikoff had already proved long ago that they defend themselves against morbid agents by phagocytosis, i.e. by intracellular digestion. It is always to be found in cases of immunity and is indispensable to it, on the same grounds as in unicellular beings. The organism of multicellular animals possesses various cells which play the part of phagocytes. There are some in the blood and humors, as also in the divers organs and in the tissues. These phagocytes are either mobile—leucocytes, or fixed—tissue-cells. However, all those cells may be classed into two principal groups: the microphages and the macrophages. Both categories of cells are capable of digesting microbes, but it is chiefly done by the microphages, whilst macrophages more especially digest figured elements (cells) of animal origin and poisons. It may be said that the microphages are vegetarians whilst the macrophages are chiefly carnivorous.

What, then, is the mechanism of phagocytic digestion?

Intracellular digestion by phagocytes is accomplished by means of digestive ferments, similar to those of our own digestive organs. “In both cases,” says Metchnikoff, “a diastasic action is due to soluble ferments produced by living elements. In intracellular digestion, the diastases digest within the cells, whereas in extracellular digestion the phenomenon takes place outside the cells, in the cavity of the gastro-intestinal tube.”

Only gradually has intracellular digestion given place to the digestion by secreted juices. The link between these two modes is to be found in certain transparent Invertebrates, such as the floating mollusc PhyllirhoË. The nourishment is first digested in the cavity of the digestive tube by secreted juices, and its treatment is completed within the amoeboid cells of the cÆcum.

In higher animals, the digestion of food is due to several digestive ferments (rennet, pepsin, trypsin, enterokinase, etc.) produced by divers organs (stomach, pancreas, intestines). The phagocytes also manufacture several digestive ferments; their principal digestive juice is a soluble ferment of the trypsin category, to which Metchnikoff gave the name of cytase.[25]

To the morphological difference of the phagocytes corresponds also a difference in the properties of their cytases, which are suited to the digestion of this or that food. The cytases are kept within the interior of the cells and only escape into the humors when the phagocytes are damaged (Pfeiffer’s phenomenon). This kind of ferment does not withstand a temperature above 55° to 58° C. In natural immunity, it plays the principal part by digesting morbid agents inside the phagocytes like any other food. But, in artificial immunity, other soluble ferments come into play, developed in consequence of vaccination.

The principal of those is the fixator.[26] It is less sensitive than cytasis to high temperatures and can bear a temperature of 65° to 68° C. It is incapable, by itself, of killing and digesting, but by fixing on them, it bites them, so to speak, and makes them sensitive to the action of the phagocytic cytases, which can thus digest them more easily.

The fixator may be compared to enterokinase, a special ferment in the small intestine of higher animals which also does not by itself digest food but which activates in a high degree the digestive power of pancreatic ferments. However, it has the property of fixing itself on fibrin; it is obvious that enterokinase and the fixator have the same essential properties. This similarity again proves that the destruction of morbid agents by the phagocytes really corresponds with actual digestion.

It is in consequence of the digestion of vaccinal products that the phagocytes manufacture the fixator. Created at the expense of a given vaccinal substance, the fixator has a specific character which corresponds with that substance, whereas the cytase already existing within the phagocytes never has a specific character.

Artificial immunisation generally produces the formation of so great a quantity of fixators that the phagocytes are unable to retain them and excrete them in part in the ambient humors, i.e. the blood plasma, or serum. When, afterwards, virulent morbid agents (microbes or figured elements) are introduced into an organism which has been immunised against them, they are at once faced, in the humors, with fixators, which immediately exert a biting action on them and render them sensitive to the action of the intracellular cytasis of the phagocytes. The same mechanism explains the specificity of the serums of vaccinated animals.

The quantity of specific fixators in the humors depends on the surplus production of that ferment by the phagocytes and is not always the same. That is why different serums are preventive in different degrees. They are inactive if the phagocytes have not produced enough fixators to pass any out into the humors. For a serum is only preventive when it brings into the new organism into which it is injected a sufficient quantity of fixators ready to sensibilise the morbid agents afterwards introduced into the organism.

The over-production of antibodies—fixators or antitoxins—corresponds up to a certain point with the frequency and quantity of vaccinal injections; that is why serums are usually preventive in artificial immunity and very rarely so in natural immunity. Through successive inoculations, the cells become accustomed to digesting the microbes, or figured elements, and manufacture, in consequence of that digestion, growing quantities of fixators.

In natural conditions, on the other hand, morbid agents do not usually penetrate into the organism in massive or repeated doses; therefore digestion under natural conditions results in a less abundant production of fixators which can be contained in the interior of the phagocytes without leaking into the humors in sufficient quantities to render the latter preventive.

It might be thought that immunity against pathogenic microbes is accompanied by immunity against their toxins. In reality that is not always the case, and very often the organism, now made refractory to certain microbes, remains sensitive to their toxic products. Thus antimicrobian immunity and antitoxic immunity constitute in most cases two distinct properties. In order to confer antitoxic immunity recourse must be had to vaccination by soluble poisons and toxins.

Immunity, acquired naturally, is so especially against microbes and not against toxins, for, in nature, it is almost always by microbes that the organism is threatened. As to antitoxic immunity, it is very probably due to the intracellular digestion of toxins by the different macrophages. This hypothesis is supported by the experiments quoted in the preceding chapter. During antitoxic vaccination, the macrophages manufacture, probably at the expense of vaccinal toxins, a certain quantity of antitoxins, substances which offer a great similarity with the fixators. Like them, they are specific; they are also produced in great quantities and excreted into the humors, which they render antitoxic when sufficiently abundant; finally, they are not very sensitive to high temperatures. That is why, in spite of the impossibility of proving their origin directly, it is quite probable that it is analogous to that of the fixators and that antitoxins are manufactured by cellular elements, the macrophages in particular. For it is they which absorb and digest toxins as well as soluble poisons.

This deduction is also supported by the antitoxic immunity which may be conferred on unicellular beings in which the cell alone enters into play.

Phagocytes no doubt manufacture many other soluble ferments corresponding with the elements which they absorb, for, in a vaccinated organism, divers new specific properties of the serum are to be found, such as that of agglutination, precipitation, etc. Humoral properties may be more or less durable, in proportion as the products manufactured by the phagocytes are more or less rapidly evacuated by the organism.

All these humoral properties, traced back to their first source, depend upon the digestive activity of the phagocytes, since they are the products of that digestion. In cases where it has not yet been possible to make a direct demonstration of this, it becomes evident through analogy and experiments pointing in that direction.

To sum up, according to Metchnikoff, “Immunity in infectious diseases is linked with cellular physiology, namely, with the phenomenon of the resorption of morbid agents through intracellular digestion. In a final analysis, the latter (as also the digestion of food in the gastro-intestinal tube) reduces itself to phenomena of a physico-chemical order; however, it is a real digestion accomplished by the living cell.... The study of Immunity, from a general point of view, belongs to the subject of Digestion.”

Immunity against diseases is but one of the manifestations of an immunity on a much larger scale, always based, in final analysis, on the sensitiveness of the living cellular protoplasm. The sensitiveness of the nervous cells extends this phenomenon to the psychical domain. They also are capable of becoming accustomed to external irritations of all kinds, hence constituting a psychical immunity for the organism. We all know that one can become accustomed to many painful or violent sensations; and, as Metchnikoff says: “... It is very probable that the whole gamut of Habit, starting from the unicellular beings, who accustom themselves to live in an unsuitable medium, to cultured men who acquire the habit of not believing in human justice, rests on one and the same fundamental property of living matter.”