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.
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.
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.
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.
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.
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.
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.