Immunity

IMMUNITY. Contents: History and current state of the doctrine of immunity.

Immunity in protozoan and spirochetal infections.

Immunity (from Latin immunitas - freedom from public service, exemption from something), insusceptibility. The term immunity is generally used to denote insusceptibility to something, most frequently the insusceptibility of an organism to a contagion, but also to any foreign substances in general. History and current state of the doctrine of immunity. The science of immunity is called immunology and is one of the oldest fields of human knowledge, as it concerns questions of exceptional practical importance, specifically, questions on methods of protecting oneself and one's livestock from epidemic diseases. This explains why, already in deep antiquity, the practical problems of immunity were actively pursued by the popular masses themselves as well as by their rulers, legislators, and even religious figures. Thus, starting from idolatry to later religions—confucianism, buddhism, judaism, christianity, mahometanism, and so forth—everywhere one finds carefully systematized rules for protecting oneself from contagion, which are presented to believers in the form of divine commandments and for the violation of which sinners are threatened with eternal torments. In the traditions and daily life of the most primitive peoples, one frequently encounters preventive instructions developed through the hard experience of previous generations, which are striking in their expediency and fully correspond to the modern level of immunology. Travelers (Rochebrune, Serpa Pinto) and historians (Barbels, Pagel, Haeser, and others) recount, for example, that the Moors and Peuls of Senegambia from time immemorial knew how to protect their cattle by means of inoculations of negligible doses of virus against contagious pleuropneumonia, that the Chinese, Persians, Circassians, and Georgians had long practiced anti-smallpox vaccination among their children and women, that the wild Watuasu tribe (eastern coast of Africa) from time immemorial possessed the secret of protecting themselves from the fatal bite of venomous snakes, and so on. However, immunology received its first scientific foundation only in 1795, when Edward Jenner published the results of his twenty years of observations on the anti-smallpox vaccine. The works of L. Pasteur, Roux, and Chamberland on the vaccinating action of attenuated cultures of chicken cholera (1878–80), as well as the discoveries of R. Koch, introduced immunology into the circle of exact experimental sciences. Over the course of the last 50 years, immunology has been enriched with its own highly perfected and almost mathematically exact methodology. This has allowed it to gather a multitude of extremely valuable facts and has drawn into the circle of its investigations not only questions of medical practice, but also questions of major general biological significance. In the field of practical medicine, immunology has introduced a number of clinical and epidemiological methods, such as: methods of serodiagnosis of infections, vaccine prophylaxis and vaccine therapy, chemotherapy and serum therapy, biological tests for the state of insusceptibility, and so on. As facts accumulated, the very theoretical foundations of immunity gradually changed. Modern immunologists distinguish two main states of insusceptibility: absolute immunity and relative immunity. An example of absolute immunity can serve the insusceptibility of animals and plants to a huge number of so-called non-pathogenic microbes (saprophytes), which are incapable under any conditions of causing disease. To absolute insusceptibility also belongs the immunity of certain species of animals and plants to pathogenic microbes that infect other species of animals and plants, for example, the human immunity to the microbe of cattle plague, the immunity of the dog, horse, and so forth to human venereal diseases, and so on. An example of relative insusceptibility can serve the insusceptibility of the chicken to anthrax until the normal body temperature (41–42°) of the chicken is artificially lowered. To the state of relative insusceptibility also belongs the so-called labile, or partial, immunity encountered in chronic infections such as tuberculosis, syphilis, gonorrhea, malaria, and so on. With labile, or partial, immunity, usually no symptoms of the disease are observed despite the fact that a microbial focus persists in the organism. The presence of this focus maintains the animal's insusceptibility at a certain level. Removal of the focus is accompanied by the fact that the animals again become easily susceptible to the given infection. Thus, a tuberculous guinea pig responds to the subcutaneous administration of a new portion of tubercle bacilli by the formation of an abscess at the injection site, which then opens and scars over. In a healthy guinea pig, however, the injection of tubercle bacilli entails the formation of a long-non-healing ulcer in which vigorous multiplication of tuberculosis bacilli takes place. In addition, inflammation of neighboring lymph glands appears, which subsequently undergo caseous degeneration. The cited experiment proves that the presence of a tuberculous focus in the body of the guinea pig imparts to it a relative, "partial" immunity to a new tuberculosis infection. The very reaction of the guinea pig, which is under the influence of the tuberculous focus, to its new infection bears the name of "Koch's phenomenon" and is altered ("allergic") compared to the reaction to tuberculosis in a healthy guinea pig. The case under consideration can also serve as an example of "non-sterile" immunity, that is, immunity not accompanied by the liberation of the organism from the infection. Morgenroth showed that white mice having a chronic streptococcal infection tolerate without harm to themselves an additional infection (superinfection) with doses of streptococcus that are even lethal to normal animals. A type of relative immunity when a chronic infection renders an animal insusceptible to additional infection was called by Morgenroth "Depressionsimmunität". Along with absolute and relative immunity, one must distinguish general immunity, that is, the insusceptibility of the entire organism, from local, "histogenic" immunity, when insusceptibility to contagion is exhibited only by specific and even some single tissue of the given organism. The doctrine of local immunity is intensively developed by Besredka and his adherents, although the independent significance of this kind of immunity is disputed by Bordet and other researchers. The concept of local and general immunity is closely connected with the concept of local and general infection, with the dose of the infecting agent playing a prominent role. According to its internal content, immunity can be directed against the microbe itself or against the toxic products secreted by it. Hence a new distinction: antimicrobial immunity and antitoxic immunity. An example of the former is the absolute insusceptibility of fish to anthrax or frogs to the cholera vibrio. An example of the latter can serve the insusceptibility of reptiles, spiders, and frogs to tetanus toxin, rats to diphtheria toxin, snakes and scorpions to their own venom, and so on. According to its origin, the state of insusceptibility is 1) a state of natural, or congenital, immunity, and 2) a state acquired during individual life. The first type of immunity is inherited, whereas the second is not inherited. However, the proposition that individually acquired immunity is not inherited requires additional clarifications. Immunologists distinguish two types of individually acquired insusceptibility: 1) actively acquired immunity and 2) passively acquired immunity. When an organism actively acquires immunity, tissues and organs participate in its production, undergoing corresponding changes in the process of fighting the contagion. Therefore, for example, the blood serum of an animal that has safely survived diphtheria, that is, has acquired active immunity against diphtheria, will neutralize diphtheria toxin. By parenterally introducing such an antitoxic antidiphtheritic serum into a fresh animal that has not had diphtheria, one can make it artificially passively insusceptible to diphtheria intoxication. And this passively acquired insusceptibility will last in the given animal until the foreign antidiphtheritic antitoxic serum is eliminated from its organism (usually several weeks, whereas actively acquired immunity lasts months, years, and even decades). Actively acquired immunity is reflected in the properties not only of blood serum, but also of other body fluids. Ehrlich showed that female mice actively immunized with plant poisons (ricin, abrin) impart passive antitoxic immunity to these poisons to their offspring during the lactation period. Abel, Pischl, and others believe that during pregnancy the transfer of passive immunity to offspring can take place from an actively insusceptible mother through the placenta, but this is not hereditary immunity in the exact sense of the word, but a temporary, passive immunity transmitted via the womb. It goes without saying that the father cannot transmit actively acquired immunity. Natural immunity. Natural, congenital, inherited immunity is usually a species trait in animals and plants. Along with such species immunity, racial congenital immunity is sometimes encountered. Examples of the latter can serve Yorkshire pigs, which are less susceptible to swine erysipelas (Rotlauf) than other breeds of pigs, Algerian sheep, which exhibit increased resistance to anthrax, and so on.

The basis of racial immunity, alongside certain features of organization, apparently lies in those living conditions due to which individuals of a given race must frequently come into contact with the corresponding infection and develop an individual immunity to it. Thus, according to data from Charles Nicolle, the natives of Tunisia, an endemic focus of dysentery, are less susceptible to this infection compared to Europeans. The state of natural non-susceptibility, both species and racial, is composed of the action of a twofold kind of major factors. Some of them play the role of simple mechanical barriers protecting the internal territory of the body from microbes and other elements alien to the body. Others belong to the reactive protective properties of the cells and fluids of the body as a complex physicochemical whole. The role of mechanical barriers in the human body is played by the skin and mucous membranes. The integrity of the skin prevents the penetration of microbes into the body. The constant shedding of layers of the keratinized epidermis mechanically removes numerous microbes, its inhabitants, from the skin surface. This process is facilitated by the secretion of their products by sweat and sebaceous glands, which carry out to the skin surface the microbes that have penetrated into these glands. No less important a role than the skin is played by the mucous membranes, the integrity of which protects the body from the invasion of microbes from the conjunctiva of the eye, the mucosa of the nasopharynx, and from the respiratory, digestive, and urogenital tracts. The protective function of the mucous membranes is facilitated by the work of the ciliated epithelium, which sweeps away with its cilia, like brooms, the microbes that find themselves in areas covered by this epithelium. In addition, glands (lacrimal, salivary, digestive, etc.) moistening various mucous membranes with their secretions wash microbes off them and even, according to the observations of some authors (Bernheim, Wurtz, Lermoyez), are capable of significantly damaging them. About the extent of the daily self-cleaning work of the body, freeing it from the resident microbes of the skin and mucous membranes, one can judge by approximate calculations given by Strasburger. According to these calculations, 1/4 to 1/5 part of the dry matter of human daily excrement consists of microbes (about 85 billion). Among the latter, pathogenic ones are not infrequently encountered. A characteristic feature of the mechanical factors of the body's self-defense is that they represent adaptations determined by the very anatomical structure of the given naturally non-susceptible species. They continue to act in full volume under all conditions of the body's existence until its anatomical integuments are damaged. They do not exhibit any specificity in their action and with equal success prevent the penetration of the most diverse pathogenic and non-pathogenic microbes into the internal territories of the body. But at the base of natural immunity lies not only a species anatomical structure providing the body with mechanical protection from external harms. The state of natural species (resp. racial) non-susceptibility depends no less on the physicochemical properties of the cellular and humoral systems of the body. The difference in normal blood alkalinity in various animal species (Behring), testifying to species differences in metabolism itself within the body, the difference in the species structure of protein even in closely related species, confirmed by numerous biological tests, the difference in normal body temperature as an indicator of metabolic intensity, the difference in hair coloration in the same species (nigritin and albino rabbits according to the experiments of Barykin and Zdrodovsky)—all this leaves its imprint on the protective reactive properties of the body's colloids and finds expression in one or another sign of natural immunity characteristic of a given species or race. Fluctuations in the physicochemical, resp. reactive properties of the body's biocolloids inevitably entail fluctuations in the intensity of natural immunity even within the limits of the very same species and race. These fluctuations in natural immunity bear the character of individual fluctuations. These include fluctuations in natural immunity depending on age, on individual anatomical features of the body, on constitution, on diatheses, on dietary regime, on climatic, living, social conditions, etc. As for the influence of age on the intensity of natural immunity, it has long been known that children are little susceptible to some infectious diseases of adults, and vice versa. Thus, children are little susceptible to typhoid fever, typhus, etc., and adults to measles, scarlet fever, poliomyelitis, etc. However, the low susceptibility of children makes itself felt mainly at an infant age; later on, with respect to most infections, the children's organism, on the contrary, is more susceptible. From a physicochemical point of view, in explaining age-related fluctuations in non-susceptibility, one should keep in mind that the colloidal systems of the body throughout individual life undergo steady change toward their aging (Ruzicka, Marinesco, Loeb, etc.), which has been named "hysteresis." Thus, at various periods of life, the same organism exhibits varying degrees of susceptibility and non-susceptibility to infections, and we observe the same thing in animals in this regard as in man. Thus, puppies are especially susceptible to canine distemper, young guinea pigs to experimental typhus, which is little contagious to adult guinea pigs, and so on. But here a whole series of other organic features is also of essential importance, such as, for example, the difference in the degree of permeability of mucous membranes to microbes, the unequal intensity of neutralization of microorganisms that have penetrated through the mucosa in neighboring lymph nodes (Neufeld), and the like. The significance of anatomical features for the state of immunity is clearly revealed by Freund, who showed that pulmonary tuberculosis is especially frequently accompanied by anomalies in the anatomical structure of the chest. The significance of constitution and associated with it the endocrine system was established in the field of immunity by the works of Malvoz, Munk, Kepinov, Metalnikov, and others. Epidemiological works showing that the morbidity of some infectious diseases is in direct dependence on the harvest and prices of rye; direct experiments of Glukhov, in which starving rabbits proved incapable of producing immunity against typhoid fever and cholera; finally, data from the Rockefeller Institute proving that food rich in vitamins increases non-susceptibility to infections—all this leaves no doubt about the significance of the dietary regime for the state of immunity. Speaking of the state of the body's biocolloids and the associated protective reactions of the latter, which lie at the base of its natural non-susceptibility, one should keep in mind two types of such biocolloids, namely: 1) biocolloids with a definite morphological structure (this includes various cellular formations) and 2) biocolloids devoid of this structure, which are the intercellular substance and humoral systems of the body. Corresponding to the indicated division, the study of immunity has long proceeded along two main lines: first, cellular and second, humoral protective reactions of the body were studied. The significance of cellular defense in natural non-susceptibility was indisputably proven in 1882 by Mechnikov and his co-workers, although even before Mechnikov many researchers had seen microbes located in leukocytes (Haeckel, Hayem, Klebs, Panum, Grawitz). However, the fact of the penetration of microbes into leukocytes was regarded as a method of generalization of infection. To Mechnikov belongs the credit of establishing a diametrically opposite view of the indicated fact. Mechnikov proved that leukocytes themselves capture microbes, destroy them, and thus free the host organism from them. Mechnikov developed his observations into a coherent doctrine of phagocytosis in its not only medical, but also general biological significance. According to the phagocytic theory of immunity, whenever microbes overcome the mechanical barriers of the body and penetrate into its internal territories, leukocytes accumulate at the site of their introduction, striving to capture them with their false feet (pseudopodia), draw them into the protoplasm, and destroy them there by digestion in a specially formed digestive vacuole filled with an acidic secretion. The role of phagocytes is played not only by polynuclear white blood cells, which have been named microphages, but also by its mononuclear cells, or macrophages, which also include numerous fixed mesenchymal cells of organs (brain glia, Kupffer's stellate cells of the liver, etc.). Unlike microphages, which take part in protecting the body from acute infections of bacterial origin, according to Mechnikov's teaching, macrophages fight infections of protozoan origin, as well as chronic bacterial and spirochetal infections (tuberculosis, syphilis, actinomycosis, etc.). However, there are not a few exceptions to this rule (e.g., the protective role of the reticuloendothelial system in the fight against pneumococcal infection). The force that attracts phagocytes to the site of introduction of the microbe into the body is, according to Mechnikov's theory, the tactile and chemical sensitivity of mesodermal cells to changes introduced into the body by elements alien to it.

This sensitivity was thoroughly studied by Ranvier, Massart, Bordet, and contested by Voronin for leukocytes. Experiments by the named authors established that leukocytes, much like microbes in Pfeiffer's experiments, possess the ability to approach certain stimuli and move away from others, i.e., they possess, in modern terminology, positive (approach) and negative (removal) tropic reactions, which are widespread in nature. Lebeau is credited with the exceptional merit of elucidating the nature and physicochemical mechanism of these reactions. Experiments on leukocytes further showed that substances lowering the organism's sensitivity, e.g., narcotic agents, lower and even paralyze both the migration of leukocytes to the site of microbial invasion and their phagocytic activity. Mechnikov's doctrine on the phagocytic properties of fixed mesodermal cells in recent years, under Aschoff's initiative, developed into a special chapter bearing a new name: the «Doctrine of the Reticulo-Endothelial System». Mechnikov's phagocytes play a prominent role in both natural and acquired immunity. In natural immunity, phagocytes successfully defend the organism against microbes that have accidentally penetrated its internal territories thanks, for example, to damage to the skin or mucous membranes. Furthermore, in the normal state of the organism, a constant migration of phagocytes to the surface of mucous membranes subjected to one or another external irritation is observed. Such are, for example, the phenomena of leukocyte migration during irritation of the conjunctiva, nasopharynx, lungs (dust cells, etc.). To the same category belong periodic accumulations of leukocytes along the wall of the digestive tract during the daily passage through it of the main food mass (the «Šter_phenomenon»). The cellular, phagocytic theory of immunity for quite a long time did not meet with recognition, mainly on the part of German scientists, who put humoral protective reactions of the organism in the foreground. Already since the 1880s, various researchers began to discover in the blood and fluids of immune animals a special ability to act on corresponding microbes. Thus, Grohmann, Nuttall, and Fodor showed that the blood of such animals in some cases is able to damage and even destroy bacteria; Buchner and Bouchard linked the bactericidal action of normal and immune blood serums with the presence in them of a special substance—alexin (see). Then there were described in blood serums: «antitoxins» (Behring, Kitasato), «bacteriolysins» (Pfeiffer, Isaev), «agglutinins» (Gruber, Durham), «precipitins» (Kraus), «opsonins» (Wright, Douglas), «tropins» (Neufeld, Rimpau), «cytolysins» and «hemolysins» (Bordet, Ehrlich, Morgenroth), «alexin-fixing substances» (Bordet, Gengou), «thrombocytobarins» (Krichevsky, Cherikover), giving the so-called Rieckenberg phenomena, and so on. All these substances of normal and immune serums are called «antibodies»—«normal» in natural immunity and «immune» in actively acquired immunity. Their significance for natural immunity is debatable. Mechnikov, for example, completely denies this significance; conversely, Nuttall, Flügge, and others prove that natural immunity, just like acquired immunity, depends entirely on the bactericidal substances of the blood. According to these authors, a secondary role in immunity falls not to the serum «antibodies», but to Mechnikov's phagocytes, which cleanse the organism of the corpses of microbes killed by serum «antibodies». Mechnikov's dispute with the humoralists was resolved by the discovery of «opsonins» of normal serums and «tropins» of immune ones. With the help of these substances, it was proved that the cellular and humoral reactions of immunity complement, rather than exclude, each other. The «opsonins» of normal serums and «tropins» of immune ones act on microbes subject to phagocytosis and alter them in such a way that after treatment with «opsonins» and «tropins», the microbes are particularly energetically attracted to phagocytes (Savchenko, Barykin) and become the prey of the latter (Wright, Douglas, Neufeld, Rimpau). Research by Savchenko and Barykin, confirmed by Levaditi and Muttermilch, showed that the act of phagocytosis, both in the presence of «opsonins» and «tropins» and without them, is a reaction of the adsorption type. In the reactions of «opsonization» and «tropinization», there is a striking example of the combined protective action of cellular and humoral systems. The coordination in the action of these systems is a particularly characteristic feature of active, individually acquired immunity. Actively acquired immunity. The state of active, individually acquired immunity is even more complex than the state of natural immunity considered above. In actively acquired immunity, all those protective adaptations and reactions continue to function which were discussed above in the analysis of natural immunity. But to these protective factors in actively acquired immunity there is added, as its most characteristic feature, the increased and selectively directed activity of phagocytes toward the pathogenic microbe and an equally specific action on this microbe by the humoral systems of the organism (blood serum, lymph, etc.). If under normal conditions human phagocytes are weakly capable of devouring both the dysentery bacillus, and the typhoid fever microbe, and the cholera vibrio, and this human blood serum just as weakly agglutinates and opsonizes the named microbes, then from the moment of his acquisition of immunity, for example to cholera, both the phagocytes and the blood serum sharply intensify and specifically concentrate their action on the cholera vibrio, remaining as before weakly active against the bacteria of dysentery and typhoid fever. A person who has acquired immunity against cholera becomes insusceptible only to cholera, but not to typhoid fever, dysentery, etc. Since the specificity of acquired immunity finds its main expression in the serum antibodies of this immunity, work on the study of the latter has also focused on the humoral reactions accompanying it. Here, the question first arose as to how much such reactions are inseparable from acquired immunity. Researchers' opinions on this issue diverge. Thus, Bordet believes that there can be no acquired immunity without specific antibodies, whereas Besredka completely denies the necessity of the latter, referring to the fact that the quantity and character of these antibodies do not at all express the degree and character of immunity, and that the state of acquired immunity, for example after a successfully endured typhoid fever, can last a lifetime, while antibodies are no longer detectable a few months after recovery. True, the latter circumstance may depend not on the fact that the organism has ceased to produce antibodies, but on the fact that immunologists do not know how to detect them by methods available to them. In the indicated cases, the organism, as a rule, upon a new irritation by the corresponding antigen, reacts with a rapid and energetic production of antibodies and thereby differs from the non-immune organism. An excessive dose of antigen, for example cholera or typhoid vaccine, etc., can cause a temporary decrease in the antibodies present in the blood. This period of temporary decrease in antibodies is called the «negative phase of immunity» (see Anaphylaxis). The latter is replaced after 3–5 days by the «positive phase of immunity», when the amount of antibodies begins to increase again. The question of the dependence of acquired immunity on specific antibodies in turn raises new questions about the very origin of these antibodies, their nature, properties, and mechanism of action. However, not a single one of these questions has yet received a definitive solution. Immunologists know very little, for example, about the origin of specific antibodies. According to some researchers, these antibodies in acquired immunity are clearly distinct from the corresponding antibodies of natural immunity, whereas according to others, there is no fundamental difference between them. The very nature of antibodies remains unknown, since none of them has been successfully isolated by any researcher from blood serum in a pure form. As different antibodies were discovered, almost every one of them was attributed a decisive role in the construction of immunity. However, at present it can be considered established that the state of immunity is ensured not by any single antibody, but in each case by a motile combination of cellular and humoral reactions of the organism. In view of the disputability of cardinal questions relating to the very nature of immunity and its reactions, in the further presentation it will be necessary to touch upon numerous hypotheses proposed to explain the essence of this state of the organism. According to the «depletion theory» proposed by Pasteur and Klebs, the organism becomes insusceptible because the microbe that has penetrated it «depletes» in it all the reserves of nutrient substances necessary for subsequent generations of this microbe. According to Chauveau's theory, pathogenic microbes «retain» in the organism substances harmful to their further development. According to Grawitz, immunity depends on the «habituation» of the organism's cells to microbes. Buchner taught that immunity is conditioned by the «salutary» forces of the inflammatory reaction. All the listed theories of immunity at present have only historical interest.

Even at the time they did not enjoy great confidence, and for the modern immunologist their unconvincingness is obvious. A much deeper and more prolonged influence on the minds of researchers was exerted by the so-called "side-chain theory" proposed by P. Ehrlich and stubbornly defended both by himself and his numerous supporters. To explain the origin of specific antibodies, Ehrlich utilized the doctrine of the secretory activity of cells in the act of their nutrition. A cell is capable of attaching a nutrient substance to itself only if it possesses a corresponding chemical receiver, a "receptor," possessing a chemical affinity for the given nutrient substance. Since the nutrition of the cell can take place at the expense of the most diverse substances, the cell must also have at its disposal a whole assortment of various receptors ("nutriceptors"). By analogy with chemical compounds, protoplasm is constructed in such a way that it consists of a functional nucleus (Leistungskern), determining the biological essence of the given protoplasmic formation (cell), with "side chains" (Seitenkette) attached to it, or "receptors," i.e., atomic groups with the help of which the nucleus attaches nutritive and other substances to the protoplasm. If the receptors enter into a bond with substances not assimilable by the protoplasm, they are lost to the cell, and the latter produces them anew and moreover produces them in an excess quantity exceeding that amount which would be needed for the simple replenishment of the sustained loss. The excessive production of receptors can reach such proportions that their bond with the Leistungskern of the protoplasm is weakened and finally disrupted, so that the corresponding atomic groupings, receptors, appear in the blood and juices of the organism in a free state. Then the blood and juices acquire the ability, thanks to the presence in them of free receptors, to enter into specific reactions with the substance that served as the stimulus for the excessive production of receptors. This substance was named the antigen, and the free receptors the specific or immune antibodies. The significance of such antibodies is obvious. Whenever an antigen (microbe or its toxin) begins to enter the organism, it will no longer be in a state to reach the cell susceptible to it, since on the way to it in the blood and juices of the organism it will meet and enter into a chemical compound with antibodies specific to it (free receptors), as a result of which it will either be destroyed or bound and completely neutralized. According to their internal structure and the character of their action, receptors can belong to the following three types: 1) the first-order receptor (antitoxins, antienzymes) represents a chemical ("haptophoric") group directly combining with the antigen (toxin, enzyme) and neutralizing the latter, just as an acid neutralizes a base; 2) the second-order receptor (agglutinins, precipitins) consists of two groups—a haptophoric group, chemically combining with the antigen (bacterial or generally foreign cell or protein), and a functional, or "zymophoric," group acting on the antigen; 3) the third-order receptor (bacterio-, cyto-, hemolysins, Bordet-Gengou antibodies) also consists of two groups: a haptophoric group, chemically attaching the antigen to the receptor, and a complementophilic group, attracting the complement or alexin present in the blood to act on the antigen. Satisfactory in the first years of its existence, Ehrlich's theory subsequently encountered a number of rather substantial difficulties, for the interpretation of which within the framework of the same concept certain superstructures were required. Ehrlich's proposition, according to which the reaction between toxin and antitoxin is a chemical reaction and as such obeys the "law of multiple proportions" (Gesetz der Multiple), was refuted by the experiments of Danysz, Bordet, and others. The conclusions of Danysz and Bordet were confirmed by Eisenberg and Volk for other humoral reactions of immunity, and by Savchenko and Barykin for the phagocytosis reaction. A certain artificiality in some cases of Ehrlich's concept prompted Madsen in 1913 and Arrhenius in 1917 to make an attempt to interpret the reaction between immune serum and antigen, in particular between antitoxic serum and toxin, as a reaction of a physicochemical nature, subordinate to the law of mass action (Guldberg, Waage) and having as its prototype the combination of a weak acid with a weak base (e.g., boric acid and ammonia). According to the Guldberg-Waage law, knowing the masses of the reacting toxin and antitoxic serum, at any moment of the reaction it can be predicted how much toxin has managed to combine with the serum and how much of both toxin and serum still remains free in the mixture. However, soon after the publication of the physicochemical theory of Arrhenius and Madsen, Madsen himself, and then Nernst, Sachs, Gengou, and others showed that in practice the reaction between toxin and antitoxic serum does not obey theoretical physicochemical calculations. The explanation for this must be sought in the fact that Arrhenius and Madsen took as the basis of their theory an unproven and erroneous assumption, having supposed that in immunity reactions we are dealing with simple physicochemical systems, and not with the most complex and as yet unstudied colloidal systems of the macro- and microorganism. The erroneousness of identifying immune reactions with ordinary chemical and physicochemical laboratory reactions was especially convincingly revealed in that branch of immunology which deals with the avidiness of antibodies and antigens. Enzyme theories. To explain the essence of immunity, alongside chemical and physicochemical hypotheses, propositions were advanced attempting to interpret this state of the organism from the standpoint of the enzymatic activity of its cells. Essentially, both Metchnikoff's phagocytic theory, which linked the origin of serum antibodies with leukocyte enzymes secreted into the blood, and Ehrlich's humoral theory, which proceeded from the idea that antibodies are the product of the secretory activity of cells during the act of their nutrition, both of these theories can be called enzymatic theories of immunity. The significance of enzymes for explaining the processes of infection and immunity is especially persistently and consistently pursued and defended by Wolff-Eisner, Vaughan, Wheeler, Jobling, and Slovtsov. Slovtsov believes that enzymes lie at the basis of the vital activity of the bacterial cell (antigen); enzymes, by cleaving proteins, participate in the formation of poisonous products of the toxin type, and enzymes also promote the formation of antibodies. Goad thinks that the antigen is a complex of protein and enzyme. While they are connected to each other, the enzyme is in a zymogenic state. Upon dissociation, it manifests its poisonous action and combines with new protein molecules, from which a certain radical is split off in the process, producing bodies called by Goad artificial immune antienzymes or "immunins" (Ehrlich's antibodies). Other supporters of enzymatic theories of immunity, such as Kassowitz and Ziegenböck, Zdravomyslov, Nastyukov, and others, give different explanations for the process of enzymatic antibody formation and attribute the properties of specific catalysts now to antibodies (Nastyukov), now to antigens (Kassowitz), and finally seek confirmation of the enzymatic theory in experiments on the artificial production of antibodies by treating the antigen with an enzyme (Zdravomyslov). The idea that antibodies are formed from the antigen was developed even by Buchner, but this idea still encounters serious objections, of which it is sufficient to mention the following: 1) antibodies are produced by animals in quantities completely disproportionate to the amount of antigen injected into them (Knorr, Pfeiffer, Gamaleya, Korshun, etc.); 2) after bloodletting, the amount of antibodies in the blood of an immune animal is restored without any additional injection of antigen; and 3) antibodies appear not only after the injection of antigen into the animal, but also upon a conditioned reflex established in the animal in connection with this injection. The experiments of some authors who attempted to obtain antibodies in vitro from antigens, such as Ostromyslensky's experiments on the artificial production of antitoxins and Zdravomyslov's experiments on obtaining agglutinins, hemolysins, etc., in vitro by enzymatic means, do not find confirmation in other authors (Afanasyeva, Dobrodin, etc.). A completely special place in the doctrine of the fate of foreign protein (antigen) during its parenteral digestion is occupied by Abderhalden's theory of protective enzymes (see Abderhalden reaction). Osmotic theory of Baumgarten and Holzinger. Alongside the aforementioned theories, a peculiar place is occupied by the so-called osmotic theory, according to which microbes perish in the organism thanks to the difference between the osmotic pressure existing in the organism and that to which the microbes are accustomed in the external environment. In 1900, a theory appeared in immunology that exerted a deep and prolonged influence on all subsequent development of this science. The theory belonged to the most authoritative immunologist of our day, the Belgian J. Bordet.

It was named the adsorption theory of I. Bordet. Touching little upon the essence of immunity and the nature of antibodies, Bordet set as his main task to elucidate the mechanism of the combination of these antibodies with the antigen. Through a series of brilliant experiments, he and his coworkers succeeded in proving with exhaustive conviction that reactions between antibodies and antigen belong to the type of adsorption compounds, that is, compounds where surface forces play the decisive role. Adsorption proceeds the more energetically the more strongly developed is the surface of the adsorbing body (the "adsorber"). The adsorption reaction ceases at the moment when equilibrium is established between the concentrations of the substance being adsorbed in the liquid and in the adsorber. The following precisely established facts speak in favor of the adsorption nature of immunity reactions: 1) reversibility—partial or complete—in the first phase of these reactions; 2) dependence of the reactions on the physical and chemical composition of the medium where they take place; 3) the zone of inhibition in these reactions, inexplicable from a chemical standpoint, when either the antigen or the immune serum is taken in excess (Ehrlich's theory, it is true, gave its own explanation of this phenomenon, but it undoubtedly suffers from a certain artificiality); 4) the influence on the outcome of immune reactions of the order of mixing of the reagents (the "Danosz phenomenon", etc.); and finally 5) the complete subordination of immune reactions to the Freundlich adsorption formula, which depicts the "adsorption isotherm" (see Adsorption). All these facts establish with complete clarity that the first phase of the reaction between immune serum and antigen is their adsorption compound. The adsorption reaction as a surface reaction is feasible only under the condition that the combining substances are in a state of colloidal or close to it comminution. Thus, the analysis of the mechanism of immune reactions leads to the conclusion that in immunity, the self-defense of the organism is ensured by the colloidal or close to the latter state of its cellular and humoral systems. In this regard, the merit of Bordet's theory was that it heralded and cleared the path for colloidal theories of immunity. Having established the adsorption character of immune reactions, Bordet thereby proved that the optimum of the reaction coincides not with the maximum of reacting bodies, but with a definite ratio of their concentrations, whence the name given by Bordet to his theory: the "theory of diverse proportions." On this point, Bordet's theory sharply diverges from the views of Ehrlich, Arrhenius, and Madsen. Just as starch can adsorb various amounts of iodine, so a toxin or other antigen, according to Bordet's theory, adsorbs various amounts of immune serum antibodies. According to the theories of Ehrlich, Arrhenius, and Madsen, the amount of required antibodies for combination with a definite amount of antigen is predetermined; in the case, for example, of the reaction between toxin and antitoxin, it is prescribed by the law of multiple proportions (Ehrlich) or the law of mass action (Arrhenius and Madsen). Simultaneously with the substantiation and development of the adsorption theory, attempts are made to explain the phenomena of immunity from the standpoint of colloid chemistry. However, the initial colloidal theories of immunity, such as the theories of Zangger, Landsteiner, Herzfeld, Klinger, and others, could not avoid the shortcomings associated with the far from perfect state of the colloid science of that time. The authors of the colloidal theories of immunity persistently sought to emphasize exclusively the physical properties of colloids and thereby contrast their views with the influence that Ehrlich's theory had in Germany and other countries. Nevertheless, despite the imperfection of colloid science, already in 1911 Traube succeeded in outlining extremely interesting and important physical features of immune reactions. According to Traube's "resonance theory," which is far from recognized by everyone, the introduced antigen disturbs the equilibrium in the state of the organism's colloids and produces a peculiar rearrangement in the molecular complexes of those upon which it acts. The rearrangement proceeds in the direction of the physical adaptation of the surfaces of these colloids to the irritant-antigen. Such a rearranged colloid, "tuned" to the antigen, acquires the properties of a specific antibody. Just as a tuning fork resonates to another tuning fork tuned identically to it, so a similar colloid enters into a specific combination with its antigen. Since Loeb's classical work on gelatin in 1920 and Sorensen's detailed studies in 1921 on egg albumin, the proposition must be considered firmly established that the colloidal state of a substance cannot be understood without knowledge of its purely chemical properties. From this it is obvious that any attempt to contrast the physical properties of colloidal reactions with the chemical nature of the reacting bodies is naturally doomed to failure. The works of Loeb and Sorensen gave convincing evidence in favor of the electrochemical micellar theory of colloids formulated by J. Duclaux as early as 1909, but which received little attention at the time. Duclaux showed by a number of experiments that the colloidal state depends on the presence in the intermicellar medium of micelles constructed of two unequal parts: 1) an inert granule, or block, and 2) the active part of the micelle, which causes the formation of an electrical double layer on the surface of the granule and is the most important factor in the physicochemical transformations of colloids, in their adsorption compounds, and so on. Duclaux's theory, which united the physical and chemical sides of colloids, formed the basis of the colloidal doctrine of immunity in M. Nicolle, Barykin, and others. In recent years, it would be difficult to point to an immunologist who, in his theoretical constructions, would not take into account not only the physical but also the chemical side of the phenomena of immunity. On the other hand, Loeb's brilliant studies have apparently finally secured for colloids the main place in the doctrine of immunity. Keeping this basic premise in mind, a number of authors in recent years have tried to present in a systematic exposition the modern physicochemical foundations of immunity. To these must be referred the monographs and generalizing articles by: Bordet, Zinsser, Wells, A. Lumière, M. Nicolle, V. Barykin, N. Gamaleya, and others. It is important to note that for none of the listed researchers does the colloidal nature of immunity reactions present any doubts. Then many of the modern immunologists stand from the point of view of the unity of antibodies. Every antigen causes the formation of a single antibody, say Nicolle, Zinsser, Wells, Friedberger, and others. Barykin distinguishes two stages of the action of this antibody: coagulation of the antigen and peptization of it. Reactions of the coagulation type include: agglutination, precipitation, detoxification, opsonization, and tropinization in the period of attraction and adhesion of the phagocytosis object to the phagocyte. Reactions of the peptization type include: bacterio-, vibrio-, hemo-, and cytolysis and digestion of the phagocytosis object in the cytoplasm of the phagocyte. The immune reaction may be limited to the first stage alone—coagulation of the antigen—or pass into the next stage of peptization of the antigen, which is a further development of the same colloidal reaction. Morphological differences in the immune reaction depend not on the multiplicity of antibodies, but on the physicochemical properties of the antigen with which the given single antibody combines. Various authors invest different content into the concept of the antibody itself. Most researchers see in the antibody a special body newly formed by the organism under the influence of the introduced antigen ("differentiated globulin" of M. Nicolle). Others believe that the immune antibody has its prototype in the corresponding normal antibody and differs from the latter not in the qualitative, but only in the quantitative side of its action. The mechanism of excessive antibody production in acquired immunity and the specific action of the antibody on the antigen became accessible to experimental investigation only after the laws of ionic compensation in the organism were found. The elucidation of these laws was facilitated by the application to the organism's colloids of the Le Chatelier principle, according to which any influence disrupting equilibrium leads to a reaction counteracting this influence. The application of the Le Chatelier principle to immunity phenomena was insisted upon as early as 1909 by Le Dantec. Experimental verification of the Le Chatelier principle in staphylococcal and diphtheria local infections (Schade), as well as its application in cases of malignant tumors (Kulikov), show that following this principle, the organism responds to the ions introduced into it by the mobilization and accumulation of antagonistic ions in amounts 100,000 times greater than is necessary for the simple neutralization of the introduced ions by antagonist ions in a crystalloidal medium. Such excessive compensation (hypercompensation) in the organism is explained by the buffering capacity of its colloidal systems (see Buffer properties). According to the Le Chatelier principle, it can be assumed that the immune properties of the humoral and cellular colloids of the organism are caused not by the appearance in them of special counter-antibodies in the sense of Ehrlich, but by a change in their state under the influence of excess antagonistic ions accumulated in them.

Hence the doctrine of immunity as a function of the physicochemical state of the body's colloids (V. Barykin's theory). As proof that the concept of an "antibody" conceals not a special substance in the sense of Ehrlich, M. Nicloux, and others, but merely a function associated with the state of immune serum, one may cite the experiments of Zilber, in which the protection of immune serum against temperature coagulation (by fermentoid, by Bayer), i.e., against a change in its state, is accompanied by the fact that such a serum, heated almost to boiling (80-90°), i.e., to temperatures that destroy all Ehrlich's counter-antibodies in it, continues to exhibit its specific agglutinating properties. Having entered into a selective adsorption reaction with the corresponding antigen, the immune serum will behave depending on the further course of the reaction, on the strength of the resulting adsorption compound, on possible substitution reactions, and finally on purely chemical interaction between this serum and the antigen (the irreversible stage of the reaction). If modern scientific data lead us to the conclusion that the state of immunity is the biological expression of those inevitable physicochemical changes in the body's colloids that necessarily follow the action of the antigen upon them, then a priori one might think that it would be useless to look for signs of immanent, vitalistic purposiveness in immunity reactions. There is no doubt that the majority of immunity reactions are in most cases reactions that are useful to the organism. Only that living form whose structure provides it with response reactions to the influences of the external world that are favorable for its existence, only such a form can survive in the struggle for existence. This explains why biologists have to deal almost exclusively with such relatively purposefully arranged living forms. Immunity reactions are no exception in this respect. But that their occurrence in the organism is caused not by the commands of a vitalistic entelechy, but by objective regularities inherent in the animal and plant world—this is proved, among other things, by the fact that among the majority of useful immunity reactions there are also reactions interpreted by some authors as useless and even harmful, although essentially their meaning is not clear in all cases. As examples of such reactions, one can name: 1) the phagocytosis of leprosy bacilli and gonococci, 2) the encapsulation of infectious foci in furunculosis, 3) the phagocytosis of microphages by macrophages, which is useless for the organism, 4) the harmful zone of inhibition in serum immunity reactions. Finally, one can also include here a state of the organism that has the same mechanism as immunity, but is unconditionally harmful and often fatal to the organism. This state, in contrast to immunity (non-susceptibility), bears the name of anaphylaxis—hypersensitivity (see Anaphylaxis).

V. Barykin. Immunity as a Phenomenon of Adaptation. All facts obtained by immunobiology leave no doubt that immunity is a phenomenon of adaptation, that its manifestations in most cases represent relatively purposive mechanisms that protect the organism from the harmful influences of its surrounding biological environment and consequently arose by way of natural selection. If, however, such a concept cannot fundamentally raise doubts at present, it does not by any means follow that to explain the origin of any phenomenon of immunity it is sufficient to approach it with this general principle. On the contrary, each category of phenomena united by the concept of immunity requires in this sense its specific explanation. In this direction, it is necessary first of all to distinguish between the phenomena of so-called natural and acquired immunity. The former can be conceived in such a way that the ancestors of a given species, having once encountered the infection in question, perished from the invasion of the latter. Only those individuals survived and subsequently multiplied that accidentally possessed certain genotype features protecting them from contracting the corresponding infection. But mutatis mutandis one should also take into account the reverse possibility: not only macro- but also microorganisms adapted—in the very sense that out of the latter only those survived that accidentally possessed biological features giving them the ability to multiply in the organism of the corresponding species. Historically, one can therefore imagine two series of phenomena running, as it were, parallel to each other: the evolution of the macroorganism and the evolution of the microorganism. At the same time, these two series do not run independently of each other, but a change in one of them entails in phylogeny a correlative change in the other. This correlation, however, is not of a physiological order and does not consist in the fact that a change, for example, in a microorganism by direct induction entails an adequate change in the macroorganism (or vice versa). This correlation can only be conceived in such a way that certain genotypic changes, e.g., of a microbe, make a host previously immune to it non-immune and, perhaps, perishing upon encountering it. Only those of the macroorganisms survive which accidentally possess the genotypic property of neutralizing the infectious agent that has penetrated them. Finally, it is conceivable to represent certain cases of "natural" immunity not as a phenomenon of adaptation—arising therefore not in the order of natural selection; it is easy, for example, to assume that a certain microbe, upon coming into contact with a macroorganism, found the latter in a state of insusceptibility to it. The explanation of the phenomena of acquired immunity must be approached somewhat differently. This point must also be differentiated in two directions: 1) the mechanism of the production of immune bodies in response to invasion, and 2) the fact of the preservation of acquired immunity for a long time (sometimes for life) after recovery. According to point 1, the course of reasoning can be analogous to that set forth with respect to natural immunity: those individuals survived mainly that possessed the ability to produce the corresponding antibodies. The question of whether the course of reasoning set forth above with respect to natural immunity (change, e.g., of the macroorganism and correlative change of the microbe) is always applicable in this case should be left open for the time being, since there are facts of bacillary carrier state after a past infection and the acquisition of immunity thereby; from these facts it follows that at least in some cases the adaptive change of the macroorganism in this sense (the ability to produce immune bodies) can remain indifferent to the microbe. From what has been said, incidentally, it follows that the division of immunity into natural (hereditary) and acquired has the conditional meaning that only the fact of immunity is acquired, while the ability to produce it (the norm of reaction) is genotypic. Finally, the question regarding the preservation of acquired immunity stands apart. There is no need to consider it in isolation as an adaptive trait, since we know that a repeated disease usually does not proceed more severely than the primary one; if, therefore, individuals surviving the primary infection could survive in the struggle for existence, there are no grounds to assume that organisms historically had to develop a special apparatus protecting them from a secondary disease. One therefore has to consider doubtful the idea of acquired immunity to repeated infection as an independent adaptive trait (however obvious its purposiveness) and look at it as a function arising from the mechanism of the production of immune bodies in response to invasion. In other words, acquired immunity takes place because during the primary disease the organism reacted by the production of antibodies (which is unquestionably an adaptive trait), which are then preserved thereafter. In general, it must be recognized that the question touched upon here (immunity as a phenomenon of adaptation) is extremely poorly elaborated. S. Levit. Local immunity is a state of insusceptibility not of the entire organism as a whole, but only of its individual organs and tissues. The idea of local immunity of organs and tissues is not new. It was first expressed by Büchner, who noted the increased resistance to a new infection of an organ that had previously undergone the same infection; but this thought was abandoned even by the author himself under the pressure of striking facts proving the connection of immunity with the appearance of specific antibodies in the blood and organs of the immunized animal. N. Blagoveshchensky gives a literary reference that as early as 1893, i.e., in the era of the greatest dominance of the humoral theory of immunity, the Italian scientist Eugenio Centanni published a work in which he argued that immunity does not depend on the active blood serum of the immunized animal, and expressed thoughts very close to those expressed in recent times by Besredka and which formed the basis of the modern doctrine of local immunity. After a considerable hiatus, the idea of local immunity in connection with the accumulation of new facts in immunology is being reborn again (V. Kraus, Prowazek, and others). The basis of local immunity as a rule is phenomena of a histogenic order, and its characteristic feature is the absence of specific antibodies in the blood. According to the concepts of Ehrlich's theory, the mechanism of histogenic immunity is associated with the absence in cellular elements of corresponding receptors for union with the antigen, or immunity can be caused by the insusceptibility of cellular elements to the toxophoric group of the poison. Others explain it by the local formation of protective counter-bodies (e.g., local immunity of the eye to abrin) or by the presence of especially favorable conditions for phagocytosis in a given organ or tissue. In modern times, Besredka constructed his theory of immunity, according to which local immunity imparted to an organ or tissue can in some cases cause general immunity of the entire organism. Thus, the organism can become insusceptible as a whole thanks to the immunization of only a single organ in the event that this organ is the only one sensitive in a given animal species to a given infection. An excellent example of this kind can serve, according to Besredka, the guinea pig, intracutaneously or percutaneously pre-immunized against anthrax. The only organ sensitive to anthrax, in Besredka's opinion, is the skin cover in this animal species, through which alone the animal can be infected with anthrax. By way of immunizing the skin, the guinea pig is deprived of the only organ sensitive in it to anthrax, and thus general immunity is imparted to it. However, it must be stipulated that the majority of authors, recognizing along with Besredka a special sensitivity to anthrax in the skin cover, nevertheless consider that infection with it is possible in another way as well, just as a number of authors succeeded in obtaining immunity to anthrax in sensitive rodents while bypassing the skin. The difference in sensitivity to infection of individual organs can be explained by the difference in conditions (predominantly on the part of the energy of phagocytosis) that the microbe encounters in them. Thus, according to Besredka, in the doctrine of the mechanism of animal susceptibility to infection and immunity to it, it is necessary to reckon with the autonomy of organs, and the question of the immunity of organs and tissues is most closely intertwined with the question of their sensitivity to the antigen. It is precisely in this plane that the question of local immunity was posed by Besredka. When studying each infection and immunity to it, it is necessary first of all to resolve the question of whether the animal organism possesses any organ exclusively or predominantly sensitive to the corresponding virus, and if the question of artificial immunization is posed, one should try to solve it by vaccination of the sensitive tissue. In addition to anthrax, where, according to Besredka, the sensitive organ is the skin, this author demonstrated the selective sensitivity of the skin to staphylococcal and streptococcal infection; in dysentery, typhoid fever, paratyphoid fevers, and cholera, the sensitive organ is the intestine.

The selective affinity of a pathogenic microbe for the intestine in enterotropic infections is demonstrated particularly clearly by the fact that no matter how the virus is administered to an animal—through the bloodstream or subcutaneously, by injection of living or killed microbes—this virus is always found in the thickness of the intestinal wall and in the intestinal cavity, while being absent in other organs and in the blood. A rabbit, as a rule, resists these infections when infected per os, which is explained by a number of circumstances, the main ones being the integrity of the intestinal walls and other mechanical and chemical factors that prevent the microbes from penetrating the intestinal wall (the mucus layer on the intestinal wall, the action of enzymes, the reaction of the intestinal contents, the presence of nutrients, etc.). But Besredka's experiments showed that a rabbit can also be infected per os if a highly virulent culture administered on an empty stomach is used, and in particular if the microbes' access to the intestinal walls is facilitated, which in turn is most easily achieved by sensitizing the intestine through prior administration of bile to the animal per os. The role of bile in this case as an accessory and sensitizer consists, according to Besredka, in the fact that it prevents the coagulation of mucus on the intestinal wall, as a result of which the mucus remains in a dissolved state; in addition, the introduced bile, together with the abundantly secreted own bile of the animal, cleans off the mucus from the intestinal wall "like a broom" and, by desquamating the surface layer of the epithelium, opens a breach where the microbes penetrate; it is further possible that bile eliminates the destructive effect of gastric juice on the antigen, increasing the swellability of the antigen and its absorption by the intestinal wall. In connection with the strong toxic effect of bile on the intestinal wall noted in some cases (Klyukhin, Vygodchikov on experimental animals, Russel during mass vaccination of people), other agents have been proposed as sensitizers: bile acids, sodium benzoate (Neuberg-Wassermann), cocoa powder (as a cholagogue; Glukhov), killed dysentery culture (Nedrigailov, 10 percent soda solution (Vesternik), provencal oil (Neri), alcoholized vaccine (Zabolotny). The carriers of local tissue sensitivity are, according to Besredka, sessile phagocytes: such are the cells of the reticulo-endothelial tissue of the skin, the lymphoid follicles of the intestine, etc. Only they possess the ability to react with a specific virus, "as a result of which," says Besredka, "a third substance is released, which is a product of secretion or of the breakdown of the microbe." The accumulation of this substance predetermines the fate of the infection, since it has the property of paralyzing the phagocytic activity of leukocytes, which—in the absence of this substance, resp. in a tissue devoid of sensitive cells—would easily cope with the causative agents of infection. Local tissue immunity arises when sensitive cells are desensitized. The desensitization of sensitive cells, the blunting of their sensitivity in relation to the antigen falls to the share of a soluble product enclosed in the bodies of microbes, the so-called antivirus, which possesses, like the virus, a specific elective affinity for sensitive cells and the ability to combine with them, saturating their affinity for the virus and thus depriving them of the ability to enter into combination with the virus. Within the organism, the antivirus is released from bacterial bodies when they are digested by leukocytes; in broth cultures in vitro, as a result of the breakdown of bacterial bodies under the influence of the prolonged stay of cultures in a thermostat. The filtrates of such cultures, according to their chemical composition, are mostly alkaline, low-molecular, dialyzable breakdown products of the nutrient substrate molecule and bacterial bodies. The question of the existence of a special specific substance in the antivirus, in the sense of Besredka, is disputed by many authors who reduce the therapeutic action of the antivirus to nonspecific protein therapy. In general, Besredka's views on the mechanism of local sensitivity and local immunity are subjected to severe criticism. Bordet points out that the possibility of establishing a stable acquired immunity without the appearance of antibodies in the blood has still never been unconditionally proven; as for the selective sensitivity of one or another tissue for the development of one or another microbe, this is connected with the different distribution of defense forces to which pathogenic microbes are most sensitive, rather than the presence or absence of special sensitive cells; the phenomena of local immunity are explained by the local localization of general factors of immunity, rather than the desensitization of sensitive cells. If the choice of an easily vulnerable place is important during vaccination, this occurs not because it possesses properties particularly favorable to immunization, but because, thanks to its susceptibility, the virus gets the opportunity to penetrate the organism and by its attack prompt it to a more energetic defense (Bordet). Practical conclusions from the ideas of local immunity have led to the development of methods of local vaccination of humans and animals against a whole range of infections; the method of cutaneous vaccination of domestic animals against anthrax is beginning to find wide application, replacing the classic Pasteur method; giving an extremely weak reaction compared to the subcutaneous method, causing the rapid (after 2-7 days) onset of a stable and sufficiently prolonged immunity even with the single vaccination method, the method of cutaneous vaccination of domestic animals has apparently proven itself. In humans, apart from the use of antivirus as a prophylactic and mainly therapeutic agent in purulent infections, the idea of local vaccination finds application predominantly in enterotropic infections, among which it is first necessary to indicate dysentery, then typhoid and paratyphoid diseases and cholera. For the purpose of vaccinating the intestinal tissue sensitive to these infections, vaccination with dry vaccines in tablets or liquid vaccines per os is used. The most favorable results in humans have been obtained with enterovaccination against dysentery. Being completely harmless, enterovaccination produced a reduction in dysentery diseases among the vaccinated by 2–4 and even 10 times (Antonovelsky) compared to unvaccinated ones. Less satisfactory and rather contradictory results were obtained with enterovaccination against typhoid infections (experiments in the Department of Pas-de-Calais, at the La Flèche military school with results not inferior to subcutaneous vaccination; observations of Cantacuzène and Panaitescu in Romania, Antonovsky in New Peterhof with satisfactory results, observations of Solovyov, Gandelsman and Kerchiker with doubtful and even negative results). Finally, as regards enterovaccination against cholera, the material concerning cholera in the foci of India (Graham, Russel) shows that enterovaccination is not inferior in its effectiveness to the subcutaneous method, yielding a reduction in morbidity among the vaccinated by 4.6–5.8 times compared to unvaccinated ones.

B.

Aristovsky. Immunity to animal poisons is generally difficult to define, since the relationship of various animal species to poisons of animal nature is very diverse. The criterion for determining the toxicity of a given substance is usually taken to be its effect on humans and on ordinary laboratory animals. Proceeding from such standards of comparison, one can cite many examples where a strong poison has no effect whatsoever on certain animals. Insusceptibility to a poison may be of an individual character or else be a property characteristic of an entire species. Individual immunity is either congenital or acquired. Thus, some people are naturally insensitive to mosquito bites (Phlebotomus), while others, on the contrary, suffer greatly from them. Cases of individual resistance to the action of bee venom and others are known. Along with this, habituation to it upon repeated bee stings is noted, which is observed in old beekeepers or specially achieved in treatment with increasing doses of bee venom. The accidental acquisition of immunity from a poisonous snake bite (the site of the bite, dose, and nature of the poison) explains the rare examples, which have entered the literature, of some people's insensitivity to a viper bite. It must be noted that such insusceptibility was maintained from time to time by intentional bites from this snake. Such facts did not escape popular observation and were empirically used by some wild tribes for preventive vaccination against snake venom. This vaccination is achieved by scratching a human's skin with a dried poisonous fang of a snake and rubbing into the bleeding wound a mixture of various substances, among which the crushed head of the snake (respectively, its poison glands) plays the actual role. During this procedure, a small dose of poison is practically introduced into the organism, which causes the formation of antitoxin in the organism. (On artificial immunization with snake venom, see Snake venom.) Examples of species immunity are diverse. The frog eats bees without harm to itself. Sheep and hens do the same with the poisonous karakurt spider, the bite of which is fatal to camels. Desert rodents (Gerbillus) are 300 times less sensitive to the poison of the scorpion Buthus quinquestriatus than the guinea pig. Similarly resistant to scorpion venom are the hedgehog, monitor lizard, cuckoo, and other animals. Of particular interest is the insusceptibility of various animals to various sorts of snake venom. The hedgehog is immune to viper venom. Poisonous snakes are devoured by weasels, martens, ferrets, foxes, wild boars, and various birds. Cats are insusceptible to the poison of Vipera aspis. Classical examples of immune animals are the ichneumon, or Pharaoh's rat (Herpestes ichneumon) and the mongoose (H. griseus), which destroy cobras and other snakes. Mammals of South America possess various degrees of immunity to snake venoms: Conepatus chilensis, the opossum (Didelphys), Canis vetulus, Tayra barbara, and Coendu villosus. The effect of the venom of snakes of the family Viperidae on snakes of the family Colubridae is very insignificant, but not vice versa. Some non-venomous snakes are immune to the bite of venomous relatives; moreover, the latter can become the prey of the former; thus, the non-venomous mussurana (Oxyrhopus cloelia) kills, by dislocating the cervical vertebrae, and devours venomous Lachesis. -- The causes of species immunity are diverse; they are only partially uncovered in relation to snake venoms. In some cases, insusceptibility is non-specific; for example, pigs do not suffer from rattlesnake bites because they have a thick layer of fat under the skin, very poor in blood vessels, which greatly impedes the absorption of the poison; at the same time, pig blood serum does not neutralize snake venom in any proportion. Other animals possess a certain degree of specific immunity. The blood serum of the mongoose contains natural antitoxins, since it neutralizes snake venom in certain proportions not only in vivo, but also in vitro. The same can be noted for the serum of the hedgehog. The insusceptibility of both animals has a limit. The mongoose tolerates a sixfold lethal dose of cobra venom for a rabbit, but dies from an eightfold dose of the same venom. The hedgehog, in turn, dies from forty lethal doses of viper venom for a guinea pig. Poisonous animals are practically non-poisonous to themselves and to each other within the limits of the species. This depends on the presence in their blood of an antitoxin to their own venom. Calmette repeatedly injected rabbits with non-lethal doses of diluted cobra blood and thereby made them insensitive to multiple lethal doses of its venom. However, the insusceptibility of venomous snakes and scorpions to their own venom is relative, since both the snake and the scorpion can be poisoned by their own venom; the whole matter lies in the dose, as well as in the method of administration of the venom. Along with humoral (i.e., blood-associated) immunity (examples of which are given above), there is a known insusceptibility of individual organs (respectively, tissues, cells) of the organism to the poison; such immunity is called cellular. It is known that for the cat, the minimum lethal dose of cobra venom is 20 times greater than the analogous dose for a rabbit. The isolated cat heart washed free of serum stops from the passage of a cobra venom solution 4 times stronger than necessary to stop a rabbit heart. Similarly, the isolated intestine of the cat is more resistant to cobra venom than that of the rabbit. The erythrocytes of the cat, however, are more sensitive to the hemolytic action of cobra venom compared to rabbits. In animals acquiring artificial immunity by vaccination with cobra venom, the tissues of the heart and intestine become more resistant to the action of this poison, which is completely independent of the production of antitoxin in the blood. Thus, during the immunization of an animal, its organism acquires both humoral and cellular insusceptibility. It is further remarkable that the washed erythrocytes of an immunized rabbit are more sensitive to the hemolysin of cobra venom than those of a normal animal. Consequently, both in natural and artificial immunity to cobra venom, one cannot see any correlation between the general resistance of the animal to the poison and the resistance of its erythrocytes to hemolysis from the same poison. In the present state of knowledge, immunity to animal poisons must be judged in the vast majority of cases only by the external manifestations of the very fact of the animal's resistance to the poison. The analysis of the causes of insusceptibility is incomplete and has been carried out only in certain cases. It must be remembered that any immunity is relative and depends on the constitutional, humoral, and cellular characteristics of the organism.

E. Pavlovsky. Immunity in protozoan and spirochetal infections. Explaining the mechanism of immunity in protozoan and spirochetal infections, some authors assigned the main role to the phagocytosis of protozoa by cellular elements (Metchnikoff), while others assigned it to the action of antibodies on them (Gabrichevsky). And indeed, many data can be adduced in favor of each of these views. When animals are immunized with non-pathogenic protozoa—free-living infusoria and amoebas—antibodies that act specifically on antigenic forms are apparently produced, stopping their movement, promoting their clumping, encystment, etc. In this way, it is possible to differentiate very closely related forms of protozoa (Schuckmann; 1920). In various protozoan infections, the serum of convalescent animals acquires parasiticidal properties, which many authors explain by the appearance in it of special parasitolysins that disappear, however, upon heating to 56°. In experiments with the rat trypanosome (Trypanosoma lewisi), it turned out that 0.5 cm³ of serum from a convalescent rat protects a fresh rat from subsequent experimental infection. The strength of parasiticidal antibodies can be judged by the fact that the serum of chickens that have undergone spirochetosis acts on spirochetes even at a dilution of 1:1,000 (Neufeld, Prowazek). The serum of patients with visceral leishmaniasis (kala-azar) kills cultures of leishmanias (Hindle, Hou, and Patton; 1926); the serum of rabbits immunized against Weil's disease inhibits the growth of Leptospira icterohaemorrhagiae in dilutions up to 1:1,000 (Uhlenhuth, Grossmann; 1926). On the other hand, in protozoan diseases, phagocytosis of parasites is undoubtedly also observed. In the blood of sick rats, Laveran and Mesnil observed phagocytosis of trypanosomes (Trypanosoma lewisi). By injecting trypanosomes into the abdominal cavity of rats that had already undergone infection, these authors also observed phagocytosis of trypanosomes in the peritoneal cavity. In general, however, the number of unquestionable observations relating to the role of phagocytes in protozoan infections is small. In some cases, it was possible to show that the action of phagocytes is associated in a certain way with the presence of antibodies. By injecting serum from an immune rat mixed with trypanosomes into the abdominal cavity of a normal rat, Laveran and Mesnil observed vigorous phagocytosis of the trypanosomes. In control experiments without immune serum, which would possess such opsonizing properties, this phenomenon was not observed. A peculiar and very specific immunity reaction was described by Rieckenberg in trypanosome infections. It consists in the fact that when the blood of a trypanosome-infected mouse is mixed with the blood of a correspondingly immune mouse, the trypanosomes become coated with blood platelets. This reaction is also observed in spirochetoses (Spirochaeta duttoni) and, according to Krichevsky, occurs under the influence of special antibodies named by him thrombocytic barins, which promote the loading of spirochetes with platelets. In some protozoan infections, for example in trypanosomiasis and experimental amebiasis, precipitins have been described. The complement fixation reaction in protozoan infections is practically used only in dourine of horses (Trypanosoma equiperdum). The antigen here is rat blood containing trypanosomes (Watson). In malaria, this reaction was studied by Savchenko, who used an extract of the liver of malarial patients as an antigen. Thus, in protozoan infections, the formation of antibodies apparently also plays an extremely important role in the immune activity of organisms. The emergence of the antibodies themselves is attributed by many authors to reticuloendothelial cells located both within the spleen and outside it. Krichevsky showed that in infection of mice with a non-lethal strain of Spirochaeta duttoni, blockade of the reticuloendothelium alone with iron sugar increases their mortality from 0% to 46.15%, splenectomy increases it to 89%, and splenectomy combined with blockade of the remaining part of the reticuloendothelium increases it to 90%. Fatal cases of tertian and quartan malaria in individuals with congenital or traumatic absence of the spleen also belong here. In these cases, flooding of the blood with parasites and a fulminant course of the disease with a fatal outcome were observed (Krylova; 1924). To judge the mechanism of immunity in protozoan infections, cases of experimental infection of animals with such parasites that are unusual for them under natural conditions are of particular interest. Thus, rabbits do not contract relapsing fever under either natural or experimental conditions. Thus, the rabbit could be considered immune with respect to Trypanosoma recurrentis. However, in reality, its immunity is expressed only in the fact that when spirochetes are introduced, general septicemia does not occur in it. Meanwhile, in individual cases, in the corresponding tissues, spirochetes can take root for at least some time. Thus, when Trypanosoma recurrentis is introduced into the skin, they persist in it for at least 14 days. When introduced into the peritoneal cavity, the spirochetes quickly disappear from it and accumulate in the brain tissue (Plaut; 1926). Thus, in this case, a peculiar form of immunity is observed that does not extend to the entire organism (atrepsia). The dependence of immunity phenomena on the specific features of various tissues or organs is also encountered in other spirochetal infections. The course and outcome of protozoan infections depend on the strength of the hosts' resistance and the virulence of the parasites. As for the number of inoculated parasites, it is far from always having a decisive significance. With susceptibility, infection can occur even from a single parasite specimen. Such an experiment was performed with Trypanosoma gambiense. With resistance, however, infection fails regardless of the number of inoculated specimens. The dependence of the nature of the infection on the virulence of the causative agent is clearly seen from the following example: in mice infected with weakly virulent Trypanosoma recurrentis (from a case of experimental human relapsing fever), the infection proceeds in a sluggish, subacute form. Superinfection of the same mice with more virulent spirochetes obtained through a series of passages leads to a sharp exacerbation of the process (Steiner and Steinfeld; 1926). The host's resistance is expressed a) in its passive, natural resistance or b) in its active reaction, which can lead to recovery and the development of acquired resistance. Natural resistance has a species character and in most cases is absolute, whereas individual resistance is most often relative. Natural resistance underlies the specificity of parasitism phenomena, limiting the range of hosts of a given parasite, and in relation to Protozoa this specificity is generally more sharply expressed than in relation to plant microorganisms. An example of natural resistance of a species character is the absolute resistance to human malaria of all animal species except man. There are, however, indications that Plasmodium vivax—the causative agent of 3-day fever—took root for some time in the blood of chimpanzees (Mesnil and Roubaud; 1920). An example of relative individual resistance is the resistance to malaria of certain people. In experimental infection, individual subjects stubbornly resist malarial infection, but nevertheless some were successfully infected after 4-5 attempts (Mühlens and Kirschbaum, 1924; Epstein and Rubinstein, 1925). However, sometimes even natural species resistance can lose its absolute character. Thus, man is generally resistant to Trypanosoma brucei of cattle. Nevertheless, hunger and ancylostomiasis so lowered the resistance of the population in some localities of Central Africa (Mwanza) that in 1919 an acute trypanosomiasis broke out among them, and a trypanosome of the Trypanosoma rhodesiense type, apparently identical with Trypanosoma brucei, was found in the blood of the patients. In some cases, a decrease in the host's resistance is not even required for the development of the infection, and among many hundreds of resistant representatives of a given species, one can be found who is susceptible under the same conditions. Thus, inoculation of the Canadian strain of Trypanosoma equiperdum into white mice succeeded only after 600 unsuccessful attempts (Watson; 1920). On the other hand, animals naturally susceptible to a particular infection can become resistant to it under certain natural conditions. Thus, the marmot, normally susceptible to trypanosomiasis, becomes resistant to the same infection during its hibernation at 6°. No less influence on the outcome of a protozoan infection is exerted by the virulence of the microorganism, which for a given species can fluctuate within the widest limits. In some cases, it is possible to change it experimentally, mainly by passages through other hosts, and with various combinations of this method, one can achieve both an increase and a decrease in virulence. Thus, with respect to laboratory animals, Trypanosoma gambiense is very slightly pathogenic, and in some cases it takes a whole year for a given strain of this trypanosome to kill the host. However, by means of passages, one can achieve a reduction of this period to 10 2-3 weeks.

The dependence of immunity on the species characteristics of the host is illustrated by the observation that the duration of immunity after experimental relapsing fever in white rats is 180–300 days, whereas for white mice it is 60–70 days (Steiner u. Steinfeld, 1920). Protozoan or spirochetal infection may end in recovery and lead to the development of a greater or lesser degree of non-susceptibility. The host's reaction consists in the appearance of antibodies in its serum, upon the quantity and potency of which the outcome of the infection ultimately depends. Thus, in these infections we encounter all transitions, ranging from a very weak defensive reaction of the organism and even its complete absence (whereby the disease ends in death, often having a very acute course) up to the strongest immune reaction, immediately ensuring complete sterilization of the organism from parasites, accompanied frequently by the onset of complete, so-called sterilizing, or absolute immunity. Between these extreme states, we encounter incomplete sterilization of the organism associated with a chronic or relapsing course of the disease. In many cases, this incomplete sterilization leads to a state of non-sterilizing infectious, or relative, immunity characteristic of protozoan and spirochetal infections [Infektionsimmunität (Kolle), partial immunity, tolerance immunity, premunite (Sergent)]. The latter is the expression of a definite equilibrium between the host and the parasite and can manifest itself in various ways: a) the parasites do not all perish, but their reproduction is halted to such an extent that detecting them under normal conditions is impossible; b) the reproduction of the parasites does not stop, their number does not decrease, yet the toxic action of the parasites weakens and may even disappear entirely. Such a state is often designated as partial immunity with respect to the toxin (Giftimmunitat) or as the phenomenon of parasite resistance to serum (Serumfestigkeit). Clinically, all such infections may proceed completely unnoticed, and the designation of mute infections [“stumme Infektion” (Reiter)] has been proposed for them. To characterize the state of infectious immunity, insofar as it is associated with the serum resistance of the corresponding parasites, the following observation is of great interest: dogs that have undergone pyroplasmosis become chronic carriers of pyroplasms in the blood, whereas the serum of such dogs is parasiticidal with respect to pyroplasms. Consequently, the administration of virulent blood mixed with such immune serum to naive dogs fails to cause infection. Thus, the recovered dog acquired immunity, while its parasites became serum-resistant. Cases are known where the preservation of parasites in the immune organism is apparently not associated with the development of resistance by them. Thus, spirochetes surviving in the brain during relapsing fever owe this, as is believed, not only to their resistance to serum antibodies, but also to the circumstance that these antibodies do not penetrate into the brain tissue at all. This is proved by the fact that homologous immune serum kills these very same spirochetes (Steiner u. Steinfeld, 1925). Serum resistance can be experimentally achieved not only in vivo, but also in vitro. Thus, it was possible to achieve resistance of L. icterohaemorrhagiae to homologous immune serum (E. Hermann). Experimental transplantation to an animal of another species or the natural transfer of the parasite to the organism of an intermediate host (resp. vector) can apparently break down the serum resistance developed in the organism of the vertebrate host. The loss of serum resistance by parasites upon transition to the intermediate host leads in some cases to peculiar epidemiological relations. In Central Africa, in the distribution area of tsetse flies (Glossina morsitans), all game (antelopes, zebras) is universally infected with trypanosomes (Tr. brucei); their infection usually occurs at the very earliest age; recovered animals enter a state of non-sterile immunity and for the rest of their lives become carriers of relapsing serum-resistant trypanosomes. Upon reaching glossinae, the trypanosomes apparently lose their relapsing properties. Consequently, a bite can cause trypanosome infection only in naive, non-immune animals. As for immune animals, they are apparently guaranteed against superinfection by such trypanosomes that have lost their resistance. Regarding immunity, the following types of protozoan infection are distinguished: a) acute course and death in the first attack; b) acute course and recovery after the first attack with the development of prolonged, apparently sterilizing, and in some cases lifelong immunity; c) acute relapsing course with a tendency to transition into a latent state with the development, in most cases, of sterilizing, yet not lifelong immunity; d) acute relapsing course with transition into a chronic and even latent state, with the development for the most part of non-sterilizing immunity. Infections of the first type (a) include fatal cases of coast fever (Theileria parva) and Texas fever (Pirosoma) of cattle, Weil's disease (L. icterohaemorrhagiae), relapsing fever (Tr. recurrentis et al.), sodoku (Sp. morsus muris), as well as avian spirochetosis (Tr. gallinarum) and rat trypanosomiasis (Tr. lewisi). Infections of the second type (b) are those cases of diseases listed in the previous item that did not end in death. In these cases, antibodies appear in the serum in a quantity sufficient to cause complete sterilization of the organism (sterilisatio magna), and in some cases lead to absolute immunity as well. Most cattle that have survived coast fever possess such lifelong sterilizing immunity (regarding Texas fever, see below). The immunity of humans to infectious jaundice, as well as of rats to Trypanosoma lewisi, apparently bears the same character. With respect to their spirochetes, chickens acquire immunity that is sterilizing, yet not lifelong. The third type (c) of infections includes the majority of cases of human relapsing fever and other spirochetoses, Weil's disease, and sodoku. Ending in natural recovery after several attacks, these diseases leave behind a more or less marked immunity. However, in some cases of experimental spirochetoses (Sp. Duttoni), it has been proved that after recovery and seemingly complete sterilization of the organism, live spirochetes nevertheless persist in the internal organs for a long time. This tendency to pass into a latent state leads to the following type (d) of infections. These include, for example, malaria, syphilis, certain trypanosomiases, Texas fever, and amoebic dysentery. With these diseases, complete spontaneous cure almost never occurs, and in most cases, sterilizing immunity also never ensues. Usually, the disease passes into a latent state, and the organism acquires non-sterilizing immunity. The latent state of the disease is accompanied in most cases by the complete or almost complete disappearance of parasites from the blood, intestinal contents, etc. But they persist in the internal organs: spirochetes in the central nervous system, in gummas; malaria plasmodia in the spleen and bone marrow; dysentery amoebas in the intestinal wall, etc. At the same time, malaria plasmodia pass into the state of macrogametocytes and schizonts, dysentery amoebas form so-called pre-cystic forms, and in such a form can serve as a constant source of relapses for an indefinitely long time. In other cases, for example in Texas fever, the causative agent may remain in the blood of the surviving host for years, no longer causing any harm, but serving as a source of infection for naive animals. In this respect, Piana ulcer stands somewhat apart—a chronic skin disease with a subacute course that resolves spontaneously and possibly leaves lifelong non-susceptibility. Apparently, the local immunity arising after recovery from this disease, limited to the skin alone, coincides in its extent with the general sterilizing immunity of the entire organism with respect to Leishmania tropica. A chronic course and the consequent emergence of non-sterilizing immunity are characteristic not only of protozoan and spirochetal, but also of certain bacterial diseases. However, among the former, it is apparently more widespread and can be considered a characteristic feature. For non-sterilizing immunity, it is essential that while live causative agents persist in the recovered organism and, as a consequence, there is a constant possibility of relapse, with rare exceptions, superinfection is in most cases impossible. The mechanism of non-sterilizing immunity has not yet been finally elucidated, but in any case, a mandatory condition for it is the presence in the organism of live parasites from the previous infection. According to Morgenroth, their presence inhibits the development of fresh parasites introduced during superinfection and prevents the development of a new acute infection. Consequently, Morgenroth considers non-sterilizing immunity to be a depressive immunity.

Compared to conventional immunity, the non-sterilizing infectious immunity of an infected organism is distinguished by a smaller radius of action. With few exceptions, it protects the animal from superinfection by the same strain that served for the initial infection, but it is usually powerless both against a natural relapse from this same strain and against superinfection from without by parasites of any other strain of the same species, including its relapse strains. Thus, organisms that have undergone one attack of trypanosomiasis or spirochetosis (relapsing fever) are immune to the original strains of trypanosomes and spirochetes, but susceptible to their relapse strains. This corresponds to the fact that antibodies against the spirochetes of previous attacks are found in the serum of subsequent attacks. In other cases, the described phenomena appear even more complex. Thus, for syphilis, where superinfection was considered impossible, it has been proven that sometimes the absence of superinfection is only apparent. In these cases, only local, cutaneous immunity is observed, by virtue of which a chancre indeed does not form on the skin, but which nevertheless does not prevent spirochetes from penetrating into the lymph nodes, where they can easily be detected. For therapeutic and preventive purposes, the phenomena of immunity in protozoan infections have generally not acquired widespread application. There are three paths in this direction: a) active immunization with living parasites, b) active immunization with killed parasites, and c) passive immunization with immune serum. The essence of the first method boils down to causing a mild disease in the animal being immunized and then a state of non-sterile immunity. Since this method is associated with turning the animal into a chronic carrier of the infection, it may present a danger from an epidemiological standpoint. Active immunization is used with success in coast fever and hemoglobinuria of cattle, as well as in equine piroplasmosis. In view of the fact that in cutaneous leishmaniasis a single attack confers lifelong immunity, in some localities it is customary to inoculate an ulcer on covered parts of the body in order to prevent the possible formation of an ulcer on the face. In some cases, it has been proposed to inject trypanosomes attenuated by passage through animals. Thus, in nagana, good results have been obtained from the vaccination of oxen with trypanosomes passed through a rat and a dog. In Weil's disease, successful experiments have been carried out with the vaccination of guinea pigs with pure cultures of spirochetes isolated from rats and attenuated by passages through artificial media, and immunity is also developed in guinea pigs against spirochetes isolated from man. In the second method, vaccination is performed with extracts of parasites killed by heating, drying, or chemical agents. This method has been proposed for the prevention of animal trypanosomiases. Vaccination with killed spirochete cultures gave good results in Weil's disease in laboratory animals. In relapsing fever (in view of the difficulty of obtaining cultures), vaccination was used only on animals with heated spirochetal blood, as well as on humans with killed cultures of Tr. recurrentis (Aristovsky), and immunity was obtained here as well. The possibility of passive immunization has been proven for trypanosomes. Serum of rats that have undergone trypanosomiasis protects fresh rats from infection. Upon immunization of rabbits with Tr. equiperdum, a prophylactic serum is obtained for mice. However, passive immunization has acquired practical significance only in certain spirochetoses. In Weil's disease, the serum of convalescents or immunized horses exerts a strong prophylactic and therapeutic effect. In relapsing fever, it is also possible to prepare a serum that yields good results under laboratory conditions.

g. Epstein. Immunity to metazoan parasites (multicellular) can only be evaluated from the standpoint of external relations, which are characterized by the fact that a given host is not infected by a specific parasite or does not react with any reactions to the action of its active principles. With respect to many metazoan parasites, e.g., worms, immunity does not exist; thus, throughout his life, a person can be repeatedly infected with the same species of parasite. With respect to certain parasites, e.g., the human ascaris, no particularly sharp fluctuations in its frequency at various ages are noted; in any case, even in adults, the frequency of ascariasis can be such that it is not possible to think of acquired immunity after previously suffered ascariad invasions. The highest frequency of echinococcus infection falls, according to Tokarenko and Nadezhdin, at the age from 20 to 40 years. The subsequent drop in infectibility is not connected with the acquisition of immunity to echinococcus. Along with this, dogs undergoing an infection of Strongyloides make them truly refractory to repeated invasion and superinvasion (Sandground). A horse that has undergone an infection with the blood fluke (Schistosomum) is guaranteed against reinfection by these same parasites (Fuzinami). Chicks older than 100 days of age acquire, as a result of previous invasions, a high degree of immunity to the nematode Ascaridia perspicillum (Herrick). Similar phenomena are observed for Syngamus and chicks, in the trachea of which this roundworm lives (Hanson). According to Yokogawa, dogs older than one year in rare cases are infected with ascarids, whereas puppies are, as an exception, free from these parasites; it goes without saying that animals living under identical conditions under which infection is possible are compared. A gradual drop in the infectibility of cows by the ox warble fly (Hypoderma bovis) is also noted, if this phenomenon is judged by the number of adult larvae under the skin of the animal. Graphically, this drop is expressed by a regular curve. However, the causes of non-infection (determined by the general term "refractoriness to a given parasite") can be very different and in a number of cases have no relation to the development of specific resistance of the host organism to the parasite. With age, various constitutional features of the host organism that are unfavorable to the process of infection by the parasite or its development in the body of the host may change. Regarding the reaction of the host to the active principles entering it from the parasites, the possibility of "habituation" to the latter is noted. Some people, strongly reacting with skin inflammatory processes to the puncture and entry of the toxic saliva of some bloodsucker (lice, fleas, mosquitoes, sandflies, etc.), eventually become resistant or completely insensitive to the action of the same agent. Such immunity can apparently sometimes acquire a racial character. For example, the black race is less sensitive to helminthic toxins than the white race. In those cases where the host organism does not acquire the ability to resist reinfection by parasites, special substances of the antibody type may still be produced in it. They develop under the influence of the entry into the blood of toxins produced by helminths living in the position of tissue parasites (echinococcus) or in the digestive organs. In connection with this, the blood serum of a person infected with the broad tapeworm, echinococcus, or other helminths has the ability to precipitate an extract from the corresponding parasite. Such a precipitin reaction can serve as an auxiliary diagnostic tool for detecting echinococcus. More complex and specific is the complement fixation test (see Weinberg reaction), and the intradermal reaction is considered the best. Thus, various immunobiological reactions are based on the antigenic properties of parasites, which are increasingly attracting attention for the purpose of improving and refining helminthological diagnostics in cases where the latter cannot be based on direct methods. Similar to the Rickenberg "load phenomenon" (spirochetes and Bizzozero plaques) is the recently established reaction of leukocyte attraction (adhesion phenomenon) to Microfilaria nocturna under the action of the serum of people suffering from elephantiasis (S. Pandit et al.). If this side of the study of antigenic and antiparasitic properties of organisms is provided by the determined interest of bacteriologists, serologists, clinicians, and parasitologists, the study of immunity to the parasite infection itself is still in its embryonic stage. In this direction, only isolated attempts have been made so far, of which the most interesting is the work of Blacklock and Gordon. These authors experimented with the larvae of the fly Cordylobia anthropophaga, which parasitize the skin of mammals and produce severe myiasis phenomena in humans (Africa). By infecting pigs with these larvae for the first time, one can observe the survival of half of the larvae for a period of up to 6 days. Upon repeated infection of the same animals, the vast majority of the larvae die within 40 hours. Undoubtedly, the emerging immunity is not associated with eosinophilia; it may be present or absent. Under the influence of the action of Cordylobia larvae, precipitins are not produced in the body of immune pigs; likewise, the complement fixation reaction is negative. At the same time, the immune properties of pigs are associated with the properties of the skin. If the immunized area of the skin is removed (i.e., the site where the penetration of larvae inside and their resorption took place), the skin regenerate also exhibits immune properties. The same was observed when transplanting immune skin to a fresh pig. In the removed skin kept in vitro, these properties disappear. The blood serum of immunized pigs is unable to kill Cordylobia larvae in vitro. Skin immunization cannot be achieved by intraperitoneal or subcutaneous injections of emulsions from Cordylobia larvae. Immunity appears only in the order of natural infection of animals with these parasites. It was also not possible to obtain phenomena of anaphylaxis or an ophthalmic reaction. These circumstances gave the authors reason to conclude that the discovered immunity to a metazoan parasite is governed by laws that differ significantly from those operating in bacterial immunity. The existence of immunity phenomena in relation to parasitic worms is evidenced by experiments on the immunization of puppies with subcutaneous injections or feeding with Belascaris emulsion (Ohira). As a result of such immunization, puppies became less susceptible to infection with eggs of the corresponding worms than controls. Similar phenomena were observed in guinea pigs. With respect to Ankylostoma and Schistosomum, immunization was unsuccessful. Thus, taking the question as a whole, it must be emphasized that immunity to metazoan parasites is a conditional term encompassing completely heterogeneous and still unexplained concepts. Therefore, in the present state of knowledge, metazoan immunity should not be equated in essence with bacterial immunity. Even in the same host, the fate of the parasites contained in it can be sharply different. In the earthworm, the larvae of the fly Pollenia parasitize. When they are in the body cavity of the worm, they are surrounded by phagocytes that form a real cyst around them. However, the larvae can get out of it. In case of accidental injuries to larvae by each other, the damaged larva dies and is resorbed (Keilin). N. Meyer observed the formation of cysts from blood elements (phagocytes) around the larvae of ichneumon flies parasitizing caterpillars, and sometimes the parasites died in the cysts. Thus, cellular relations in the interaction of parasite and host can vary in the same cases. E. Pavlovsky. Immunity in plants has been studied theoretically rather weakly, although there is a lot of empirical data here. As in animals, absolute and relative immunity are distinguished here. The first is the complete refractoriness of the plant to a given parasite, the second is partial susceptibility: infection can occur under favorable conditions, but the parasite does not reach full development, and the disease is weakly expressed. Between complete immunity and complete susceptibility, one can find all transitions, sometimes even among varieties of a single botanical species (e.g., in wheat varieties in relation to yellow rust). Among wild plants, immunity is mostly of a generic nature, i.e., it covers all or a significant part of the species of an entire botanical genus. Such immunity has little practical value. Therefore, the main attention is drawn to species and especially varietal immunity observed in many groups of cultivated plants. Using it, it is possible to introduce into cultivation another variety that is immune to a given disease and economically replaces the previous susceptible one. In a number of cases, it is possible to newly select such a variety through crosses, since immunity turns out to be mostly a trait transmitted to offspring according to Mendel's laws. As for the causes of immunity of some varieties and susceptibility of others, they are different in different cases and are far from being sufficiently elucidated.

Undoubtedly, in a number of cases, anatomical features—chiefly of the integumentary tissues, such as an especially thick cuticle, a waxy coating, and, thanks to this, poor wettability of the surface, etc.—are of importance here. In other cases, the character of the cellular contents plays a role, e.g., the accumulation of tannins, high acidity of the cell sap, etc. Such causes determine so-called passive immunity and do not have universal significance. Active immunity must be considered more significant as a manifestation of the reaction of the protoplasm to the introduction of a parasite. It must be thought that there are relationships here analogous to antigens and antibodies; however, this aspect has been poorly studied, chiefly because fluids corresponding to serum cannot be obtained from a plant in order to operate with them in in vitro; the sap expressions, which are sometimes used for these purposes, represent too diverse and poorly defined mixtures. Some approximation to an understanding of the phenomenon is provided by in vivo observation. In cases of infection of a susceptible variety, its cells react even to the introduction of the parasite into their cavity as a certain stimulus that increases their vital activity, so that at first there is perhaps observed something like symbiosis. Only after a certain, sometimes prolonged, incubation period do the relations change, and the cells of the affected plant begin to die off under the influence of the strengthened parasite. In the case of an immune variety, the parasite also often penetrates into the plant's cells, but they die off rapidly in the process, and along with them the parasite also dies off, seemingly killed by the products of cell breakdown. The described pictures are observed in fungal infections, which are generally the most widespread in plants, and are typical upon infection by the most specialized, so-called obligate parasites (e.g., rust fungi). Upon exposure to less specialized facultative parasites, the rapid dying off of cells is also observed in susceptible varieties, but in them the parasite grows further through tissues that are already dead to a significant extent. Along with the indicated phenomena, which seemingly reduce to the interaction of soluble substances produced by the plant and the parasite, i.e., have the character of humoral phenomena, something similar to phagocytosis is observed in plants. In some cases, immunity is expressed by the fact that the parasite, having penetrated into the cells, does not cause them to die off and, conversely, dissolves itself almost without a residue. This property is observed only in certain cells, usually lying deep within the tissue. Although they are devoid of motility, they can be compared to phagocytes according to the indicated function. Practically, in plants one has to deal only with natural immunity. True, there are a number of indications of the appearance of artificial immunity after a plant has undergone a mild infection, but these indications are still too few and need verification. Also of no great importance is the artificial introduction into the plant of certain substances poisonous to the parasite or nutritious to the plant in order to thereby increase its resistance and create a kind of immunity. In view of the fact that individual properties are still not taken into account in plants, their individual immunity has not been established; however, data exist regarding age-related immunity; thus, our cereal grains at a young age are more or less immune to rust and, conversely, snow mold (Fusarium nivale) does not affect them in the adult state. The indicated features of plant immunity have been established chiefly in relation to fungal parasites, but similar phenomena are also observed in relation to bacterial diseases and flowering parasites (broomrape, mistletoe, etc.).

L. Kursanov.