Anaphylaxis

ANAPHYLAXIS (from Greek ana- opposite and phylaxis protection, defense), designation, most often, of a state opposite to immunity, a state not only of helplessness but also of increased sensitivity of the organism to repeated parenteral (and sometimes also enteral) administration of antigen (see), usually a foreign protein. The possibility of increased sensitivity to certain substances under certain conditions was already known to Magendie. The study of immunity phenomena led to the discovery of a number of paradoxical perversions of reaction, so-called allergies (see). There is no doubt that at present the concept of allergies encompasses a range of phenomena, often very different in their pathogenesis. Similarly, the concept of A., one type of allergy, which has received particular attention, also lacks sufficient definiteness. The initial concept of A., formulated by the French physiologist Richet, who also proposed the term in 1902, has undergone significant changes at present. Richet showed that parenteral administration to dogs of certain substances poisonous to dogs (extract from sea anemone tentacles, eel serum, etc.) could sometimes cause, instead of a preventive, immunizing effect, a state opposite to it - increased sensitivity, or A. A necessary condition for the development of A., according to Richet, was the use of very small, approximately 1/100th of the usual immunizing dose of extract. Richet describes the picture of this state in an experiment with a dog named "Neptune": "This was an exceptionally strong and healthy dog. First, 0.1 cubic cm of glycerin extract from sea anemone tentacles, which did not cause any pathological phenomena, was injected into it. After 22 days, when the dog was in excellent condition, I injected it with the same dose. After a few seconds the dog was severely ill: labored breathing, dyspnea; it could barely move, lay on its side; bloody vomiting and diarrhea; sensitivity was depressed; after 25 minutes - death." A further major step forward in the study of A. was the establishment of the fact that parenteral administration of minute and completely non-toxic doses of protein solutions (according to some data - also of lipid emulsions), for example, 0.01-0.001 cubic cm, and sometimes even 0.000001 cubic cm of horse serum or milk, creates in guinea pigs a state of A., and secondary parenteral administration of a larger dose of this substance causes in such a made hypersensitive - anaphylactized, or sensitized - guinea pig acutely developing phenomena of anaphylactic shock. These facts and a number of others, which formed the basis of the modern doctrine of A., were established primarily by the research of Otto, Rosenau, Anderson, and Bezredka. The impetus for their research was the so-called phenomenon of Theobald Smith, who observed that guinea pigs used to determine the strength of antidiphtheritic serum and receiving a mixture of toxin with antitoxic serum showed increased sensitivity to horse serum. The picture of anaphylactic shock in the guinea pig, the best object for this type of experiment, presents phenomena of extreme excitation of the sensory, motor, and autonomic nervous systems, followed by rapidly developing paralysis. Extreme restlessness, dyspnea, convulsions in a few minutes are replaced by phenomena of collapse, a drop in temperature sometimes by several degrees, involuntary urination and defecation, suffocation, often ending in the death of the animal. A sharp decrease in complement content and reduced blood coagulability are always noted. The described state of anaphylaxis can be briefly characterized by the following points: 1. A. develops after parenteral administration of foreign protein. 2. In order to sensitize (anaphylactize) an animal, a certain period of time must pass, usually not less than 10-12 days, which lengthens if large doses of antigen are used for sensitization. 3. A. is specific with respect to the type of antigen, however, less strictly than some (for example, precipitin) immunity reactions. 4. In cases where the attack of A., developing immediately after the second injection of antigen (test for A.), does not end in death, the recovered animal is desensitized, acquires a state of anti-anaphylaxis; the administration of new portions of antigen no longer causes any pathological phenomena. 5. The state of anti-anaphylaxis can last for months and corresponds to a certain degree to immunity; at the same time, antibodies against the corresponding antigen that caused A. can be detected in the serum. Over time, the state of desensitization, the state of anti-anaphylaxis, is replaced again by A. 6. Similar to passive immunity, a state of passive A. can also be caused by administering serum from an anaphylactized animal to a normal one. 7. Hereditary transmission of A. is possible only from mother to offspring during the intrauterine period. Serum sickness. The phenomena of serum A. have acquired great practical importance, as the state of innate or acquired as a result of previous serum injection A. explain the phenomena of so-called serum sickness, which sometimes develops after the injection of therapeutic sera. Serum sickness, especially with intravenous administration of serum, can manifest in humans in the form of an acute attack of anaphylactic shock, already described above, in the form of local manifestations of A. in the form of urticaria, swelling and painfulness of joints, edema, polyneuritis, albuminuria, etc., often accompanied by an increase in temperature. With regard to the possibility of serum sickness, the physician should be guided by the following positions established by clinical and experimental data. First of all, it must be borne in mind that even a single injection of serum often causes in humans, unlike guinea pigs, the above-mentioned symptom complex usually after 8-12 days. This, however, is not A. in the strict sense of the word, but rather an expression of allergic individual sensitivity to horse protein. With repeated injections, however, the organism becomes sensitized, its sensitivity increases, which is expressed both in a shortening of the incubation period and in a stronger reaction. Thus: 1. Previous injection of serum, if it was performed not less than a month ago, predisposes to the development of serum sickness. 2. The attack of general A., developing after the injection of serum, is replaced by a state of anti-anaphylaxis, so that new portions of serum can be administered to the body immediately after the end of the acute shock phenomena. 3. By first injecting a small dose of serum under the skin, it is possible to achieve desensitization of the body, a state of anti-anaphylaxis, without the development of severe acute general phenomena; after this, larger doses of serum can be administered after an hour. 4. The presence of anti-anaphylaxis only guarantees against the possibility of an anaphylactic shock attack, but does not exclude the later development of the above-mentioned local symptoms of serum sickness. The desire to avoid phenomena of anaphylactic shock and serum sickness when applying serotherapy has led to a number of attempts at prevention of A. Experiments aimed at reducing the toxicity of serum without violating its therapeutic strength have not yielded significant results. On the contrary, some of the methods of individual desensitization and anti-anaphylactic vaccination are of great theoretical and practical interest. Ru and Bezredka showed that in an anaphylactized guinea pig it is impossible to cause anaphylactic shock if the animal is first put to sleep with ether or alcohol. Of undoubted practical importance is vaccination of a sensitized organism with small, non-reactive doses of the corresponding serum. The subcutaneous administration of 1/100th of the minimal lethal dose of serum to an anaphylactized guinea pig makes it insensitive to a lethal dose after 1/2 hour. Desensitization can be achieved even faster by repeated intravenous administration of extremely small doses of serum. By administering serum intravenously, it is also possible to prevent the development of the Arthus phenomenon. Desensitization by subcutaneous administration of serum is especially indicated when the administration of large doses of serum into the blood or, as in cerebrospinal meningitis, into the spinal canal is contemplated. Local A. The local manifestations of serum sickness find some analogy in experimental local A., obtained in rabbits. This is the so-called Arthus phenomenon, which consists in that repeated subcutaneous injections at six-day intervals of 5 cubic cm of horse serum, starting from the 4th injection, cause slowly resorbing infiltrates, and after the 6th - aseptic necroses, which heal extremely slowly. It can be assumed, however, that between the Arthus phenomenon and the phenomena of general A. there is an essential difference in pathogenesis.

For the development of A., a small single sensitizing dose is required, and after the second injection, anti-anaphylaxis already develops, whereas pathological phenomena in the Arthus phenomenon begin to appear only after the fourth injection of large doses of antigen and increase under the influence of further injections. It is therefore more correct to consider the Arthus phenomenon as one of the manifestations of allergy, without insisting on its identity with A. It is possible, however, that the basis for both anaphylactic shock and the local manifestations of serum disease and the Arthus phenomenon is the same cause: a specific increase in the adsorption of antigen by cells with subsequent intracellular flocculation phenomena, the consequence of which is the inactivation of catalytic processes in the cells. Mechanism of A. The abundance of mechanical, physical, physicochemical, and biochemical theories proposed to explain the pathogenesis of anaphylactic shock shows the difficulty of the problem and the absence of a completely satisfactory solution to it. Most of the newest theories agree that an attack of A. is the result of acute poisoning of the organism, mainly of the cellular elements of the nervous system. But what is the nature of the poison and where is the place of its formation? The old assumption of Friedberger about the appearance of a specific precipitate in nerve cells upon the secondary introduction of antigen, as the cause of anaphylactic shock, has been abandoned by the author himself for a new hypothesis, according to which the poison of A., anaphylatoxin, is formed in the blood as a result of the action of specific serum antibodies on the antigen, formed under the influence of the first injection of antigen. At this point, there is a return to the already forgotten theory, according to which A. is the result of self-poisoning of the organism by poisons formed under the influence of the breakdown of foreign protein (antigen) in the blood of a sensitized animal. From the point of view presented, A. is the result of poisoning of the organism by products of parenteral protein breakdown. Some similarity in the picture of poisoning with peptone to the phenomena of A. is the only and quite insufficient argument in favor of this analogy, which has, however, acquired a certain popularity. The theory of Lumière explains anaphylactic shock by the formation of floccules in the blood, which, through the nervous system, cause a fall in vascular tone. The treatment of sera with kaolin, agar, and other adsorbent substances makes the sera poisonous, and the symptoms of poisoning resemble the clinical picture of anaphylactic shock. Bordet, however, sees in this picture not a superficial analogy but identity. Hence the adsorption theories of A., supported by Bordet, according to which, upon its secondary introduction into the organism, the antigen adsorbs substances of the blood plasma that neutralize its natural poisons or (another hypothesis) makes it poisonous due to the formation in it, under the influence of adsorption, of poisonous substances. The artificiality of all these theoretical constructions is obvious. The hypotheses presented do not explain either the necessity of preliminary sensitization, or the obligatoriness of small doses for rapid anaphylaxis, or the mechanism of anti-anaphylaxis, which is again replaced by increased sensitivity, nor the phenomena of passive A., nor, finally, the specificity of A. Along with the humoral theories of anaphylactic shock, the viewpoint is gradually gaining ground that anaphylactic shock is the result of processes occurring inside cells and, predominantly, physically exerting their harmful effect. There is a return (Krichevsky, Bogomolets, etc.) to the original views of Friedberger, Bezredka. However, the latter's hypothesis that under the influence of sensitization, some special substance (antisensibillin) is formed in cells, which upon meeting with a sensibilligen (antigen) mechanically causes shock due to the rapid combination of the antigen with its antibody inside the cells, is also not sufficiently substantiated and in essence has no advantages over the theory of intracellular precipitation. The cellular theory of A. Some authors are inclined to consider as more correct that the processes underlying anaphylactic phenomena occur inside cells. The research of Schultz and Dale, the work of Sirotinin, carried out in 1926 in Bogomolets' laboratory, and the pathohistological data of Krichevsky are especially convincing proofs of the correctness of this viewpoint. Schultz and Dale showed that a piece of intestine or uterus of a sensitized guinea pig, under the influence of the addition of antigen to the nutrient fluid, begins to contract intensely. At the same time, Dale made the observation that these contractions do not occur if the animal is previously desensitized. On the other hand, Sirotinin, by direct experiments on dogs, showed that under the influence of anaphylactic shock, there is a blockade of the physiological system of connective tissue, and the suppression of the adsorptive function of this system under the influence of anaphylactic shock in intensity exceeds the suppression caused by all other methods. On the basis of these experiments, anaphylactic shock and other manifestations of A. should be considered as the result of an intracellular reaction of inactivation (adsorption) of complement. The entire picture of anaphylactic shock indicates a stop or sharp slowing down of catalytic processes in cells. From this point of view on A., the phenomena of suppression of the nervous system, a fall in body temperature, a decrease in the phagocytic energy of leukocytes, and finally, the reduced content or complete disappearance of complement from the blood serum in anaphylactic shock are in perfect agreement. It should be recalled that there is little or no complement in the plasma. It passes into the serum during blood clotting as a result of phagolysis. The disappearance of complement in the serum after an attack of anaphylactic shock shows that it was inactivated (probably adsorbed) during the attack inside leukocytes. The same process of suppression of catalytic phenomena also took place in other cells, in particular in nerve cells. The mechanism of intracellular inactivation of complement is in full agreement with the modern concept of antibody production. A necessary condition for the accumulation in a cell of a large amount of antibodies is their enhanced production by the cell under the influence of repeated stimulation of it by sufficient doses of antigen. In these cases, the cell is as if overflowing with antibodies and, remaining saturated with them, releases their excess into the blood. In cases of immunization with negligible small doses of antigen, the cell also produces a certain amount of receptors, including, of course, amboceptors. However, these receptors, expressed in the terms of Ehrlich's theory, remain fixed on the cells, and their transition into the blood is possible only upon the disintegration of cellular elements, for example, leukocytes—during blood clotting or in the process of leukocytolysis. According to what has been said, the anaphylactizing substance is the amboceptor fixed on the cell, and the essence of anaphylactic shock lies in the reaction of binding, resp. inactivation of the complement contained in the cells with the antigen introduced during the test for A., with the mediation of the amboceptor. The catalytic function of complement (the complex of intracellular enzymes) is thus eliminated and the biological processes are correspondingly suppressed or cease altogether. The absence of complement or its significant decrease in the serum after anaphylactic shock thus becomes understandable: the binding (adsorption) of complement occurred inside the cells during the shock. The inactivation of leukocyte complement also explains the suppression of their phagocytic activity. Passive A. from this point of view is explained by the transfer with the serum of a sensitized animal of specific amboceptors that enter it upon the destruction of leukocytes in too small a quantity to be detected in the serum by the Bordet-Gengou reaction, but sufficient to, when adsorbed by cells, create an affinity for antigen. The question remains, why—if we assume the identity of amboceptors formed during immunization and anaphylaxis—a serum rich in amboceptors cannot cause a state of passive A. One can think that the introduction of a large amount of amboceptors causes its particles to bind simultaneously with both antigen and complement and thus eliminates the possibility of fixation of cellular complement by antigen (the phenomenon of complement deviation according to Neisser-Wechsberg). Anti-anaphylaxis develops as a result of the saturation of the haptophoric groups of amboceptors fixed on cells and then passes into a state of immunity. The latter is already characterized by the entry of antibodies into the blood. Such, in brief, is the hypothesis of the mechanism of anaphylactic shock, presented in still generally accepted terms but criticized by all in the terms of Ehrlich's side chain theory. Fundamentally, this viewpoint fully coincides with the previous cellular theories of A. by Bezredka and Friedberger. In the terms of physical chemistry, the proposed hypothesis can be stated much more briefly and clearly.

The essence of the anaphylactic shock of the cell consists of 1) adsorption by the cell of the antigen (anaphylactogen), 2) coagulation of antigen particles inside the cell, 3) adsorption by the resulting precipitate of intracellular enzymes. The first two moments were already indicated by Friedberger. The clarification of the latter, fundamental for understanding the shock, moment also became possible with the appearance of research by Jungu and later works by numerous authors, who showed that in the formation of floccules (precipitates) in immunity reactions, alexin fixation can occur. Other forms of allergy. It has already been pointed out above that the concept of A. is often given too broad an interpretation. Paradoxical phenomena of increased sensitivity of the organism in those cases where, according to generally accepted schemes, phenomena of immunity could be expected, may have very little in common in their pathogenesis with A., and it would be more correct to single them out into special groups of allergies. Let us give several examples that allow us to make some general conclusions about the essence of immunity and A.-Allergy to tuberculin. As is known, tub. patients show increased sensitivity to the introduction of endotoxins of tub. bacteria into their organism. The reaction to the injection of an extract of tub. microbes-tuberculin-manifests itself in the form of general intoxication of the organism, increase in t° and focal phenomena, expressed in increased breakdown of tub. tissue and intensification of the inflammatory reaction around it. Rubbing tuberculin into the scarified skin of a tub. patient causes a transient local reaction in the form of swelling, edema and inflammatory hyperemia in a limited area of skin (the so-called Pirquet reaction). The introduction of highly diluted tuberculin into the conjunctival sac causes in a tub. patient the most severe conjunctivitis. Similar phenomena are also observed in glanders (mallein test). One cannot help but notice that such a permanent existence of A. with the constant presence in the organism of the corresponding antigen, as would have to be assumed in tub. patients, if one considers A. their increased sensitivity to tuberculin,-is in complete contradiction with the concept of sensitization, the necessary incubation period, test for A. and the subsequently developing state of anti-anaphylaxis. Hypersensitization in tbc, leading to an allergic state of the organism, manifesting in the form of local and general reactions to tuberculin, appears to be partly a possible consequence of insufficiently vigorous production of antibodies. Under such conditions, the latter remain fixed in the cells, causing their increased affinity for the introduced endotoxins and thus creating sensitivity to infinitesimally small doses of the latter. This anaphylactic moment is summed up, however, with the poisoning effect of the endotoxin itself. Tub. infection by non-specific stimulation often makes the organism of the patient highly sensitive (especially, in foci of infection--local allergy) to various proteins when introduced parenterally. In the Arthus phenomenon we have partly a similar phenomenon in regard to pathogenesis. The accumulation in the skin cells of specific antibodies with repeated injections of large portions of foreign protein, possibly leads to the adsorption by the cells of significant quantities of it, since the circulating antibodies (precipitins) in the blood prove insufficient to prevent its adsorption at the site of injection. In other words, the Neisser-Wexberg phenomenon cannot develop to a sufficient extent, the essence of which probably amounts to a decrease in the dispersion of the colloid-antigen, making it incapable of adsorption. The combination of antigen with antibody and here, as in anaphylactic shock, can cause inhibition of catalytic processes inside the cells. It is possible, however, along with this, also toxic breakdown of the adsorbed protein inside the cellular elements.-The negative phase of immunity. It has been noted more than once that before immunity develops under the influence of vaccination, it is preceded by a negative phase of immunity-a brief period when the organism shows particularly strong sensitivity to a given infection. Usually the occurrence of the negative phase of immunity is explained by the binding by the vaccine of a small amount of natural antibodies present in the blood, as a result of which the organism becomes temporarily defenseless. Partly, however, in the development of the negative phase, the temporary allergy that arises during vaccination also has significance. Before antibodies enter the blood in large quantities and create immunity, their enhanced formation under the influence of the vaccine in the cells creates an increased affinity of the latter for the antigen. Probably something similar also takes place in the incubation period of infections. The allergic state that occurs for a short time after the injection of a vaccine, as well as the one that develops after the expiration of its immunizing effect, has practical significance in epidemiological prevention. Non-specific vaccine therapy. A special form of allergy is also the result of so-called non-specific vaccine therapy. The latter is based on the fact that any infection creates an allergic state of the organism in relation to many other microbes. Thus, for example, into the organism of a patient with typhoid fever, a vaccine from the colon bacillus is introduced. The consequence of such an introduction is usually a sharp drop in t°, sometimes after a preliminary brief rise, often, when the vaccine is injected into the blood, accompanied by collapse and other phenomena resembling A. Having recovered from them, the organism often more successfully and vigorously begins to fight the infection.-Protein therapy. Very close to allergies are the phenomena observed in so-called protein therapy. The essence of the method consists in the parenteral introduction into the organism of foreign protein (sterilized milk, normal foreign serum, etc.), causing local and general reaction of the organism, quite typical and uniform when various means are introduced. The general reaction of the organism fully coincides qualitatively with the reaction just described in non-specific vaccine therapy. Upon cessation of this, usually brief, reaction, stimulation of the functions of the physiological systems of the organism is observed, contributing to the elimination of the infectious disease. The stimulating effect of parenteral introduction of protein preparations on the organism can hardly be due to the chemical effect on the cells of any specific products of parenteral enzymatic breakdown of the introduced protein. With intravenous introduction of it, the general reaction sometimes occurs almost instantly, accompanied in some cases by phenomena of collapse. Apparently, in the reaction to protein therapy, we are dealing with physicochemical processes-adsorption of protein particles by cells and temporary violation of catalytic processes in them. Subsequently, with favorable course, enhanced chemical regeneration of catalysts occurs. One of the important conditions determining the intensity of the organism's reaction to protein therapy is the presence in it of general or local allergy with respect to the acting agent. These non-specific allergic states undoubtedly arise in processes of disturbed metabolism under the influence, for example, of infection. Their origin is based on non-specific stimulation of cellular elements.-Idiosyncrasies. To the allergic reactions of the organism also belong the various forms and manifestations of idiosyncrasy (see) to various food and medicinal substances. The so-called hay fever is also usually included here. In all manifestations of idiosyncrasy, both local and general, there is often a very strong disturbance of the functions of the autonomic nervous system. The pathogenesis of these states remains, however, to this day completely unclear.-The relationship of allergy to immunity. The basic phenomena of allergy briefly presented here, generally and A. in particular, are often considered as states opposite to immunity. Such a view, however, hardly corresponds to the truth. The reactions of some forms of allergy and the reactions of immunity are very closely related in their pathogenesis. Both stem from the mechanism of the organism's struggle with infection or intoxication and represent only different aspects, and sometimes (in A.) only different stages of the same process. Both the phenomena of immunity and some forms of allergy are based on catalytic and anti-catalytic processes arising in the organism as a reaction to the parenteral introduction of antigens. All reactions of immunity-are in their essence enzymatic reactions. The phenomena occurring in the organism under the influence of infection and then actively participating in the development of stable immunity, which may subsequently be replaced by a state of allergy and one of its forms-A., represent only one manifestation of metabolic disorder. The laws governing the latter, the laws of biological and physical chemistry, are fully applicable for the interpretation of states of immunity and allergy of the organism.

A. Bogomolets.

Phys. -chem. theory of A. strives to establish general laws that would encompass both cellular and humoral phenomena characterizing A. and anaphylactic shock. Many works are dedicated to clarifying the essence and internal mechanism of anaphylactic shock. The starting point for these works was the observation of Bordet, who showed that if fresh guinea pig serum is mixed with a weak agar suspension and left for 2-3 hours at 37°, the serum centrifuged from the agar, when injected intravenously into a guinea pig, kills the latter with typical symptoms of anaphylactic shock. Bordet's observations were confirmed and significantly expanded by Nathan, Kopaczewski, Ritz, Sachs, and many others, and it was established that not only contact with agar, but also with kaolin (Ritz and Sachs, Bauer et al.), with barium sulfate (Muttermilch), with inulin (Ritz, Sachs, Nathan), and some other substances makes normal serum toxic and capable of causing anaphylactic shock. Bordet, Zuntz, Jobling, and Petersen put forward the hypothesis that the substances with which the serum is steeped adsorb from it elements that prevent self-digestion of the serum by pre-existing enzymes in it, and as a result of such self-digestion the serum becomes toxic and acts on the animal like peptone. However, de Kruif and Germann, then Bachmann, experimentally refuted such an interpretation of the experiment. Bachman, for example, using an interferometer, found no traces of serum protein cleavage in Bordet's experiment. Furthermore, Nathan noted that only inulin suspensions, but not its solutions, can make serum toxic, and Kopaczewski added that of the 3 gels of silicic acid (electropositive, electronegative, and amphoteric), only the electronegative one makes serum toxic. Finally, Novy and de Kruif, testing the effect on serum of the same agar but in three different colloidal states (agar-sol, gel, and agar-sol-gel), convinced themselves that agar in the sol state makes serum 2-3 times more toxic than the same agar but in the other two colloidal states. From these experiments it could be concluded that for the transformation of serum into a toxic substance, it is not the chemical composition of the substance with which it comes into contact that is important, but its physical (colloidal) state. What explanation, from this point of view, could be given to Bordet's experiment? Contact of serum with agar makes it not only toxic but also cloudy, i.e. it changes its degree of dispersion in the direction of a more coarse division of its colloidal particles. It is true that Bordet points out that the serum that has become cloudy in his experiment, even if freed from the cloudiness by filtration, still remains toxic and causes anaphylactic shock. But control experiments by Lumière showed that Bordet was wrong. Lumière, observing the gradual coagulation (clotting) of serum under the influence of an electric current and copper sulfate, established that serum in the initial stages of coagulation may appear completely transparent to the naked eye, and yet it is already toxic. However, if such an apparently transparent serum is subjected to centrifugation in a very strong centrifuge and the toxicity of the upper layers of serum is tested on animals, it is easy to see that these layers have lost their toxicity. Lumière obtained the same results with sera treated with agar according to Bordet. Lumière's data found their full confirmation in the experiments of Kopaczewski and others. Kopaczewski observed a decrease in the degree of dispersion (coagulation) in sera directly in the ultramicroscope. Sera that had become toxic represented a suspension of the finest flakes. Dold further showed that the toxicity of serum lies within certain limits of its clotting. Serum that has clotted to the formation of coarse flakes visible to the naked eye ceases to be toxic and does not cause anaphylactic shock. Confirmation of this is provided by the research of Doerr, Moldovan, and Schultz, according to which blood at a certain stage of clotting causes anaphylactic shock in guinea pigs, but at a further stage of coagulation ceases to be toxic. All these data established with certainty that a decrease in the degree of dispersion of serum (coagulation) is the essential condition for the occurrence of anaphylactic shock. From this point of view, the experiments of Krichevsky became understandable, in which, by injecting into the blood the juice of the plant Cothiledon, which coagulates serum, he observed shock in animals, clinically and patho-anatomically completely identical with the classic anaphylactic shock of Richet and Portier. The same results were obtained by Lumière with a finely divided suspension of barium sulfate. An indirect proof of the correctness of the above physico-chemical interpretation of anaphylactic shock is the well-known fact that during anaphylactic shock the animal's serum loses its alexin function (complement according to Ehrlich). The alexin function, as proved by Hecht and others, disappears in serum every time the degree of dispersion of the serum decreases, i.e. coagulation sets in. This includes heating the serum, prolonged storage of it, shaking, treatment with agar, at which the hydrogen number (pH) of the serum sharply decreases and approaches the isoelectric point of serum proteins (Mendeleev), etc. Thus, the explanation of the clinical picture of anaphylactic shock must be sought in the coagulation of both humoral and cellular (Dale, Schultz, Manwaring, Krichevsky and others) colloids of the organism. The finest flakes, if they form, e.g., during coagulation of blood, mechanically disrupt the circulation, clog the fine capillaries, damage the endothelium (Kopaczewski and Dold), but if coagulation occurs in the cellular territory, then deep destructive processes occur in the cell itself (Krichevsky). What is the cause of this universal coagulation? Its cause is common to both the state of A. and immunity. Change in the degree of dispersion is one of the most characteristic signs not only of anaphylactic shock, but also of immune reactions, e.g., agglutination, precipitation, detoxification (Ramon), phagocytosis in the presence of immune serum (Savchenko, Barykin), etc. A special serodiagnostic test—the Ascoli mastix reaction—is even based on this change in the degree of dispersion when immune serum meets antigen. Ascoli showed that when antigen meets immune serum in their mixture, a decrease in surface tension occurs, easily determined by an increase in the 63B number of drops by means of Traube's stalagmometer, i.e., according to the Gibbs-Thomson law, adsorption of one colloid (immune serum) by another (antigen) occurs. As a result of this adsorption, a change in the degree of dispersion of the colloids joining each other occurs. Thus, the physico-chemical processes that characterize anaphylactic shock also characterize the body's immune reaction. Hence it is understandable why anaphylactic state, like a shadow, accompanies the state of infection and immunity. Both immunity and anaphylaxis are identical in their causes (reorganization of the body's colloids under the influence of a foreign protein-antigen introduced into it) and also in their internal mechanism (combination of antigen with humoral and cellular colloids of the body that react to it). Only the outcome of the reaction between the body's colloids and the antigen determines whether this reaction is a useful, protective reaction for the body, or is accompanied by fatal consequences for it, as in anaphylactic shock. A brilliant confirmation of the correctness of the physico-chemical theory of A. and anaphylactic shock, in particular, is provided by the research in this field by Lumière and others. Lumière showed that there is no difference, either clinically or patho-anatomically, between the classic serum anaphylactic shock and that shock which can be caused by a single injection into the blood of substances that directly cause coagulation of the body's colloids. Friesze and Silber, for example, observed the picture of typical anaphylactic shock when colloidal iron was injected into a rabbit's vein. But, if the internal mechanism of such a direct shock is indeed identical with anaphylactic shock, if both are based on the coagulation of the body's colloids, adsorbing in the first case a heavy metal and in the second a protein antigen, then it is natural to expect that substances preventing the coagulation of the body's colloids will protect animals with equal success from both direct and anaphylactic shock. And indeed, according to the experiments of Kopaczewski, Lumière, Silber, and others, a number of substances that protect colloids from clotting also protect from anaphylactic shock; these include, for example, bile salts, urea, saponin, soaps, sodium hyposulfite, etc.

According to the research of Girard and Reuge, eosinate and erythrosinate of the heaviest of the alkali metals—cesium—strongly increase the degree of dispersion of sera, protecting the animal from both direct and anaphylactic shock. It should be noted, finally, that the old experiments of Rou, Besredka, Richet, and others concerning the protective effect of narcotic agents against anaphylactic shock find an interesting physicochemical interpretation in the research of Kopachevsky and his colleagues. Kopachevsky showed that during anesthesia, the physicochemical constants of blood plasma change. By introducing narcotics intravenously, the author also observed almost complete suppression of anaphylactic shock. Thus, shock does not occur even without anesthesia. And this indicates that the protective effect of the narcotic in shock does not depend on anesthesia as such. The explanation for this effect should not be sought in the decreased sensitivity of nerve cells in the narcotized animal, but in the general physicochemical changes that occur in the body's colloids as a result of the action of narcotic agents. V. Barykin. Anaphylatoxin, a hypothetical poison that forms in the blood upon the secondary introduction of an antigen (anaphylactogen) into the body of a sensitized animal. The formation of this poison is attributed to the occurrence of anaphylactic shock phenomena. Various hypotheses about the mechanism of formation of this poison in the blood—by, for example, the lytic action on the introduced foreign protein of the serum of a sensitized animal or Bordet's adsorption theory—form the basis of the incorrect humoral theory of the pathogenesis of anaphylaxis. Many authors (Besredka, Bogomolets, and others) completely deny the formation of a specific anaphylatoxin in the blood.