Sensitization

SENSITIZATION (from the Latin sensibilis - sensitive), the increase in the reactive sensitivity of cells and tissues. The concept of sensitization serves as the foundation upon which the entire doctrine of allergy (see) or allergic diseases is built: a particular disease is included in the group of allergic ones if sensitization takes place in its occurrence and course, or if such can at least be presumed. In addition to specific allergy, sensitization is also of significance in paraltergy (Moro and Keller), in which the allergen (sensitizing agent) and the eliciting factor are not identical, but distinct from one another. The nature of sensitizing agents, i.e., those substances and energies that can cause changes in the reactive sensitivity of the organism, is extremely diverse. This includes the most varied factors of our surrounding world. The constituent elements of air and light, the most diverse substances of the animal and plant kingdoms, including the products of bacterial vital activity, various manifestations of electrical and chemical energy, etc., can under certain circumstances play the role of sensitizing agents. At the same time, a difference is noted in relation to the sensitizing action between the normal organism and one with an already altered reactive sensitivity. Far from all of the listed factors possess the ability to sensitize a normal organism. The latter is characteristic chiefly of proteins. For other agents, such an ability has not yet been proven. In some cases, sensitization of the normal organism is accomplished indirectly. This applies, for example, to sensitization by light: it is assumed that photic inflammation resulting from the action of light leads to the absorption of proteins, which then sensitize the organism (Peterson, Sorgo). An organism with already altered reactive sensitivity can easily undergo sensitization (secondarily) under the influence of the most diverse agents, even non-specific ones incapable of producing the same effect in individuals with normal reactive sensitivity. At the same time, in an organism already sensitized by some agent, reactive sensitivity generally becomes labile, as a result of which further fluctuations in sensitivity easily arise under the influence of the most varied causes. Under these conditions, insolation, for example, can cause such reactive processes on the skin (urticaria, eczema, dermatitis) as are not observed in the skin of a normal individual with the same strength of impact of the same factor. The pathways for the penetration of sensitizing agents into the organism can be various organs and tissues, such as: the lungs (bronchial asthma), intestines (various food allergies), skin, etc. The parenteral introduction of the sensitizing agent also plays an essential role. Experimentally, the process of sensitization is accomplished gradually over the course of several weeks. Anaphylactogenic sensitization is accomplished already by the 12th day from the moment of introduction of the sensitizing agent. The connection of the sensitizing agent with the tissue serving subsequently as the arena for the manifestation of the allergy is likewise different in different cases: thus, in some cases, such as during the action of light on exposed skin, sensitization is accomplished apparently directly; in other cases, on the contrary, a more complex connection is assumed—via a reflex. This includes various manifestations of skin allergy after the ingestion of certain food substances and even after emotional experiences (psychogenic dermatoses). Regarding bacterial allergies, it remains unresolved whether direct contact plays a role here, or rather the action mediated through the nervous system. In anaphylactogenic sensitization, the adsorption of antigen by the reticulo-endothelium is essentially important. Finally, in yet another category of cases, such as sensitization under the influence of so-called photodynamic substances, the presence of an additional agent is necessary (see below on the mechanism of sensitization). The volume or size of the sensitization process also varies in different cases. In the majority of cases, one or another single system is involved, e.g., the respiratory tract (bronchial asthma), the skin (urticaria in food allergies), mucous membranes (hay fever). In another series of cases, however, one has to observe symptoms of hypersensitivity in a whole series of organs: thus, for example, asthmatics frequently suffer from eczema or urticaria of an allergic nature. The significance of constitutional factors stands out extremely saliently in the process of development of sensitization processes (familial allergies), with attention being drawn in a number of cases to such features of the organization as a special vulnerability and instability of the skin and mucous membranes, which can become the gateway for the gradual entry of certain sensitizing agents. Such factors as gender, age, amount and quality of skin pigment, and in women, pregnancy, etc., also have significance. The role of constitutional factors in the regard under discussion is rated so highly by some authors that they find it possible to speak of congenital idiosyncrasies, i.e., they admit the possibility of the appearance of hypersensitivity even where the moment of sensitization essentially is absent. According to Doerr, however, what is congenital is not the specific idiosyncrasy itself, but the predisposition to the development of such, while specificity is acquired during the life of the individual depending on contact with one or another sensitizing substance. Ultimately, it must be said that, however great the significance of constitution in the development of sensitization processes, nevertheless under certain conditions almost any organism can sooner or later become allergic in one way or another, and constitutional conditions only facilitate sensitization. Alongside sensitization, there also exists the opposite state, or process of desensitization, which is consequently characterized by a decrease in the reactivity of the organism or its individual organs and tissues. Desensitizing factors in the majority of cases can be the same agents that produce sensitization, and regarding specificity, a similar difference is noted here between anaphylaxis and other types of allergy; anaphylactogenic sensitization as a rule is specific, i.e., shock requires, with rare exceptions, the repeated introduction of the same antigen as the first time, whereas in other types of sensitization such specificity is insufficiently expressed: thus, upon sensitization to quinine, the same is simultaneously observed to antipyrine, upon sensitization to the pollen of one plant species—increased sensitivity to the pollen of other plant species, and so on. Desensitization processes with regard to their specificity must be considered to proceed mainly according to the latter type (with some limitation of what has been said only, again, regarding anaphylaxis), i.e., the majority of desensitizers can apparently carry out their action in relation to various sensitizers and, conversely, hypersensitivity to one or another sensitizer can be eliminated by the application of various desensitizers. Thus, the skin in relation to tuberculin can be desensitized with tuberculin, and ultraviolet rays, and X-rays, and on the other hand, the same preparation may prove effective in a number of the most diverse diseases (treatment of bronchial asthma with tuberculin; food allergies—with various types of peptone; application of sunlight in massive doses for the most diverse lesions). One may think that protein, lacto-, auto-, and heteroserotherapy are also partly obligated for their therapeutic effect in the most diverse cases to such a non-specific ability to desensitize tissue. Between sensitization and desensitization there exists the same interrelation as between anaphylaxis and immunity: these are different sides or stages of development of the same basic phenomenon—the reactivity of the organism, wherein one state replaces another, and sometimes in a certain sense they can even coexist, as it were intertwining with one another (immunity to smallpox in vaccinated individuals, with simultaneous symptoms of hypersensitivity to the vaccine virus upon revaccination). Thus, primary positive anergy (initial non-sensitivity to one or another agent) leads by way of the development of the sensitization process to hyperergy (hypersensitivity), only to be replaced under certain conditions by anergy; but the desensitization stage is at times interrupted by phases of hypersensitivity, and so on. The methods of desensitization in anaphylaxis are various (see Anaphylaxis), whereas as regards other kinds of allergies, generally speaking, they boil down to the application of sensitizing agents in a relatively larger dose compared to those acting during sensitization. However, what has been said cannot be understood in the sense that a single large dose is always sufficient for desensitization; on the contrary, often massive doses at first can produce a similar effect as small ones, i.e., cause sensitization instead of desensitization. (In anaphylaxis, large doses of antigen introduced secondarily at the appropriate time interval produce shock rather than desensitize the organism, and conversely—small doses, but introduced prematurely, transfer the organism into a state of antianaphylaxis.) Therefore, the method of gradual habituation of the organism to increasing doses of the sensitizing agent is usually employed.

In food allergies, for example, they usually try first to establish the nature of the allergen by the intracutaneous administration of an extract of the test substances, with the presence or absence of a skin reaction serving as the criterion for hypersensitivity (which, however, is far from always giving a clear result). Then the substance representing the causative factor of the condition is administered in gradually increasing doses per os or, more often, subcutaneously. Some authors recommend polyvalent peptone (beef, fish, milk, and egg; 1.0 × 3 one hour before meals) as a practically universal desensitizing agent in such cases. Desensitization is carried out by the same route in other allergies as well. Pathological conditions in the basis of which sensitization is presumed include the following: 1) cases of hypersensitivity to certain toxic products in certain infectious patients (reaction to tuberculin in tuberculosis; to malleine in glanders; to trichophytins in trichophytosis; here one can also include the reaction to the fluid of echinococcus cysts in echinococcus patients; reactive phenomena in relation to Ascaris in persons working with the latter *); 2) various forms of cutaneous tuberculosis, presenting certain specific features ("tubercle reaction"—formation of tubercles with a negligible amount of the tuberculosis virus, whereas rare cases of primary lesion through the skin yield a banal inflammatory infiltrate; cutaneous syphilis (pathological-anatomical changes in the 1st and 2nd periods of the disease boil down mainly to banal inflammatory infiltrates, and only in the 3rd do manifestations of mainly tubercular character set in); 3) various kinds of toxicoderma of a non-infectious character, such as dermatitis from the application of iodine tincture; certain cases of eczema; 4) an extensive group of so-called alimentary allergies; 5) certain cases of bronchial asthma, hay fever; 6) serum sickness; 7) optical sensitization diseases (to light) both simple and caused by the participation of special sensitizers of exogenous (fluorescent substances) and endogenous character (porphyrism; hematoporphyria). To the same optical * In persons working with Ascaris, phenomena characteristic of allergic diseases have long been noted: urticaria, conjunctivitis, rhinitis, cough (up to asthma sometimes). Far from all those who come into contact with Ascaris fall ill. The phenomena sometimes persist even after the cessation of work with Ascaris. Eosinophilia observed in helminthiasis is considered by some to be an anaphylactic manifestation. group belong so-called hydroa aestivalis and lupus erythematosus. In addition, there is a whole series of diseases at the basis of which lies prior sensitization and subsequent manifestation of changes under the influence of a triggering factor. This includes rheumatism, croupous pneumonia, etc., periarteriitis nodosa, Buerger's thromboangiitis, Fahr's malignant nephrosclerosis, etc. In a number of diseases, allergic changes associated with preceding sensitization may be observed as complications, e.g., changes in the vascular apparatus in scarlet fever, typhus, dysentery, meningitis, chronic sepsis. Sensitization during the course of certain infectious diseases affects the character of the process in different periods of the disease (e.g., in tuberculosis). Upon the occurrence of sensitization, the reactive cellular apparatus apparently rearranges itself, and a lowering of its threshold of irritability occurs, but the mechanism of this process still remains unknown. In any case, no morphological changes are stated in this regard, and it is apparently a matter of subtle physicochemical changes. The phenomenon has nothing in common with cumulation, which is evident both from the fact that sensitization often develops already as a result of a single exposure to the allergen, as for example in the classical experiment with anaphylactic shock, and from the fact that in sensitization processes the summation of exposure often leads precisely to the opposite phenomenon—a lowering of the reactive capacity (desensitization; see above). The majority of authors recognize the participation of the autonomic nervous system in the process of sensitization, and in some cases—also of the endocrine glands. However, there are as yet no definite indications of the connection of this process with a specific state of tone of any of the divisions of the autonomic nervous system, and both sympathicotonia and vagotonia phenomena can be observed here. True, the anaphylactic symptom complex, at the basis of which, as is known, lies the process of preliminary sensitization, is treated as vagotonic, but, generally speaking, during sensitization one has to observe fluctuations in the indicated respect: the period of vagus excitation can be replaced by excitation of the sympathetic nerve, and the sympathicotonia observed in the initial period of the development of sensitization is subsequently replaced by vagotonia. In practice, desensitizing treatment often has the purpose of raising the excitability of the sympathetic nervous system, but in general, clinical ascertainment of increased excitability of the autonomic nervous system during manifestations of hypersensitivity is far from always successful. On the other hand, there is also the view (Szondi) that there is no causal connection between the tone of the autonomic nervous system and the development of the hypersensitivity process, and that both of these supposedly represent only coordinated phenomena caused by one and the same cause. The role of the endocrine system in the process of sensitization has not yet been elucidated. There are some indications of the significance of the thyroid gland in this respect (Kepinow: thyroidectomy prevents the development of anaphylactic shock), as well as the spleen and liver: in particular, splenectomy likewise supposedly under certain conditions prevents anaphylactic shock, however, according to Mautner's data, only in those cases when it is performed before or at the beginning of sensitization, and not in animals already sensitized. Conversely, Sakharov, proceeding from the fact established by him of the shutdown of the leukocytolytic function of the spleen in the process of sensitization in anaphylaxis, on the one hand, and the detoxifying role of leukocytes in various kinds of intoxications, on the other, raised for development the question of the possible role of the spleen in the discussed regard in precisely the opposite sense. As for the liver, Moldovan, based on his experiments with the blockade of this organ with India ink, which prevented the onset of shock, came to a tentative conclusion regarding the production by the liver under the influence of irritation by India ink of a supposedly special substance that desensitizes the organism. On the other hand, there are indications that the liver is necessary for sensitization in anaphylaxis. Moreover, the blockade of the reticulo-endothelium also prevents sensitization in anaphylaxis, which is apparently explained by the difficulty under such conditions of the adsorption of antigen by this system, which is necessary for sensitization. When analyzing the mechanism of sensitization in different cases, one has to come to the conclusion that the latter is apparently not always the same. Here it is first of all necessary to distinguish anaphylactogenic sensitization and sensitization in other types of allergies. Initially, as is known, both of these groups of phenomena were identified, but subsequently they came to the conclusion of the necessity of still differentiating them in view of the presence here and there of certain distinctive features, with simultaneously great similarity between them in other respects. First of all, it must be noted that sensitization in anaphylaxis is accompanied by the production of antibodies, which by no means can be said about all other allergies, in accordance with which a difference is also noted regarding the role of serum here and there, as well as the possibility of transferring hypersensitivity from one individual to another: the transfer of serum from an sensitized individual to a non-sensitized one imparts to the latter the properties of the former, i.e., transfers sensitization to him (passive anaphylaxis), whereas a number of other allergies give a negative result in this regard. Sensitization in anaphylaxis could therefore easily be explained from the standpoint of the fixation on cellular elements (in particular of the nervous system) of antibodies produced in negligible amounts by the organism as a result of the first introduction of the antigen, with all the consequences flowing therefrom, as was postulated by some authors, if such an interpretation were not contradicted by the fact of the existence of passive anaphylaxis. Conversely, in the aspect of the intoxication theory of anaphylaxis, the mechanism of sensitization in these cases should be represented not so much in the sense of any special changes in the cells, as the production of antibodies with the possibility of subsequent cleavage of toxic atomic complexes from the antigen, and from the standpoint of the physicochemical concept—by the sensitization of colloids (see below). That the mechanism of sensitization in different cases is not the same is evident from some observations on sensitization of the so-called photodynamic character, namely: both the simplest organisms and the cells of multicellular ones, as is known, are sensitized to sunlight by fluorescent substances (experiments of Tappeiner and Jodlbauer on paramecia; Sakharov and N.)

Sachs's with hemolysis), but the matter here, as clarified by the aforementioned researchers, is nothing other than the effect of oxygen, and the photodynamic effect reduces to the acceleration of the oxidation of the substrate subject to oxidation (paramecia, erythrocytes, etc.) with the participation of the peroxide of the fluorescent substance formed under the indicated conditions (eosin peroxide, etc.). The concept of sensitization is used in biology and medicine in three other ways. First, one speaks of the sensitization of colloids, meaning by this such a recharging of colloidal particles that upon subsequent exposure to one or another agent, the phenomenon of flocculation occurs. Second, in immunology, Bordet's school calls the amboceptor (see) substance sensibilisatrice, wishing thereby to emphasize that the mechanism of action of the latter on the antigen reduces to preparing it for the action of complement. Finally, by sensitized vaccines are understood bacterial cultures previously brought into contact with specific serum and having fixed a portion of antibodies onto themselves as a result, as a result of which such vaccines, according to Besredka, produce a weaker reaction when introduced into the organism (the serum itself is subsequently washed off from the agglutinated bacteria).