The body has no processes and reactions focused only on damage. All of them have an adaptive and protective character and only under certain conditions or defects in them can have a damaging effect and serve as a basis for the development of pathological processes. This fully applies to allergies as well.
However, from the time of Clemence Pirke, who introduced the term allergy in 1906, which means a different action (allos - a different ergon - action) until today, allergies refer only to damage resulting in disease. Moreover, the evolution of the idea of allergy as a damaging reaction has become more and more specific over time. For example, in 1906 K. Pirke gave the following definition of allergy: "Changed sensitivity to substances with which the body had previously come into contact". In 1994, A.D. Ado already defined allergy as "the immune response of the body to any substances of antigenic or haptogenic nature, accompanied by damage to the structure and function of cells, tissues and organs".
A reflection of this view is also the classification of the leading mechanisms of tissue damage in immune processes, proposed by Gell and Coombs in 1969:
- Type I - Immediate hypersensitivity reaction (ITH)
- Type II - a complement of dependent cytotoxic reactions (rheumatoid arthritis, myasthenia, autoimmune hemolytic anemia, SKV, etc.).
- Type III - immunocomplex reactions (diffuse glomerulonephritis, hemorragic vasculitis, etc.).
- Type IV - delayed hypersensitivity reactions (DTH).
In recent years, another type 5 has been isolated, which is associated with the presence of antibodies to physiologically important determinants of the cell membrane - receptors (acetylcholine receptors, beta-adrenor receptors, insulin receptors, receptors for TTG). The reaction of these antibodies with the receptors can either stimulate or block the effect of these cells.
It is important to note that the secretion of type 5 allergic reactions calls into question the necessity of damage to structure and function in an allergy.
Traditionally, of all the variants of tissue damage in immune processes, types I and IV are associated with allergies - immediate hypersensitivity and delayed hypersensitivity. It is these two types of reactions that seem to be the classic ones for allergies that need to be understood in more detail.
Reactive (IgE) type of allergy reactions (immediate hypersensitivity, ITH)
Protective role of the ITH
Until a certain point, a ITH is a typical example of a humoral immune response. The main actors in ITH are B-cells, Tx2, IL-4, IL-5, IgE, basophils, mast cells (tissue analogues of basophils), eosinophils. Unlike other immunoglobulins, IgE are highly cytophilic, i.e. they can attach to the cell (Fc-fragment) at one end and bind the antigen (Fab-fragment) at the other end. These immunoglobulins play a major role in allergic reactions, which led them to have a second name - reactions. This name reflects their main difference from other immunoglobulins, which are called protective or protective. IgE participate in (reactive) defense reactions, but do not perform it themselves. The same applies to the participation of IgE in pathological processes.
Under the influence of T-helpers of the second type, producing interleukins 4 and 5 (which have a key role in the development of allergies) and the antigenic stimulus is the activation of B-cells towards the synthesis of IgE, specific to this antigen. It should be noted that in both normal and pathological conditions, IgE synthesis occurs mainly in the lymphatic tissue associated with mucous membranes, including mesenteric and bronchial lymph nodes. Lymfoid tissue of mucous membranes is also the main producer of IgA. Data on the antagonistic relationship between IgA and IgE are very interesting, which may be due to the priority in the lumen of mucosal antigens overseen by these immunoglobulins. It is supposed that the peculiarity of microenvironment of lymphoid tissue of the mucosa is the main factor that orients B-cells towards IgA and IgE synthesis. It is the mucous membranes, especially the intestines, which are the place where these immunoglobulins realize their protective functions.
IgA has an independent role in the protection of the mucous membranes, neutralizing the penetrating pathogens. The neutralization effect is manifested by immobilization of the microorganism, limitation of its overcoming the tissue barrier, weakening of the connection of the microbe with the mucosa, which contributes to its removal.
Another mechanism is at the heart of the protective action of IgE, which is mainly focused on parasites (such as helminths). As already noted, IgE do not have an independent protective effect, but serve as initiators of reactions aimed at the destruction and removal of parasites. In this respect, their predominant presence in the mucosa and, especially, in the intestinal mucosa is symbolic, since the main localization of parasites is the gastrointestinal tract.
Previously, it was believed that receptors to IgE are found only in basophiles and mast cells, but recently, IgE receptors are found in other cells (neutrophils, macrophages, lymphocytes, platelets, etc.), but unlike the receptors of mast cells and basophiles, they are low affinity (they bind IgE less firmly). This allows us to focus on basophils and mast cells in the future.
So, IgE is fixed on mast cells and basophiles. The concentration of IgE on the membranes of these cells can reach 400,000 IgE molecules per cell. It is important to remember that fixation of IgE on mast cells is very strong and long (up to 12 months), in contrast to free IgE half-life of which is 2 days. This is the meaning and the end of the stage of sensitization to this specific antigen, which is a prerequisite for allergic reactions. At the same time, IgE is fixed on the parasites (Fab-fragment).
We have considered the immune system response to primary contact with the parasite antigen, or immunological stage of allergic reactions. As can be seen from the above, apart from fixing IgE on the parasite, there are no other effects aimed at its destruction and removal. Therefore, it continues to exist, causing repeated antigenic irritation.
Repeated contact of the antigen with IgE fixed on mast cells and basophiles causes degradation of these cells and release of a large number of biologically active substances (histamine, serotonin, platelet activation factor, leukotrienes, prostaglandins, chemotactic factors, proteoglycans, enzymes, etc.). This is the so-called biochemical stage of ITH. The protective meaning of this stage is realized in two directions: a) attraction of eosinophils to the reaction site; b) smooth muscle spasm, edema and increased secretion of mucosa glands. Both of these mechanisms are protective in nature, although the second mechanism is considered to be the pathophysiological stage of ITH and is associated with clinical manifestations of allergic diseases.
However, let us consider these reactions. The migration of eosinophils to the reaction zone plays a crucial role in antiparasitic protection. The fact is that eosinophils are the main cells in the immune system that perform extracellular cytolysis. All other effector cells are focused on intracellular digestion of pathogens, however, in the analyzed case the pathogen is so large that intracellular digestion is impossible and eosinophils are the only acceptable effectors for such cases. Eosinophils contain a large number of substances with proteolytic properties (peroxides, acid phosphatase, collagenase, elastase, glucoronidase, cathepsin, RNA-az, myeloperoxidase, etc.). However, the main biologically active substance of eosinophils is the main alkaline protein, which performs extracellular cytolysis.
Eosinophils have a great affinity for the Fc fragment of IgE. Fixation of eosinophils to IgE triggers the mechanism of extracellular cytolysis and destruction of the parasite due to degradation and release of proteolytic substances. Additional mechanisms for the fastest sanitation of the body from the parasite are swelling and increased secretion of mucous membrane glands (especially important for parasites with mechanisms of fixation to the mucous membrane) and the reduction of smooth muscle muscles, peristaltic movements expelling the parasite or products of its decay from the body.
Thus, the ITH, which is associated with the majority of allergic diseases, is essentially an immune response option designed to protect against pathogens that require an extracellular cytolysis in the final stage of their immune response.
Damaging role of ITH
So why is ITH so often transformed into its opposite and serves as the basis for damage typical of allergic diseases? Unlike other immune response options, there are many more risk factors in the mechanisms of ITH implementation that easily transform a protective reaction into its opposite.
An attempt to characterize these "Achilles' heels" of ITH would be worthwhile.
Perhaps we should start with extracellular cytolysis and its main protagonist, eosinophils. Extracellular cytolysis is a very powerful and dangerous reaction for the body, which is relatively harmless when realized outside the tissues (lumen of the intestinal tube, bronchi, etc.) and is totally unacceptable for the tissues, because it is always accompanied by massive destruction. From this perspective, it is clear why the main participants of the ITH are localized.
mainly in the mucous membranes. In all other variants of the immune response, this risk factor is absent, since the final stage of the immune response takes place either by intracellular cytolysis in the effector cells (micro- and macrophages) or in the target cells by initiating cytotoxic lymphocytes apoptosis in them. Thus, the final stage of ITH - extracellular cytolysis - carries a high risk of damage if this reaction is realized in tissues. And such conditions exist. They are as follows. Eosinophils circulate in the blood from half an hour to several hours, after which they are localized in the tissues, where their lifespan is up to 24 days. Eosinophils also have receptors to IgE, which can be fixed on intracellular eosinophils and at repeated contact with them the antigen can cause the whole chain of events described above, ending with extracellular cytolysis, directed to their own tissues. This explains the severity of the course of eosinophilic pneumonia, as it is destructive pneumonia.
The next risk factor is a long and strong fixation of IgE on fat cells. The main place of localization of mast cells - serous membranes, spleen, epithelium and submucosal layer of gastrointestinal, respiratory and urogenital tract, skin, connective tissue of capillary clutches - is precisely in the places that are associated with the main clinical manifestations of allergy. Most often, the secretion of IgE and its binding by mast cells occurs in the same areas of the mucous membrane, but it is proved that there is a single system of lymphatic tissue of the mucous membranes, which creates conditions and determines the possibility of migration of activated (sensitized) cells to other regions. Sensitization of the gastrointestinal tract therefore has a fairly rapid effect on the mucous membrane of the respiratory tract and vice versa. On the other hand, specific IgE entering the bloodstream can be fixed by fat cells of the skin, connective tissue of the capillary clutches. Thus, the long-term existence of sensitized (loaded with specific IgE) mast cells of different localization and determines the possibility of allergic diseases in case of repeated contact of these cells with the antigen.
The next risk factor is the wide prevalence of IgE receptors on other cells (neutrophils, macrophages, lymphocytes, platelets, etc.). In contrast to the receptors for mast cells and basophils, they are low affinity (the second type of receptors to IgE). However, the affinity of these receptors, as well as the number of cells carrying them, may increase. Macrophages and platelets deserve special attention in the context of the discussed problem. IgE can react with membrane receptors of macrophages and directly cause the effect of antibodies-dependent cell cytotoxicity. Thrombocytes, in addition to their main function - regulation of blood aggregation, are the depot of biologically active substances (serotonin, cationic proteins, proteases, etc.). The presence on them receptors for specific IgE at repeated contact with antigens can contribute to their degradation with all the ensuing consequences and clinical manifestations of allergic diseases caused by structural and functional damage. Rather wide distribution of autoimmune thrombocytopenia may be connected with IgE fixation on platelets.
The next important factor is the presence of the biochemical stage of the ITH, which is based on the release of a large number of different biologically active substances. If the mechanisms of their degradation are disrupted, the long-term existence of high concentrations of biologically active substances in itself, without the antigen, can cause the degradation of basophils and fat cells, the process becomes self-sustaining and uncontrollable, leading to damage and clinical signs of allergic diseases. One more fact is important here. At present, there is a unanimous opinion that allergic diseases can develop only as a result of the failure of immunoregulatory mechanisms and, above all, the violation of immunoregulatory cells function. In this respect, histamine deserves the most attention. Histamine activates the suppressor functions of CD8 cells through H2-receptors; inhibits cytotoxic and helper activity of T-lymphocytes; inhibits the response to mitogens, synthesis of antibodies, production of a factor depressing the migration of macrophages. These histamine effects play a positive role in the reverse development of ITH; however, if the inactivation and degradation mechanisms of histamine are disrupted, these same properties cause the immunoregulatory mechanisms to fail.
The risk factors presented here make it clear that ITH can indeed easily, compared to other immune response options, transform into their opposite and serve as a basis for allergic diseases. It should be stressed that not all risk factors are presented here, but the most obvious ones lying on the surface. In fact, there are much more of them, but this is the subject of a separate conversation.
However, acquaintance with risk factors does not give an answer to the main question - what is the reason for the transformation of ITH from protective to damaging. Logically, the impression presented here is that the primary trigger for allergic diseases is contact with parasites, particularly helminths, and that this contact leaves a state of sensitization for a long time, if not for life. This thesis, however, does not stand up to the criticism, because it does not correspond to the life expectancy of sensitized cells, should provide for a mass spread of worm infestation, and most importantly, does not correspond to clinical practice that shows a wide spread of allergic diseases associated with a variety of antigens. At the same time, the role of primary parasitic infestation cannot be completely excluded, and in all cases of allergic diseases, especially with eosinophilia, examination in this direction is necessary.
In order to find the causes, it is necessary to return to the origins of the doctrine of allergy.
In 1923, A. Coca and R. Cooke introduced the concept of "atopy" to describe a hereditary predisposition to allergic diseases. Carl Dresler defined atopy in 1988 as "a genetically determined predisposition to pathological immune reactions in response to stimuli (allergens) that are harmless to most people (80-90%)". Currently, atopy is understood as an allergic disease associated with IgE.
Thus, the search for the main causes of allergic diseases can be initially narrowed to clarify the factors of hereditary predisposition, including excessive synthesis of IgE, as the central figure in the ITH.
Currently, there are some advances in understanding the causes of IgE over synthesis. The key role of Type 2 T-helpers (Tx2) in the development of ITH has been established. There is a shift in the differentiation of "naive" T-helpers (Tx0) in persons predisposed to allergic diseases towards the preferential formation of Tx2, whose interleukins (IL-4, IL-5, IL-3, IL10) under certain conditions facilitate the switch of B-lymphocytes to IgE synthesis instead of IgG. There are speculations (A. A. Yarilin, 1999) that factors intensifying the differentiation of Tx0 into T-helpers of the first type (Tx1) will inhibit the development towards Tx2 and may become an effective treatment for allergic diseases. Such factors should include, first of all, IL-12 and interferon-gamma.
Besides this main way of regulation of IgE synthesis, there are additional ones. It was found that T-cells produce factors that enhance and inhibit the synthesis of IgE (substances of protein nature with a mass of 15000-60000). The strengthening factor produces CD23 T-cells; the suppressing factor is CD8 T-cells. The important role of the lymphocyte suppressor fraction in the pathogenesis of allergic diseases is evidenced by the data (G.V. Poryadin, 1999) that in 68% of patients with atopic bronchial asthma the induced suppressor activity of lymphocytes was cancelled completely already in the first 5 years of the disease.
Botvineva V. V. (1998) presents data that the IgG deficit allows IgE to realize its membrane attack action. We also find evidence of this in A.A. Yarilin (1999): since IgG and IgE antibodies are identical in specificity to the antigen that caused them, IgG binds the antigen (allergen) and blocks ITH manifestations (blocking antibodies). This is the basis for one of the areas of allergy treatment and prevention - strengthening the IgG response with adjuvants that increase the immunogenicity of the allergen. IgG4, with which the main role in blocking IgE is associated, deserve special attention in this respect. It is significant that IgG4 deficiency is very often accompanied by recurrent and chronic infections. It seems that IgG4 deficiency not only increases the clinical manifestations of allergic diseases, but also contributes to their development, since it is accompanied by immune deficiency.
To some extent, the condition of skin and mucous membranes, especially the latter, should be attributed to hereditary factors. These are the two most powerful barriers, violation of permeability, which leads to the entry of antigens in normal conditions, either not coming in or coming in only limited. To some extent, this thesis is confirmed by the frequent development of allergies to exotic food products (citrus, seafood, etc.), i.e. to antigens that are not included in the normal diet of the population of a particular area. At the same time, most often violations of the barrier function of skin and mucous membranes are an acquired factor, which may be associated with the action of chemical, physical and biological initiatives. Intestinal infections are of particular importance in this regard. It seems that the intake of "forbidden" in the normal state of skin and mucous membrane antigens disorients the immune system when choosing the best immune response to them, and it is possible to choose extracellular ITH cytolysis, which, provided the excessive circulation of IgE promotes allergic diseases. It is possible that the orientation of the immune response to ITH with extracellular cytolysis is associated with the fixation of antigens that have penetrated through the mucosa and skin on cells and tissues of the body. A. A. Yarilin (1999) provides very interesting information on the circumstances that contribute to the manifestation of antigen allergenicity: the small size of the antigen molecule, allowing it to penetrate through the mucous membranes; a low dose, which favors the formation of Tx2; intake through the mucous membranes - concentration of the main population of fat cells and the place of IgE migration. Generally, the state of the mucous membranes is one of the most important, if not the main, factors for the development of allergic diseases, since most antigens come through the mucous membranes; the microenvironment of the mucous membranes is the most powerful of the known factors of differentiation of Tx0 to Tx2 and switching of B-cells to IgE synthesis. This is also facilitated by IL-4, which is most likely to be produced by fat cells of the mucous membranes.
The data of G.A. Samsygina (2000) and D.G. Soldatova (1997) are essential in understanding the causes of ITH.
In Samsygina's opinion, changes in the immune status of chlamydia infection are very close to those of ITH, including hyperIgE and eosinophilia, and chlamydia infection may be a real candidate for one of the trigger mechanisms of allergic diseases. This is all the more likely because according to V.I. Pokrovsky and I.N. Gnutov (1996) the true spread of chlamydia infection is unknown, but it is widespread among domestic and wild animals.
However, viral infections, in particular respiratory pathogenic viruses, are the most realistic candidates for ITH cause factors. Joint research conducted by the Research Institute of Pulmonology and the Lomonosov Institute of Virology. D.I. Ivanovsky Institute of Virology (D.G. Soldatov, 1997) showed that respiratory viruses, especially respiratory syncytial viruses, influenza and parainfluenza viruses have a powerful sensitizing effect, causing a marked rise in viral specific IgE in the blood. However, in 5-6 days the competitive relationship of interferons and interleukins in influence on IgE synthesis led to normalization of IgE level. Respiratory syncytial viruses (PC viruses) were an exception: they induced a steady and pronounced rise of IgE level in practically healthy persons. According to D.G. Soldatov (1997), this is due to the oppression of PC viruses with interferon products and he believes that PC infection may induce the development of atopic predisposition in healthy individuals. However, in our opinion, similar mechanisms may also exist for other viral infections (herpesviruses, adenoviruses, enteroviruses, rheoviruses, etc.), since clinicians are well aware of the facts of exacerbation of atopic diseases against their background and have data on the dependence of IgE levels on the frequency and severity of relapses of herpes simplex, as well as on the marked sensitization effect of the Epstein-Barr virus. Especially since viruses (at least PC viruses) can activate the production of general and specific IgE to non-virus allergens. An additional argument in favor of the causal role of respiratory viruses in the genesis of GHBs is the increased release of histamine by basophils when they come into contact with these viruses (Clementsen P. et al., 1990).
Definition of immediate hypersensitivity.
This section concludes with a definition of a ITH that reflects the information and facts described above.
A ITH is a variant of a specific immune response that is implemented when necessary in the final stage of extracellular cytolysis. In the presence of certain conditions and failure of immunoregulatory mechanisms, which are often genetically determined, this variant of immune response focuses on damage to the body's own structures and underlies the formation of allergic diseases and other immunopathological options.
Hypersensitivity of the delayed type (DTH)
Protective role of DTH
The main protagonists of DTH are Tx1, macrophages, dendritic cells (Langerhans cells when the antigen enters through the skin), IL-2, interferon-gamma, tumor necrosis factor alpha (FNO-Alpha), lymphotoxin, granulocytic-macrophagal colony stimulating factor (GM-CSF).
DTH is a variant of cellular immune response, however, in contrast to the typical variant of cellular immune response, where the effector link is an antigen-specific cytotoxic lymphocytes, the effector link of DTH is an immune inflammation - inflammation that develops in response only to a specific antigen (specific inflammation). The need for this variant arose due to the presence of intracellular pathogens, the destruction and elimination of which is impossible with a typical variant of cellular immune response.
Cellular and humoral immune responses in their typical variant provide effective protection from the bulk of antigens, however, they do not overlap the entire spectrum of pathogens and evolution has created additional variants of these responses (ITH and DTH), which in combination with the main ones are oriented to all cases. Thus, the choice of the optimal variant of the immune response is entirely related to the characteristics of the pathogen. In the case of DTH, the importance of the presence of lipid components in the microorganism in the choice of this variant of immune response has been proved. Mycobacteria are a typical example of intracellular pathogens, in which the standard variant of cellular immune response is ineffective. It is on their example that it seems reasonable to disassemble the protective role of DTH.
When tuberculosis mycobacteria enters through the mucous membranes, they are absorbed and treated by dendritic cells (Langerhans cells through the skin). Dendritic cells transport peptide fragments of the antigen in the membrane molecules of GKGS class II to the nearest lymph node, where this antigen Tx0 is presented. In response to the antigenic stimulus, they are activated and produce IL-2, which promotes their proliferation and differentiation into the Tx1 antigen sensitized to this antigen. These lymphocytes, also called pre-dactivated Tx1, leave the lymph node and move to different parts of the immune system. This ends the primary contact with the antigen, the main consequence of which is the appearance of lymphocytes sensitized to a specific Tx1 antigen. The sense of sensitization lies in the formation of blank forms of lymphocytes (pre-dactivated Tx1). These lymphocytes practically do not secrete cytokines, which play a major role in the development of immune inflammation.
By analogy with ITH, Tx1 sensitized cells can be called reactive cells, as they do not directly perform the effect function, but initiate the reaction of other components of the immune system, ending with a pathogen-specific immune inflammation.
The re-injection of the antigen implements the following chain of events. In the place of re-introduction, the antigen is absorbed by macrophages, which present the antigen to sensitive Tx1 cells. The result of repeated contact of these cells with the antigen is the completion of their differentiation into the so-called "inflammatory" Tx1 cells, which begin the active production of cytokines - inducers of immune inflammation (IL-2, interferon-gamma, lymphotoxin, FNO-Alfa, GM-CSF). These cytokines, especially interferon-gamma, cause a pronounced activation of macrophages and stimulation of their ability to destroy the pathogen. In turn, the cytokines secreted by activated macrophages cause migration to the place of localization of the pathogen monocytes, which infiltrate this place and actively join the macrophages in their attempt to destroy and eliminate the pathogen. If the joint efforts reach the goal, the DTH reaction ends there, the infiltration is dissolved and the immune inflammation is eliminated. However, quite often, especially in the case of the tuberculosis causative agent we are considering, these efforts are insufficient and granuloma begins to form. A.A. Yarilin (1999) gave a very precise description of granuloma: "In fact, granuloma is a newly formed morphological structure designed to isolate a pathogen or other foreign object, the destruction and elimination of which is impossible".
Granulema is a morphological structure with the causative agent in its center, infected macrophages, merged macrophages (giant cells), cell detritus, and on the periphery a cell barrier mainly made of T-lymphocytes, separating the pathogen control arena from healthy tissue. Further evolution of granuloma is a destruction starting from the center, which in case of pulmonary tuberculosis forms a cavern.
To conclude the description of the protective role of DTH, there are two important points to consider, which will help to be more specific in those situations where this reaction is the only choice in protecting the body from the pathogen. These are the migration of monocytes to the location of the pathogen and the presence of giant cells (merged macrophages). DTH and its effector mechanism - immune inflammation is realized only in cases when the "killing force" of one or more macrophages is not enough to destroy and eliminate the pathogen. This is the meaning of immune inflammation - attraction of specifically oriented additional forces (monocytes) for collective elimination of the pathogen. Moreover, destruction attempts are not only joint efforts of many macrophages aimed at the pathogen, but also their fusion into one large cell to enhance the lytical potential. The coordinating role here seems to be played by T-helpers. The formation of a cellular barrier around the granuloma is therefore more likely to be due to T-lymphocytes.
Damaging role of DTH
The specificity of DTH is immune inflammation and is a damaging mechanism. Unlike ITH, it is not a risk factor that can become damaging under certain conditions or defects in the immune system. All that is needed to achieve the damaging effect of immune inflammation is the failure of attempts to destroy and eliminate the pathogen.
Thus, the damaging effect of DTH is associated not with certain defects in the immune response or heredity, but with the peculiarities of the antigen itself and its resistance to the effector mechanisms of the immune system.
Another mechanism of damage is the location of the granules themselves, which, having a mechanical effect on tissues and organs can cause damage and functional defects.
Definition of the concept of delayed type hypersensitivity.
DTH is a variant of a specific immune response, which is implemented if necessary in the final stage of immune inflammation. The damaging effect of DTH is fully related to the features of antigenic irritation.
Allergy and immune system
One of the mandatory conditions for allergic reactions is repeated contact of the antigen with the body structures sensitized to this antigen. At the same time, repeated contact is also the essence of immunity (secondary immune response). A. A. Yarilin (1999) formulated this very clearly: "The word immunity, which gave the name to the science of immunology, does not mean immune processes that counteract infectious agents, but a state of resistance to their action that prevents the development of infection". This is the essence of immunological memory, which is formed after the primary immune response and is essentially a high sensitivity (sensitization) and immediate readiness to react to the reintroduction of this particular antigen.
There are the following immune response options:
- Humoral immune response.
- Hypersensitivity of the immediate type (ITH).
- Cellular immune response.
- Hypersensitivity of the delayed type (DTH).
We would like to emphasize - four variants of immune system responses, depending on the quantity and quality of antigenic irritation, designed to protect against foreign antigens and preserve body freedom of life. Humoral immunity - protection against bacterial infections and foreign proteins; ITH - a variant of humoral immunity if necessary in the final stage of extracellular cytolysis; cell immunity - protection against viral infections and foreign cells; DTH - a variant of cellular immune response if necessary in the final stage of immune inflammation.
A protective allergic reaction occurs when the immune system is unable to neutralize the pathogen at the first attempt. It is for such cases of immunity failure that allergy, which can still be called the second echelon of immune protection, is intended, since its effector mechanisms are implemented only on repeated contact with the antigen.
Thus, there are no fundamental differences between immunity and allergies. The concept of allergy reflects the historical stage of immunology development; the stage when the available amount of knowledge did not allow comprehending this phenomenon as one of the typical variants of the immune response, which predetermined the appearance of the term allergy (another action). At the same time, the terms allergies, allergens and sensitization should not be abandoned as a guide for a physician on those immune response options that are much more often than others accompanied by the development of pathological processes - allergic diseases.
It seems reasonable to give, in our opinion, a modern interpretation of the concept of allergies.
Allergies are immune response variants based on ITH or DTH and which, due to their peculiarities, are accompanied by structural and functional damage of cells, tissues, organs more often than others in case of repeated contact with the antigen.
At the same time, if by allergy we understand the pathological orientation of not only ITH and DTH, but also cellular and humoral immune responses, then the classification of Gell and Coombs will be valid, but such interpretation seems inappropriate due to the following circumstances. First, in practical medicine, the circle of nosologies included in the group of allergic diseases has been quite clearly formed and it makes no sense to change these traditions. Secondly, autoimmune and immunocomplex diseases also have a traditional circle of nosologies, which orients the doctor in a very specific diagnostic and therapeutic tactics, and there is no point in combining them with allergies. Third, and most importantly, the anaphylactic (ITH), cytotoxic, immunocomplex, cellular-mediated (DTH) and antireceptor types of immune damage are fundamentally different mechanisms, each requiring its own diagnostic, therapeutic and preventive approaches. It is on this path that we see real opportunities for progress in the treatment of diseases associated with these mechanisms.
It seems expedient to give a brief description of immune response options and the main stages of protection against antigenic aggression for a clearer orientation in immune damage mechanisms.
Evolution has created a perfect and deeply echelonized defense system to protect its own antigenic constancy and ensure the bodily freedom of life.
As a rule, the first contact with the antigen occurs on skin and mucous membranes. The state of these barriers and the peculiarities of the antigen determine the condition or failure of this first line of defense and the need to implement the remaining stages of the immune response. This is a very important stage that predetermines the correct orientation of the immune response or the possibility of developing its damaging variants. According to I. S. Gushchin (2000), "the state of histogematic barriers (namely, skin and mucous membranes) is a factor making an allergic response unnecessary or, on the contrary, forcing a response. Previously mentioned features of the antigen that make it an allergen - small molecule size and low dose. Such characteristics of the antigen determine the possibility of its unobstructed penetration through the mucous membranes and the orientation of differentiation Tx0 to Tx2 with the dominance of IgE secretion.
However, let us return to the first stage of immune protection - the skin and mucous membranes and their lymphatic system. Depending on the peculiarities of the antigen and the state of this barrier, two options are possible for further development of events. If the antigen damages tissue structures - a typical protective inflammatory reaction develops; if no damage occurs - the antigen penetrates the nearest lymphatic structures.
Immune response in case of inflammation
Inflammation is the first line of immune protection and is realized by cells and humoral factors, for which the stimulus of their functional activity is the damage itself. However, it is not only the damage that initiates inflammation. We cannot exclude the participation in this process of bacterial lipopolysaccharides and peptidoglycans, which are not typical for normal cells. However, we believe that the most universal target for the orientation of immunocompetent cells and humoral factors on the implementation of the inflammatory reaction is the end sugars (mannose) of membrane glycoproteins and glycolipids, released as a result of damage, transformation, increased proliferation or aging of the cell. This is a so-called "universal foreigner" without differentiation into individual antigens. A. A. Yarilin (1999) is quite right, who says that "on the level of the first line of defense the concept of antigen makes no sense". We will not dwell on the details and stages of the inflammatory process, which are quite well described and known to everyone. We will single out only the main thing necessary for understanding the logic of immunity and possible mechanisms of its participation in damage.
The main protagonists of inflammation are neutrophils, macrophages/monocytes, NK cells, sometimes eosinophils, complement system, inflammatory cytokines (IL-1, IL-6, FNO-Alpha, interferons), acute phase proteins, biologically active substances (quinines, histamine, heparin, prostaglandins, leukotrienes, etc.). In their interaction, they help localize and destroy the pathogen. Neutrophils and macrophages/monoses take the main blow in this process. Neutrophils not only phagocyte, but can also perform extracellular cytolysis, as well as the secretion of cytokines and other biologically active substances. Due to the possibility of the development of extracellular cytolysis, long-term inflammation may contribute to the damage of their own tissues and acquire all the features of a local autoimmune process, especially if eosinophils, known for their priority in the implementation of extracellular cytolysis, are involved in the elimination of the pathogen.
Participation in inflammation of macrophages/monocytes is extremely important. It becomes clear that such an important role of these cells in the presentation of the antigen and the triggering of a specific immune response. By primary contact with the pathogen, macrophages/monocytes not only participate in its elimination, but also by presenting its antigens initiate the addition of the next more powerful stage, which includes the entire arsenal of the immune system (cellular, humoral immunity, DTH, ITH) already specifically oriented to these antigens. Of course, this is true for thymus-dependent antigens, but recently data have also emerged about the existence of thymus-dependent antigens. The specific stage is not only a more powerful, but also a higher quality stage of protection, because the specific orientation practically excludes the possibility of damage to normal body structures, which exists under normal inflammation. The specific stage limits the possibility of organism damage by the pathogen. It should be thought that connection of a specific stage eliminates the need for an inflammatory reaction, and the time of deployment of this stage determines the duration of the clinical picture of the disease. The logical conclusion of this stage is not only complete and high-quality sanitation from the pathogen, but also the creation of immunological memory, providing operational protection in case of repeated exposure to the antigen without any damage to the body.
Thus, the long existence of the inflammatory process (chronic inflammation) clearly indicates the failure of the specific stage of the immune response associated with structural or functional defects in the immune system and is always a risk of immunopathology
The above data allow to present more clearly the logic of interrelation of non-specific and specific in ensuring rational and qualitative immune response. At the same time, there is no consensus on the central role of macrophages/monocytes involved in the inflammatory response in the initiation of a specific stage. A. A. Yarilin (1999) believes that these cells cannot significantly participate in the presentation of the antigen because they do not migrate to lymph nodes and in the activated state divide the antigen into too small fragments. However, the known fact of a better immunity after the disease than the vaccination suggests that the presentation of the antigen from the inflammation center provides a better immune response than other sources. At least for the skin, such cells are known to be Langerhans cells or white epidermyocytes, which, capturing in the focus of the antigen, migrate to lymph nodes along the way transforming into dendritic cells. As for mucosa - further research is required, but the importance of macrophages/mono-cytes in this process cannot be ignored at this time.
Immune response in the absence of inflammation
Marked features of the antigen or violation of the barrier role of skin and mucous membranes contribute to the transit of the pathogen into lymphatic structures, where it meets with immunocompetent cells. This pathway is much more dangerous and significantly increases the risk of immunopathology formation. This is due to a number of conditions and circumstances. Let us analyze some of them. The point is that lymphatic structures are the place where full variants of immune response are formed. If we can put it this way, it is the "intimacy" where the entry of strangers is undesirable. Contact with extraneous (antigens) is carried out through the presentation, i.e. in a convenient way. Contact of the "wild" antigen with the entire repertoire of immunocompetent cells in the lymph node may cause a violation of the usual and most rational logic of interaction of immunocompetent cells and become a risk of immunopathology, including allergies. From this perspective, it is clear why the low molecular weight of the antigen, which facilitates its transit through the mucosa into lymphatic structures, is one of the conditions for allergenicity of this antigen. Direct contact of low doses of this antigen with T cells can cause the formation of immunological tolerance, because it is well known that the induction of T-cell tolerance requires 100-1000 times less antigen doses than for mature B-cells (G.W. Siskind, 1988).
Direct contact with the lymphatic structures of pathogens is especially dangerous, because their damaging potential is realized in the place where the immune response is formed and, along with a violation of the logic of interaction of immunocompetent cells, can break this logic directly damaging them. The risk for human diseases with such mechanism (syphilis, tuberculosis, brucellosis, toxoplasmosis, lymphoproliferative diseases, etc.) is well known. At the same time, it is difficult to imagine skin and mucous membrane areas free from the control of antigen-presenting cells (APC), which would create the possibility of antigen contact in untreated form with lymphatic structures. This is most likely possible under certain conditions:
- significant defects or long-term irritation of the skin and mucous membranes;
- features of the antigen that would allow it to "escape" from the APC;
- 3intense or frequent contact of the antigen with the APC, which would exhaust their antigen-representative capabilities;
- functional or structural defects of the APC.
Concluding this section we can conclude that the most dangerous for the body in terms of the possibility of immunopathology and allergic diseases is direct contact of the antigen with the immune system, bypassing the protective inflammatory response. At the same time, the most optimal two-stage reaction of the immune system (inflammation is a specific immune response) also carries the possibility of immune damage. At the same time, the central link, it seems to us, is the quantity and quality of the antigen that starts and orients the immune response adequate to the antigenic irritation. The quality of primary contact also determines the quality of the immune response. Monocytes are the most available for control from this cell group. It is thought that studying the relationships between immunoglobulins (in particular, IgE) and monocytes can provide indirect but valuable information about the quality of the mechanism of representation of antigens and will serve as an additional criterion for diagnosis and prognosis of allergic diseases (immunopathology), as well as the development of new allergy treatment options on this basis.
Subsequent consideration of the principles of clinical diagnosis of allergic diseases and the resulting pathophysiologically sound therapy is impossible without a brief mention of the so-called "pseudoallergy". The emergence of this term is associated with the identification of A. D. Ado in 1969 in addition to the true allergic reactions of false allergic reactions that we have considered. In terms of external manifestations, pseudoallergic reactions resemble true allergic reactions, but the development of the clinical picture in them occurs without previous sensitization to the pathogenic factor. In other words, in the pathogenesis of false allergy there is no presence of immunological mechanisms, which is an important difference between true and false allergic reactions. In other words, pseudoallergic condition is based on non-specific liberalization of mediators from target cells of allergy, induced by direct contact of certain substances with cell membranes (L.V.Luss, 1999). However, at present, a number of others are considered as well as the abovementioned basic cellular mechanism of false allergy.
In this connection, three groups of mechanisms of pseudoallergic reactions development can be distinguished.
The first group of mechanisms is actually related to hyperproduction of the main mediator of histamine allergy. Nonspecific liberalization of histamine from the allergy target cells can be achieved by destroying cells under the influence of X-rays, infective agents, chemicals (cytotoxic release) or through activation of the cell receptor apparatus (cytotoxic release) by "liberators" of the mediator, which include calcium ions, trypsin, neuropeptides, X-ray-contrast substances, etc. In the case of pseudoallergenic reactions, the allergy target cells are allergic.
It should be kept in mind that pseudoallergic symptoms in a person develops under the condition of increase of free histamine concentration in plasma. In this case, the normal plasma content of histamine is extremely low (1 nanogram/ml).
The increase of histamine level in the blood may be associated with a pathology of the process of its inactivation. Violation of histamine inactivation may occur with prolonged use of some rich products, taking a number of medications, diseases of the liver and intestines, reducing the activity of histaminase.
The second group of mechanisms of pseudoallergic reactions is associated with the activation of the complement system. This may be, for example, in the acquired shortage of some inhibitors of this system. A typical example is the appearance of "allergic" symptomatology under stress.
And the third pathogenetic group may occur in cases of arachidonic acid metabolism disorder. The action of some compounds formed in this case may cause a number of effects that take place in the clinical and physiological stage of anaphylactic shock.