Theories of the occurrence of autoimmune diseases. Autoimmune diseases: causes and mechanisms

Autoimmune diseases continue to be one of the most challenging problems in clinical immunology. For almost a hundred years now, one of the main dogmas of immunology, formulated by Paul Ehrlich, is the idea that normally the immune system should not develop an immune response against its own tissues, since this can lead to the death of the body. P. Ehrlich called this “horror autotoxicus”. Currently, this phenomenon is known as “immune tolerance,” which develops in the embryonic and early postnatal period and consists in the fact that conditions are created in the body under which the immune system does not react with autoantigens (self-antigens) (this has already been mentioned in the corresponding chapter).

Thus, autoimmunity is characterized by the loss (impairment, disappearance) of tolerance, or natural unresponsiveness to self-antigens. As a consequence, the produced autoantibodies and/or cytotoxic cells lead to the development of the disease.

However, the ability immune system recognizing an autoantigen does not always carry pathological potential. For example, recognition of one’s own molecules of the major histocompatibility complex during the implementation of an immune response, anti-idiotypic response against self-idiotypes, etc.; all this allows the immune system to perform its main function of immune surveillance.

Currently, a very large number of autoimmune diseases have been described. It is assumed that the immune system, under appropriate conditions, can develop an immune response against any autoantigen.

Autoimmune diseases are divided into two groups:

• organ-specific - for example, myasthenia gravis, Hashimoto's thyroiditis, Graves' disease (thyrotoxicosis with diffuse goiter), etc.;
• systemic (non-organ-specific) - for example, systemic lupus erythematosus, rheumatoid arthritis, etc.

Autoimmune diseases (incomplete list intended to show the occurrence of this pathology in almost all medical specialties)

• Systemic lupus erythematosus
• Rheumatoid arthritis
• Scleroderma
• Dermatopolymyositis
• Mixed diseases connective tissue
• Sjögren's syndrome (sicca syndrome)
• Psoriasis
• Vitiligo
• Dermatitis herpetiformis
• Pemphigus vulgaris
• Bullous pemphigoid
• Disease (Reiter's syndrome)
• Ankylosing spondylitis
• Multiple multiple sclerosis
• Acute (post-)infectious polyneuritis (Guillain–Barré syndrome)
• Myasthenia Gravis
• Hashimoto's thyroiditis (autoimmune)
• Graves' disease (thyrotoxicosis with diffuse goiter)
• Insulin-dependent diabetes mellitus (type I)
• Autoimmune disease of the adrenal glands (Addison's disease)
• Autoimmune polyendocrinopathy
• Sarcoidosis
• Idiopathic pulmonary fibrosis
• Nonspecific ulcerative colitis
• Crohn's disease (regional enteritis)
• Autoimmune gastritis, type A
• Primary biliary cirrhosis
• Chronic active hepatitis
• Autoimmune enteropathy
• Celiac disease (gluten-sensitive enteropathy)
• Glomerulonephritis
• Goodpasture's syndrome
• Autoimmune orchitis
• Autoimmune infertility
• Primary antiphospholipid antibody syndrome
• Autoimmune uveitis
• Sympathetic ophthalmia
• Autoimmune conjunctivitis
• Polyarteritis nodosa
• Giant cell granulomatous arteritis (polymyalgia rheumatica)
• Pernicious anemia
• Autoimmune hemolytic anemia
• Autoimmune thrombocytopenia
• Autoimmune neutropenia, etc.

Although most of the ~80 identified autoimmune diseases are rare, they still affect millions of people worldwide. For example, in the United States, 5% of the population is affected - approximately 14 million people. In Ukraine, according to theoretical calculations, approximately 2.3 million people are affected.

In some cases, the development of autoimmunity (breakdown of tolerance) can be primary and serve as the cause of the development of the disease, in others, especially with long-term chronic diseases (for example, chronic pyelonephritis, chronic prostatitis, etc.), it can be secondary and be a consequence of the disease, closing the “ vicious circle“pathogenesis.

Often the same patient develops several autoimmune diseases, especially autoimmune endocrinopathies.

Autoimmune diseases are often associated with lymphoid hyperplasia, malignant proliferation of lymphoid and plasma cells, immunodeficiency states - hypogammaglobulinemia, selective IgA deficiency, deficiency of complement components, etc. Systemic autoimmune diseases often develop in adulthood.

Currently, about two dozen theories have been proposed to explain the reasons for the breakdown of tolerance and, as a consequence, the development of autoimmunity. Let's list the main ones.

1.The theory of “forbidden” clones. It is known that with the induction of tolerance at certain stages of development (maturation) of the immune system, elimination (destruction) of those T- and B-lymphocytes occurs that have autoreactivity - the ability to react with auto (self) antigens. According to the theory of “forbidden” clones, for one reason or another in the thymus and bone marrow There is no complete elimination of autoreactive T- and B-lymphocytes, which in the future, under certain circumstances, can lead to a breakdown of tolerance.

2.Theory of sequestered (barrier) antigens. It is known that certain tissues are protected by histohematic barriers (gonads, tissues of the eye, brain, thyroid gland and etc.). In this regard, when the immune system matures, the antigens of such tissues do not come into contact with lymphocytes and the corresponding cell clones are not eliminated. When the histohematic barrier is disrupted and antigens enter the bloodstream, their own immunocompetent cells recognize them as foreign and trigger the entire mechanism of the immune response.

3. Theory of immunological regulation disorder (Maintaining tolerance in the periphery).

• Decreased function of suppressor T lymphocytes. Suppressor T cells are thought to suppress the ability of B cells to produce antibodies against their own tissues, thereby maintaining a state of tolerance. When the number or function of suppressor T cells decreases, potentially autoreactive B cells begin to react to self-tissue antigens, and the resulting autoantibodies lead to the development of an autoimmune disease.
• Impaired function of T-lymphocyte helpers. In particular, when it increases, conditions can be created that are favorable for the initiation of a response from autoreactive B lymphocytes to their own antigens, even with normal T-suppressor function. Thus, the potential for the development of autoimmunity present in the body is realized due to normally functioning immunological regulatory mechanisms, including, first of all. T lymphocytes are suppressors and helpers.
• In recent years, the hypothesis has become increasingly popular according to which autoimmune pathology is based on disorders of immune regulation caused by disruption of the production of corresponding cytokines by T-helper lymphocytes of types I and II, as well as T-regulatory cells.
• Ignoring is explained by the absence (or insufficiency) of antigen presentation, or the absence of T cells with a receptor for the corresponding antigenic peptide located in the groove of the MHC molecule. These so-called “holes” in the T-cell repertoire, which are explained by the fact that in the early period of tolerance maturation, the corresponding clones of auto-reactive T cells underwent clonal deletion in the thymus.
• Anergy is explained by the absence of co-stimulation signals. In this case, the T cell, with its antigen recognition signal, recognizes the antigen in the groove of the MHC molecule, but since there is no additional costimulatory signal, such a T cell undergoes apoptosis.
• Regulation is explained by the existence of special regulatory T cells (T-reg), which are capable of suppressing the function of T-helper type 1 and T-helper type 2 due to the cytokines TGF and IL-10. In addition, on the surface of T-reg there is a CTLA4 molecule, which, by binding to the CD80/86 molecule on the surface of the APC, prevents the latter from binding to the CD28 molecule on the surface of the T-lymphocyte, thus blocking the co-stimulatory signal. In turn, the CTLA4 molecule, through the CD80/86 molecule, transmits a reverse signal to the antigen-presenting cell, increasing the expression of the enzyme indoleamine 2,3-dioxygenase, which reduces the amount of tryptophan in the T lymphocyte, thus suppressing its activity.

4.Theory of violation of idiotype-anti-idiotypic interactions.

Current models of immune response suggest that the immune system is self-regulating and can respond to its own products with subsequent suppression or stimulation of this response. It is known that antibodies against one’s own Ig can be detected in the blood serum of sick and healthy individuals (the first antibody of this type discovered in humans was rheumatoid factor). The idiotypic determinant (idiotype) is closely related to the individual structure of the active center of the Ig molecule. Initially, it was believed that the production of autoantibodies against one’s own Igs was the result of a disruption in the process of “self” recognition, and this was either the cause or a symptom of the disease. However, many researchers subsequently discovered antiimmunoglobulins in the blood serum of healthy linden trees, on the basis of which they assumed that the production of antiimmunoglobulins was a physiological rather than a pathological process. On this basis, a model of the immune system was developed in which control and regulatory influences depend on many interacting components, and antiimmunoglobulins directed against the active center of a specific antibody molecule (anti-idiotypic antibodies) play a leading role. It was suggested (N. K. Erne, 1974) that the recognition of idiotypic determinants and the development of an anti-idiotypic immune response is a central mechanism for the control and regulation of antibody biosynthesis. This theory is called the network theory of immune response regulation.

In Erne's theory, two main provisions can be distinguished:

• Immunoglobulins, as well as immunoglobulin receptors on the surface of antigen-reactive T- and B-lymphocytes have determinants that have (auto-) antigenic properties and are called “idiotype” (idiotypic determinants);
• Lymphocytes preexist in the body and are normally capable of recognizing idiotypic determinants with their receptors and implementing an anti-idiotypic response. The anti-idiotypic antibody can also be recognized and anti-anti-idiotypic antibodies produced against it until the immune response subsides. It is believed that the idiotype and the anti-anti-idiotype are identical structures.

Recent studies confirm important role idiotype-anti-idiotypic interactions in the regulation of the immune response. It is necessary to highlight the following main provisions:

• The anti-idiotypic response develops simultaneously with the normal immune response to foreign antibodies;
• idiotype - anti-idiotypic interactions determine the possibility of both stimulation and suppression of lymphocytes under the influence of anti-idiotypic antibodies. Taking these data into account, it becomes clear that the anti-idiotypic response, which develops simultaneously with the usual immune response, stimulating or inhibiting the first, depending on certain circumstances, ensures its self-regulation according to the feedback type.

Thus, when an immune response occurs, antibodies, immune complexes, and/or a cell-mediated immune response develop. In order to balance these mediators of immunopathology and prevent them from “working” against one’s own tissues, a regulatory mechanism is simultaneously activated, which is a complex network of T-, B-cells and antibodies, coordinated as an anti-idiotypic immune response. This mechanism provides the control necessary to prevent damage to target organs during the myriad immune responses generated by the “host” within the body's own body.

From the above, it is clear that disruption of idiotype-anti-idiotypic interactions will contribute to the development of autoimmune diseases.

5.Theory of polyclonal activation of B-lymphocytes. It has been discovered that many chemical or biological nature have the ability to induce activation of B lymphocytes, which leads to their proliferation and antibody production. As a rule, such antibodies belong to class M immunoglobulins. In the event that autoreactive B lymphocytes producing autoantibodies undergo polyclonal activation, the development of an autoimmune disease is possible.

Polyclonal B-lymphocyte activators lipopolysaccharide Purified tuberculin protein Protein A Staphylococcus aureus Lipid A-associated protein T cell and macrophage lymphokines Fc fragment Ig

Proteolytic enzymes (for example, trypsin) Polyanions (for example, dextran sulfate) Antibiotics (for example, nystatin, amphotericin B) Mycoplasma

6.Theory of the development of autoimmunity under the influence of superantigens.

Bacterial superantigens get their name due to their ability to activate large numbers of T and B lymphocytes, regardless of the antigen specificity of these cells. It was mentioned above that in the classical version of antigen recognition, the T-helper is activated under the influence of the interaction of the T-cell antigen recognition receptor (TAGR) and a peptide that is presented by the antigen presenting cell (APC) in association with a molecule of the major histocompatibility complex class II. In this case, only one (or several) T-helper lymphocytes can be activated. Activation of helper T lymphocytes under the influence of superantigens occurs in a completely different way. In this case, the superantigen is not taken up by the antigen-presenting cell and does not undergo normal digestion (processing) to form a peptide. In this case, the superantigen bypasses this stage necessary for specific recognition and nonspecifically binds to the variable part of the beta chain of the T-cell recognition receptor outside its antigen-specific zone (site). A peculiar cross-linking of the molecules of the major histocompatibility complex of the antigen-presenting cell with the T-cell recognition receptor occurs. In the case of such a mechanism of activation of helper T lymphocytes, simultaneous activation of a large number of them is possible.

Thus, distinctive features stimulation of T lymphocytes under the influence of superantigens are as follows:

1. For this, there is no need for digestion (processing) of the antigen in the antigen-presenting cell;
2. Such stimulation does not depend on the antigen specificity of the HLA complex molecules and the T-cell recognition receptor;
3. Superantigen is capable of stimulating 103-104 times more lymphocytes than processed antigen;
4. An allogeneic (foreign) superantigen can stimulate both helper (CD4+) and killer (CD8+) T lymphocytes;
5. Autologous (self) superantigen can stimulate only T-lymphocytes-helpers (CD4);
6. For full stimulation of T-lymphocytes by a foreign superantigen, an additional, costimulatory signal is required.

Foreign superantigens have been described for Staphylococcus aureus (enterotoxins A, B, C, etc., toxin that causes toxic shock syndrome, exfoliative toxins). Streptococcus pyogenes (erythrogenic toxin, toxins A, B, C, D); for Mycoplasma arthritidis. Under the influence of these superantigens, the following diseases (conditions) can develop: food poisoning, toxic shock syndrome, scaly skin, rheumatic fever, arthritis, etc.

It has also been established that some tumor viruses, located in the cell genome in the form of a provirus, can encode the production of a protein that causes stimulation of T-lymphocytes, acting as a superantigen.

Three possible mechanisms for the participation of superantigens in the development of autoimmune disorders are considered.

A. Activation of autoreactive T lymphocytes. It has been proven that superantigens can directly activate autoreactive T lymphocytes, which then migrate to the corresponding tissues and cause autoimmune disorders, producing cytokines and/or realizing its killing function.

B. Activation of autoreactive B lymphocytes. It is carried out due to the fact that the superantigen binds molecules of the HLA class II complex, present on B lymphocytes, with the T-cell antigen recognition receptor molecule. In this case, activation of T lymphocytes occurs without specific antigen recognition, but nonspecifically under the influence of a superantigen. However, such a T lymphocyte produces appropriate cytokines that cause the activated autoreactive B lymphocyte to begin producing autoantibodies. The latter form immune complexes and, settling in tissues, cause their damage. It is possible that B lymphocytes can also be activated through their own antigen-recognizing immunoglobulin receptor.

B. Activation of antigen presenting cells. Superantigens can activate antigen-presenting cells such as macrophages. This leads to the release of cytokines, superoxide anions and other inflammatory mediators. Activation of macrophages can also lead to impaired digestion (processing) of antigens with subsequent presentation of autoantigens to autoreactive T lymphocytes.

7.Theory of genetic predisposition. According to modern data, there is a genetically determined predisposition to the development of autoimmune diseases. This predisposition is controlled by at least six genes located on different chromosomes. Some of them are located in the human major histocompatibility complex (HLA), whose role in the implementation of the immune response is paramount.

It has been established that most autoimmune diseases are associated with the presence of the following antigens in the human HLA phenotype: DR2, DR3, DR4 and DR5. For example, rheumatoid arthritis is associated with HLA-DR4, Hashimoto's thyroiditis with HLA-DR5, multiple sclerosis with HLA-DR2, systemic lupus erythematosus with HLA-DR3.

It has also been proven that autoimmune diseases develop much more often in women than in men. For example, the incidence of systemic lupus erythematosus in women is 6-9 times higher than in men. It is believed that sex hormones play an important role in this case.

Within the framework of the theory of genetic predisposition, several hypotheses have been put forward to explain the participation of HLA complex products in the pathogenesis of diseases in general and autoimmune diseases in particular.

A. According to the receptor hypothesis, one of the earliest, certain HLA antigens are receptors for viruses, facilitating their fixation and penetration into the cell. This hypothesis has many arguments both in its favor and against. For example, with a disease of obvious viral etiology, such as polio, as well as with infectious mononucleosis no significant correlation with HLA antigens is found.

B. Hypothesis about the modification (change) of an autologous, self, antigen (altered self). According to this hypothesis, a modified autologous antigen is recognized by the immune system as nonself, which leads to a breakdown of tolerance.

B. Hypothesis about the influence of a hypothetical Ir gene on susceptibility to diseases (impaired selection of antigenic determinants, the presence of “holes” in the repertoire of T-lymphocytes, impaired suppression mediated by T-lymphocytes).

D. Hypothesis about the influence of non-classical genes mapping within the HLA system. For example, the genes HSP-70, TNF, C4A, C2 deficiency are associated with systemic lupus erythematosus and pyogenic infection.

8.Theory of molecular mimicry. The term “mimicry” was once proposed to explain the similarity and identity of the antigenic determinants of some microorganisms to the antigenic determinants of the host, and therefore their recognition by the immune system does not occur, which determines the development infectious disease. Currently, the theory of molecular mimicry has changed and is presented in two versions.

A. According to the first version of the theory, some microorganisms actually have cross-reactivity with antigenic determinants of the host, perhaps not due to identity, but due to fairly pronounced similarity (homology). This circumstance has its own explanation. Indeed, the most important (and, apparently, initial) role of the immune system is to protect the body from infections. For this purpose, the main cells of the immune system - T- and B-lymphocytes - are equipped with antigen recognition receptors of very different specificity, which allows them to recognize any infectious agent that has entered the body.

Having recognized a foreign agent, the immune system defends itself by two main mechanisms: 1) the production of humoral antibodies; 2) generation of cytotoxic T-lymphocytes. In the first defense mechanism, antibodies attack extracellular infectious agents and their toxins, forming immune complexes; with the second mechanism, in order to save the entire organism, cytotoxic T-lymphocytes have to destroy their own cells in which intracellular pathogens are hidden.

Thus, immunity to infectious agents quite often has an immunological component, either in the form of immune complexes or in the form of cytotoxic T lymphocytes. It follows that, when developing an anti-infective response, the immune system must “choose” the strength with which it defends itself: the response must be sufficient to eliminate the pathogen, but harmless to the body. This balance depends on many conditions: a) the severity and duration of the infection; b) the damaging effect of the pathogen and the degree of the immune response; c) the number and significance of those host cells that were destroyed during an attempt to eliminate the intracellular pathogen.

Microorganisms express a variety of antigens that are similar, if not identical, to host antigens. If all T and B lymphocytes capable of reacting with these antigens were eliminated during the period of tolerance, then there would be large gaps in the protective abilities of the immune system, which would allow these microorganisms to invade the body unhindered. However, this is not the case; therefore, those T and B lymphocytes that recognize infectious agents that have antigens similar to host antigens (cross-reacting antigens) can react with their own cells, i.e., they have autoreactivity.

Thus, when tolerance is created in the embryonic and early postnatal period, complete destruction of autoreactive T- and B-lymphocytes does not occur. By preserving auto-reactive T- and B-lymphocytes, the body increases the ability of the immune system to resist infectious agents that have similar antigenic structures. And as a consequence, the development of a protective anti-infectious immune response under certain conditions can lead to the development of an autoimmune response.

However, it should be borne in mind that the autoimmune response (especially in the form of the production of humoral autoantibodies after infectious diseases) does not always end in the development of an autoimmune disease.

B. According to the second version of the theory of molecular mimicry, the host’s own (auto-, self-) antigens can be modified under the influence of various factors: prolonged exposure to infectious agents, the influence of free radicals. N0, xenobiotics, drugs, exposure to environmental factors (ionizing and ultraviolet radiation, exposure low temperatures and so on.). As a result of such influences, autoantigens change and are recognized by the immune system as foreign (non-self). Produced autoantibodies and cytotoxic lymphocytes bind not only to modified autoantigens, but also to true autoantigens due to the same cross-reactivity (mimicry, similarity).

All those effector mechanisms by which the immune system protects the body from exogenous intervention - humoral antibodies, immune complexes, cytotoxic T-lymphocytes and cytokines - take part in the immunological mechanisms of tissue damage in autoimmune diseases. In the development of the pathological process, these factors can act both separately and together.

At direct action autoantibodies on cells and tissues of the body, as a rule, the complement system is activated, which contributes to their destruction. It is possible to “turn on” the mechanism of antibody-dependent cell-mediated lysis, i.e. with the participation of K cells. In some cases, autoantibodies directed against functionally important cellular receptors stimulate or inhibit specialized cell function without destroying it.

In the case when circulating immune complexes consisting of auto-antigen and autoantibodies are formed, different reasons can cause their sedimentation in the microvasculature various organs(kidney, joints, skin, etc.) or in hemodynamically stressed areas with pronounced turbulent flow (bifurcations, discharge of large vessels, etc.). In places where immune complexes are deposited, complement is activated, granulocytes and monocytes accumulate, secreting various enzymes. All this leads to the death of cells in the “shock” organ and the development of inflammation.

The maturation of cytotoxic T-lymphocytes leads to their accumulation in the affected tissue (perivascular infiltration) with the subsequent development of a killing effect, attracting a large number of inflammatory cells.

As a rule, the development of autoimmune diseases involves immune mechanisms corresponding to types I, III and IV of immune reactions according to the classification of Gehl and Coombs.

Self-antigens (peptides) are produced by antigen-presenting cells during the processing of engulfed cellular fragments (eg, apoptotic bodies) and can be presented by HLA class I or class II molecules. The presentation of intracellular autopeptides by HLA class I molecules promotes the maturation of autocytotoxic T lymphocytes; in turn, the presentation of extracellular autopeptides by HLA class II molecules promotes the maturation of autoantibodies.

IN last years In the development of autoimmune damage to cells and tissues, much attention is paid to pro-inflammatory cytokines - IL-1, alpha-ONF, gamma-INF, IL-2, as well as the inclusion of apoptosis mechanisms. Today there is evidence that autoimmune tissue damage can be realized through the mechanism of nonspecific binding of Fas + FasL and the activation of apoptosis. This is due to the fact that the Fas receptor appears on the surface of cells, for example, pancreatic B cells and oligodendrocytes, under the influence of various stimuli (primarily cytokines). Autoreactive T lymphocytes expressing FasL can bind to the Fas receptor and induce apoptotic death of target cells.

The following observations are also interesting. It is believed that the constitutive (initial) expression of FasL on the surface of cells of privileged organs (for example, eyes, testes) is protective, allowing the induction of apoptosis in Fas-positive lymphocytes when they enter the corresponding tissues. But the presence of a Fas receptor and a Fas ligand on the surface of the same cell may be the cause of autocrine suicide of such a cell. A similar mechanism is considered as one of the reasons for the development of Hashimoto’s thyroiditis (thyrocytes have FasL, and under certain influences, Fas receptors begin to be strongly expressed on the thyrocyte membrane).

The presence of autoantibodies in itself does not indicate the development of the disease. In low titers, autoantibodies are constantly found in the blood serum of healthy individuals and are involved in maintaining homeostasis, ensuring the removal of metabolic products, idiotypic control and other physiological processes.

Based on the data presented, we can define the concepts of “autoimmune process” and “autoimmune disease”.

Autoimmune process (autoimmunity)– this is a form of immune response induced by autoantigenic determinants under normal and pathological conditions; is one of the mechanisms for maintaining homeostasis. The severity of autoimmune processes under normal conditions is insignificant.

Autoimmune disease is a pathological process in the pathogenesis of which autoantibodies and/or cellular autoimmune response play an important role.

The signs by which a particular disease can be classified as autoimmune were formulated by L. Vitebsky (1961).

1. The presence of autoantibodies or cytotoxic T lymphocytes directed against the antigen associated with the disease.
2. Identification of the autoantigen against which the immune response is directed.
3. Transfer of an autoimmune process using serum containing antibodies or cytotoxic T-lymphocytes.
4. The possibility of creating, by introducing an autoantigen, an experimental model of the disease with the development of corresponding morphological abnormalities characteristic of the disease.

The general principles of immuno-laboratory diagnosis of autoimmune diseases are based on the following features:

• The presence of specific autoantibodies;
• The presence of specific cellular sensitization (detected using the blast transformation reaction - RBT and the leukocyte migration inhibition test in the presence of the corresponding autoantigen);
• Increased levels of gamma globulin and/or IgG;
• Changes in the number of T-helpers, T-suppressors and T-regulatory cells, leading to a breakdown in tolerance;
• Decrease in the level of C3 and C4 complement components;
• Deposits of immune complexes in affected tissues (IgG, IgM, C3, C4 and fibrin);
• Lymphoid cell infiltration of affected tissues;
• Determination of HLA phenotype.

In normal animals, neither the introduction of autologous proteins (without amplifiers of the immune response) nor the release of autoantigens into the circulation from damaged tissues serve as a trigger event for the development of autoimmune pathology.
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Factors providing predisposition to autoimmune processes

Often genetic predisposition linked to MHC genes. In organ-specific cases, antigens B8 and DR3 are more likely to be detected.

Predisposition or resistance to the development of insulin-dependent diabetes is determined by a difference in one residue at position 57 of the HLA-DQ molecule (resistance is due to the presence of an aspartic acid residue, predisposition is due to the presence of valine, serine or alanine residues).

Among non-genetic factors, gender plays a role (as a rule, women develop these diseases more often) and age (with age, the likelihood of developing the disease increases).
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Mechanisms of activation of autoimmune processes

• 
  central nervous system,
• 
  internal environments eyes,
• 
  internal parts of the testes,
• 
  thyroid follicles, etc.

• 
  "sympathetic ophthalmia" (involvement of pathology healthy eye with the development of an inflammatory process in the injured eye),
• 
  lesions of both testicles in autoimmune orchitis initiated by injury to one of them.

Thus, induction of an autoimmune process requires a combination of:

• 
  immunization with a “barrier” antigen,
• 
  effects on the immune system causing hyperactivation of Th1 cells.

In the case of the cellular nature of the lesion, the situation is different, since immunologically “privileged” areas of the body are lined with cells expressing the Fas ligand, which protects them from attack by cytotoxic T cells armed with the Fas receptor.

2.Somatic cells become antigen-presenting cells.

Normally, body cells (with the exception of antigen-presenting cells) do not express MHC class II molecules and are not recognized by T helper cells. If cells of certain organs begin to express these molecules, they become a potential target for their own immune system.

Examples of diseases associated with this mechanism include insulin-dependent diabetes, thyrotoxicosis, autoimmune hepatitis.

The reasons for the unusual expression of MHC class II molecules are unknown. Increased expression of these molecules and their appearance in unusual places may cause interferon.

IF is a major product of Th1 cells, which may explain the ability of Freund's complete adjuvant to induce autoimmune processes. In all cases of this type of disease, a cell-type autoimmune process is induced.

3. Antigenic mimicry.

Bacteria have antigenic determinants that cross-react with normal antigens. Normally, unprimed autoreactive clones are not activated, because on professional agro-industrial complexes, autoantigens are present in low concentrations, and there are no costimulatory molecules on non-professional APCs. The appearance of cross-reactive bacterial antigen in large quantities will lead autoreactive clones to an active state.

Another mechanism is also possible. Normally, autoreactive B lymphocytes do not produce antibodies, as they lack T helper help. But as an APC, a B lymphocyte captures a cross-reacting bacterial antigen, breaks it down into fragments, presents these fragments, and among them there may be a foreign one, to which T cells will react. As a result, non-autoreactive T helper cells begin to help autoreactive B lymphocytes.

Immunodominant antigen group A streptococci is -D-N-acetylglucosamine. The same sugar determines the specificity of the keratin molecule on epithelial cells. Infection with group A streptococci can lead to the formation of antibodies that can react with and damage epithelial cells. Fortunately, in most cases, keratin molecules are inaccessible to the action of antistreptococcal antibodies, as they are masked by sialic acid.

1. 
   Antibodies to pneumococcal polysaccharide cross-react with some tissue antigens of the heart and kidneys.
2. 
   Antibodies detected in ulcerative colitis interact with some strains E.coli.
3. 
   Autoimmune damage to the heart muscle in Chagas disease is associated with the induction of cross-reacting antibodies to Trypanosoma cruzi.
4. 
   In ankylosing spondylitis – cross-reactivity between cell components Klebsiela and the HLA-B27 molecule.
5. 
   Common epitopes are found in the TSH receptor and Yersinia.

The addition of haptens leads to the formation of epitopes, which include, in addition to the hapten, part of the protein molecule. In the case of cross-recognition of normal autologous epitopes by T- and B-cell receptors, an autoimmune reaction develops.

-methyl-DOPA induces autoimmune hemolytic anemia, in which molecules of the D (Rh) antigen become the target of antibodies.

Penicillinamide and procainamide cause systemic autoaggression up to lupus syndrome.

Isoniazid may cause the formation of antinuclear antibodies with clinical manifestations in the form of polyarthritis.

-adrenergic agonists – status asthmaticus.

However, there is no strict evidence of a direct connection between the induction of the autoimmune process and the modification of autoantigens.

5. Violation of the process of negative selection.

Disruption of the process of negative selection in the thymus or in the periphery can lead to incomplete elimination of autoimmune clones. The reason for this may be functional impairment dendritic cells that cull autoimmune clones.

In mice with mutations in the genes that determine the Fas receptor and Fas ligand, lupus syndrome with vasculitis, accumulation of autoantibodies, and kidney damage is formed. Obviously, due to the blockade of Fas-dependent apoptosis, there is no culling of autoreactive clones both in the thymus and in the periphery.

In systemic lupus erythematosus, the mechanism of apoptosis is not impaired, but can be suppressed due to the accumulation in tissue fluids of a soluble form of the Fas receptor, synthesized by activated cells.

6. Increased CD5 activity + -B1 cells.

In mice carrying the mutation me (moth eaten - moth eaten), there is an increase in the content of B1 cells, an increase in their production of IgM autoantibodies to DNA, antigens of granulocytes and other autologous cells and, as a result, the development of fatal autoimmune pathology.

The mechanism of development of the lesion (usually systemic) can be represented as follows: B1 cells produce a small amount of autoantibodies. Autoantibodies interact with antigens to form immune complexes. These complexes are captured by macrophages, cleaved, and fragments including antibody idiotypes are presented. Autoreactive T cells are activated and begin to help B cells that produce autoantibodies.

7. Direct activation of autoreactive B lymphocytes .

The Epstein-Barr virus and bacterial envelope lipopolysaccharides are capable of activating non-eliminated autoreactive B lymphocytes without the help of T cells (but the antibody titer is low and the affinity is low).
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Immunological mechanisms of autoimmune lesions

• 
  antibody-dependent cytotoxicity – type II hypersensitivity (hemolytic anemia and other autoimmune lesions of blood cells),
• 
  immunocomplex – type III hypersensitivity (systemic lupus erythematosus),
• 
  stimulating (autoantibodies to TSH receptors in thyrotoxicosis).

Autoimmune processes of the cellular type are usually more severe and less sensitive to therapeutic effects.

The main variants of cellular mechanisms of autoimmune damage are cytotoxic - cytolysis mediated by CD8 + cells (insulin-dependent diabetes mellitus), as well as HRT - destruction by macrophages (activated Th1) and their products with the subsequent formation of a focus of chronic immune inflammation (multiple sclerosis and rheumatoid arthritis).

With the cytotoxic mechanism, the damage is more localized, less destructive, and the consequences are associated with the uniqueness of the affected cells (diabetes mellitus). With the development of HRT, significant amounts of tissue are involved in the pathology, and the damage is more pronounced.
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Main types of autoimmune diseases

(according to E. Vitebsky).

• 
  antibodies must be detected;
• 
  the antigen with which they react can be identified and isolated;
• 
  it is possible to induce antibodies to the autoantigen in experimental animals and thereby develop a disease with corresponding symptoms.

Due to the constant persistence of the autoantigen (it is a normal component of cells), autoimmune diseases are always protracted with signs of self-maintenance. The disease is subject to the laws of development of immune reactions. Therefore, factors that suppress the immune response have therapeutic effect, and immunostimulants support the pathological process.

Differences between systemic and organ-specific autoimmune diseases.

It is typical that autoimmune diseases at one end of the spectrum often occur together. Diseases from different regions are combined with each other relatively rarely.

Autoimmune lesions of the thyroid gland.

• 
  Hashimoto's thyroiditis,
• 
  primary myxedema,
• 
  thyrotoxicosis ( Graves' disease, or Graves' disease).

In thyrotoxicosis, the autoantigen is the cell membrane receptors for thyroid-stimulating hormone. Interaction of autoantibodies with it stimulates cells, which manifests itself as hyperthyroidism.

Insulin-dependent diabetes mellitus (diabetes mellitus type I)

The main mechanism of immune damage is cellular, caused by the activity of cytotoxic CD8 + lymphocytes.

The nature of the autoantigen(s) is not clearly understood. The main “candidates” for their role are intracellular glutamic acid decarboxylase and p40 protein. Autoantibodies to insulin are also detected, but their role in pathogenesis is controversial.

Myasthenia gravis (myasthenia gravis))

The disease is caused by the accumulation of autoantibodies that interact with acetylcholine receptors and compete with acetylcholine.

This leads to disturbances in the transmission of nerve impulses to the muscles and muscle weakness, including disruption of the diaphragm.

Often combined with thymus pathology:

• 
  hypertrophy with the formation of follicles in the medullary part,
• 
  development of thymoma,
• 
  less often, thymic atrophy.

Possible viral etiology. Damage is caused by CD4 + cells of the Th1 type. Autoantigen at multiple sclerosis not exactly established. There may be several of them, and among them is myelin basic protein. Experimental model– autoimmune encephalomyelitis caused by the administration of myelin basic protein in Freund's complete adjuvant.

Rheumatoid arthritis

The main factor of damage is CD4 + cells of the Th1 type. Various substances can serve as autoantigens, in particular RANA - “nuclear antigen of rheumatoid arthritis”.

At rheumatoid arthritis IgG glycosylation is impaired (terminal D-galactose residues are missing), which causes a change in the conformation of the molecule in the region of CH 2 domains. Antibodies to IgG (class IgM - rheumatoid factor), collagen, histone, DNA, and cytoskeletal components are detected.

As a result of the interaction of autoantigens with antibodies, immune complexes are formed and deposited in the vascular endothelium, including in the joints. Immune complexes initiate local inflammation in the joint cavity. Macrophages are involved in this process. Factors produced by macrophages cause synovial hyperplasia and cartilage damage. Synovial cells are also activated and produce cytokines that support inflammation.

Systemic lupus erythematosus

The etiology has not been established. Both humoral and T-cell mechanisms are involved in the formation of pathology.

The following act as autoantigens:

• 
  DNA (including double-stranded DNA, antibodies to which cannot normally be obtained; one of the main diagnostic tests at systemic lupus), RNA, nucleoproteins, histones,
• 
  cardiolipin, collagen, cytoskeletal components,
• 
  soluble antigens of the cell cytoplasm (Ro, La),
• 
  membrane antigens of blood cells (including lymphocytes).

Almost all organs are involved in the pathological process, but kidney damage is usually fatal. Many typical manifestations of immunopathology may be associated with the deposition of immune complexes ( immune complex disease).

Diseases of the blood system.

• 
  autoimmune hemolytic anemia,
• 
  idiopathic thrombocytopenic purpura,
• 
  idiopathic leukopenia.

Anti-erythrocyte antibodies are divided into:

• 
  thermal - belong to IgG and cause predominantly extravascular hemolysis caused by the FcR-dependent action of macrophages or NK cells,
• 
  cold - belong to IgM, manifest their effect when the body temperature in the periphery decreases to 30-32 ° C (natural cold autoantibodies specific to the substance of blood groups I are known).

The immune system is a complex mechanism consisting of cells and organs. Its main task is to protect humans from the influence of foreign agents. Perfectly distinguishing “strangers” from “our own”, it protects the body from many various pathologies. But sometimes it fails. The immune system loses the ability to distinguish between its cells. The body begins to produce antibodies that attack healthy tissue. In this case, doctors conclude: disturbed autoimmune processes are occurring. What does this mean? And how to deal with such phenomena?

Autoimmune processes in the body - what is it?

Most people who hear about such phenomena immediately associate them with severe incurable diseases. This is true. But only if the autoimmune processes are disrupted. If they are normal, then they perform very necessary and important functions.

Let's figure out what an autoimmune process means. During human life, any disturbances may occur in cells. In this case, they become foreign and can even cause harm. This is where the immune system comes into play. It cleanses the body and rids it of foreign agents. The immune system eliminates dead cells. It is difficult to even imagine what would happen to the body if such a function did not exist. A person would turn into a real cemetery of dead cells. It is this function that is called the “autoimmune process in the body.”

In case of failure, the immune system begins to attack its own cells. It perceives healthy tissues as foreign elements. As a result, their own immune system damages them. Against the background of this phenomenon,

Reasons for violations

Before today doctors are not ready to say why autoimmune processes are disrupted. The reasons for such phenomena are not fully understood. There is an opinion that such pathologies can be triggered by injuries, stress, hypothermia, and various infections.

Doctors identify the following sources that trigger such disorders in the body:

1. Various infectious pathologies provoked by microorganisms whose protein structure is very similar to human tissues and organs. For example, very often the source of the problem is streptococcus. This infection invades a cell, disrupts its functioning and infects neighboring ones. The protein resembles healthy tissue cells. The immune system is unable to distinguish between them. As a result, a person may develop ailments such as arthritis, autoimmune glomerulonephritis, and gonorrhea.
2. In the body, as a result of a number of reasons, pathological disorders such as necrosis or tissue destruction can be observed. The immune system, trying to cope with them, begins to attack not only the affected cells, but also healthy tissues. For example, hepatitis B often becomes chronic.
3. Rupture of blood vessels. Many organs do not come into contact with this liquid. After all, blood does not fill the entire cavity of the body, but flows through special vessels. But sometimes veins can rupture. In this case, bleeding will begin. The body will immediately react to this phenomenon, perceiving the cells as foreign, and will launch the production of antibodies. Such disorders can lead to thyroiditis and autoimmune prostatitis.
4. The source of the problem may be an immunological imbalance or a hyperimmune state.

At-risk groups

The autoimmune process in the body can be disrupted in any person. However, doctors identify certain groups of people who are most susceptible to this pathology.

1. Women in childbearing age. It has been noticed that young ladies suffer from these disorders much more often than men. In this case, the pathology often develops during reproductive age.
2. People with similar illnesses in their family. Some autoimmune pathologies are genetic in nature. Such a disease is Hereditary predisposition, especially in combination with other factors, often becomes a trigger for the development of pathology.
3. Individuals who have a lot of contact with certain components of the environment. Some substances can become a source of disease development or aggravate existing ones. Such provoking factors are: bacterial, viral infections; chemicals; active sun.
4. People of a certain ethnicity. Doctors state that mainly white people develop a pathology such as type 1 diabetes. in severe stages, most often affects Spaniards and African Americans.

General symptoms

Each case of this disease is quite unique. The symptoms that occur in a person depend on which tissues are attacked. However, there are common marker symptoms that indicate a disturbed autoimmune process.

Signs characterizing a malfunction in the body:

1. The patient experiences dizziness, general weakness, and low-grade fever.
2. Most autoimmune pathologies occur in a chronic form. Stages of remission alternate with exacerbations. Sometimes the pathology progresses rapidly, leading to severe complications literally in a few days, weeks, months.

Diseases and symptoms

Let us consider in more detail what ailments can develop as a result of such a condition as a disturbed autoimmune process. Symptoms depend entirely on the pathology. Therefore, it is impossible to talk about them separately.

So, if the autoimmune system is disturbed, the following may develop:

Alopecia areata

Are under attack hair follicles. This pathology is usually general state does not affect health. But it significantly worsens the appearance.

The disease is characterized by following symptoms: There are no patches of hair on the head and other areas of the body.

Autoimmune hepatitis

With this pathology, the immune system destroys the liver. As a result, organ compaction, cirrhosis, and liver failure may occur.

• liver enlargement,
• skin itching,
• weakness,
• jaundice,
• joint pain,
• discomfort in the gastrointestinal tract.

Antiphospholipid syndrome

Against the background of thrombosis of veins and arteries, damage to blood vessels occurs.

The development of such a pathology is indicated by:

• presence of blood clots,
• mesh rash on wrists, knees,
• spontaneous abortions.

Celiac disease

With this pathology, people are gluten intolerant. This is a substance found in rice, grains, and barley. When these foods or certain medications are taken, the system attacks the intestinal lining.

Symptoms:

• pain, bloating;
• upset or constipation;
• weight loss or weight gain;
• weakness, rash, itching on the skin;
• disturbed menstrual cycle, miscarriage, infertility.

Graves' disease

This is a pathology in which a disturbed autoimmune process occurs in thyroid gland. The affected organ begins to produce a lot of hormones.

The disease is characterized by:

• irritability,
• increased sweating,
• weight loss,
• insomnia,
• trembling hands
• minor menstruation,
• hair section,
• high heat demand
• bulging eyes,
• muscle weakness.

Type 1 diabetes

In this case, those cells that produce insulin are attacked. This hormone provides normal level blood sugar. Without insulin, the norm is significantly exceeded. As a result, damage to the heart, kidneys, eyes, teeth, and nerves may occur.

The symptoms of this disease are:

• feeling of thirst,
• feeling tired, hungry,
• itching, dry skin,
• frequent urination,
• poor wound healing,
• involuntary weight loss,
• tingling or loss of sensation in the limbs,
• visual impairment (the image is perceived as blurred).

Multiple sclerosis

Characteristic damage to the nerve sheath. Damage affects the head and spinal cord. Symptoms vary depending on the extent and area of ​​the lesion.

The following signs may be observed:

• poor coordination, loss of balance, weakness;
• speech problems;
• tremor;
• paralysis;
• tingling, numbness of the limbs.

Psoriasis

The disease develops as a result of the active production of new skin cells in the deep layers. They begin to accumulate on the surface of the epidermis.

The disease manifests itself with the following symptoms:

• red, rough spots that resemble scales;
• they appear on the elbows, knees, head;
• pain and itching appears.

A specific form of arthritis may develop that affects the joints of the fingers. When the sacrum is involved in the process, pain and discomfort occurs in the back.

Hashimoto's disease

This is another disease in which the autoimmune process in the thyroid gland is disrupted. But this pathology is characterized insufficient output hormones.

The disease is indicated by:

• fatigue, weakness;
• sudden weight gain;
• increased sensitivity to cold;
• discomfort in muscle tissue;
• poor joint mobility;
• constipation;
• swelling of the face.

Rheumatoid arthritis

The immune system begins to attack the lining of the joints.

The following manifestations are characteristic:

• pain, poor mobility in joints;
• joints become swollen and deformed;
• movements are significantly limited;
• fatigue, fever appears;
• Knob-like subcutaneous formations may be observed, most often on the elbows.

Diagnosis of pathology

How can you determine the development of the disease? In diagnosing diseases, one of the most important points is identifying the immune factor that provoked tissue damage.

In addition, the hereditary factor is taken into account. It is very important to inform your doctor about all symptoms that arise, even those that, at first glance, seem insignificant.

Special tests are required. Autoimmune inflammatory process cannot go unnoticed. It can be detected by testing for antibodies in the blood. Various immunological laboratory examination methods may also be prescribed.

Who to contact?

Quite often, people whose autoimmune processes are disrupted do not know which doctor to visit. This is not surprising, because pathology can affect a variety of systems.

It is best to consult a therapist initially. Depending on which organs are affected, the doctor will refer the patient to a specialist.

This could be: endocrinologist, gastroenterologist, dermatologist, hepatologist, rheumatologist, hematologist, gynecologist, urologist.

In addition, you will need the help of a psychotherapist, psychologist and nutritionist.

Treatment methods

Is it possible to fight this pathology? Today, treatment of the autoimmune process is carried out quite successfully thanks to numerous studies by specialists. When prescribing medications, doctors take into account that the immune system is the main factor that negatively affects the body. Accordingly, therapy is designed to reduce its activity or restore the necessary balance.

For autoimmune diseases, medications are prescribed:

1. Immunosuppressants. Such drugs have a depressing effect on the functioning of the immune system. This category includes: antimetabolites, cytostatics, corticosteroid hormones, some antibiotics. The use of these drugs allows you to stop the inflammatory process and significantly reduce the activity of the immune system. However, immunosuppressants have a number of negative reactions. After all, they affect the entire body. Sometimes hematopoiesis may be impaired, high susceptibility to infection may occur, and internal organs may be affected. That is why these medications can only be prescribed by a doctor, after full check body. In this case, therapy must be carried out under the supervision of a competent specialist.
2. Immunomodulators. These medicines are prescribed to achieve a balance between the various components of the immune system. As a rule, these medications are of natural origin. The most commonly prescribed drugs are: Alfetin, Echinacea purpurea, Rhodiola rosea, Ginseng extract.

Lifestyle

People who have impaired autoimmune processes need to follow certain rules. They will help improve your well-being and reduce the number of exacerbations. But they should be performed regularly.

1. Work with a nutritionist to develop an appropriate diet. Patients need to eat enough vegetables, fruits, low-fat dairy products, whole grains and plant proteins. And it is better to avoid excess sugar, salt, and saturated fats.
2. Play sports. Be sure to discuss with your doctor what kind of activity is recommended for you. Exercise is very beneficial for people suffering from joint and muscle pain.
3. Provide adequate rest. It allows the body to recover. For people who don't get enough sleep, symptom severity and stress levels increase significantly. As a rule, a person needs to good rest 7-9 hours.
4. Protect yourself from stress. Constant anxiety can lead to an exacerbation of an autoimmune disease. That is why patients need to find methods and techniques to cope with stress. Enough effective techniques are: self-hypnosis, meditation, visualization.

Conclusion

Unfortunately, it is impossible to get rid of an autoimmune disease. But this does not mean that you cannot enjoy life with such an illness. Be sure to follow all the doctor’s recommendations, take the treatment prescribed by him, and visit the doctor according to the prescribed schedule. This will significantly reduce unpleasant symptoms, which means you can continue to enjoy life.

Autoimmune diseases- diseases in the pathogenesis of which the leading role is played by autoreactive lymphocytes, which recognize the antigens of their own body as foreign and trigger pathological processes characterized by the destruction of target cells and target tissues, as well as disruption of their functions (both decrease and increase) and, as usually the development of chronic inflammation. The effector processes of autoimmune diseases are realized through humoral (autoantibodies) and/or cellular (autoreactive lymphocyte clones) immune reactions. Overproduction of proinflammatory cytokines accompanies almost all autoimmune diseases.

AZ classification:Organ-specific- autoantibodies are induced against one or a group of components of one organ. Most often, these are barrier antigens to which there is no natural (innate) tolerance. These include: Hoshimoto's thyroiditis, thyrotoxicosis, pernicious anemia, Addison's disease, non-insulin-dependent diabetes (type II).

System- autoantibodies react with a wide range of antigens present on different cells and tissues. Molecules in various organs and tissues become autoantigens that are not isolated. Autoantibodies to cell nuclei, etc. AutoAT against the background of pre-existing IT. It is systemic in nature and manifests itself in a multiplicity of lesions. To such pathological processes include systemic lupus erythematosus, discoid erythematous lupus, dermatomyositis (scleroderma), rheumatoid arthritis. Mixed diseases include both of the above mechanisms. If the role of autoantibodies is proven, then they must be cytotoxic against the cells of the affected organs or act directly through the antigen-antibody complex, which, deposited in the body, cause its pathology (ulcerative colitis, biliary cirrhosis, Schergen's syndrome).

Immune complex ADs:(glomerulonephritis, serum sickness) – those ADs that are type III AR.

The main method for diagnosing autoimmune hemolytic anemia is the Coombs test. It is based on the ability of antibodies specific to IgG or complement components (especially C3) to agglutinate erythrocytes coated with IgG or C3.

Mechanisms of tissue damage: AR types II, III and IV.

Treatment is symptomatic.

19. Hypotheses of the occurrence and etiology of autoimmune diseases.

Etiology and pathogenesis. Therefore, the manifestation of an autoimmune destructive process is initiated by a pathogenic external factor.

Reasons underlying the launch of AZ:

Antigenic mimicry of pathogens;

Microbial superantigens

Tissue destruction by pathogen

Dysfunction of regulatory T lymphocytes

Imbalance between proliferation and apoptosis of lymphocytes

Association of AD with certain MHC antigens

The barrier antigen hypothesis. The body has so-called barrier antigens, to which there is no natural (innate) tolerance. Such antigens are contained in the lens, other elements of the eye, gonads, brain, and cranial nerves. After injuries, during severe inflammatory processes, they enter the blood, and autoantibodies are formed against them.

The cross-reacting antigen hypothesis. Some microorganisms have antigens that cross-react with antigens of normal tissues of the host body. When such antigens remain in the body for a long time, B-lymphocytes are activated. This breaks natural tolerance and causes the appearance of autoantibodies with auto-aggressive properties. For example, the presence of such antigens in group A β-hemolytic streptococcus leads to rheumatic damage to the valvular apparatus of the heart and joints.

The forbidden clone hypothesis. In the body, autoaggressive clones of lymphocytes may arise that interact with antigens of normal tissues and destroy them. At the same time, previously hidden autoantigens, endogenous stimulants and mitogens are released, enhancing these reactions.

Fudenterg's hypothesis. It is assumed that there is a genetically programmed weakness of the immune response to a specific antigen. Such selective immunity causes the release of various autoantigens, against which autoantibodies and sensitized lymphocytes are produced.

T-suppressor deficiency hypothesis. Weakness of T-suppressor cells (decreased content or inhibition of function) leads to the fact that B cells escape feedback control and begin to react to normal tissue antigens with the formation of autoantibodies.

Hypothesis of “blinding” of lymphocytes. Autoantibodies, under certain conditions, block the perceptive receptors of lymphocytes, which recognize “self” and “foreign”. This leads to a breakdown of natural tolerance.

Trigger factors: infections, drugs, environment, hormones.