Acquired (secondary) immunodeficiencies. Yarilin - immunology

– these are diseases of the immune system that occur in children and adults, not associated with genetic defects and characterized by the development of repeated, protracted infectious and inflammatory pathological processes that are difficult to treat etiotropically. There are acquired, induced and spontaneous forms of secondary immunodeficiencies. Symptoms are caused by decreased immunity and reflect a specific lesion of a particular organ (system). Diagnosis is based on analysis of the clinical picture and data immunological research. Vaccination is used in treatment replacement therapy, immunomodulators.

General information

Secondary immunodeficiencies are immunity disorders that develop in the late postnatal period and are not associated with genetic defects, occur against the background of the body’s initially normal reactivity and are caused by a specific causal factor that caused the development of the immune system defect.

The causative factors leading to impaired immunity are diverse. Among them are long-term adverse effects of external factors (environmental, infectious), poisoning, toxic effect medications, chronic psycho-emotional overload, malnutrition, trauma, surgical interventions and severe somatic diseases, leading to disruption of the immune system, decreased body resistance, and the development of autoimmune disorders and neoplasms.

The course of the disease may be hidden (complaints and clinical symptoms absent, the presence of immunodeficiency is revealed only by laboratory testing) or active with signs inflammatory process on the skin and subcutaneous tissue, upper respiratory tract, lungs, genitourinary system, digestive tract and other organs. In contrast to transient changes in immunity, with secondary immunodeficiency pathological changes persist even after the elimination of the causative agent of the disease and relief of inflammation.

Causes

Lead to a pronounced and lasting decrease immune defense the body can be affected by a wide variety of etiological factors - both external and internal. Secondary immunodeficiency often develops with general exhaustion of the body. Long-term malnutrition with a deficiency in the diet of protein, fatty acids, vitamins and microelements, impaired absorption and breakdown nutrients in the digestive tract lead to disruption of the maturation processes of lymphocytes and reduce the body's resistance.

Severe traumatic injuries to the musculoskeletal system and internal organs, extensive burns, serious surgical interventions are usually accompanied by blood loss (along with plasma, proteins of the complement system, immunoglobulins, neutrophils and lymphocytes are lost), and the release of corticosteroid hormones intended to maintain vital functions(blood circulation, breathing, etc.) further inhibits the functioning of the immune system.

Pronounced violation metabolic processes in the body with somatic diseases (chronic glomerulonephritis, renal failure) and endocrine disorders (diabetes, hypo- and hyperthyroidism) leads to inhibition of chemotaxis and phagocytic activity of neutrophils and, as a consequence, to secondary immunodeficiency with the appearance of inflammatory foci of various locations (most often pyoderma, abscesses and phlegmon).

Immunity decreases with long-term use of certain medications that have a suppressive effect on the bone marrow and hematopoiesis, disrupting the formation and functional activity of lymphocytes (cytostatics, glucocorticoids, etc.). Radiation exposure has a similar effect.

In malignant neoplasms, the tumor produces immunomodulatory factors and cytokines, as a result of which the number of T-lymphocytes decreases, the activity of suppressor cells increases, and phagocytosis is inhibited. The situation gets worse with generalization tumor process and metastasis to the bone marrow. Secondary immunodeficiencies often develop when autoimmune diseases, acute and chronic poisoning, in humans old age, with prolonged physical and psycho-emotional overload.

Symptoms of secondary immunodeficiencies

Clinical manifestations are characterized by the presence in the body of a protracted, resistant to etiotropic therapy, chronic infectious purulent-inflammatory disease against the background of decreased immune defense. In this case, changes can be transient, temporary or irreversible. There are induced, spontaneous and acquired forms of secondary immunodeficiencies.

The induced form includes disorders that arise as a result of specific causative factors ( x-ray radiation, long-term use cytostatics, corticosteroid hormones, severe injuries and extensive surgical operations with intoxication, blood loss), as well as in severe somatic pathology (diabetes mellitus, hepatitis, cirrhosis, chronic renal failure) and malignant tumors.

In the spontaneous form, the visible etiological factor that caused the disruption of immune defense is not determined. Clinically, this form is characterized by the presence of chronic, difficult to treat and often exacerbating diseases of the upper respiratory tract and lungs (sinusitis, bronchiectasis, pneumonia, lung abscesses), digestive tract And urinary tract, skin and subcutaneous tissue(boils, carbuncles, abscesses and cellulitis), which are caused by opportunistic microorganisms. Acquired immunodeficiency syndrome (AIDS), caused by HIV infection, is classified as a separate acquired form.

The presence of secondary immunodeficiency at all stages can be judged by the general clinical manifestations of the infectious and inflammatory process. This may be a prolonged low-grade fever or fever, enlarged lymph nodes and their inflammation, muscle and joint pain, general weakness and fatigue, decreased performance, frequent colds, repeated tonsillitis, often recurrent chronic sinusitis, bronchitis, repeated pneumonia, septic conditions etc. At the same time, the effectiveness of standard antibacterial and anti-inflammatory therapy is low.

Diagnostics

Detection of secondary immunodeficiencies requires integrated approach and participation in the diagnostic process of various medical specialists - allergist-immunologist, hematologist, oncologist, infectious disease specialist, otolaryngologist, urologist, gynecologist, etc. This takes into account the clinical picture of the disease, indicating the presence chronic infection, difficult to treat, as well as identifying opportunistic infections caused by opportunistic microorganisms.

It is necessary to study the immune status of the body using all available techniques used in allergology and immunology. Diagnostics is based on the study of all parts of the immune system involved in protecting the body from infectious agents. In this case, the phagocytic system, the complement system, and subpopulations of T- and B-lymphocytes are studied. Research is carried out by conducting tests of the first (approximate) level, which allows us to identify gross general disorders immunity and the second (additional) level with identification of a specific defect.

When conducting screening studies (level 1 tests, which can be performed in any clinical diagnostic laboratory), you can obtain information on the absolute number of leukocytes, neutrophils, lymphocytes and platelets (both leukopenia and leukocytosis, relative lymphocytosis, increased ESR), the level of protein and serum immunoglobulins G, A, M and E, hemolytic activity of complement. In addition, necessary skin tests can be performed to detect delayed-type hypersensitivity.

An in-depth analysis of secondary immunodeficiency (level 2 tests) determines the intensity of phagocyte chemotaxis, completeness of phagocytosis, subclasses of immunoglobulins and specific antibodies to specific antigens, production of cytokines, T-cell inducers and other indicators. Analysis of the data obtained should be carried out only taking into account the specific condition of the patient, concomitant diseases, age, the presence of allergic reactions, autoimmune disorders and other factors.

Treatment of secondary immunodeficiencies

The effectiveness of treatment of secondary immunodeficiencies depends on the correctness and timeliness of identifying the etiological factor that caused the appearance of a defect in the immune system and the possibility of eliminating it. If a violation of the immune system occurs against the background of a chronic infection, measures are taken to eliminate foci of inflammation using antibacterial drugs, taking into account the sensitivity of the pathogen to them, carrying out adequate antiviral therapy, using interferons, etc. If the causative factor is malnutrition and vitamin deficiency, measures are taken to developing the right diet with a balanced combination of proteins, fats, carbohydrates, microelements and the required calorie content. Also, existing metabolic disorders are eliminated, normal hormonal status is restored, conservative and surgical treatment of the underlying disease (endocrine, somatic pathology, neoplasms) is carried out.

An important component of the treatment of patients with secondary immunodeficiency is immunotropic therapy using active immunization (vaccination), replacement treatment with blood products (intravenous administration of plasma, leukocyte mass, human immunoglobulin), as well as the use of drugs immunotropic action(immunostimulants). The expediency of prescribing one or another remedy and dosage selection is carried out by an allergist-immunologist, taking into account the specific situation. With the transient nature of immune disorders, timely detection of secondary immunodeficiency and selection of the correct treatment, the prognosis of the disease can be favorable.

Age-related features of the immunological status of animals

During the embryonic period, the immunological status of the fetal body is characterized by the synthesis of its own protective factors. At the same time, the synthesis of natural resistance factors is ahead of the development of specific response mechanisms.

Of the natural resistance factors, cellular elements appear first: first monocytes, then neutrophils and eosinophils. During the embryonic period, they function as phagocytes, possessing capture and digestive abilities. Moreover, the digestive ability predominates and does not change significantly even after newborn animals receive colostrum. By the end of the embryonic period, lysozyme, properdin and, to a lesser extent, complement accumulate in the fetal bloodstream. As the fetus develops, the levels of these factors gradually increase. During the prefetal and fetal periods, immunoglobulins appear in the fetal blood serum, mainly class M and, less often, class G . They function primarily as partial antibodies.

In newborn animals, the content of all protective factors increases, but only lysozyme corresponds to the level of the mother’s body. After taking colostrum in the body of newborns and their mothers, the content of all factors, with the exception of complement, is equalized. The concentration of complement does not reach the level of the maternal body even in the serum of 6-month-old calves.

Saturation of the bloodstream of newborn animals with immune factors occurs only through the colostral route. Colostrum contains in decreasing amounts IgG 1, IgM, IgA, IgG 2. Immunoglobulin Gl approximately two weeks before calving, it selectively passes from the bloodstream of cows and accumulates in the udder. The remaining colostral immunoglobulins are synthesized by the mammary gland. It also produces lysozyme and lactoferrin, which, together with immunoglobulins, represent the humoral factors of local immunity of the udder. Colostral immunoglobulins pass into the lymph and then the bloodstream of the newborn animal by pinocytosis. In the crypts of the small intestine, special cells selectively transport colostrum immunoglobulin molecules. Immunoglobulins are absorbed most actively when calves are fed colostrum in the first 4..5 hours after birth.

The mechanism of natural resistance changes in accordance with the general physiological state animal body and with age. In old animals, there is a decrease in immunological reactivity due to auto immune processes, since during this period there is an accumulation of mutant forms of somatic cells, while immunocompetent cells themselves can mutate and become aggressive against normal cells of their body. A decrease in the humoral response was established due to a decrease in the amount of formed plasma cells in response to the introduced antigen. Activity also decreases cellular immunity. In particular, with age, the number of T-lymphocytes in the blood is significantly less, and a decrease in reactivity to the introduced antigen is observed. With regard to the absorption and digestive activity of macrophages, no differences have been established between young animals and old ones, although the process of freeing the blood from foreign substances and microorganisms is slowed down in old ones. The ability of macrophages to cooperate with other cells does not change with age.

Immunopathological reactions .

Immunopathology studies pathological reactions and diseases, the development of which is due to immunological factors and mechanisms. The object of immunopathology is various violations of the ability of the body’s immunocompetent cells to distinguish between “self” and “foreign”, self and foreign antigens.

Immunopathology includes three types of reactions: a reaction to self-antigens, when immunocompetent cells recognize them as foreign (autoimmunogenic); a pathologically strong immune reaction to an allergen; a decrease in the ability of immunocompetent cells to develop an immune response to foreign substances (immunodeficiency diseases, etc.).

Autoimmunity.It has been established that in some diseases tissue breakdown occurs, accompanied by the formation of autoantigens. Autoantigens are components of one’s own tissues that arise in these tissues under the influence of bacteria, viruses, drugs, ionizing radiation. In addition, the cause of autoimmune reactions can be the introduction into the body of microbes that have common antigens with mammalian tissues (cross antigens). In these cases, the animal’s body, reflecting the attack of a foreign antigen, simultaneously affects components of its own tissues (usually the heart, synovial membranes) due to the commonality of antigenic determinants of micro- and macroorganisms.

Allergy. Allergy (from Greek. alios - other, ergon - action) - altered reactivity, or sensitivity, of the body in relation to a particular substance, more often when it is re-entered into the body. All substances that change the reactivity of the body are called allergens. Allergens can be various substances of animal or plant origin, lipoids, complex carbohydrates, medicinal substances, etc. Depending on the type of allergens, infectious, food (idiosyncrasy), drug and other allergies are distinguished. Allergic reactions manifest themselves due to the inclusion of specific protective factors and develop like all others. immune reactions, in response to the penetration of an allergen into the body. These reactions can be increased compared to the norm - hyperergy, they can be decreased - hypoergy, or completely absent - anergy.

Allergic reactions are divided according to their manifestation into immediate-type hypersensitivity (IHT) and delayed-type hypersensitivity (DHT). GNT occurs after repeated administration of the antigen (allergen) after a few minutes; HRT manifests itself after a few hours (12...48), and sometimes days. Both types of allergies differ not only in the speed of clinical manifestation, but also in the mechanism of their development. GNT includes anaphylaxis, atopic reactions and serum sickness.

Anaphylaxis(from Greek ana - against, phylaxia - protection) - a state of increased sensitivity of a sensitized organism to repeated parenteral administration of a foreign protein. Anaphylaxis was first discovered by Portier and Richet in 1902. The first dose of antigen (protein) that causes increased sensitivity, called sensitizing(lat. sensibilitas - sensitivity), the second dose, after administration of which anaphylaxis develops, - permissive, Moreover, the resolving dose should be several times higher than the sensitizing dose.

Passive anaphylaxis. Anaphylaxis can be artificially reproduced in healthy animals by a passive method, i.e., by administering the immune serum of a sensitized animal. As a result, after a few hours (4...24) the animal develops a state of sensitization. When a specific antigen is administered to such an animal, passive anaphylaxis occurs.

Atopy(Greek atopos - strange, unusual). HNT includes atopy, which is a natural hypersensitivity that spontaneously occurs in people and animals predisposed to allergies. Atopic diseases more studied in humans - this bronchial asthma, allergic rhinitis and conjunctivitis, urticaria, food allergy to strawberries, honey, egg whites, citrus fruits, etc. Food allergies have been described in dogs and cats to fish, milk and other products, in large cattle An atopic reaction such as hay fever was noted when transferred to other pastures. IN last years Atopic reactions caused by drugs - antibiotics, sulfonamides, etc. - are very often recorded.

Serum sickness . Serum sickness develops 8...10 days after a single injection of foreign serum. The disease in humans is characterized by the appearance of a rash resembling urticaria, and is accompanied by severe itching, fever, impaired cardiovascular activity, swelling of the lymph nodes and is non-fatal.

Delayed-type hypersensitivity (DTH). This type of reaction was first discovered by R. Koch in 1890 in a tuberculosis patient with subcutaneous injection of tuberculin. It was later found that there are a number of antigens that stimulate predominantly T-lymphocytes and mainly determine the formation of cellular immunity. In an organism sensitized by such antigens, on the basis of cellular immunity, a specific hypersensitivity is formed, which manifests itself in the fact that after 12...48 hours an inflammatory reaction develops at the site of repeated introduction of the antigen. A typical example is the tuberculin test. Intradermal injection of tuberculin into an animal with tuberculosis causes edematous, painful swelling at the injection site and an increase in local temperature. The reaction reaches a maximum at 48 hours.

Increased sensitivity to allergens (antigens) of pathogenic microbes and their metabolic products is called infectious allergies. It plays an important role in the pathogenesis and development of infectious diseases such as tuberculosis, brucellosis, glanders, aspergillosis, etc. When the animal recovers, the hyperergic state persists for a long time. The specificity of infectious allergic reactions allows them to be used for diagnostic purposes. Various allergens are prepared industrially in biofactories - tuberculin, mallein, brucellohydrolysate, tularin, etc.

It should be noted that in some cases there is no allergic reaction in a sick (sensitized) animal; this phenomenon is called anergy(unreactivity). Anergy can be positive or negative. Positive anergy is observed when immunobiological processes in the body are activated and the body’s contact with the allergen quickly leads to its elimination without the development of an inflammatory reaction. Negative anergy is caused by the unresponsiveness of body cells and occurs when defense mechanisms suppressed, which indicates the defenselessness of the body.

When diagnosing infectious diseases accompanied by allergies, the phenomena of paraallergy and pseudoallergy are sometimes noted. Paraallergy - a phenomenon when a sensitized (sick) body reacts to allergens prepared from microbes that have common or related allergens, for example, Mycobacterium tuberculosis and atypical mycobacteria.

Pseudoallergy(heteroallergy) - the presence of a nonspecific allergic reaction as a result of autoallergies of the body by tissue breakdown products during development pathological process. For example, an allergic reaction to tuberculin in cattle suffering from leukemia, echinococcosis or other diseases.

There are three stages in the development of allergic reactions:

· immunological - the combination of the allergen with antibodies or sensitized lymphocytes, this stage is specific;

· pathochemical - the result of the interaction of the allergen with antibodies and sensitized cells. Mediators, a slowly reacting substance, as well as lymphokines and monokines are released from the cells;

· pathophysiological - the result of the action of various biologically active substances on fabric. It is characterized by circulatory disorders, spasm of smooth muscles of the bronchi, intestines, changes in capillary permeability, swelling, itching, etc.

Thus, with allergic reactions we observe clinical manifestations, not typical for direct action antigen (microbes, foreign proteins), but rather similar symptoms characteristic of allergic reactions.

Immunodeficiencies

Immunodeficiency conditions characterized by the fact that the immune system is not able to respond with a full immune response to various antigens. An immune response is not just the absence or reduction of an immune response, but the inability of the body to carry out one or another part of the immune response. Immunodeficiencies are manifested by a decrease or complete absence of the immune response due to a violation of one or more parts of the immune system.

Immunodeficiencies can be primary (congenital) and secondary (acquired).

Primary immunodeficiencies characterized by a defect in cellular and humoral immunity (combined immunodeficiency), either only cellular or only humoral. Primary immunodeficiencies occur as a result of genetic defects, and also as a result of inadequate feeding of mothers during pregnancy, primary immunodeficiencies can be observed in newborn animals. Such animals are born with signs of malnutrition and are usually not viable. For combined immunodeficiency note the absence or hypoplasia of the thymus, bone marrow, lymph nodes, spleen, lymphopenia and low levels of immunoglobulins in the blood. Clinically, immunodeficiencies may manifest as delayed physical development, pneumonia, gastroenteritis, sepsis caused by opportunistic infection.

Age-related immunodeficiencies observed in young and old organisms. In young people, a deficiency of humoral immunity is more common as a result of insufficient maturity of the immune system during the neonatal period and up to the second or third week of life. In such individuals, there is a lack of immunoglobulins and B-lymphocytes in the blood, and weak phagocytic activity of micro- and macrophages. IN lymph nodes and the spleen have few secondary lymphoid follicles with large reactive centers and plasma cells. In animals, gastroenteritis and bronchopneumonia occur due to the action opportunistic microflora. The deficiency of humoral immunity during the neonatal period is compensated by full-fledged colostrum from the mother, and at a later time - by full feeding and good conditions content.

In old animals, immunodeficiency is caused by age-related involution of the thymus, a decrease in the number of T-lymphocytes in the lymph nodes and spleen. Such organisms often develop tumors.

Secondary immunodeficiencies occur due to illness or as a result of treatment with immunosuppressants. The development of such immunodeficiencies is observed in infectious diseases, malignant tumors, long-term use of antibiotics, hubbub, and inadequate feeding. Secondary immunodeficiencies are usually accompanied by impaired cellular and humoral immunity, i.e. are combined. They are manifested by involution of the thymus, devastation of the lymph nodes and spleen, and a sharp decrease in the number of lymphocytes in the blood. Secondary deficiencies, unlike primary ones, can completely disappear when the underlying disease is eliminated.Against the background of secondary and age-related immunodeficiencies, medications may be ineffective, and vaccination does not create intense immunity against infectious diseases. Thus, immunodeficiency states must be taken into account when breeding and developing therapeutic and preventive measures on the farm. In addition, the immune system can be manipulated to correct, stimulate, or suppress certain immune responses.This effect is possible with the help of immunosuppressants and immunostimulants.

This group of immunological deficiency includes conditions caused by severe inflammatory and toxic processes, deficiency of proteins, including immunoglobulins, as a result of abundant and prolonged bleeding; in newborns, due to weak activity of the immunological system, transient immunological failure may occur.

An autosomal recessive form of combined immunological deficiency (Louis-Bar syndrome) has been identified, in which the functions of the T- and B-immune systems are deeply impaired; it is gender-linked (boys are affected) and is a consequence of protein metabolism disorders.

A sharp increase in the frequency of immunological deficiency was noted malignant tumors.

With frequent administration of an antigen or when it is administered in large doses, immunizing inhibition may occur, in which the body will not respond to the action of the antigen by further developing immunity. When strong and weak antigens are simultaneously introduced into the body, suppression of the response to the weak antigen may occur.

When an excess of antigen is introduced into the body, immunological paralysis occurs. The body loses the ability to be immunized with obviously vaccinating doses. It is believed that immunological paralysis is caused by the binding of antibodies to an antigen that persists for a long time in the body. In this case, a blockade of the lymphoid-macrophage system occurs.

The formation of antibodies is greatly influenced by nutrition, ionizing radiation, hormone production, cooling and overheating, and intoxication. In case of fasting or malnutrition protein nutrition antibody production decreases. The state of hypovitaminosis also delays the synthesis of antibodies. The most sensitive to the effects of ionizing radiation are cells in the inductive phase of antibody production, i.e., during the period of cell fixation of antigen. The state of stress causes a sharp decrease in the overall resistance of the body, including humoral immunity. The production of antibodies to pathogens of infectious diseases in some cases is reduced under the influence of antibiotics administered to treat patients in early stages diseases.

Thus, for maximum development of immunity, chemical composition, physicochemical characteristics, conditions of administration, intervals and dose of antigen, state of the body and external environment.

Current theories of antibody formation attempt to explain this difficult process from different points of view.

Rice. 1. Antibody formation.

1 - under the control of an antigen that acts as a matrix; 2—under the control of genes of plasma cell clones.

According to the theory of the direct Haurowitz-Polite matrix, antigens penetrate into the field of protein synthesis of the cell - into ribosomes (Fig. 1). Contact with newly formed immunoglobulin molecules leads to a change in its primary and secondary structures, as a result of which it acquires a specific affinity for the antigen and becomes an antibody.

The Burnet-Fenner indirect matrix theory suggests that an antigen, acting on DNA or RNA, specifically changes the self-regulating nucleoprotein structures of the cell. The antigen in this case may serve as an inducer in the synthesis of adaptive enzymes, disinhibiting the naturally repressed immunological abilities of the cell.

According to Jerne's theory of natural selection, antibodies are formed as a result of selection of normal antibodies. The antigen combines with the corresponding normal antibodies in the body, the resulting antigen-antibody complex is absorbed by the cells, which cause the production of antibodies.

Burnet's clonal selection theory provides that the population of lymphoid cells is genetically heterogeneous, each clone of cells (B-lymphocytes) has a different affinity for antigens. As a result of contact with the antigen, cell clones with the greatest affinity for it intensively proliferate, transforming into plasma cells that produce antibodies. According to this theory, selection of immunocompetent cells occurs under the influence of antigens. As a result of immunization, mutations of this clone may occur, followed by their proliferation. This theory largely explains previously unknown phenomena in immunology, but it is not able to reveal the mechanism of the pre-existence of numerous cellular clones, ready in advance to produce immunoglobulins.

Thus, the formation of antibodies is subject to the laws of protein biosynthesis, occurs in the ribosomes of plasma cells and is controlled by the DNA-RNA system of the cell. The antigen probably performs a trigger function without then taking part in the formation of antibodies.

In the general complex of mechanisms of immunity, specific and nonspecific, cellular and humoral protective reactions are effective system, ensuring the preservation of constancy internal environment macroorganism. They manifest themselves at the molecular, cellular and organismal levels, which gives them a wide range of action against pathogenic agents.

Along with protective functions, immune reactions in some cases can cause the occurrence of pathological conditions: autoimmune processes, allergies, etc.

Rice. 4.49. Dynamics of the content of the virus itself and antibodies to its two proteins in the blood of people infected with human immunodeficiency virus

T cells, which allows them to escape pressure from T cell immunity. Thus, the cellular immune response is not able to eliminate the virus from the body due to the high adaptability of the virus, based on variability. NK cells are also ineffective, although they are not directly infected by the virus.

The relationship between HIV infection and the macroorganism is reflected in the dynamics of the content of viral antigens in circulation

And antiviral antibodies (Fig. 4.49). Antigenemia surge in early period development HIV infection (2–8 weeks after infection) reflects intensive replication of viruses that have entered cells. When the host's immune system is intact, this causes the production of neutralizing antibodies (mainly to the surface proteins gp120, gp41, and the group-specific gag antigen p17), which can be detected by an increase in the titer of serum antibodies to these antigens, starting from the 8th week from the moment of infection. This change from the circulation of antigen to the presence of antibodies in the bloodstream is referred to as “seroconversion”. Antibodies to envelope (env) proteins persist stably throughout the disease, whereas gag-specific antibodies disappear at certain stages of disease development, and viral antigens reappear in the bloodstream. Simultaneously with the accumulation of antibodies to viral antigens in the blood serum, the concentration of all serum immunoglobulins, including IgE.

Circulating antibodies are able to neutralize free virus

And bind its soluble proteins. In response to gp120, this is most true for antibodies specific to the immunodominant epitope 303–337, localized in the 3rd hypervariable domain (V3) of the molecule. This is supported by the fact that passively administered antibodies can protect against HIV infection. Neutralizing antibodies, especially those directed against gp120, are able to block infectious

cell formation. This probably plays a role in the initial containment of HIV infection and to some extent determines the long latent period characteristic of this disease. At the same time, the effector activity of these antibodies is limited and their protective role in HIV infection cannot be considered proven.

Formation of immunodeficiency in acquired immunodeficiency syndrome

(see table 4.20)

The main cause of immunodeficiency in AIDS is the death of CD4+ T cells. The obvious reason for the death of infected cells is the cytopathogenic effect of the virus. In this case, the cells die through the mechanism of necrosis due to a violation of the integrity of their membrane. So, when infected HIV cells blood, the number of CD4+ T cells, starting from the 3rd day, sharply decreases simultaneously with the release of virions into the medium. The population of CD4+ T cells in the intestinal mucosa is most affected.

In addition to this mechanism of death of infected cells in AIDS, high level apoptosis. The damage to the T-cell component of the immune system significantly exceeds what would be expected based on an estimate of the number of infected cells. In lymphoid organs, no more than 10–15% of CD4+ T cells are infected, and in the blood this amount is only 1%, but a much larger percentage of CD4+ T lymphocytes undergo apoptosis. In addition to those infected, a significant portion of cells not infected with the virus apoptote, primarily CD4+ T-lymphocytes specific to HIV antigens (up to 7% of these cells). Inducers of apoptosis are the gp120 proteins and the Vpr regulatory protein, which are active in a soluble form. The gp120 protein reduces the level of the anti-apoptotic protein Bcl-2 and increases the level of the pro-apoptotic proteins p53, Bax, and Bak. The Vpr protein disrupts the integrity of the mitochondrial membrane, displacing Bcl-2. Cytochromas exits the mitochondria and activates caspase 9, which leads to apoptosis of CD4+ T cells, including uninfected, but HIV-specific ones.

The interaction of the viral protein gp120 with the membrane glycoprotein of CD4+ T lymphocytes causes another process that occurs during HIV infection and is involved in the death and functional inactivation of host cells - the formation of syncytium. As a result of the interaction of gp120 and CD4, cells merge with the formation of a multinuclear structure that is unable to perform normal functions and is doomed to death.

Among the cells infected with HIV, only T-lymphocytes and megakaryocytes die, undergoing cytopathogenic effects or entering apoptosis. Neither macrophages nor epithelial or other cells infected with the virus lose viability, although their function may be impaired. Dysfunction can be caused not only by HIV as such, but also by its isolated proteins, for example, gp120 or the product of the gene tat p14. Although HIV is not capable of causing malignant transformation of lymphocytes (unlike, for example, the HTLV-1 virus), the tat protein (p14) is involved in the induction of Kaposi's sarcoma in HIV infection.

A sharp decrease in the content of CD4+ T-lymphocytes is the most striking laboratory sign of HIV infection and its evolution into AIDS. Conditional

The limit of the content of these cells, which is usually followed by clinical manifestations of AIDS, is 200–250 cells in 1 μl of blood (in relative figures - about 20%). The CD4/CD8 ratio at the peak of the disease decreases to 0.3 or lower. During this period, general lymphopenia appears with a decrease in the content of not only CD4+, but also CD8+ cells and B-lymphocytes. The response of lymphocytes to mitogens and the severity of skin reactions to common antigens continue to decline to complete anergy. Added to the various reasons for the inability of effector T cells to eliminate HIV is the high mutability of HIV with the formation of ever new epitopes that are not recognized by cytotoxic T cells.

Naturally, among the immunological disorders in AIDS, disorders of T-cell and T-dependent processes dominate. Factors that determine these violations include:

– decreased CD4 count+ T-helpers due to their death;

– weakening of CD4 functions+ T cells influenced by infection and the action of soluble HIV products, especially gp120;

– population imbalance T cells with a shift in the Th1/Th2 ratio towards Th2, while Th1-dependent processes contribute to protection against the virus;

– induction of regulatory T cells by the gp120 protein and the HIV-associated protein p67.

A decrease in the body's ability to immune defense affects both its cellular and humoral factors. As a result, a combined immunodeficiency is formed, making the body vulnerable to infectious agents, including opportunistic ones (hence the development of opportunistic infections). Deficiency of cellular immunity plays a certain role in the development of lymphotropic tumors, and the combination of immunodeficiency and the action of certain HIV proteins plays a role in the development of Kaposi's sarcoma.

Clinical manifestations of immunodeficiency in human immunodeficiency virus infection and acquired immunodeficiency syndrome

The main clinical manifestations of AIDS are the development of infectious diseases, mainly opportunistic ones. The following diseases are most characteristic of AIDS: pneumonia caused by Pneumocystis carinii; diarrhea caused by cryptosporidium, toxoplasma, giardia, amoeba; strongyloidiasis and toxoplasmosis of the brain and lungs; candidiasis of the oral cavity and esophagus; cryptococcosis, disseminated or localized in the central nervous system; coccidioidomycosis, histoplasmosis, mucormycosis, aspergillosis of various localizations; infections with atypical mycobacteria of various localizations; Salmonella bacteremia; cytomegalovirus infection lungs, central nervous system, digestive tract; herpetic infection skin and mucous membranes; Epstein–Barr virus infection; multifocal papovavirus infection with encephalopathy.

Another group of pathological processes associated with AIDS are tumors, which differ from those not associated with AIDS in that they develop at a younger age than usual (up to 60 years). With AIDS, Kaposi's sarcoma and non-Hodgkin's lymphomas, localized primarily in the brain, often develop.

The development of the pathological process is facilitated by certain macroorganism reactions provoked by HIV infection. Thus, activation of CD4+ T cells in response to the action of viral antigens contributes to the implementation of the cytopathogenic effect, especially the apoptosis of T lymphocytes. Most of the cytokines produced by T cells and macrophages favor the progression of HIV infection. Finally, the autoimmune component plays an important role in the pathogenesis of AIDS. It is based on homology between HIV proteins and some body proteins, for example between gp120 and MHC molecules. However, these disorders, aggravating immunodeficiency, do not form specific autoimmune syndromes.

Already at the preclinical stage of HIV infection, there is a need to use immunological diagnostic methods. For this purpose, enzyme-linked immunosorbent test kits are used to determine the presence of antibodies to HIV proteins in blood serum. Existing test systems are based on enzyme-linked immunosorbent antibody testing (ELISA). Initially, test kits were used using viral lysates as antigenic material. Later, for this purpose, recombinant HIV proteins and synthetic peptides were used that reproduce epitopes with which serum antibodies of HIV-infected people interact.

Due to the extremely high responsibility of doctors who make a conclusion about HIV infection based on laboratory tests, the practice of repeating antibody tests (sometimes using alternative methods, such as immunoblotting, see section 3.2.1.4), as well as determining the virus using polymerase chain reaction.

Treatment of AIDS is based on the use of antiviral drugs, the most widely used of which is zidovudine, which acts as an antimetabolite. Progress has been made in controlling the course of AIDS, significantly increasing the life expectancy of patients. The main therapeutic approach is the use of nucleic acid antimetabolites in the form of highly active antiretroviral therapy ( High active antiretroviral therapy- HAART). An effective supplement Antiretroviral therapy includes the use of interferon drugs, as well as the treatment of concomitant diseases and viral infections that contribute to the progression of AIDS.

The mortality rate from AIDS is still 100%. Most common cause deaths are due to opportunistic infections, especially Pneumocystis pneumonia. Other causes of death are concomitant tumors, central lesions nervous system and digestive tract.

4.7.3. Secondary immunodeficiencies

Secondary immunodeficiency conditions - these are violations of the body’s immune defense due to the action of non-hereditary inductor factors (Table 4.21). They are not independent nosological forms, but only accompany diseases or the action of immunotoxic factors. To a greater or lesser extent, immune disorders

theta accompanies most diseases, and this significantly complicates determining the place of secondary immunodeficiencies in the development of pathology.

Table 4.21. The main differences between primary and secondary immunodeficiencies

It is often difficult to differentiate the contribution to the development of immune disorders from hereditary factors and inductive influences. In any case, the reaction to immunotoxic agents depends on hereditary factors. An example of the difficulties in interpreting the basis of immunity disorders can be diseases classified as “frequently ill children”. The basis of sensitivity to infection, in particular respiratory viral infection, is a genetically (polygenically) determined immunological constitution, although specific pathogens act as etiological factors. However, the type of immunological constitution is influenced by environmental factors and previous diseases. The practical significance of accurately identifying the hereditary and acquired components of the pathogenesis of immunological deficiency will increase as methods for differentiated therapeutic effects on these forms of immunodeficiency are developed, including methods of adaptive cell therapy and gene therapy.

The basis of immunodeficiencies not caused by genetic defects can be:

– death of cells of the immune system - total or selective;

– dysfunction of immunocytes;

– unbalanced predominance of the activity of regulatory cells and suppressor factors.

4.7.3.1. Immunodeficiency conditions caused by the death of immunocytes

Classic examples of such immunodeficiencies are immunity disorders caused by the action of ionizing radiation and cytotoxic drugs.

Lymphocytes are one of the few cells that respond to a number of factors, in particular those damaging DNA, by developing apoptosis. This effect manifests itself under the influence of ionizing radiation and many cytostatics used in the treatment of malignant tumors (for example, cisplatin, which penetrates into the double helix of DNA). The reason for the development of apoptosis in these cases is the accumulation of unrepaired breaks, registered by the cell with the participation of ATM kinase (see section 4.7.1.5), from which the signal arrives in several directions, including to the p53 protein. This protein is responsible for triggering apoptosis, the biological meaning of which is to protect a multicellular organism at the cost of the death of single cells that carry genetic disorders that carry a risk of cell malignancy. In most other cells (usually resting), this mechanism is counteracted by protection from apoptosis due to increased expression of the Bcl-2 and Bcl-XL proteins.

Radiation immunodeficiencies

Already in the first decade after its opening ionizing radiation Their ability to weaken resistance to infectious diseases and selectively reduce the content of lymphocytes in the blood and lymphoid organs was discovered.

Radiation immunodeficiency develops immediately after irradiation of the body. The effect of radiation is mainly due to two effects:

– disruption of natural barriers, primarily mucous membranes, which leads to increased access of pathogens to the body;

– selective damage to lymphocytes, as well as all dividing

cells, including immune system precursors and cells involved in the immune response.

The subject of study of radiation immunology is mainly the second effect. Radiation cell death is realized by two mechanisms - mitotic and interphase. The cause of mitotic death is unrepaired damage to DNA and the chromosomal apparatus, which prevents the implementation of mitoses. Interphase death affects resting cells. Its cause is the development of apoptosis via a p53/ATM-dependent mechanism (see above).

If the sensitivity of all cell types to mitosis is approximately the same (D0 - about 1 Gy), then in sensitivity to interphase death lymphocytes are significantly superior to all other cells: most of them die when irradiated at doses of 1–3 Gy, while cells of other types die at doses exceeding 10 Gy. The high radiosensitivity of lymphocytes is due, as already mentioned, to the low level of expression of the anti-apoptotic factors Bcl-2 and Bcl-XL. Different populations and subpopulations of lymphocytes do not differ significantly in their sensitivity to apoptosis (B cells are somewhat more sensitive than T lymphocytes; D0 for them is 1.7–2.2 and 2.5–3.0 Gy, respectively). In the process of lymphopoiesis, sensory

susceptibility to cytotoxic effects changes in accordance with the level of expression of anti-apoptotic factors in cells: it is highest during periods of cell selection (for T-lymphocytes - the stage of cortical CD4+ CD8+ thymocytes, D0 - 0.5–1.0 Gy). Radiosensitivity is high in resting cells; it further increases by initial stages activation and then sharply decreases. The process of proliferative expansion of lymphocytes is characterized by high radiosensitivity, and upon entering proliferation, cells that were previously exposed to radiation and that carry unrepaired DNA breaks may die. Formed effector cells, especially plasma cells, are resistant to radiation (D0 - tens of Gy). At the same time, memory cells are radiosensitive to approximately the same extent as naive lymphocytes. Innate immune cells are radioresistant. Only periods of their proliferation during development are radiosensitive. The exception is NK cells, as well as dendritic cells (they die at doses of 6–7 Gy), which, in terms of radiosensitivity, occupy an intermediate position between other lymphoid and myeloid cells.

Although mature myeloid cells and the reactions they mediated are radioresistant, in the early stages after irradiation it is the failure of myeloid cells, primarily neutrophils, caused by radiation disruption of hematopoiesis that is most manifested. Its consequences affect the earliest and most severely neutrophil granulocytes as populations of cells with the fastest turnover of the pool of mature cells. This causes a sharp weakening of the first line of defense, the load on which increases significantly during this period due to the breakdown of barriers and the uncontrolled entry of pathogens and other foreign agents into the body. The weakening of this part of the immune system is the main cause of radiation death in the early stages after irradiation. In more late dates the consequences of damage to innate immune factors are much weaker. The functional manifestations of innate immunity themselves are resistant to the action of ionizing radiation.

3–4 days after irradiation at doses of 4–6 Gy, more than 90% of the lymphoid cells in mice die and the lymphoid organs are devastated. The functional activity of surviving cells decreases. The homing of lymphocytes is sharply disrupted - their ability to migrate during the process of recycling to secondary lymphoid organs. Adaptive immune responses when exposed to these doses are weakened in accordance with the degree of radiosensitivity of the cells that mediate these reactions. Those forms of the immune response, the development of which requires the interactions of radiosensitive cells, suffer the most from the effects of radiation. Therefore, the cellular immune response is more radioresistant than the humoral one, and thymus-independent antibody production is more radioresistant than the thymus-dependent humoral response.

Radiation doses in the range of 0.1–0.5 Gy do not cause damage to peripheral lymphocytes and often have a stimulating effect on the immune response due to the direct ability of radiation quanta,

generating reactive oxygen species, activate signaling pathways in lymphocytes. The immunostimulating effect of radiation, especially in relation to the IgE response, naturally manifests itself during irradiation after immunization. It is believed that in this case the stimulating effect is due to the relatively higher radiosensitivity of the regulatory T cells that control this form of the immune response compared to effector cells. The stimulating effect of radiation on innate immune cells is manifested even at high doses, especially in relation to the ability of cells to produce cytokines (IL-1, TNF α, etc.). In addition to the direct stimulating effect of radiation on cells, the stimulation of these cells by products of pathogens entering the body through damaged barriers contributes to the manifestation of an enhancing effect. However, increased activity of innate immune cells under the influence of ionizing radiation is not adaptive and does not provide adequate protection. In this regard, the negative effect of radiation prevails, manifested in the suppression (at doses exceeding 1 Gy) of the adaptive antigen-specific immune response (Fig. 4.50).

Already during the period of developing devastation of lymphoid tissue, they turn on recovery processes. Recovery occurs in two main ways. On the one hand, the processes of lymphopoiesis are activated due to the differentiation of all types of lymphocytes from hematopoietic stem cells. In the case of T-lymphopoiesis, the development of T-lymphocytes from intrathymic precursors is added to this. In this case, the sequence of events repeats to a certain extent,

7 Dendritic

Medullary 3 thymocytes

1 Cortical

thymocytes 0.5–1.0 Gy

Answer: T cells

IgM: antibodies to

in SCL - 1.25 Gy

EB - 1.0–1.2 Gy

Answer B: cells

Education

in vitro on LPS -

IgG: antibodies to

EB - 0.8–1.0 Gy

Rice. 4.50. Radiosensitivity of some cells of the immune system and the reactions mediated by them. The values ​​of D0 are presented . EB - sheep red blood cells

characteristic of T-lymphopoiesis in embryonic period: γδT cells are formed first, then αβT cells. The recovery process is preceded by rejuvenation of thymus epithelial cells, accompanied by an increase in their production peptide hormones. The number of thymocytes increases rapidly, reaching a maximum by the 15th day, after which secondary atrophy of the organ occurs due to the depletion of the population of intrathymic progenitor cells. This atrophy has little effect on the number of peripheral T-lymphocytes, since by this time the second source of restoration of the lymphocyte population is turned on.

This source is the homeostatic proliferation of surviving mature lymphocytes. The stimulus for the implementation of this mechanism of lymphoid cell regeneration is the production of IL-7, IL-15 and BAFF, which serve as homeostatic cytokines for T-, NK- and B-cells, respectively. The recovery of T lymphocytes occurs most slowly, since contact of T lymphocytes with dendritic cells expressing MHC molecules is necessary for the implementation of homeostatic proliferation. Number dendritic cells and the expression of MHC molecules (especially class II) on them is reduced after irradiation. These changes can be interpreted as radiation-induced changes in the microenvironment of lymphocytes - lymphocyte niches. This is associated with a delay in the restoration of the lymphoid cell pool, which is especially significant for CD4+ T cells, which is not fully realized.

T cells formed during the process of homeostatic proliferation have the phenotypic characteristics of memory cells (see section 3.4.2.6). They are characterized by recycling pathways characteristic of these cells (migration into barrier tissues and non-lymphoid organs, weakening of migration into the T-zones of secondary lymphoid organs). That is why the number of T-lymphocytes in the lymph nodes is practically not restored to normal, while in the spleen it is restored completely. The immune response developing in the lymph nodes also does not reach normal levels when it is completely normalized in the spleen. Thus, under the influence of ionizing radiation, the spatial organization of the immune system changes. Another consequence of the conversion of the T-lymphocyte phenotype in the process of homeostatic proliferation is an increase in autoimmune processes due to an increased likelihood of recognizing autoantigens during migration to non-lymphoid organs, facilitating the activation of memory T-cells and lagging regeneration of regulatory T-cells compared to other subpopulations. Many of the changes in the immune system induced by radiation resemble those of normal aging; This is especially evident in the thymus, the age-related decline in activity of which is accelerated by irradiation.

Variation of the radiation dose, its power, the use of fractionated, local, internal irradiation (incorporated radionuclides) gives a certain specificity to immunological disorders in the post-radiation period. However, the fundamental principles of radiation damage and post-radiation recovery in all these cases do not differ from those discussed above.

The effect of moderate and small doses of radiation has acquired particular practical significance in connection with radiation disasters, especially

but in Chernobyl. It is difficult to accurately assess the effects of low doses of radiation and differentiate the effects of radiation from the role of external factors (especially stress). In this case, the already mentioned stimulating effect of radiation may appear as part of the hormesis effect. Radiation immunostimulation cannot be considered as a positive phenomenon, since, firstly, it is not adaptive, and secondly, it is associated with an imbalance of immune processes. It is still difficult to objectively assess the impact on the human immune system of the slight increase in natural background radiation that is observed in areas adjacent to disaster zones or associated with the characteristics of industrial activities. In such cases, radiation becomes one of the unfavorable environmental factors and the situation should be analyzed in the context of environmental medicine.

Immunodeficiency conditions caused by non-radiation death of lymphocytes

Mass death of lymphocytes forms the basis of immunodeficiencies that develop in a number of infectious diseases of both bacterial and viral nature, especially with the participation of superantigens. Superantigens are substances that can activate CD4+ T lymphocytes with the participation of APCs and their MHC-II molecules. The effect of superantigens differs from the effect of normal antigen presentation.

Superantigen is not cleaved into peptides and is not integrated into anti-

gene-binding cleft, but is connected to the “side surface” of the β-chain of the MHC-II molecule.

Superantigen is recognized T cells by their affinity not to the antigen-binding center TCR, but to the so-called 4th hypervariable

mu region - sequence 65–85, localized on the side surface of TCR β-chains belonging to certain families.

Thus, superantigen recognition is not clonal, but is determined by the TCR belonging to certain β-families. As a result, superantigens involve a significant number of CD4+ T lymphocytes in the response (up to 20–30%). Thus, the response to staphylococcal exotoxin SEB involves CD4+ T cells from mice expressing TCRs belonging to the Vβ7 and Vβ8 families. After a period of activation and proliferation, accompanied by hyperproduction of cytokines, these cells undergo apoptosis, which causes a significant degree of lymphopenia, and since only CD4+ T cells die, the balance of lymphocyte subpopulations is also disturbed. This mechanism underlies T-cell immunodeficiency, which develops against the background of certain viral and bacterial infections.

4.7.3.2. Secondary immunodeficiencies caused by functional disorders lymphocytes

It is likely that this group of secondary immunodeficiencies is predominant. However, at present, there is practically no accurate data on the mechanisms of decreased lymphocyte function in various somatic diseases and exposure to harmful factors. Only in isolated cases is it possible to establish the exact mechanisms

Zolotareva N.A.

All-Russian NIVI Pathology, Pharmacology and Therapy

In farm animals, the most common cause of secondary immunodeficiency is a violation of the transmission of maternal antibodies to the offspring with colostrum. The state of humoral immunity in animals in the first months of life depends almost entirely on the quality, quantity and timely feeding of colostrum (Karput I.M. et al., 1990; Bondarenko G.U., 1995, etc.). Therefore, humoral immunity in young farm animals in the first 3-4 months of life, and especially after birth, is not functionally developed.

Nonspecific resistance, in contrast to humoral immunity, in young farm animals has greater physiological maturity and does not differ so significantly from the indicators of adult animals. This is due to the fact that the synthesis of all its components is genetically determined, and they are present in the body at the time of birth. In the first months of life, the state of nonspecific resistance plays a key role in protecting the animal’s body from infectious agents (Emelyanenko P.A., 1976, etc.)

The animal body is especially sensitive to stress in the first 3-4 months of life, and the maternal body is especially sensitive to stress in the last period of pregnancy and the first 2-3 months after birth. A direct relationship has been established between the level of nonspecific resistance of the mother’s body, on the one hand, and the intrauterine development of the embryo, the state of health and safety of newborns, on the other hand. For example, calves obtained from cows with subclinical pathology have signs of intrauterine malnutrition, increased morbidity and reduced safety, and in their mothers the terms of placenta separation are extended, the level of gynecological diseases, indicators of reproductive capacity and the content of lactoglobulins in colostrum decrease, culling of broodstock increases before the period of its maximum productivity. There are many reasons for this type of disturbance, but the main ones are stressful situations, the age of animals, infectious and non-communicable diseases, as well as environmental problems, causing a decrease functions of the immune system, leading to disruption of the nervous, endocrine and other systems.

As for express methods for detecting secondary immunodeficiencies in adult animals, this issue still remains problematic. Many researchers believe that by determining the content of T- and B-lymphocytes, immunoglobulins, neutrophils, and complement activity, one can judge the presence or absence of immunodeficiency. However, numerous blood tests conducted in pigs and piglets, cows and calves do not give us grounds to assert that a single blood test for these indicators is sufficient to conclude the presence or absence of immunodeficiency in these animals. In this regard, we tested a method for determining the natural inhibitory factor (NIF) of macromolecular antibodies (Ig M), the presence of which indicates secondary immunodeficiency. Moreover, according to N.K. Rodosskaya. (2001), an EIF value of 1.2 or more indicates the presence of immunodeficiency, regardless of the etiology that caused it.

We conducted studies of blood serum of cows in the dry period and 1-105 day old calves obtained from the same animals. It was found that during the initial study of pregnant cows, only 11.1% had a positive EIF index (1.2 - 1.25), and the rest reacted negatively. When analyzing cow sera after 21 days, 30% of animals reacted positively (EIF index 1.37). Subsequent multiple studies of blood serum of cows and calves with an interval of 7 days showed that EIF is detected no later than 14 days from the moment of its appearance. A correlation was revealed between the course of the disease in calves and the detection of EIF. However, we have not yet proven the connection between maternal and fetal immunodeficiency.

Thus, the presented data indicate that if there is a timely and reliable diagnosis of a deficiency in the body’s nonspecific resistance, humoral or cellular immunity, it is possible to correct the immunological status and natural resistance in animals.

In practice, to stimulate the phagocytic, lysozyme and complementary activities of blood serum, immunoglobulin preparations, blood serum and blood, adaptogens, tissue preparations, etc. are used. Moreover, drugs used to stimulate nonspecific resistance have a selective effect on its various parts, and diseases often cause specific changes in the body’s resistance. Therefore, practitioners are faced with the problem of choosing means of stimulating nonspecific resistance in the prevention and treatment of a particular pathology.

In this regard, you need to know:

– administration of immunomodulators to sick animals can lead to exacerbation of the disease and possible death;

– introduction of activators of the inflammatory response, such as lipopolysaccharides, adjuvants, certain mediators, etc. can also intensify the symptoms of the disease and accelerate death in some infections;

– the introduction of inhibitors of the inflammatory response can lead to the elimination of the symptoms of the disease, but does not prevent the persistence of viruses.

Consequently, the widespread use of immunomodulators and adjuvanted vaccines may lead to adverse events.