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

Human immunodeficiency (primary, secondary), causes and treatment. Immunodeficiency conditions caused by the death of immunocytes

– 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 from immunological studies. Treatment uses vaccination, replacement therapy, and 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 effects of drugs, chronic psycho-emotional overload, malnutrition, injuries, 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 can be latent (complaints and clinical symptoms are absent, the presence of immunodeficiency is revealed only by laboratory testing) or active with signs of an 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

A wide variety of etiological factors, both external and internal, can lead to a pronounced and persistent decrease in the body’s immune defense. 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 of nutrients in the digestive tract lead to disruption of the maturation 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, respiration, etc.) further inhibits the functioning of the immune system.

A pronounced disturbance of metabolic processes in the body in 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 ( more often these are 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 is aggravated when the tumor process generalizes and metastasizes to the bone marrow. Secondary immunodeficiencies often develop with autoimmune diseases, acute and chronic poisoning, in elderly people, and 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 of cytostatics, corticosteroid hormones, severe injuries and extensive surgical operations with intoxication, blood loss), as well as severe somatic pathology (diabetes mellitus, hepatitis, cirrhosis, chronic renal disease). deficiency) 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 phlegmons) , 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, swollen lymph nodes and their inflammation, pain in muscles and joints, general weakness and fatigue, decreased performance, frequent colds, repeated sore throats, often recurrent chronic sinusitis, bronchitis, repeated pneumonia, septic conditions, etc. etc. At the same time, the effectiveness of standard antibacterial and anti-inflammatory therapy is low.

Diagnostics

Identification of secondary immunodeficiencies requires an 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 of a chronic infection that is difficult to treat , as well as the identification of 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 (indicative) level, which allows identifying gross general disorders of the immune system, and the second (additional) level, identifying 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), protein levels 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 immunotropic drugs (immunostimulants). The advisability of prescribing a particular medicinal product and the selection of dosage 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.

Immunodeficiency states or immunodeficiency are a group of various pathological conditions characterized by disruption of the human immune system, against the background of which infectious and inflammatory processes recur much more often, are difficult, and last longer than usual. Against the background of immunodeficiency, people of any age group develop serious diseases that are difficult to treat. Due to this process, cancerous tumors can form that pose a threat to life.

This condition, depending on the causes, can be hereditary or acquired. This means that the disease often affects newborn babies. Secondary immunodeficiency is formed against the background of many factors, including trauma, surgery, stressful situations, hunger and cancer. Depending on the type of disease, various symptoms may appear, indicating damage to the internal organs and systems of a person.

Diagnosis of immune dysfunction is based on general and biochemical blood tests. Treatment is individual for each patient, and depends on the factors that influenced the occurrence of this condition, as well as the degree of manifestation of characteristic symptoms.

Etiology

There are many causes of immunodeficiency, and they are divided into several groups. The first consists of genetic disorders, and the disease can manifest itself from birth or at an early age. The second group includes complications from a wide range of pathological conditions or diseases.

There is a classification of immunodeficiency states, divided depending on the factors that caused this condition to form:

primary immunodeficiency – caused by a genetic disorder. It can be transmitted from parents to children or occurs due to a genetic mutation, which is why there is no hereditary factor. Such conditions are often diagnosed in the first twenty years of a person's life. Congenital immunodeficiency accompanies the victim throughout his life. Often leads to death due to various infectious processes and complications from them;
Secondary immunodeficiency is a consequence of many conditions and diseases. A person can get this type of immune disorder for the reasons mentioned above. It occurs several times more often than the primary one;
severe combined immunodeficiency is extremely rare and is congenital. Children die from this type of disease in the first year of life. This is due to a decrease in the number or disruption of the functioning of T and B lymphocytes, which are localized in the bone marrow. This combined condition differs from the first two types, in which only one type of cell is affected. Treatment of such a disorder is successful only if it is identified in a timely manner.

Symptoms

Since the classification of the disease includes several types of disorder, the expression of specific symptoms will differ depending on the form. Signs of primary immunodeficiency are frequent damage to the human body by inflammatory processes. Among them:

abscess;

In addition, immunodeficiency in children is characterized by digestive problems - lack of appetite, constant diarrhea and vomiting. There are delays in growth and development. The internal manifestations of this type of disease include the spleen, changes in the composition of the blood - the amount of and decreases.

Despite the fact that primary immunodeficiency is often diagnosed in childhood, there are several characteristic signs that indicate that an adult may have this type of disorder:

frequent attacks of purulent otitis media and sinusitis more than three times a year;
severe inflammatory process in the bronchi;
recurring skin inflammations;
frequently recurring diarrhea;
the occurrence of autoimmune diseases;
undergoing severe infectious processes at least twice a year.

Symptoms of secondary immunodeficiency are those signs that are characteristic of the disease that provoked it. In particular, the symptoms of the lesion are noted:

upper and lower respiratory tract;
upper and deeper layers of the skin;
gastrointestinal organs;
genitourinary system;
nervous system. In this case, a person feels chronic fatigue, which does not go away even after a long rest.

Often people experience a slight increase in body temperature, seizures, as well as the development of generalized infections that affect several internal organs and systems. Such processes pose a threat to human life.

Combined immunodeficiencies are characterized by the presence in children of delayed physical development, a high level of susceptibility to various infectious and inflammatory processes, and chronic diarrhea.

Complications

Depending on the type of disease, different groups of consequences of untimely treatment of the underlying disorder may develop. Complications of immunodeficiency in children may include:

various infectious processes of a viral, fungal or bacterial nature that are repeated with high frequency;
the formation of autoimmune disorders, during which the immune system acts against the body;
high likelihood of various diseases of the heart, gastrointestinal tract or nervous system;
oncological neoplasms.

Consequences of secondary immunodeficiency:

pneumonia;
abscesses;
blood poisoning.

Regardless of the classification of the disease, death occurs with late diagnosis and treatment.

Diagnostics

People with immunodeficiency conditions have clear signs that they are sick. For example, a sickly appearance, pale skin, the presence of diseases of the skin and ENT organs, a severe cough, sore eyes with increased tear production. Diagnosis is primarily aimed at identifying the type of disease. To do this, the specialist needs to conduct a thorough interview and examination of the patient. After all, treatment tactics depend on whether the disease is acquired or hereditary.

The basis of diagnostic measures is various blood tests. A general analysis provides information about the number of cells of the immune system. A change in the amount of any of them indicates the presence of an immunodeficiency state in a person. To determine the type of disorder, a study of immunoglobulins is carried out, i.e. the amount of proteins in the blood. The functioning of lymphocytes is being studied. In addition, an analysis is carried out to confirm or deny genetic pathology, as well as the presence of HIV. After receiving all the test results, the specialist makes a final diagnosis - primary, secondary or severe combined immunodeficiency.

Treatment

To choose the most effective tactics for treating primary immunodeficiency, it is necessary to determine at the diagnostic stage the area in which the disorder has occurred. In case of immunoglobulin deficiency, patients are prescribed injections (for life) of plasma or serum from donors that contain the necessary antibodies. Depending on the severity of the disorder, the frequency of intravenous treatments can range from one to four weeks. For complications of this type of disease, antibiotics are prescribed in combination with antibacterial, antiviral and antifungal medications.

Prevention

Since congenital immunodeficiency is formed against the background of genetic disorders, it is impossible to avoid it with preventive measures. People need to follow several rules to avoid recurrence of infections:

do not use antibiotics for a long time;
undergo vaccinations recommended by specialists in a timely manner;
carefully follow all personal hygiene rules;
enrich the diet with vitamins;
Avoid contact with people who have a cold.

Prevention of secondary immunodeficiency includes vaccination, depending on the doctor’s prescription, protected sexual contact, timely treatment of chronic infections, moderate exercise, a balanced diet, and taking courses of vitamin therapy.

If any manifestations of immunodeficiency conditions occur, you should immediately seek advice from a specialist.

Is everything in the article correct from a medical point of view?

Answer only if you have proven medical knowledge

Antibodies to p24

Antibodies to gr120

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). A surge of antigenemia in the early period of 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, increases.

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. Thus, when blood cells are infected with HIV, 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, a high level of apoptosis is detected. 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 p14 gene product. 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

4.7. Immunodeficiencies

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 of the lungs, central nervous system, digestive tract; herpetic infection of the 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 addition to antiretroviral therapy is 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%. The most common cause of death is opportunistic infections, especially Pneumocystis pneumonia. Other causes of death are concomitant tumors, damage to the central 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

4.7. Immunodeficiencies

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

Criterion	Primary	Secondary
	immunodeficiencies	immunodeficiencies

Presence of genetic
defect with installed
ny type of hereditary


The role of the inducer


Early manifestation	Expressed	Time of manifestation of the immune system
immunodeficiency		but the deficit determines-
		due to the action of induc-
		factor

Opportunistic	Develop primarily	Develop after action
infections		Via inducing


	Substitute, anti-	Elimination of induction
	infectious therapy.	influencing factor.
	Gene therapy	Substitute, anti-
		war-infectious therapy

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 the discovery of 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 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

4.7. Immunodeficiencies

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 in the initial stages of 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 neutrophil granulocytes early and most severely, as the cell population with the most rapid 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. At a later date, the effects of damage to innate immune factors are much less pronounced. 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, restoration processes are activated. 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

4.7. Immunodeficiencies

characteristic of T-lymphopoiesis in the embryonic period: first, γδT cells are formed, then αβT cells. The recovery process is preceded by rejuvenation of thymic epithelial cells, accompanied by an increase in their production of 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. The number of dendritic cells and the expression of MHC molecules (especially class II) on them are 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 of lymphocytes

It is likely that this group of secondary immunodeficiencies is predominant. However, at present, there is virtually 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

Immunodeficiency is called secondary if it occurs as a result of a disease of a non-immune nature or the action of a certain agent on the body - radiation, drugs, etc.

In the world, the most common cause of secondary immunodeficiencies is insufficient and unhealthy nutrition. In developed countries, secondary immunodeficiencies may be caused by drugs used in anticancer therapy and immunosuppressants used in organ transplantation and autoimmune diseases. The occurrence of secondary immunodeficiencies is often observed as a consequence of the development of autoimmune diseases, with severe bacterial and viral infections.

Immunodeficiencies caused by lack of nutrition. Protein and energy deficiencies are common in developing countries and are associated with impaired cellular and humoral immunity in response to microorganisms. The leading cause of morbidity and mortality in undernourished people is infectious diseases. The causes of these immunodeficiencies have not yet been precisely established, but it is suggested that severe metabolic disturbances in affected individuals, indirect by abnormal intake of proteins, fats, vitamins and minerals, affect the maturation and function of immune system cells.

One of the signs of malnutrition is atrophy of lymphoid tissue. Malnourished children often develop the so-called “nutritional thymectomy”, which is characterized by disruption of the structure of the thymus, a general decrease in the number of lymphocytes in it and atrophy of the thymic periarteriolar areas of the spleen and paracortical areas of the lymph nodes.

Insufficient protein supply and consumption of low-energy foods often result in suppression of cellular immunity, as evidenced by a decrease in the number of CD4 T lymphocytes. Lymphocytes have a reduced ability to respond with proliferation to mitogens. Such changes in the number and function of T cells may be due to a decrease in the activity of thymic hormones. Insufficient provision of food with proteins and energy in weakened individuals leads to changes in the phagocytic function of macrophages, i.e. to disrupt the ability of these cells to destroy absorbed microbes. There is a decrease in the levels of complement components C3, C5 and factor B, a decrease in the production of cytokines IL-2, TNF, IFN.

Drug-induced immunodeficiencies. Immune modulatory drugs can significantly suppress the functions of the immune system.

Glucocorticoids are quite strong natural modulators of the immune system. first, they influence the composition of circulating leukocytes. The action of glucocorticoids induces lymphopenia, and CD4 ^ cells are sensitive, and their number decreases to a greater extent than T lymphocytes of other subpopulations. In addition, awns were noticed in human blood

monocytes, eosinophils and basophils. Injection of steroid drugs> to

neutrophilia due to the release of mature cells from the bone marrow and their retention in circulation. Steroid drugs also affect certain functions of immune system cells. Steroids have been shown to inhibit the activation and proliferation of T cells and inhibit the production of TNF and IL-1 by monocytes. It has been noted that after the administration of steroid drugs, the production of a number of cytokines decreases: IFN-Y, IL-1, IL-2, IL-6, IL-10.

The formation of immunodeficiency states can be caused by drugs used for immunosuppression during allotransplantation. For example, cyclosporine A and its analogue tacrolimus, which inhibit the conduction of activation signals from cytokine receptors, have a restraining effect not only on lymphoid cells, but also on cells of non-lymphoid origin, since the molecular targets of these drugs are widely represented in various tissues. Drugs such as sirolimus and everolimus: activation signal from costimulatory molecules and cytokine receptors.

They inhibit the synthesis of nucleic acids in stimulated cells. Side effects of these. "Erigate in different cell types. In addition, in patients treated with these

There is an increase in the incidence of pneumonia. In patients receiving

n suppression of bone marrow cell maturation, dysfunction of the digestive system

canal and complicated infections caused by fungi.

Various drugs used in anticancer therapy can significantly suppress the functions of the immune system. Suppression of the immune response can be caused by antimetabolites such as azathioprine and mercaptopurine, which disrupt the synthesis of RNA and DNA due to inhibition of inosinic acid, a precursor to the synthesis of adenine and guanine. Methotrexate, an analogue of folic acid, blocks the metabolic processes that occur with its participation and are necessary for DNA synthesis. After using methotrexate, there is a long-term decrease in the blood levels of immunoglobulins of all classes. Chlorambucil and cyclophosphamide alkylate DNA and were first used to treat cancer patients. However, studies of their cytotoxic effect on lymphocytes have led to the use of these drugs as immunosuppressive therapeutic agents.

Infectious immunodeficiencies. Various types of infections can lead to the development of immunosuppression. One of the most well-known viruses that directly attacks cells of the immune system is the human immunodeficiency virus (HIV).

Acquired immunodeficiency syndrome (AIDS) is caused by HIV and is characterized by various clinical manifestations, including profound immunosuppression associated with a number of opportunistic infections and tumors, and nervous system disorders.

The human immunodeficiency virus was described in 1983 simultaneously by French and American scientists. The virus is a retrovirus in which the genetic material is in the form of RNA and is converted into DNA using reverse transcriptase.

There are two types of HIV-HIV 1 and VIL2. They are 40 - 60% similar at the genome level, but VIL2 is less contagious and pathogenic than HIV1.

Viral particles that initiate infections can be found in various body fluids, including blood, seminal fluid, and enter the body of another person during sexual contact or medical procedures (blood transfusion, use of unsterile needles). It has been proven that 75% of HIV1 infections occur as a result of heterosexual relationships.

The virus particle consists of two identical chains of viral RNA, each 9.2 kb long, packaged in the core of the viral proteins and surrounded by a bilipid layer of the plasma membrane of the host cell. On the surface of the membrane there are viral glycoproteins necessary for the adsorption of the viral particle on sensitive cells and entry into the latter.

The HIV genome has a structure characteristic of retroviruses. Long terminal repeats (LTRs) are required for integration into the host genome and replication of viral genes. The gag region of the genome encodes cow structural proteins, and env encodes the surface glycoproteins gp120 and gp41. The Roya sequence encodes reverse transcriptase, protease, and integrases, proteins necessary for viral replication. The virus genome also contains a number of regulatory genes rev, tat, vif, nef vpr and vpu, the products of which regulate the formation of viral particles. Adsorption of the virus on sensitive cells occurs as a result of the interaction of the surface glycoprotein complex of the gp120/gp41 virion with the complementary structures of CD4 and the G-binding receptor (GCR), or, as it is also called, coreceptors, on the surface of sensitive host cells. The process of penetration of the HIV virus into a cell has not yet been fully studied. The interaction of gp120 with CD4 induces conformational changes in gp120, resulting in the exposure of previously cryptic domains that interact with coreceptors. In this case, a ternary gp120-CD4-coreceptor complex is formed. The formation of the ternary complex gp120-CD4-coreceptor leads to additional conformational changes in gp120, which are transmitted to the viral transmembrane glycoprotein gp41 and induce changes in the structure of the latter. As a result, the N-terminal fusion sequence of gp41 is directed to the cell membrane, where it enters the lipid bilayer and initiates the fusion of the viral and cellular membranes.

Most of the GCRs used by HIV to enter cells are receptors for chemokines. The first coreceptor identified, CXCR4, is used by T-clitinotron and syncytium inductive (SI) strains of HIV. Another co-receptor, CCR5, is used by non-syncytium-forming macrophage (NSI) viruses. It is believed that these two types of coreceptors are most commonly used by the virus and therefore play a major role in maintaining HIV infection in vivo. There are also other GCRs that have been shown in vitro to promote cell infection by certain strains of HIV: CCR2b, CCR3, CCR8, CCR9, CX3CR1, etc. For example, CCR3 promotes infection of macrophages and microglia. The primary target of infection in this case is the nervous system. After the virus enters the cow's cell, the virion proteins are disrupted and the HIV RNA genome, using reverse transcriptase, is converted into the form of subvirion DNA, which enters the nucleus of the infected cell. Viral integrase promotes the incorporation of viral DNA into the genome of the host cell. In this transcriptionally inactive state, the virus can exist for months, or even years. Under such conditions, weak production of viral proteins occurs. This period of infection is called latent.

The expression of certain HIV genes can be divided into two periods. During the early period, early regulatory genes nef, tat and rev are expressed. Late genes include the gag and env swarms, the products of which are structural components of the virus particle. The mRNA encoding various HIV proteins is produced by alternative splicing of the common transcript of the entire viral genome. Some viral proteins are produced by cleavage of a common protein precursor by cellular proteases. For example, the env gene product of the common precursor gp160 is cleaved into two components, gp120 and gp41, which are non-covalently linked and form a complex in the plasma membrane of the cell. The composition of viral particles begins with the packaging of RNA transcripts of the virus into nucleoprotein complexes with core proteins and enzymes necessary for the next round of virus integration. The nucleoprotein complex is then enveloped by the plasma membrane of the cell with the viral proteins gp120/gp41 exposed on it and is released from the cell. This process becomes spontaneous, and the target cell dies.

The sites where the virus is located in the body can be divided into cellular and anatomical. Lymph nodes are active anatomical sites of viral replication. The main cells that are affected during HIV infection are OT4-positive cells, which are primarily T-helper cells, which contain about 99% of the replicative virus in the host. The activity of the virus depletes the population of T helper cells, which leads to disruption of the homeostasis of the entire immune system. The OT4 antigen is also carried by macrophages, dendritic cells, and a certain population of activated CD8 T lymphocytes. There is still uncertainty as to which cells are the most important targets during primary HIV infection. Infected macrophages, which make up less than 1% of all infected cells, are critical for the spread of the virus in the body. The number of infected macrophages is small, but macrophages are resistant to the cytopathic effect of HIV and live relatively long, releasing viral particles during this time. Langerhans cells and mucosal dendritic cells are important targets of HIV for sexual transmission. Recently, it was shown that the dendritic cell receptor (DC-SIGN) is recruited to efficiently bind HIV and transmit the virus to T lymphocytes. DC-SIGN - a homolog - dC-SIGnR - expressed on endothelial cells of liver sinusoids, endothelial cells of lymph nodes and placental microvilli may play a role in the transmission of HIV to lymph node cells or in the vertical transmission of the virus. + The course of AIDS is determined by the number of viral particles in the blood plasma and the number of CD4 T-lymphocytes. A few days after the virus enters the body, viremia develops. Intense replication of the virus is observed in the lymph nodes. It is believed that it is the affected dendritic cells, which are not sensitive to the cytopathic effect of the virus, that transport the virus to the lymph nodes and contribute to the damage of lymphocytes through direct intercellular contacts. Viremia promotes the spread of the virus throughout the body and infection of T cells, macrophages and dendritic cells of peripheral lymphoid organs. The immune system, which has now already recognized viral antigens, begins to respond to them by strengthening the humoral and clitorin-mediated immune response. The immune system at this stage partially controls the infection and virus production. This control results in a reduction in the number of viral particles in the blood to low levels over a period of about 12 months. During this phase of the disease, the immune system remains competent and deftly neutralizes infectious agents of a different nature. No clinical manifestations of HIV infection are recorded. A small amount of virions is observed in the blood serum, but the majority of OT4T lymphocytes in peripheral blood are free of the virus. However, the impairment of CD4T lymphocytes in lymphoid tissues gradually progresses, and the number of CD4T lymphocytes in the periphery steadily decreases, despite the fact that this population of lymphocytes is constantly renewed.

As AIDS progresses, the patient's immune response to other infectious agents can stimulate the spread of the virus and its damage to lymphoid tissue. Activation of HIV gene transcription in lymphocytes can occur in response to activation cytokines. AIDS reaches its final phase when there is a significant decrease in peripheral blood CD4 T lymphocytes and lymphoid tissues are affected. The number of viral particles in the blood increases again. Affected individuals suffer from a variety of opportunistic infections and neoplasms because the activity of CD4 T lymphocytes, essential for cell-mediated and humoral immune responses, is sharply reduced. Patients experience problems with the functioning of the kidneys and nervous system.

The second form of immune deficiency is post-radiation carcinogenesis, one of the most common and dangerous manifestations of remote pathology, developing after exposure to ionizing radiation.

In each specific case, it is almost impossible to accurately determine due to the combination of what factors the so-called spontaneous DNA defects are formed, which often lead to the development of tumors with age. It has been shown that when exposed to radiation, tumors are more often observed after irradiation with a dose of 2 -2.5 Gy. However, the scale of radiation doses that have a carcinogenic risk is much wider. There are reports that even some small (man-made) doses that were previously considered safe are carcinogenic. This may be due to a combination of radiation effects with other factors. It has been established that the likelihood of an oncological process (in the long-term post-radiation period) increases after a dose of 1 Gy or higher. Statistically, the likelihood of getting cancer increases in direct proportion to the dose. With a double dose the risk doubles. It is typical for humans that the carcinogenic risk after 30 years doubles every 9 to 10 years.

The carcinogenic process occurs at the molecular level in the form of gene mutations, but the further development of these degenerated cells depends on whether they pass the immune surveillance of lymphocytes.

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, mainly class M and less commonly class G, appear in the fetal blood serum. They have the function of predominantly incomplete 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 decreasing amounts of IgG1, IgM, IgA, IgG2. Immunoglobulin Gl, approximately two weeks before calving, 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 most actively absorbed 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 of the animal’s body and with age. In old animals, there is a decrease in immunological reactivity due to autoimmune 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 number of plasma cells formed in response to the administered antigen. The activity of cellular immunity also decreases. 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 determined by 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, and 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 the Greek alios - other, ergon - action) is an 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 body's reactivity 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 defense factors and develop, like all other 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 (DTH). 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 the Greek ana - against, phylaxia - protection) is 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), which causes increased sensitivity, is called sensitizing (Latin sensibilitas - sensitivity), the second dose, after the administration of which anaphylaxis develops, is called resolving, and 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 are more studied in humans - these are bronchial asthma, allergic rhinitis and conjunctivitis, urticaria, food allergies to strawberries, honey, egg whites, citrus fruits, etc. Food allergies have been described in dogs and cats to fish, milk and other products, in cattle Cattle showed an atopic reaction such as hay fever when transferred to other pastures. In recent years, atopic reactions caused by drugs - antibiotics, sulfonamides, etc. - have been 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 allergy. 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 (unresponsiveness). 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 the body's cells and occurs when defense mechanisms are 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 is a phenomenon when a sensitized (sick) body reacts to allergens made from microbes that have common or related allergens, for example, Mycobacterium tuberculosis and atypical mycobacteria.

Pseudoallergy (heteroallergy) is the presence of a nonspecific allergic reaction as a result of autoallergization of the body by tissue breakdown products during the development of a 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 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 tissue. 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 that are not characteristic of the direct action of the antigen (microbes, foreign proteins), but rather similar symptoms characteristic of allergic reactions.

Immunodeficiencies

Immunodeficiency conditions are 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 are 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. With combined immunodeficiency, the absence or hypoplasia of the thymus, bone marrow, lymph nodes, spleen, lymphopenia and low levels of immunoglobulins in the blood are noted. Clinically, immunodeficiencies can manifest themselves in the form of delayed physical development, pneumonia, gastroenteritis, sepsis caused by an opportunistic infection.

Age-related immunodeficiencies are 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 the lymph nodes and spleen there are few secondary lymphoid follicles with large reactive centers and plasma cells. In animals, gastroenteritis and bronchopneumonia occur due to the action of opportunistic microflora. The deficiency of humoral immunity during the neonatal period is compensated by full-fledged maternal colostrum, and at a later time by adequate feeding and good living conditions.

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 immunosuppressive drugs. 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 a violation of cellular and humoral immunity, i.e. they 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.