Natural killer cells immunology. Natural killer cells (NK, natural killer-NK cells). When the level of NK cells increases, immunity strengthens

Natural killer cells- These are large granular lymphocytes, low-differentiated descendants of a stem cell.

The membrane of natural killer cells contains receptors for γ-interferon, IL-2 and IL-12, therefore these cytokines are capable of activating natural killer cells. Natural killer cells also contain clusters CD16 and CD56, which are used for laboratory identification of these cells.

Immune tolerance

There are tissue and circulating natural killer cells. Tissue natural killer cells are found in the liver and placenta, ensuring the maintenance of immune tolerance to food antigens and fetal antigens, respectively. To do this, these natural killer cells bind to activated lymphocytes and initiate a cascade of apoptosis in them, i.e., they perform a killing effect.

Cytotoxicity

Cellular cytotoxicity

Circulating natural killer cells provide protection against spontaneously changed own cells (including tumor cells), and also take part in the destruction of virus-infected cells.

The reaction in which natural killer cells take part is called spontaneous cell-mediated cytotoxicity (SCMC) because it does not require antibodies or complement.

The SCOC mechanism is as follows (Fig. 10). With the help of the killing-activating receptor, natural killer cells interact with oligosugars of gangliosides and glycosaminoglycans on the surface structures of target cells. Since such molecules are “ubiquitous,” natural killer cells can potentially damage almost any of their own cells. Naturally, this does not happen in the body. The fact is that the activation of the natural killer is prevented by the killing-inhibitory receptor, which recognizes HLA class I molecules (only those varieties that are inherent in a particular organism). Therefore, target cells are selected based on the expression of specific HLA I molecules - in the absence of such expression or the “foreign” structure of histocompatibility molecules, the killing mechanism (the so-called kiss of death) is triggered. Material from the site

The above data indicate that natural killer cells are activated when the balance is disturbed between trigger receptors, which respond not only to microbial products, but also to the structures of actively proliferating own cells, and inhibitory receptors, which respond to class I HLA molecules (“ tags" of yours). This combination of nonspecific trigger and specific inhibitory receptors allows natural killer cells to effectively respond to a wide range of targets - from foreign microbes, xenogeneic and allogeneic cells to their own pathologically altered or even overly active cells.

The lymphoid lineage of hematopoiesis in the bone marrow is represented by B-, T- and NK-cell lines. Precursor cells have the morphological characteristics of blasts or mature lymphocytes. In the bone marrow, B and T lymphoblasts make up a very small proportion of cells (less than 0.5%), lymphocytes - 4.3-13.7%.

B-lymphoid precursors in the bone marrow, the central organ of B-lymphopoiesis, undergo an antigen-independent stage of maturation. In this case, a restructuring (rearrangement) of the immunoglobulin genes located on chromosomes 2, 22 and 14 occurs. Individual stages of differentiation are characterized by the appearance of specific macromolecules that determine the immunophenotype of cells.

On the earliest pro-B cells, stem element antigens (CD34 and CD38) are retained and specific macromolecules pan-BCD19 and then cytoplasmic CD22 appear. These antigens are characteristic of all elements of the B-lymphoid series. Then the content of stem cells on pre-B cells decreases and other B antigens appear - CD 10, CD20 and CD24. The next stage of maturation (npe-B blasts) is characterized by the appearance in the cytoplasm of cells (Ig J-chain. At the last stage of bone marrow B-differentiation, the full molecule (light and heavy chains) of IgM is expressed on the membrane of lymphoid elements.

After this, morphologically mature, but immunologically “naive” B-lymphocytes enter the blood and peripheral organs of the immune system: lymph nodes, spleen, etc. There, after contact with the antigen in the germinal centers of secondary lymphoid follicles, they undergo an antigen-dependent stage of differentiation. As a result, a pool of mature B-lymphocytes and plasma cells is formed that are capable of synthesizing and producing immunoglobulins of different classes, which allows them to take part in the regulation and implementation of the humoral response of the immune system.

T cell precursors in the bone marrow are characterized by the expression of stem cell (CD34, HLA-Dr) and T antigens (CD7, cytoplasmic CD3±). First, T-precursors migrate to the thymus, which is the central organ of T-lymphopoiesis, and then enter the peripheral lymphoid organs, where they undergo an antigen-dependent differentiation stage. In the thymus gland, the genes encoding the T-cell receptor (TCR) are rearranged, and the TCR appears on the surface membrane. This receptor, together with the protein products of the major histocompatibility complex gene, recognizes and binds antigens. Most T lymphocytes in the blood express the a and beta chains of the TCR, while T lymphocytes in the intestinal epithelium and vaginal mucosa express the y and sigma chains.

T-lymphocytes: stages of intrathymic differentiation.

The stages of intrathymic differentiation of cells from the bone marrow precursor (pre-T cells) that migrated into the organ to the mature T lymphocyte leaving the thymus are associated with changes in the expression of phenotypic T-cell markers. The main ones are: CD4 - coreceptor of T-helper cells, CD8 - coreceptor of cytotoxic T-lymphocytes (T-killer cells) and alpha-beta TCR (T-cell antigen recognition receptor). A specific combination of these surface molecules can be used as markers of cell differentiation in the thymus.

Table 1 Phenotypic markers of differentiating thymocytes

At the first stage, a common precursor for T- and B-lymphocytes is formed from a pluripotent hematopoietic stem cell (HSC) of the bone marrow, which provides myelo- and lymphopoiesis.

The closest descendant of the T-lymphocyte precursor is the prothymocyte or committed T-cell precursor (pre-T cell). A characteristic marker of bone marrow pre-T cells is one of the brain antigens (AM). The first pre-T cells migrating to the subcassular region of the thymus lose AM, but acquire a typical marker of thymocytes and peripheral T cells - Thy-1. Subcapsular zone thymocytes are mostly double negative and do not express the T cell receptor (TCR). The phenotype of such cells is CD4-CD8-alpha-beta-TCR-.

Gradually, as they move into the cortex, thymocytes begin to express both CD4 and CD8 coreceptors, as well as TCRs. The medullary zone of the thymus is the site of localization of blast forms with a phenotype characteristic of independent subpopulations of T cells (CD4+CD8-alpha-beta-TCR+ - T-helpers/inducers; CD4-CD8+alpha-beta-TCR+).

Hence their name "double negatives". They inhabit the upper part of the thymic cortex, located directly under the organ capsule - the subcapsular region. In a fully developed thymus, double negative cells constitute a small cell pool, only about 5% of the total number of thymocytes.

Mature T-lymphocytes are present in the peripheral blood, in the thymus-dependent areas of the spleen, lymph nodes, tonsils, and Peyer's patches. In the peripheral blood, the T-lymphocyte pool is represented by two fractions - helper/effector (CD4+) and suppressor/cytotoxic cells (CD8+). CD4+ T lymphocytes are divided into two subtypes: T helper 1 (Th1) and T helper 2 (Th2). Cells of the first type are capable of enhancing the synthesis and production of Ig by cells, cells of the second type are able to induce antigen-specific activity of T-suppressors.

T lymphoid cells do not synthesize or secrete immunoglobulins. They have the ability to produce proteins and hormones (cytokines) that regulate the proliferation and differentiation of other cells that take part in the cellular immune response.

Natural killer (NK) cells have an independent lineage. In peripheral blood they are morphologically characterized as large granular lymphocytes with a slightly indented nucleus and large azurophilic granules. Their phenotype is CD3-, CD16+, CD56+. They do not have TCR rearrangement and express the CR2 receptor (CM) on the membrane. Epstein-Barr virus, Fc receptor - for IgG. NK cells are capable of being responsible for spontaneous cellular cytotoxicity.

The first study is always a leukocyte count (see chapter “Hematological studies”). Both relative and absolute values ​​of the number of peripheral blood cells are assessed.

Determination of the main populations (T-cells, B-cells, natural killer cells) and subpopulations of T-lymphocytes (T-helpers, T-CTLs). For the initial study of immune status and identification of severe immune system disorders WHO recommended determination of CD3, CD4, CD8, CD19, CD16+56, CD4/CD8 ratio. The study allows you to determine the relative and absolute number of the main populations of lymphocytes: T cells - CD3, B cells - CD19, natural killer (NK) cells - CD3- CD16++56+, subpopulations of T lymphocytes (T helper cells CD3+ CD4+, T-cytotoxic CD3+ CD8+ and their ratio).

Research method

Immunophenotyping of lymphocytes is carried out using monoclonal antibodies to superficial differentiation tonsillitis on cells of the immune system, using flow laser cytofluorometry on flow cytometers.

The selection of the lymphocyte analysis zone is made based on the additional marker CD45, which is present on the surface of all leukocytes.

Conditions for taking and storing samples

Venous blood taken from the ulnar vein in the morning, strictly on an empty stomach, into a vacuum system to the mark indicated on the tube. K2EDTA is used as an anticoagulant. After collection, the sample tube is slowly inverted 8-10 times to mix the blood with the anticoagulant. Storage and transportation strictly at 18–23°C in an upright position for no more than 24 hours.

Failure to meet these conditions leads to incorrect results.

Interpretation of results

T lymphocytes (CD3+ cells). An increased amount indicates hyperactivity of the immune system, observed in acute and chronic lymphocytic leukemia. An increase in the relative indicator occurs with some viral and bacterial infections at the onset of the disease and exacerbations of chronic diseases.

A decrease in the absolute number of T-lymphocytes indicates a failure of cellular immunity, namely a failure of the cellular-effector component of immunity. It is detected in inflammation of various etiologies, malignant neoplasms, after injury, surgery, heart attack, smoking, and taking cytostatics. An increase in their number in the dynamics of the disease is a clinically favorable sign.

B lymphocytes (CD19+ cells) A decrease is observed with physiological and congenital hypogammaglobulinemia and agammaglobulinemia, with neoplasms of the immune system, treatment with immunosuppressants, acute viral and chronic bacterial infections, and the condition after removal of the spleen.

NK lymphocytes with the CD3-CD16++56+ phenotype Natural killer cells (NK cells) are a population of large granular lymphocytes. They are capable of lysing target cells infected with viruses and other intracellular antigens, tumor cells, as well as other cells of allogeneic and xenogeneic origin.

An increase in the number of NK cells is associated with activation of anti-transplant immunity, in some cases observed in bronchial asthma, occurs in viral diseases, increases in malignant neoplasms and leukemia, and in the period of convalescence.

Helper T-lymphocytes with the CD3+CD4+ phenotype An increase in absolute and relative amounts is observed in autoimmune diseases, possibly in allergic reactions, and in some infectious diseases. This increase indicates stimulation of the immune system to the antigen and serves as confirmation of hyperreactive syndromes.

A decrease in the absolute and relative number of T cells indicates a hyporeactive syndrome with a violation of the regulatory component of immunity and is a pathognomic sign for HIV infection; occurs in chronic diseases (bronchitis, pneumonia, etc.), solid tumors.

T-cytotoxic lymphocytes with the CD3+ CD8+ phenotype An increase is detected in almost all chronic infections, viral, bacterial, protozoal infections. Is characteristic of HIV infection. A decrease is observed in viral hepatitis, herpes, and autoimmune diseases.

CD4+/CD8+ ratio The study of the CD4+/CD8+ ratio (CD3, CD4, CD8, CD4/CD8) is recommended only for monitoring HIV infection and monitoring the effectiveness of ARV therapy. Allows you to determine the absolute and relative number of T-lymphocytes, subpopulations of T-helpers, CTLs and their ratio.

The range of values ​​is 1.2–2.6. A decrease is observed with congenital immunodeficiencies (DiGeorge, Nezelof, Wiskott-Aldrich syndrome), with viral and bacterial infections, chronic processes, exposure to radiation and toxic chemicals, multiple myeloma, stress, decreases with age, with endocrine diseases, solid tumors. It is a pathognomic sign for HIV infection (less than 0.7).

An increase in value of more than 3 – in autoimmune diseases, acute T-lymphoblastic leukemia, thymoma, chronic T-leukemia.

The change in ratio may be related to the number of helpers and CTLs in a given patient. For example, a decrease in the number of CD4+ T cells in acute pneumonia at the onset of the disease leads to a decrease in the index, but CTL may not change.

For additional research and identification of changes in the immune system in pathologies requiring assessment of the presence of an acute or chronic inflammatory process and the degree of its activity, it is recommended to include a count of the number of activated T-lymphocytes with the CD3+HLA-DR+ phenotype and TNK cells with the CD3+CD16++56+ phenotype.

T-activated lymphocytes with the CD3+HLA-DR+ phenotype A marker of late activation, an indicator of immune hyperreactivity. The expression of this marker can be used to judge the severity and strength of the immune response. Appears on T-lymphocytes after the 3rd day of acute illness. With a favorable course of the disease, it decreases to normal. Increased expression on T lymphocytes can occur in many diseases associated with chronic inflammation. Its increase was noted in patients with hepatitis C, pneumonia, HIV infection, solid tumors, and autoimmune diseases.

TNK lymphocytes with the CD3+CD16++CD56+ phenotype T-lymphocytes carrying CD16++ CD 56+ markers on their surface. These cells have properties of both T and NK cells. The study is recommended as an additional marker for acute and chronic diseases.

A decrease in them in the peripheral blood can be observed in various organ-specific diseases and systemic autoimmune processes. An increase was noted in inflammatory diseases of various etiologies and tumor processes.

Study of early and late markers of T-lymphocyte activation (CD3+CD25+, CD3-CD56+, CD95, CD8+CD38+) additionally prescribed to assess changes in IS in acute and chronic diseases, for diagnosis, prognosis, monitoring the course of the disease and therapy.

T-activated lymphocytes with the CD3+CD25+ phenotype, IL2 receptor CD25+ is a marker of early activation. The functional state of T-lymphocytes (CD3+) is indicated by the number of receptors expressing IL2 (CD25+). In hyperactive syndromes, the number of these cells increases (acute and chronic lymphocytic leukemia, thymoma, transplant rejection), in addition, their increase may indicate an early stage of the inflammatory process. In peripheral blood they can be detected in the first three days of illness. A decrease in the number of these cells can be observed with congenital immunodeficiencies, autoimmune processes, HIV infection, fungal and bacterial infections, ionizing radiation, aging, and heavy metal poisoning.

T-cytotoxic lymphocytes with the CD8+CD38+ phenotype The presence of CD38+ on CTL lymphocytes was noted in patients with various diseases. An informative indicator for HIV infection and burn disease. An increase in the number of CTLs with the CD8+CD38+ phenotype is observed in chronic inflammatory processes, cancer and some endocrine diseases. During therapy, the indicator decreases.

Subpopulation of natural killer cells with the CD3- CD56+ phenotype The CD56 molecule is an adhesion molecule widely present in nervous tissue. In addition to natural killer cells, it is expressed on many types of cells, including T-lymphocytes.

An increase in this indicator indicates an expansion of the activity of a specific clone of killer cells, which have less cytolytic activity than NK cells with the CD3- CD16+ phenotype. The number of this population increases in hematological tumors (NK-cell or T-cell lymphoma, plasma cell myeloma, aplastic large cell lymphoma), chronic diseases, and some viral infections.

A decrease is observed with primary immunodeficiencies, viral infections, systemic chronic diseases, stress, treatment with cytostatics and corticosteroids.

CD95+ receptor– one of the apoptosis receptors. Apoptosis is a complex biological process necessary to remove damaged, old and infected cells from the body. The CD95 receptor is expressed on all cells of the immune system. It plays an important role in controlling the functioning of the immune system, as it is one of the receptors for apoptosis. Its expression on cells determines the cells' readiness for apoptosis.

A decrease in the proportion of CD95+ lymphocytes in the blood of patients indicates a violation of the effectiveness of the last stage of culling defective and infected own cells, which can lead to relapse of the disease, chronicization of the pathological process, the development of autoimmune diseases and an increase in the likelihood of tumor transformation (for example, cervical cancer with papillomatous infection ). Determination of CD95 expression has prognostic significance in myelo- and lymphoproliferative diseases.

An increase in the intensity of apoptosis is observed in viral diseases, septic conditions, and drug use.

Activated lymphocytes CD3+CDHLA-DR+, CD8+CD38+, CD3+CD25+, CD95. The test reflects the functional state of T-lymphocytes and is recommended for monitoring the course of the disease and monitoring immunotherapy for inflammatory diseases of various etiologies.

Morphologically, NK are large granule-containing lymphocytes. Their characteristic azurophilic cytoplasmic granules are analogues of lysosomes of phagocytic cells. However, ECs do not have a phagocytic function. The nonspecific nature of their cytotoxic action distinguishes these cells from antigen-specific killer T cells and from K cells that mediate antibody-dependent cytotoxicity. Among human blood leukocytes, NK make up up to 15% (for more details, see immunocompetent cells).

Humoral factors

Lysozyme

Lysozyme is a thermostable protein of the mucolytic enzyme type. It is found in tissue fluids of animals and humans - in tears, saliva, peritoneal fluid, plasma and serum, in leukocytes, breast milk, etc.

Lysozyme is produced by blood monocytes and tissue macrophages. It causes lysis of many saprophytic bacteria, having a less pronounced lytic effect on a number of pathogenic microorganisms and is not active against viruses.

The mechanism of bacteriolytic action of lysozyme consists of hydrolysis of bonds in the polysaccharide chains of the peptidoglycan layer of the bacterial cell wall. This leads to a change in its permeability, accompanied by diffusion of cellular contents into the environment, and cell death.

The healing of wounds in the area of ​​mucous membranes that have contact with a large number of different microorganisms, including pathogenic ones, is to a certain extent explained by the presence of lysozyme.

Complement system

The complement system is a multicomponent self-assembled system of serum proteins that plays an important role in maintaining homeostasis. It can be activated during the process of self-assembly, i.e. sequential addition to the resulting complex of individual proteins, which are called components, or complement fractions. Nine such factions are known. They are produced by liver cells, mononuclear phagocytes and are contained in the blood serum in an inactive state.

The process of complement activation can be triggered (initiated) by two different pathways, called classic and alternative.

When complement is activated classic The initiating factor is the antigen-antibody complex (immune complex). Moreover, antibodies of only two classes IgG and IgM in the composition of immune complexes can initiate complement activation. When C1 joins the antigen-antibody complex, an enzyme (C1-esterase) is formed, under the action of which an enzymatically active complex (C4b, C2a) is formed, called C3-convertase . This enzyme breaks down S3 into S3 and S3b. When subfraction C3b interacts with C4 and C2, a peptidase is formed that acts on C5. If the initiating immune complex is associated with the cell membrane, then the self-assembled complex C1, C4, C2, C3 ensures the fixation of the activated fraction C5, and then C6 and C7, on it. The last three components jointly contribute to the fixation of C8 and C9. At the same time, two sets of complement fractions - C5a, C6, C7, C8 and C9 - make up the membrane-wound attack complex, after its attachment to the cell membrane, the cell is lysed due to irreversible damage to the structure of its membrane

Thus, when activating complement in the classical way, the key components are C1 and C3, the cleavage product of which C3b activates the terminal components of the membrane attack complex (C5-C9).

Peculiarity alternative The pathway of complement activation (the key component is S3) is that initiation can occur without the participation of the antigen-antibody complex due to polysaccharides and lipopolysaccharides of bacterial origin - lipopolysaccharide (LPS) of the cell wall of gram-negative bacteria, surface structures of viruses, immune complexes including IgA and IgE.

The alternative pathway of complement activation requires the participation of a serum protein called properdin, which is active only in the presence of Mg 2+ ions.

As can be seen from the described reaction cascades, many complement components, when activated, exhibit the activity of proteinases or esterases that work only within the system. In this case, during the activation of complement, proteolysis products of components C4, C2, C3 and C5 appear. Some of them (fragments C4b, C2b, C3b, C5b) are directly involved in the self-assembly and activation of the complement system itself. In contrast, low molecular weight fragments C3 and C5a, called anaphylatoxins, in terms of the totality of biological effects - the release of histamine from mast cells, chemotaxis of phagocytes, impaired vascular permeability, contraction of smooth muscles, etc. - play a significant role in the pathogenesis of diseases of immune complexes and other diseases in which the binding and activation of complement in the body sharply increases.

Complement fractions, when activated by the classical or alternative pathway, perform a number of effector functions:

- membrane attack complex mediates the cytolytic and cytotoxic effects of specific antibodies on target cells;

- anaphylotoxins participate in immunopathological reactions;

- complement components change the physicochemical properties of immune complexes; reduce the degree of aggregation and the efficiency of their phagocytosis;

- fragment SZb promotes the binding and capture of immune complexes by phagocytes, opsonizing objects of phagocytosis;

- fragments СЗb, С5а, which have the properties of chemoattractants, are involved in the development of inflammation.

Acute phase proteins

During the development of protective inflammatory reactions after infection or injury, as well as during oncogenesis and pregnancy, increased production of acute phase proteins begins in the body. This is the name given to a large group of proteins that have an antimicrobial effect, promote phagocytosis, complement activation, and the formation and elimination of an inflammatory focus. Acute phase proteins are produced in the liver under the influence of cytokines, mainly IL-1, TNF-a and IL-6. The bulk of the acute phase proteins are C-reactive protein and serum amyloids A and P. Other groups of acute phase proteins include blood coagulation factors, metal-binding proteins, protease inhibitors, complement components and some others. During inflammation, the content of most proteins in the blood increases many times, and the determination of C-reactive protein is one of the generally accepted methods for diagnosing inflammatory processes.

C-reactive protein gets its name due to its ability to attach and precipitate C-polysaccharide. It was further found that C-reactive protein (CRP) binds to phosphatidylcholine, a component of the cell membrane of any cell. It is able to attach to microorganisms, activated lymphocytes, damaged cells of various tissues, thereby activating complement. By joining neutrophil phagocytes, CRP enhances phagocytosis and elimination of objects of phagocytosis. At the same time, SRP suppresses the production of superoxide and the release of enzymes from phagocyte granules, thereby protecting tissues from damage.

Serum amyloid P is similar in structure to CRP and has the ability to activate complement.

Serum amyloid A is a lipoprotein that has the ability to chemattract neutrophils, monocytes and lymphocytes. Increased levels of this protein in the blood are observed in tuberculosis and rheumatoid arthritis.

Blood clotting factors include fibrinogen and von Willebrand factor, which promote the formation of clots in the vessels of the inflammatory zone.

Another group of acute phase proteins consists of proteins that bind iron - haptoglobin, hemopexin, transferrin - and thereby prevent the proliferation of microorganisms that require this element.

The level of protease inhibitors in the blood increases 2-3 times during inflammation. Antitrypsin, antichymotrypsin and macroglobulin prevent tissue destruction by neutrophil proteases in areas of inflammation.

Cytokines

Mediators of intercellular interactions, called cytokines, determine both the reactions of innate and acquired immunity, as well as a number of other vital functions of the body, the significance of which goes beyond the scope of immunology.

Cytokines are hormone-like mediators, produced by different cells of the body and capable of affecting the functions of other or the same groups of cells. Cytokines are peptides or glycoproteins that act as autocrine, paracrine or intersystem signals. Cytokines are formed both by activated or damaged cells and by cells without additional stimulation. Regulators of cytokine production can be other cytokines, hormones, prostaglandins, antigens and many other agents that affect the cell. Some patterns of cytokine regulation can be formulated as follows:

· Each cell produces different cytokines.

· Each cytokine can be the product of different types of cells.

· One cytokine has different effects.

· A cytokine can stimulate or inhibit the activity of a target cell.

· Each cell has receptors for different cytokines and, therefore, can be exposed to several cytokines simultaneously or at different times.

· The interaction of several cytokines per cell can be synergistic or antagonistic.

· Cytokine receptors can detach from the cell and interact with cytokines outside the cell. Under these conditions, free receptors bind the corresponding cytokines, which prevents their contact with cellular receptors.

· Cytokines, their receptors on cells and in extracellular environments constitute a complex functional network, the result of which depends on the interaction of these factors with each other and other cytokines.

· Cytokines act in low concentrations of the order of 0.001 μg/ml. To influence a cell, it is enough for the cytokine to bind to 10% of its cellular receptors.

Cytokines constitute a broad class of mediators of various origins with different properties. Their classification is conditional, since many of them have several properties at the same time and can be classified into different groups. Cytokines are grouped depending on their origin (lymphokines, monokines) and the nature of the effect (proinflammatory, anti-inflammatory). Cytokines that regulate the interactions of leukocytes between themselves and other cells are called interleukins (IL). Most cytokines are named after the action that was first discovered.

Interleukins group includes 17 cytokines, most of which play a key role in the development of a specific immune response.

IL-1 produced by macrophages and monocytes causes the proliferation of lymphocytes when inducing an immune response, and also activates T-lymphocytes and increases the production of antibodies. IL-1 acts on neutrophils, promoting chemotaxis, activation of metabolism, and the release of lysozyme and lactoferrin from cells. This cytokine is an endogenous pyrogen that causes fever by affecting the hypothalamic thermoregulation center.

IL-2 is produced by T lymphocytes (mainly Th1), activated by antigen, self-IL-2, other interleukins: IL-1, IL-6, interferon, tumor necrosis factor (TNF). Without IL-2, a positive immune response to an antigen does not occur; the lymphocyte stimulated by the antigen dies, which can lead to the development of tolerance to this antigen. Interleukins IL-4 and IL-10 suppress the production of IL-2. This promotes the development of effectors of delayed-type hypersensitivity (DTH), the formation of killer cells from CD8 + lymphocytes, and enhanced NK action. All this stimulates antitumor immunity and allows us to recommend recombinant IL-2 for the treatment of cancer patients.

Growth factors- a large group of glycoproteins that control the proliferation and maturation of hematopoietic stem cell descendants. They are produced by different types of cells and act at different stages of their development.

Colony-stimulating factors (CSF) received their name due to the fact that their property was discovered to promote the differentiation of bone marrow cells introduced into mice into mature granulocytes and/or monocytes with the formation of colonies of corresponding cells in the spleen of animals. Granulocyte CSF ensures the differentiation of granulocyte precursors into mature neutrophils. Monocyte CSF promotes the maturation of monocytes and macrophages from progenitor cells, and granulocyte-monocyte CSF stimulates the formation of granulocytes and macrophages from their common precursors.

Interferons (IF) were discovered as antiviral agents. Then their immunoregulatory properties were discovered. There are three types of IF

IFs are not detected in the blood of healthy people. Their level is increased in lupus erythematosus, rheumatoid arthritis, and scleroderma. The presence of interferon in the blood of these patients increases resistance to viral infections and tumors, but adversely affects the development of autoimmune processes characteristic of these diseases.

Interferon preparations are used to treat leukemia and some other oncological processes. To enhance antiviral protection, agents are used that increase the production of their own interferon (interferonogens). Antiviral vaccines, RNA and DNA preparations are used as inducers of endogenous interferon.

Cytotoxins. This is the name given to the group of cytokines tumor necrosis factors (TNF), which was first discovered as a component of the blood serum of animals stimulated with a bacterial toxin, causing necrotic processes in tumor tissue. TNF serves as a mediator of the body's response to microbial invasion. Endotoxins (lipipolysaccharides) of microbes stimulate producer cells to form TNF, which, in turn, ensures chemotaxis of phagocytes into the infected tissue and enhances phagocytosis of pathogens. It is now known that TNF constitutes at least two groups (alpha and beta) of mediators produced by activated macrophages, natural killer cells, as well as lymphocytes, neutrophils and mast cells.

Concluding the discussion of cytokines and their effects, it is necessary to emphasize that Two groups of oppositely acting cytokines are involved in the mechanisms of immunity. One group- proinflammatory cytokines (IL-1, IL-6, IL-8 and other lymphokines, TNF-a, as well as IF), stimulating various cells and mechanisms, enhance innate nonspecific defense, inflammation, and promote the development of specific immune reactions. Second functional group- anti-inflammatory cytokines (IL-4, IL-10, IL-13, TRF) suppresses the development of both nonspecific and specific immune reactions.

Adhesins. Among the factors that determine direct contacts of body cells with each other and with representatives of microflora, adhesion molecules or adhesins play a significant role. It is assumed that in the evolution of living things, the appearance of adhesion molecules made possible the emergence of multicellular organisms. More than 90% of the microbes that make up the normal microflora of the human body live in it thanks to adhesion molecules. Blocking the adhesion of pathogenic microorganisms to cells and tissues of the body is one of the main ways of antimicrobial protection. Adhesion molecules are expressed on cell membranes, determining their ability to contact other cells and non-cellular substrates. Receptors for adhesion molecules in the body can be other adhesion molecules on the surface of cells, carbohydrate components of membranes, and immunoglobulins. The number of adhesion molecules and receptors for them increases with antigenic or any other activation of cells.

During the immune response, adhesion molecules determine the contacts of antigen-presenting cells with lymphocytes and lymphocytes with each other. Adhesion molecules are part of the receptors of immunocompetent cells and determine the tropism of immune system cells to certain tissues or organs - homing effect. Note- house).

Adhesion molecules are conventionally divided into groups: selectins, integrins, immunoglobulin superfamily molecules.

Selectins- a family of surface adhesion molecules that determine the attachment of cells to the carbohydrate components of other structures.

Integrins- a large group of molecules that determine protein-protein interactions. Integrins play a role in intercellular contacts during inflammation, immune reactions, autoimmune tissue damage, and repair processes. Integrins are expressed on tumor cells and play a role in metastasis processes. Their determination is used to diagnose different types of malignant tumors.

To molecules of the immunoglobulin superfamily There are more than 15 variants of molecules, which are designated by capital Latin letters corresponding to the designation of their function: cell-cell adhesion or protein-protein .

The adhesion molecules of the immunoglobulin superfamily include CD4 +, CD8 + molecules of T-lymphocytes, which determine their contacts with MHC class II or I structures and the differentiation of these two classes of T-cells among themselves.

Adhesins do not formally belong to the cytokine system, but they have many functions similar to them and are involved in intercellular cooperation.

Heat shock proteins

When microbial and eukaryotic cells are exposed to unfavorable stress factors - elevated temperature, starvation, toxins, heavy metals, viruses, protective proteins are formed in them. They are called proteins heat shock, since they were first discovered when cells are exposed to heat. As a result, the thermal stability and resistance of cells increases due to the protection and correction of cellular proteins damaged by stress

In addition to maintaining cell resistance to shock, HSPs take part in the endocytosis of viral particles, the processing of antigens, and are part of some receptor complexes (steroid receptors).