The immune system. Inducible body defense factors (immune system)

Histocompatibility antigens are glycoproteins that exist on the surface of all cells. Initially identified as the major target antigens in transplant reactions. Transplantation of tissue from an adult donor to an individual of the same species (allotransplantation) or a different species (xenotransplantation) usually leads to its rejection. Experiments on skin transplantation between different strains of mice showed that transplant rejection is caused by an immune reaction to foreign antigens located on the surface of its cells. It was later shown that T cells are involved in these reactions. The reactions are directed against genetically “foreign” variants of cell surface glycoproteins, called histocompatibility molecules (i.e. tissue compatibility).

Major histocompatibility molecules are a family of glycoproteins encoded by genes that make up major histocompatibility complex (MNS - major histocompatibility complex). Within the MHC, genes are localized that control the main transplantation antigens and genes that determine the intensity of the immune response to a particular antigen - the so-called Ir genes (immune response). MHC molecules are present on the surface of the cells of all higher vertebrates. They were first found in mice and called H2 antigens ( histocompatibility-2). In humans they are called HLA(leukocyte, human leucocyte-associated), since they were originally discovered on leukocytes.

There are two main classes of MHC molecules, each of which is a collection of cell surface glycoproteins. Molecules MHC class I expressed on almost all cells, molecules class II- on cells involved in immune responses (lymphocytes, macrophages). Class I molecules are recognized by cytotoxic T cells (killer cells), which must interact with any cell in the body that is infected by the virus, while class II molecules are recognized by helper T cells (Tx), which interact mainly with other cells involved in immune responses, such as B lymphocytes and macrophages (antigen-presenting cells).

According to clonal selection theory of immunity, in the body there are numerous groups (clones) of lymphocytes that are genetically programmed to respond to one or more antigens. Therefore, each specific antigen has a selective effect, stimulating only those lymphocytes that have an affinity for its surface determinants.

At the first meeting with the antigen (the so-called primary response) lymphocytes are stimulated and undergo transformation into blast forms, which are capable of proliferation and differentiation into immunocytes. As a result of proliferation, the number of lymphocytes of the corresponding clone that “recognize” the antigen increases. Differentiation leads to the appearance of two types of cells - effector and cells memory. Effector cells are directly involved in the elimination or neutralization of foreign material. Effector cells include activated lymphocytes and plasma cells. Memory cells are lymphocytes that return to an inactive state, but carry information (memory) about an encounter with a specific antigen. When this antigen is reintroduced, they are able to provide a rapid immune response of greater intensity (the so-called secondary response) due to increased proliferation of lymphocytes and the formation of immunocytes.

Depending on the mechanism of antigen destruction, a distinction is made between cellular immunity and humoral immunity.

At cellular immunity effector cells are cytotoxic T lymphocytes, or killer lymphocytes. They are directly involved in the destruction of foreign cells of other organs or pathological own (for example, tumor) cells, and secrete lytic substances. This reaction underlies the rejection of foreign tissues during transplantation or when the skin is exposed to chemical (sensitizing) substances that cause increased sensitivity (the so-called delayed-type hypersensitivity) and other reactions.

At humoral immunity effector cells are plasma cells that synthesize and release antibodies into the blood.

Some terms from practical medicine:

· agammaglobulinemia(agammaglobulinaemia; a- + gammaglobulins + Greek. haima blood; synonym: hypogammaglobulinemia, antibody deficiency syndrome) is the general name for a group of diseases characterized by the absence or sharp decrease in the level of immunoglobulins in the blood serum;

· autoantigens(auto-+ antigens) - the body’s own normal antigens, as well as antigens that arise under the influence of various biological and physicochemical factors, in relation to which autoantibodies are formed;

· autoimmune reaction-- the body's immune response to autoantigens;

· allergy (allergy; Greek allos other, different + ergon action) - a state of altered reactivity of the body in the form of increased sensitivity to repeated exposure to any substances or to components of its own tissues; Allergy is based on an immune response that causes tissue damage;

· active immunity immunity resulting from the body's immune response to the introduction of an antigen;

· The main cells that carry out immune reactions are T- and B-lymphocytes (and their derivatives - plasmacytes), macrophages, as well as a number of cells interacting with them (mast cells, eosinophils, etc.).

Lymphocytes

· The population of lymphocytes is functionally heterogeneous. There are three main types of lymphocytes: T lymphocytes, B lymphocytes and the so-called zero lymphocytes (0-cells). Lymphocytes develop from undifferentiated lymphoid bone marrow precursors and, upon differentiation, receive functional and morphological characteristics (presence of markers, surface receptors), identified by immunological methods. 0-lymphocytes (null) are devoid of surface markers and are considered as a reserve population of undifferentiated lymphocytes.

· T lymphocytes- the most numerous population of lymphocytes, making up 70-90% of blood lymphocytes. They differentiate in the thymus gland - the thymus (hence their name), enter the blood and lymph and populate T-zones in the peripheral organs of the immune system - lymph nodes (deep part of the cortex), spleen (periarterial sheaths of lymphoid nodules), in single and multiple follicles of various organs, in which, under the influence of antigens, T-immunocytes (effector) and memory T-cells are formed. T-lymphocytes are characterized by the presence of special receptors on the plasmalemma that are capable of specifically recognizing and binding antigens. These receptors are products of immune response genes. T lymphocytes provide cellular immunity, participate in the regulation of humoral immunity, produce cytokines under the influence of antigens.

· In the population of T-lymphocytes, several functional groups of cells are distinguished: cytotoxic lymphocytes (TC), or Killer T cells(Tk), T helper cells(Tx), T-suppressors(Tch). Tcs participate in cellular immunity reactions, ensuring the destruction (lysis) of foreign cells and their own altered cells (for example, tumor cells). Receptors allow them to recognize proteins of viruses and tumor cells on their surface. In this case, the activation of TC (killers) occurs under the influence histocompatibility antigens on the surface of foreign cells.

· In addition, T lymphocytes are involved in the regulation of humoral immunity with the help of Tx and Tc. Tx stimulate the differentiation of B lymphocytes, the formation of plasma cells from them and the production of immunoglobulins (Ig). Tx have surface receptors that bind to proteins on the plasmalemma of B cells and macrophages, stimulating Tx and macrophages to proliferate, produce interleukins (peptide hormones), and B cells to produce antibodies.

· Thus, the main function of Tx is the recognition of foreign antigens (presented by macrophages), the secretion of interleukins, which stimulate B lymphocytes and other cells to participate in immune reactions.

· A decrease in the number of Tx in the blood leads to a weakening of the body’s defense reactions (these individuals are more susceptible to infections). A sharp decrease in the number of Tx in individuals infected with the AIDS virus was noted.

· Ts are capable of inhibiting the activity of Tx, B-lymphocytes and plasma cells. They are involved in allergic reactions and hypersensitivity reactions. Tc suppress the differentiation of B lymphocytes.

· One of the main functions of T-lymphocytes is the production cytokines, which have a stimulating or inhibitory effect on cells involved in the immune response (chemotactic factors, macrophage inhibitory factor - MIF, nonspecific cytotoxic substances, etc.).

· Natural killers. Among the lymphocytes in the blood, in addition to the above-described TCs that perform the function of killers, there are so-called natural killers (NK, N.K.), which are also involved in cellular immunity. They form the first line of defense against foreign cells and act immediately, quickly destroying cells. NKs in their own body destroy tumor cells and cells infected with a virus. TCs form a second line of defense, since their development from inactive T lymphocytes takes time, so they come into action later than NKs. NK are large lymphocytes with a diameter of 12-15 microns, have a lobulated nucleus and azurophilic granules (lysosomes) in the cytoplasm.

· Development of T- and B-lymphocytes

· The ancestor of all cells of the immune system is the hematopoietic stem cell (HSC). HSCs are localized in the embryonic period in the yolk sac, liver, and spleen. In the later period of embryogenesis, they appear in the bone marrow and continue to proliferate in postnatal life. From the BMSC, a lymphopoiesis progenitor cell (lymphoid multipotent progenitor cell) is formed in the bone marrow, which generates two types of cells: pre-T cells (precursor T cells) and pre-B cells (precursor B cells).

Differentiation of T lymphocytes

· Pre-T cells migrate from the bone marrow through the blood to the central organ of the immune system - the thymus gland. Even during embryonic development, a microenvironment is created in the thymus gland that is important for the differentiation of T lymphocytes. In the formation of the microenvironment, a special role is given to the reticuloepithelial cells of this gland, capable of producing a number of biologically active substances. Pre-T cells migrating into the thymus acquire the ability to respond to microenvironmental stimuli. Pre-T cells in the thymus proliferate and transform into T lymphocytes carrying characteristic membrane antigens (CD4+, CD8+). T-lymphocytes generate and “deliver” into the blood circulation and thymus-dependent zones of peripheral lymphoid organs 3 types of lymphocytes: Tc, Tx and Tc. “Virgin” T-lymphocytes migrating from the thymus gland (virgin T-lymphocytes) are short-lived. Specific interaction with the antigen in peripheral lymphoid organs serves as the beginning of the processes of their proliferation and differentiation into mature and long-lived cells (T-effector and memory T-cells), which make up the majority of recirculating T-lymphocytes.

· Not all cells migrate from the thymus gland. Some T-lymphocytes die. There is an opinion that the cause of their death is the attachment of an antigen to an antigen-specific receptor. There are no foreign antigens in the thymus gland, so this mechanism can serve to remove T-lymphocytes that can react with the body’s own structures, i.e. perform the function of protection against autoimmune reactions. The death of some lymphocytes is genetically programmed (apoptosis).

· T cell differentiation antigens. During the process of differentiation of lymphocytes, specific membrane molecules of glycoproteins appear on their surface. Such molecules (antigens) can be detected using specific monoclonal antibodies. Monoclonal antibodies have been obtained that react with only one cell membrane antigen. Using a set of monoclonal antibodies, subpopulations of lymphocytes can be identified. There are sets of antibodies to human lymphocyte differentiation antigens. Antibodies form relatively few groups (or “clusters”), each of which recognizes a single cell surface protein. A nomenclature of differentiation antigens of human leukocytes detected by monoclonal antibodies has been created. This CD nomenclature ( CD - cluster of differentiation- differentiation cluster) is based on groups of monoclonal antibodies that react with the same differentiation antigens.

· Multiclonal antibodies to a number of differentiation antigens of human T-lymphocytes have been obtained. When determining the total population of T cells, monoclonal antibodies of CD specificities (CD2, CD3, CDS, CD6, CD7) can be used.

· Differentiation antigens of T cells are known, which are characteristic either of certain stages of ontogenesis, or of subpopulations differing in functional activity. Thus, CD1 is a marker of the early phase of T-cell maturation in the thymus. During the process of thymocyte differentiation, CD4 and CD8 markers are simultaneously expressed on their surface. However, subsequently the CD4 marker disappears from some cells and remains only on a subpopulation that has ceased to express the CD8 antigen. Mature CD4+ cells are Tx. CD8 antigen is expressed on approximately ⅓ of peripheral T cells that mature from CD4+/CD8+ T lymphocytes. The CD8+ T cell subset includes cytotoxic and suppressor T lymphocytes. Antibodies to the CD4 and CD8 glycoproteins are widely used to distinguish and separate T cells into Tx and Tx, respectively.

· In addition to differentiation antigens, specific markers of T-lymphocytes are known.

· T-cell antigen receptors are antibody-like heterodimers consisting of polypeptide α- and β-chains. Each chain is 280 amino acids long, and the large extracellular portion of each chain is folded into two Ig-like domains: one variable (V) and one constant (C). The antibody-like heterodimer is encoded by genes that assemble from multiple gene segments during T cell development in the thymus.

· There are antigen-independent and antigen-dependent differentiation and specialization of B- and T-lymphocytes.

· Antigen-independent proliferation and differentiation are genetically programmed to produce cells capable of giving a specific type of immune response when encountering a specific antigen due to the appearance of special “receptors” on the plasmalemma of lymphocytes. It occurs in the central organs of the immune system (thymus, bone marrow or bursa of Fabricius in birds) under the influence of specific factors produced by cells that form the microenvironment (reticular stroma or reticuloepithelial cells in the thymus).

· Antigen dependent proliferation and differentiation of T- and B-lymphocytes occur when they encounter antigens in peripheral lymphoid organs, and effector cells and memory cells (retaining information about the active antigen) are formed.

The resulting T-lymphocytes form a pool long-lived, recirculating lymphocytes, and B lymphocytes - short-lived cells.

66. Characteristics of B-lymphocytes.

B lymphocytes are the main cells involved in humoral immunity. In humans, they are formed from red bone marrow HSCs, then enter the blood and further populate the B-zones of peripheral lymphoid organs - the spleen, lymph nodes, and lymphoid follicles of many internal organs. Their blood contains 10-30% of the entire population of lymphocytes.

B lymphocytes are characterized by the presence of surface immunoglobulin receptors (SIg or MIg) for antigens on the plasmalemma. Each B cell contains 50,000...150,000 antigen-specific SIg molecules. In the population of B lymphocytes there are cells with different SIgs: the majority (⅔) contain IgM, a smaller number (⅓) - IgG and about 1-5% - IgA, IgD, IgE. The plasmalemma of B lymphocytes also contains complement receptors (C3) and Fc receptors.

When exposed to an antigen, B lymphocytes in peripheral lymphoid organs are activated, proliferate, and differentiate into plasma cells that actively synthesize antibodies of various classes that enter the blood, lymph, and tissue fluid.

B cell differentiation

Precursors of B cells (pre-B cells) further develop in birds in the bursa of Fabricius (bursa), where the name B lymphocytes comes from, and in humans and mammals - in the bone marrow.

The bursa of Fabricius (bursa Fabricii) is the central organ of immunopoiesis in birds, where the development of B lymphocytes occurs, located in the cloaca. Its microscopic structure is characterized by the presence of numerous folds covered with epithelium, in which lymphoid nodules are located, bounded by a membrane. The nodules contain epithelial cells and lymphocytes at various stages of differentiation. During embryogenesis, a medullary zone is formed in the center of the follicle, and a cortical zone is formed at the periphery (outside the membrane), into which lymphocytes from the medullary zone probably migrate. Due to the fact that only B-lymphocytes are formed in the bursa of Fabricius in birds, it is a convenient object for studying the structure and immunological characteristics of this type of lymphocyte. The ultramicroscopic structure of B lymphocytes is characterized by the presence of groups of ribosomes in the form of rosettes in the cytoplasm. These cells have larger nuclei and less dense chromatin than T lymphocytes due to increased euchromatin content.

B lymphocytes differ from other cell types in their ability to synthesize immunoglobulins. Mature B lymphocytes express Ig on the cell membrane. Such membrane immunoglobulins (MIg) function as antigen-specific receptors.

Pre-B cells synthesize intracellular cytoplasmic IgM but do not have surface immunoglobulin receptors. Bone marrow virgin B lymphocytes have IgM receptors on their surface. Mature B lymphocytes carry immunoglobulin receptors of various classes on their surface - IgM, IgG, etc.

Differentiated B-lymphocytes enter the peripheral lymphoid organs, where, under the influence of antigens, proliferation and further specialization of B-lymphocytes occur with the formation of plasmacytes and memory B-cells (MB).

During their development, many B cells switch from producing antibodies of one class to producing antibodies of other classes. This process is called class switching. All B cells begin their antibody synthesis activities by producing IgM molecules, which are embedded in the plasma membrane and serve as receptors for the antigen. Then, even before interacting with the antigen, most B cells proceed to the simultaneous synthesis of IgM and IgD molecules. When a virgin B cell switches from producing membrane-bound IgM alone to simultaneously producing membrane-bound IgM and IgD, the switch probably occurs due to a change in RNA processing.

When stimulated by antigen, some of these cells become activated and begin to secrete IgM antibodies, which predominate in the primary humoral response.

Other antigen-stimulated cells switch to producing IgG, IgE, or IgA antibodies; Memory B cells carry these antibodies on their surface, and active B cells secrete them. IgG, IgE, and IgA molecules are collectively called secondary class antibodies because they appear to be formed only after antigenic stimulation and predominate in secondary humoral responses.

With the help of monoclonal antibodies, it was possible to identify certain differentiation antigens, which, even before the appearance of cytoplasmic µ-chains, make it possible to classify the lymphocyte carrying them as a B-cell line. Thus, the CD19 antigen is the earliest marker that allows a lymphocyte to be classified as a B-cell. It is present on pre-B cells in the bone marrow and on all peripheral B cells.

The antigen detected by monoclonal antibodies of the CD20 group is specific for B lymphocytes and characterizes later stages of differentiation.

On histological sections, the CD20 antigen is detected on B cells of the germinal centers of lymphoid nodules and in the cortex of the lymph nodes. B lymphocytes also carry a number of other (eg, CD24, CD37) markers.

67. Macrophages play an important role in both natural and acquired immunity of the body. The participation of macrophages in natural immunity is manifested in their ability to phagocytose and in the synthesis of a number of active substances - digestive enzymes, components of the complement system, phagocytin, lysozyme, interferon, endogenous pyrogen, etc., which are the main factors of natural immunity. Their role in acquired immunity is the passive transfer of antigen to immunocompetent cells (T and B lymphocytes) and the induction of a specific response to antigens. Macrophages are also involved in ensuring immune homeostasis by controlling the proliferation of cells characterized by a number of abnormalities (tumor cells).

For the optimal development of immune reactions under the influence of most antigens, the participation of macrophages is necessary both in the first inductive phase of immunity, when they stimulate lymphocytes, and in its final phase (productive), when they participate in the production of antibodies and the destruction of antigen. Antigens phagocytosed by macrophages induce a stronger immune response compared to those that are not phagocytosed by them. Blockade of macrophages by introducing a suspension of inert particles (for example, carcass) into the animal's body significantly weakens the immune response. Macrophages are able to phagocytose both soluble (for example, proteins) and corpuscular antigens. Corpuscular antigens cause a stronger immune response.

Some types of antigens, for example pneumococci, containing a carbohydrate component on the surface, can be phagocytosed only after preliminary opsonization. Phagocytosis is greatly facilitated if the antigenic determinants of foreign cells are opsonized, i.e. connected to an antibody or a complex of antibody and complement. The opsonization process is ensured by the presence of receptors on the macrophage membrane that bind part of the antibody molecule (Fc fragment) or part of complement (C3). Only IgG class antibodies can directly bind to the macrophage membrane in humans when they are in combination with the corresponding antigen. IgM can bind to the macrophage membrane in the presence of complement. Macrophages are able to “recognize” soluble antigens, such as hemoglobin.

There are two stages in the antigen recognition mechanism that are closely related to each other. The first stage involves phagocytosis and digestion of the antigen. In the second stage, polypeptides, soluble antigens (serum albumins) and corpuscular bacterial antigens accumulate in the phagolysosomes of the macrophage. Several introduced antigens can be found in the same phagolysosomes. The study of the immunogenicity of various subcellular fractions revealed that the most active antibody formation is caused by the introduction of lysosomes into the body. The antigen is also found in cell membranes. Most of the processed antigen material released by macrophages has a stimulating effect on the proliferation and differentiation of T- and B-lymphocyte clones. A small amount of antigenic material can persist for a long time in macrophages in the form of chemical compounds consisting of at least 5 peptides (possibly in connection with RNA).

In the B-zones of the lymph nodes and spleen there are specialized macrophages (dendritic cells), on the surface of their numerous processes many antigens are stored that enter the body and are transmitted to the corresponding clones of B-lymphocytes. In the T-zones of lymphatic follicles there are interdigitating cells that influence the differentiation of T-lymphocyte clones.

Thus, macrophages take a direct active part in the cooperative interaction of cells (T- and B-lymphocytes) in the body’s immune reactions.

Table of contents of the topic "Factors of nonspecific resistance of the body. Interferon (ifn). Immune system. Cells of the immune system.":

The immune system. Inducible factors of the body's defense (immune system). Major histocompatibility complex (MHC classes 1 and 2). MHC I and MHC II genes.

The immune system- a set of organs, tissues and cells that ensure the structural and genetic constancy of the body’s cells; forms the body's second line of defense. The functions of the first barrier to foreign agents are performed by the skin and mucous membranes, fatty acids (part of the secretion of the sebaceous glands of the skin) and high acidity of gastric juice, normal microflora of the body, as well as cells that perform the functions of nonspecific protection against infectious agents.

The immune system capable of recognizing millions of different substances, identifying subtle differences even between molecules that are similar in structure. Optimal functioning of the system is ensured by subtle mechanisms of interaction between lymphoid cells and macrophages, carried out through direct contacts and with the participation of soluble intermediaries (immune system mediators). The system has immune memory, storing information about previous antigenic exposures. The principles of maintaining the structural constancy of the body (“antigenic purity”) are based on the recognition of “friend or foe.”

For this purpose, on the surface of the body cells there are glycoprotein receptors (Ag), which make up major histocompatibility complex - MNS[from English major histocompatibility complex]. If the structure of these Ags is disrupted, that is, “self” changes, the immune system regards them as “foreign.”

Spectrum of MHC molecules is unique for each organism and determines its biological individuality; this allows us to distinguish “our own” ( histocompatible) from “alien” (incompatible). There are two main classes of genes and Ags MNS.

Major histocompatibility complex (MHC classes 1 and 2). MHC I and MHC II genes.

Molecules of classes I and II control the immune response. They are co-recognized by the surface CD-Ar of target cells and participate in cellular cytotoxicity reactions carried out by cytotoxic T lymphocytes (CTLs).

MHC class I genes determine tissue Ag; Ag class MHC I presented on the surface of all nucleated cells.

MHC class II genes control the response to thymus-dependent Ag; Class II Ags are expressed predominantly on the membranes of immunocompetent cells, including macrophages, monocytes, B lymphocytes and activated T cells.

MNS is formed by a large group of genes located on the short arm of chromosome 6. Based on structural and functional differences, these genes are divided into three classes, two of which, class I and class II, are HLA genes originally discovered due to their importance in tissue transplantation between unrelated individuals individuals.

Genes classes I and II encode cell surface proteins that play a decisive role in initiating an immune response, especially in the “recognition” of an antigen by lymphocytes, which cannot respond to the antigen unless it forms a complex with an HLA molecule on the surface of the cell containing the antigen. Many hundreds of different HLA class I and I alleles are known, and new alleles are being discovered every day, making them the most polymorphic loci in the human genome.

Class I genes(HLA-A, HLA-B and HLA-C) encode proteins that are an integral part of the plasma membrane of all nuclear cells. Class I proteins consist of two polypeptide subunits: a variable heavy chain, encoded within the MHC, and a non-polymorphic polypeptide, b2-microglobulin, encoded by a gene located outside the MHC and mapped to chromosome 15. Peptides derived from intracellular proteins are formed by proteolytic cleavage of large multifunctional proteases; the peptides then move to the cell surface and attach to class I molecules, forming a peptide antigen for cytotoxic T cells.

Region class II consists of several loci, such as HLA-DP, HLA-DQ and HLA-DR, encoding cell surface proteins. Each class II molecule is a heterodimer formed from the a and b subunits encoded in the MHC. Class II molecules are peptides derived from extracellular proteins that are taken up by lysosomes and processed into peptides recognized by T cells.

Within MNS loci of other genes are also present, but they are not functionally related to the HLA class I and II genes and do not determine histocompatibility or immune responses. Some of these genes are, however, associated with diseases, such as congenital adrenal hyperplasia, caused by 21-hydroxylase deficiency, and hemochromatosis, a liver disease caused by iron accumulation.

Major histocompatibility complex (HLA) alleles and haplotypes

System HLA may seem confusing at first, as the nomenclature used to define and describe different HLA alleles has undergone fundamental changes as MHC DNA sequencing has become widespread. According to the older, traditional system of HLA nomenclature, different alleles were distinguished from each other serologically. Individual HLA types were determined by how a panel of different antisera or sensitive lymphocytes reacted to the cells.

Antisera and the cells were obtained from hundreds of pregnant women who had developed an immune response against type I and type II paternal antigens expressed by the fetuses during pregnancy. If cells from two unrelated individuals produced the same response when added to a panel of antibodies and cells, they were considered to have the same HLA types and alleles, indicated by their number, for example B27 at the HLA-B class I locus or DR3 at the HLA-B locus DR Class II.

However, after identification and sequencing of the genes responsible for encoding the MHC class I and class II chains, individual initially serologically defined HLA alleles, even within a single serological allele, turned out to consist of numerous alleles defined by different DNA sequence variants. The 100 serologically defined types HLA-A, B, C, DR, DQ and DP now include more than 1300 alleles defined at the DNA sequence level.

For example, in HLA-B gene, previously identified by serological reaction as a single B27 allele, more than 24 different nucleic acid sequence variants were discovered. Most, although not all, DNA variants represent a change in the triplet codon and therefore the amino acid in the peptide encoded by that allele. Each allele that changes an amino acid in the HLA-B peptide receives its own additional sequence number, for example allele 1, 2, and so on in the group of alleles corresponding to the previously single allele B27, and is now called HLA-B*2701, HLA-B*2702 and etc.

Kit HLA alleles at various class I and II loci on a given chromosome forms a haplotype. The alleles are codominant; each parent has two haplotypes and expresses them both. These loci are located close enough to each other that in a given family the haplotype can be passed on to the child as a single block. As a result, parent and child share a common haplotype, and the chance that two siblings will inherit the same HLA haplotype is 25%.

Because the engraftment of transplanted tissues Generally consistent with the degree of similarity between the HLA haplotypes of the donor and recipient (and ABO blood group), the best bone marrow or organ donor is an ABO-compatible and HLA-identical sibling of the recipient.

In any ethnicity group of some HLA alleles are found often, while others are found rarely or never. Likewise, some haplotypes are more common than expected, while others are extremely rare or not at all. For example, most of the 3x107 theoretically possible combinations of alleles in a haplotype never occur in the white population. This limitation in the diversity of haplotypes in a population is probably caused by a situation called linkage disequilibrium and may be explained by the complex interaction of many factors.

These factors include low rates of meiotic recombination due to the short distance between HLA loci; environmental influences that provide positive selection for specific combinations of HLA alleles that form a haplotype; and historical factors, such as how long ago the population was established, the number of founders, and the intensity of immigration that occurred (see later in this chapter).

Between populations There are also significant differences in allele and haplotype frequencies. What is a common allele or haplotype in one population may be very rare in another. Differences in the distribution and frequency of alleles and haplotypes within the MHC are the result of a complex interaction of genetic, environmental and historical factors in each specific population.

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Structure of class I major histocompatibility complex molecules

In Fig. 9.3, A shows the general diagram of the molecule major histocompatibility complex (MNS) Class I human or mouse. Each MHC class I gene encodes a transmembrane glycoprotein with a molecular weight of about 43 kDa, which is designated as α or heavy chain. It includes three extracellular domains: α1, α2 and α3. Each MHC class I molecule is expressed on the cell surface in non-covalent association with an invariant polypeptide called β2-microglobulin (β2-m molecular weight 12 kDa), which is encoded on another chromosome.

Rice. 9.3. Different images of the MHC class I molecule

It has a structure homologous to the Ig single domain and is indeed a member of this superfamily. Thus, on the cell surface, the structure of MHC class I plus β2m has the form of a four-domain molecule, in which the α3 domain of the MHC class I molecule and β2m are adjacent to the membrane.

The sequences of the different allelic forms of MHC class I molecules are very similar. Amino acid sequence differences among MHC molecules are concentrated in a limited region of their extracellular domains α1 and α2. Thus, an individual MHC class I molecule can be divided into a non-polymorphic, or invariant, region (the same for all allelic forms of class 1) and a polymorphic, or variable, region (a unique sequence for a given allele). CD8 T cell molecules bind to the invariant regions of all major histocompatibility complex class I molecules.

All MHC class I molecules subjected to X-ray crystallography have the same general structure, shown in Fig. 9.3, B and C. The most interesting feature of the structure of the molecule is that the part of the molecule furthest from the membrane, consisting of domains α1 and α2, has a deep groove or cavity. This cavity in the MHC class I molecule is the binding site for peptides. The cavity resembles a basket with an uneven bottom (woven from amino acid residues in the form of a flat β-sheet structure), and the surrounding walls are represented by α-helices. The cavity is closed at both ends, so it can accommodate a chain of eight or nine amino acid sequences.

By comparing the sequences and structure of the cavity in different molecules of the major histocompatibility complex class I, one can find that the bottom of each of them is different and consists of several pockets specific for each allele (Fig. 9.3, D). The shape and charge of these pockets at the bottom of the cavity help determine which peptides bind to each allelic form of the MHC molecule. The pockets also help anchor peptides in a position where they can be recognized by specific TCRs. In Fig. 9.3, D and 8.2 show the interaction of the peptide located in the cavity and sections of the MHC class I molecule with the T-cell receptor.

Center of bound peptide- the only part of the protein not hidden inside the major histocompatibility complex molecule - interacts with CDR3-TCR α and β, which are the most variable in the T-cell receptor. This means that peptide recognition by the TCR requires contact with a small number of amino acids at the center of the peptide chain.

A single MHC class I molecule can bind to different peptides, but predominantly to those that have certain (specific) motifs (sequences). Such specific sequences are invariantly located 8 - 9 amino acid residues (anchor sequences), which have a high affinity for amino acid residues in the peptide-binding cavity of a given MHC molecule. In this case, amino acid sequences in positions that are not anchors can be represented by any set of amino acid residues.

For example, the human class I molecule HLA-A2 binds to peptides that have leucine in the second position and valine in the ninth position; In contrast, another HLA-A molecule binds only proteins whose anchor sequence includes phenylalanine or tyrosine at position 5 and leucine at position 8. Other positions in the bound peptides can be filled with any amino acids.

Thus, each MHC molecule can bind to a large number of peptides with different amino acid sequences. This helps explain why T cell-mediated responses can develop, with rare exceptions, to at least one epitope of almost all proteins and why cases of a lack of immune response to a protein antigen are very rare.

Structure of class II major histocompatibility complex molecules

The α and β genes of MHC class II encode chains weighing about 35,000 and 28,000 Da, respectively. In Fig. 9.4, A shows that MHC class II molecules, like class I, are transmembrane glycoproteins with cytoplasmic “tails” and extracellular domains similar to Ig; the domains are designated α1, α2, β1, and β2.

MHC class II molecules are also members of the immunoglobulin superfamily. Like MHC class I molecules, the MHC class II molecule includes variable, or polymorphic (different for different alleles), and invariable, or non-polymorphic (common for all alleles) regions. The CD4 T cell molecule attaches to the unchanged portion of all class II major histocompatibility complex molecules.

Rice. 9.4. Different images of the MHC moleculeII class

At the top of the MHC class II molecule there is also a notch or cavity capable of binding to peptides (Fig. 9.4, B and C), which is structurally similar to the cavity of the MHC class I molecule. However, in the class II major histocompatibility complex molecule, the cavity is formed by the interaction of domains of different chains, a and p. In Fig. 9.4, B shows that the bottom of the cavity of the MHC class II molecule consists of eight β-sheets, with domains α1 and β1 forming four of them each; helical fragments of domains α1 and β1 each form one wall of the cavity.

Unlike the cavity of the class I MHC molecule, the cavity of the class II major histocompatibility complex molecule is open on both sides, which allows the binding of larger protein molecules. Thus, the cavity of the MHC class II molecule can bind peptides whose length varies from 12 to 20 amino acids in a linear chain, with the ends of the peptide being outside the cavity. In Fig. 9.4, D shows that the TCR interacts not only with the peptide associated with the MHC class II molecule, but also with fragments of the class II major histocompatibility complex molecule itself.

Peptides that bind to various MHC class II molecules must also have certain motifs (sequences); Since the length of the peptides in this case is more variable than that of peptides that can be attached to an MHC class I molecule, the motifs are often located in the central region of the peptide, i.e. in the place that corresponds to the inner surface of the cavity of the class II major histocompatibility complex molecule.

R. Koiko, D. Sunshine, E. Benjamini

The major histocompatibility complex is a group of genes and the cell surface antigens they encode, which play a critical role in the recognition of foreign substances and the development of the immune response. The human major histocompatibility complex is called HLA. HLA was discovered in 1952 through the study of leukocyte antigens. HLA antigens are glycoproteins located on the surface of cells and encoded by a group of closely linked genes on chromosome 6. HLA antigens play a critical role in regulating the immune response to foreign antigens and are themselves powerful antigens.

HLA antigens are divided into class I antigens and class II antigens. HLA class I antigens are required for recognition of transformed cells by cytotoxic T lymphocytes.

The most important function of HLA class II antigens is to ensure interaction between T lymphocytes and macrophages during the immune response. Helper T cells recognize a foreign antigen only after it has been processed by macrophages, combined with HLA class II antigens and the appearance of this complex on the surface of the macrophage.

The ability of T lymphocytes to recognize foreign antigens only in combination with HLA antigens is called HLA restriction. Determination of HLA class I and II antigens is of great importance in clinical immunology and is used, for example, in the selection of donor-recipient pairs before organ transplantation.

The discovery of MHC occurred during the study of intraspecific tissue transplantation. The genetic loci responsible for the rejection of foreign tissue form a region in the chromosome called the major histocompatibility complex (MHC).

Then, initially in a hypothetical manner, based on cellular phenomenology, and then in an experimentally well-documented form using molecular biology methods, it was established that the T-cell receptor recognizes not the foreign antigen itself, but its complex with molecules controlled by the genes of the major histocompatibility complex. In this case, both the MHC molecule and the antigen fragment come into contact with the TCR.

The MHC encodes two sets of highly polymorphic cellular proteins called MHC class I and class II molecules. Class I molecules are capable of binding peptides of 8-9 amino acid residues, class II molecules are somewhat longer.

The high polymorphism of MHC molecules, as well as the ability of each antigen presenting cell (APC) to express several different MHC molecules, provides the ability to present a wide variety of antigenic peptides to T cells.

It should be noted that although MHC molecules are usually called antigens, they exhibit antigenicity only when they are recognized by the immune system not of their own, but of a genetically different organism, for example, during organ allotransplantation.

The presence of genes in the MHC, most of which encode immunologically significant polypeptides, suggests that this complex evolved and developed specifically for the implementation of immune forms of protection.

There are also MHC class III molecules, but MHC class I molecules and MHC class II molecules are the most important in an immunological sense.

B-cell receptor, or B-cell antigen receptor(English) B-cell antigen receptor, BCR) is a membrane receptor of B cells that specifically recognizes antigen. In fact, the B-cell receptor is a membrane form of antibodies (immunoglobulins) synthesized by a given B-lymphocyte, and has the same substrate specificity as secreted antibodies. This receptor, like antibodies, can exist in several forms depending on which class its heavy chains belong to. The B-cell receptor begins a chain of signal transmission into the cell, which, depending on the conditions, can lead to activation, proliferation, differentiation or apoptosis of B-lymphocytes. Signals coming (or not) from the B-cell receptor and its immature form (pre-B-cell receptor) are critical in the maturation of B cells and in the formation of the body's antibody repertoire.

In addition to the membrane form of the antibody, the B-cell receptor complex includes an auxiliary protein heterodimer Igα/Igβ (CD79a/CD79b), which is strictly necessary for the functioning of the receptor. Signal transmission from the receptor takes place with the participation of molecules such as Lyn, SYK, Btk, PI3K, PLCγ2 and others.

It is known that the B-cell receptor plays a special role in the development and maintenance of malignant B-cell blood diseases. In this regard, the idea of ​​using inhibitors of signal transmission from this receptor to treat these diseases has become widespread. Several of these drugs have proven effective and are currently undergoing clinical trials.