The immune system. Inducible factors of body defense (immune system). Major histocompatibility complex (MHC first and second class). 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 cells of the body; forms the body's second line of defense. The functions of the first barrier on the way of foreign agents are performed by the skin and mucous membranes, fatty acids (which are part of the secretion of the sebaceous glands of the skin) and the high acidity of gastric juice, the normal microflora of the body, as well as cells that perform the functions of nonspecific protection against infectious agents.
The immune system is capable of recognizing millions of different substances, revealing subtle differences even between molecules that are similar in structure. The optimal functioning of the system is provided by subtle mechanisms of interaction between lymphoid cells and macrophages, carried out through direct contacts and with the participation of soluble mediators (mediators of the immune system). 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”.
To do this, there are glycoprotein receptors (Ag) on the surface of the cells of the body, which make up major histocompatibility complex - WPC[from English. major histocompatibility complex]. If the structure of these antigens is violated, that is, a change in “one’s own”, the immune system regards them as “alien”.
Spectrum of MHC molecules is unique for each organism and determines its biological individuality; this allows you to distinguish "one's own" ( histocompatible) from "foreign" (incompatible). Allocate genes and Ag of two main classes WPC.
Major histocompatibility complex (MHC first and second class). MHC I and MHC II genes.
Molecules of I and II classes control the immune response. They are co-recognized by surface differentiation CD-Ar target cells and are involved in cellular cytotoxicity reactions mediated by cytotoxic T-lymphocytes (CTLs).
MHC class I genes determine tissue Ag; Ag class MHC I present on the surface of all nucleated cells.
MHC class II genes control response to thymus-dependent Ag; Class II antigens are predominantly expressed on the membranes of immunocompetent cells, including macrophages, monocytes, B-lymphocytes, and activated T-cells.
On the cytoplasmic membranes of almost all cells of the macroorganism, histocompatibility antigens. Most of them belong to the systemmain comhistocompatibility plex, or WPC(abbr. from English. Main Hystocompatibility Complex).
Histocompatibility antigens play a key role in the implementation of specific recognition of "friend or foe" And induction of an acquired immune response. They determine the compatibility of organs and tissues during transplantation within the same species, genetic restriction (restriction) of the immune response, and other effects.
Great merit in the study of the MNS, as a phenomenon of the biological world, belongs to J. Dosse, P. Doherty, P. Gorer, G. Snell, R. Zinkernagel, R. V. Petrov, who became the founders immunogenetics.
MHC was first discovered in the 1960s. in experiments on genetically pure (inbred) lines of mice in an attempt of interline transplantation of tumor tissues (P. Gorer, G. Snell). In mice, this complex was named H-2 and was mapped to the 17th chromosome.
In humans, MHC was described somewhat later in the works of J. Dosse. He was labeled as HLA (abbr. from English.human Leukocyte Antigen ), since it is associated with leukocytes.
BiosynthesisHLAdetermined by genes, localized at once in several loci of the short arm of the 6th chromosome.
MHC has a complex structure and high polymorphism. Chemically, histocompatibility antigens are glycoproteins, tightly bound to the cytoplasmmatic membrane of cells. Their individual fragments are structural homology with immunoglobulin molecules and therefore belong to the same superfamily.
Distinguish two main classes of MHC molecules.
It is conventionally accepted that MHC class I induces a predominantly cellular immune response.
MHC class II - humoral.
The main classes unite many antigens similar in structure, which are encoded by many allelic genes. At the same time, no more than two varieties of the products of each MHC gene can be expressed on the cells of an individual, which is important for maintaining population heterogeneity and the survival of both an individual and the entire population as a whole.
WPCIclass consists of two non-covalently linked polypeptide chains with different molecular weights: a heavy alpha chain and a light beta chain. The alpha chain has an extracellular region with a domain structure (al-, a2- and a3-domains), transmembrane and cytoplasmic. The beta chain is a beta-2 microglobulin that "sticks" to the a3 domain after the expression of the alpha chain on the cytoplasmic membrane of the cell.
The alpha chain has a high sorption capacity for peptides. This property is determined by al- and a2-domains, which form the so-called "Bjorkman gap" - a hypervariable region responsible for the sorption and presentation of antigen molecules. The "Bjorkman gap" MHC class I contains a nanopeptide, which in this form is easily detected by specific antibodies.
The process of formation of the MHC class I-antigen complex proceeds intracellular continuously.
Its composition includes anyendogenously synthesized peptides, including viruses. The complex is initially assembled in the endoplasmic reticulum, where, with the help of a special protein, proteasome, transport of peptides from the cytoplasm. The peptide included in the complex imparts structural stability to MHC class I. In its absence, the function of the stabilizer is performed by chaperone(calnexin).
MHC class I is characterized by a high rate of biosynthesis - the process is completed in 6 hours.
This complex expressed almost on the surface all cells, except for erythrocytes non-nuclear cells are absenttvuet biosynthesis) and villous trophoblast cells (“prevention” of fetal rejection). The density of MHC class I reaches 7000 molecules per cell, and they cover about 1% of its surface. The expression of molecules is markedly enhanced under the influence of cytokines, such as γ-interferon.
Currently, more than 200 different variants of the HLAI class are distinguished in humans. They are encoded by genes mapped to three main subloci of the 6th chromosome and are inherited and expressed independently: HLA-A, HLA-B, and HLA-C. Locus A unites more than 60 variants, B - 130, and C - about 40.
Typing of an individual for HLA class I is carried out on lymphocytes by serological methods - in the reaction of microlymphocytolysis with specific sera. For diagnosis, polyclonal specific antibodies are used, which are found in the blood serum of multiparous women, patients who received massive blood transfusion therapy, as well as monoclonal ones.
Given the independent inheritance of subloci genes, an infinite number of non-repeating combinations of the HLAI class are formed in the population. Therefore, each person is strictly unique in terms of a set of histocompatibility antigens, with the exception of identical twins, which are absolutely similar in terms of a set of genes.
Basic biologistsacademic role HLAIclass is that they define biological individualness ("biological passport") and are markers of "own" for immunocompetent cells. Infection of a cell with a virus or mutation changes the structureHLAIclass. Containingforeign or modified peptides MHC moleculeIclass has an atypicalstructure of this organism and is a signal for the activation of T-killers (CO8 + -lim-phocytes). Cells that differ inIclassdestroyed as foreign.
MHC 1 -to facilitate recognition of intracellular infection.
In the structure and function of the WHCII class has a number of fundamental differences.
First, they have a more complex structure. The complex is formed by two non-covalently linked polypeptide chains (alpha chain and beta chain) having a similar domain structure. The alpha chain has one globular region and the beta chain has two. Both chains as transmembrane peptides consist of three sections - extracellular, transmembrane and cytoplasmic.
Secondly, the “Bjorkman gap” in MHC class II is formed simultaneously by both chains. It contains a larger oligopeptide (12-25 amino acid residues), and the latter is completely "hidden" inside this gap and in this state is not detected by specific antibodies.
Thirdly, MHC class II includes peptide captured from the extracellular environmentby endocytosis, not synthesized by the cell itself.
Fourth, WPCIIexpress classon the surface of a limited numbercells: dendritic, B-lymphocytes, T-helpers, activated macrophages, mast, epithelial and endothelial cells. The detection of MHC class II on atypical cells is currently regarded as an immunopathology.
The biosynthesis of MHC class II occurs in the endoplasmic reticulum, the resulting dimeric complex is then incorporated into the cytoplasmic membrane. Before the peptide is included in it, the complex is stabilized by a chaperone (calnexin). MHC class II is expressed on the cell membrane within an hour after antigen endocytosis. The expression of the complex can be enhanced by γ-interferon and reduced by prostaglandin E g
According to available data, the human body is characterized by an extremely high class II HLA polymorphism, which is largely determined by the structural features of the beta chain. The complex includes products of three main loci: HLA DR, DQ and DP. At the same time, the DR locus combines about 300 allelic forms, DQ - about 400, and DP - about 500.
The presence and type of class II histocompatibility antigens are determined in serological (microlymphocytotoxic test) and cellular immunity reactions (mixed culture of lymphocytes, or MCL). Serological typing of class II MHC is performed on B-lymphocytes using specific antibodies found in the blood serum of multiparous women, patients who received massive blood transfusion therapy, and also synthesized by genetic engineering. Testing in the SCL reveals minor components of class II MHC that are not serologically detectable. Recently, PCR has been increasingly used.
The biological role of the MHCII class is extremely large. In fact, this complex is involved in induction acquired by himmuddy response. Fragments of an antigen molecule are expressed on the cytoplasmic membrane of a special group of cells, which is called antigen-presenting cells (APCs). This is an even narrower circle among cells capable of synthesizing MHC class II. The most active APC is considered to be the dendritic cell, followed by B-lymphocyte and macrophage.
Histocompatibility antigens are glycoproteins found on the surface of all cells. Initially identified as the main target antigens in graft reactions. Transplantation of tissue from an adult donor of the same species (allotransplantation) or another species (xenotransplantation) usually results in its rejection. Skin grafting experiments between different lines of mice showed that graft rejection is due to an immune response 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).
The major histocompatibility molecules are a family of glycoproteins encoded by the genes that make up major histocompatibility complex (WPC - 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 cell surface of all higher vertebrates. They were first found in mice and named H2 antigens ( histocompatibility-2). In humans, they are called HLA(leukocyte, human leucocyte-associated), since they were originally found on leukocytes.
There are two main classes of MHC molecules, each of which is a set 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 (killers), which must interact with any cell of the body that is infected with a virus, while class II molecules are recognized by T-helpers (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 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 that are capable of proliferation and differentiation into immunocytes. As a result of proliferation, the number of lymphocytes of the corresponding clone, which "recognized" the antigen, increases. Differentiation results in 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 a meeting with a specific antigen. With the repeated introduction of this antigen, 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, cellular immunity and humoral immunity are distinguished.
At cellular immunity effector cells are cytotoxic T-lymphocytes, or killer lymphocytes (killers). They are directly involved in the destruction of foreign cells of other organs or pathological own (for example, tumor) cells, and secrete lytic substances. Such a reaction underlies the rejection of foreign tissues in transplantation conditions or under the action of chemical (sensitizing) substances on the skin that cause hypersensitivity (the so-called delayed-type hypersensitivity) and other reactions.
At humoral immunity effector cells are plasma cells that synthesize and secrete antibodies into the blood.
Some terms from practical medicine:
· agammaglobulinemia(agammaglobulinemia; a- + gamma globulins + gr. haima blood; synonym: hypogammaglobulinemia, antibody deficiency syndrome) - the general name of a group of diseases characterized by the absence or a 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 physico-chemical factors, in relation to which autoantibodies are formed;
· autoimmune reaction- the body's immune response to autoantigens;
· allergy (allergies; Greek allos other, different + Ergon action) - a state of altered reactivity of the body in the form of an increase in its sensitivity to repeated exposure to any substances or to components of its own tissues; Allergy is based on an immune response that occurs with 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 derivatives of the latter - plasma cells), 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 progenitors and, upon differentiation, acquire functional and morphological features (presence of markers, surface receptors) detected 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, constituting 70-90% of blood lymphocytes. They differentiate in the thymus gland - 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 cortical substance), spleen (periarterial sheaths of lymphoid nodules), in single and multiple follicles of various organs, in which T-immunocytes (effector) and T-memory cells are formed under the influence of antigens. T-lymphocytes are characterized by the presence on the plasmalemma of special receptors that can specifically recognize and bind antigens. These receptors are products of immune response genes. T-lymphocytes provide cellular immunity, participate in the regulation of humoral immunity, carry out the production of cytokines under the action of antigens.
In the population of T-lymphocytes, several functional groups of cells are distinguished: cytotoxic lymphocytes (TC), or T-killers(TK), T-helpers(Tx), T-suppressors(Ts). TK are involved in cellular immunity reactions, ensuring the destruction (lysis) of foreign cells and their own altered cells (for example, tumor cells). The receptors allow them to recognize the proteins of viruses and tumor cells on their surface. At the same time, the activation of Tc (killers) occurs under the influence of 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 plasmolemma 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 that stimulate B-lymphocytes and other cells to participate in immune responses.
· 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 persons infected with the AIDS virus was noted.
· Tc are able to inhibit the activity of Tx, B-lymphocytes and plasma cells. They are involved in allergic reactions, 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 the cells involved in the immune response (chemotactic factors, macrophage inhibitory factor - MIF, non-specific cytotoxic substances, etc.).
· natural killers. Among the lymphocytes in the blood, in addition to the above-described Tc, which perform the function of killers, there are so-called natural killers (Hk, NK), which are also involved in cellular immunity. They form the first line of defense against foreign cells, act immediately, quickly destroying cells. NK in their own body destroy tumor cells and cells infected with the virus. Tc form a second line of defense, since it takes time for them to develop from inactive T-lymphocytes, so they come into action later than Hc. NK are large lymphocytes with a diameter of 12-15 microns, have a lobed 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. HSCs in the bone marrow produce a lymphopoietic progenitor cell (lymphoid multipotent progenitor cell) that generates two types of cells: pre-T cells (progenitors of T cells) and pre-B cells (progenitors of 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 the period of embryonic development, a microenvironment is created in the thymus gland, which is important for the differentiation of T-lymphocytes. In the formation of the microenvironment, a special role is assigned to the reticuloepithelial cells of this gland, which are capable of producing a number of biologically active substances. Pre-T cells migrating to the thymus acquire the ability to respond to microenvironmental stimuli. Pre-T cells in the thymus proliferate, 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 of 3 types of lymphocytes: Tc, Tx and Tc. The "virgin" T-lymphocytes migrating from the thymus (virgile T-lymphocytes) are short-lived. Specific interaction with an antigen in peripheral lymphoid organs initiates the processes of their proliferation and differentiation into mature and long-lived cells (T-effector and T-memory cells), which make up the majority of recirculating T-lymphocytes.
Not all cells migrate from the thymus gland. Part of T-lymphocytes dies. 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, 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. In 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 differentiation antigens of human lymphocytes. 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.
· Polyclonal antibodies to a number of differentiating 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.
· Differentiating antigens of T-cells are known, which are characteristic either for certain stages of ontogenesis, or for subpopulations differing in functional activity. So, CD1 is a marker of the early phase of T-cell maturation in the thymus. During the differentiation of thymocytes, CD4 and CD8 markers are simultaneously expressed on their surface. However, subsequently, the CD4 marker disappears from a part of the cells and remains only on the subpopulation that has ceased to express the CD8 antigen. Mature CD4+ cells are Th. The CD8 antigen is expressed on about ⅓ of peripheral T cells that mature from CD4+/CD8+ T lymphocytes. The subpopulation of CD8+ T cells 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 Tc, respectively.
In addition to differentiation antigens, specific markers of T-lymphocytes are known.
· T-cell receptors for antigens are antibody-like heterodimers consisting of polypeptide α- and β-chains. Each of the chains 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 are assembled from several gene segments during the development of T cells in the thymus.
Distinguish between antigen-independent and antigen-dependent differentiation and specialization of B- and T-lymphocytes.
· Antigen-independent proliferation and differentiation are genetically programmed for the formation of cells capable of giving a specific type of immune response when they encounter a specific antigen due to the appearance of special “receptors” on the plasmolemma of lymphocytes. It takes place in the central organs of immunity (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, with the formation of effector cells and memory cells (retaining information about the acting antigen).
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 the SCM of the red bone marrow, then enter the bloodstream and then populate the B-zones of peripheral lymphoid organs - the spleen, lymph nodes, 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 various SIg: the majority (⅔) contain IgM, a smaller number (⅓) contain IgG, and about 1-5% contain IgA, IgD, IgE. In the plasma membrane of B-lymphocytes, there are also receptors for complement (C3) and Fc receptors.
Under the action of the antigen, B-lymphocytes in peripheral lymphoid organs are activated, proliferate, differentiate into plasma cells, actively synthesizing antibodies of various classes that enter the blood, lymph and tissue fluid.
Differentiation of B-lymphocytes
The precursors of B cells (pre-B cells) develop further in birds in the bursa of Fabricius (bursa), whence the name B-lymphocytes came from, in humans and mammals - in the bone marrow.
Bag of Fabricius (bursa Fabricii) - the central organ of immunopoiesis in birds, where the development of B-lymphocytes occurs, is 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 epitheliocytes and lymphocytes at various stages of differentiation. During embryogenesis, a brain zone is formed in the center of the follicle, and on the periphery (outside the membrane) a cortical zone, into which lymphocytes from the brain 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 lymphocytes. 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 the 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 lack surface immunoglobulin receptors. Bone marrow virgil B lymphocytes have IgM receptors on their surface. Mature B-lymphocytes carry on their surface immunoglobulin receptors of various classes - IgM, IgG, etc.
Differentiated B-lymphocytes enter the peripheral lymphoid organs, where, under the action of antigens, proliferation and further specialization of B-lymphocytes occur with the formation of plasma cells and memory B-cells (VP).
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 activity by producing IgM molecules, which are incorporated into the plasma membrane and serve as antigen receptors. Then, even before interacting with the antigen, most of the B cells proceed to the simultaneous synthesis of IgM and IgD molecules. When a virgil B cell switches from producing membrane-bound IgM alone to simultaneously producing membrane-bound IgM and IgD, the switch is likely due to a change in RNA processing.
When stimulated with an 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 referred to as secondary class antibodies because they appear to be formed only after antigen challenge 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 attribute the lymphocyte carrying them to the B-cell line. Thus, the CD19 antigen is the earliest marker that allows one to attribute a lymphocyte to the B-cell series. It is present on pre-B cells in the bone marrow, on all peripheral B cells.
The antigen detected by monoclonal antibodies of the CD20 group is specific for B-lymphocytes and characterizes the later stages of differentiation.
On histological sections, the CD20 antigen is detected on B-cells of the germinal centers of lymphoid nodules, in the cortical substance 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 phagocytosis 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 consists in the passive transfer of antigen to immunocompetent cells (T- and B-lymphocytes), in the induction of a specific response to antigens. Macrophages are also involved in providing immune homeostasis by controlling the reproduction of cells characterized by a number of abnormalities (tumor cells).
For the optimal development of immune responses under the action 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 destruction of the antigen. Antigens phagocytosed by macrophages elicit a stronger immune response than those not phagocytosed by them. Blockade of macrophages by introducing a suspension of inert particles (for example, carcasses) into the body of animals significantly weakens the immune response. Macrophages are capable of phagocytizing both soluble (for example, proteins) and particulate antigens. Corpuscular antigens elicit a stronger immune response.
Some types of antigens, such as pneumococci, containing a carbohydrate component on the surface, can be phagocytized only after preliminary opsonization. Phagocytosis is greatly facilitated if the antigenic determinants of foreign cells are opsonized, i.e. linked to an antibody or an antibody-complement complex. The opsonization process is provided by the presence of receptors on the macrophage membrane that bind part of the antibody molecule (Fc fragment) or part of the complement (C3). Only antibodies of the IgG class 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.
In the mechanism of antigen recognition, two stages are closely related to each other. The first step is phagocytosis and digestion of the antigen. In the second stage, macrophage phagolysosomes accumulate polypeptides, soluble antigens (serum albumins), and corpuscular bacterial antigens. 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 secreted by macrophages has a stimulating effect on the proliferation and differentiation of T- and B-lymphocyte clones. A small amount of antigenic material can be stored in macrophages for a long time 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 numerous processes of which 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, interdigitating cells are located that affect the differentiation of T-lymphocyte clones.
Thus, macrophages are directly involved in the cooperative interaction of cells (T- and B-lymphocytes) in the body's immune responses.
Charles B . Carpenter (Charles IN . carpenter)
Antigens that provide intraspecific differences in individuals are designated as alloantigens, and when they are included in the process of rejection of allogeneic tissue grafts, they become known as tissue compatibility (histocompatibility) antigens. Evolution has fixed a single region of closely linked histocompatibility genes, whose products on the cell surface provide a strong barrier to allotransplantation. The terms "major histocompatibility antigens" (major histocompatibility antigens) and "major histocompatibility gene complex" (MHC) (major histocompatibility gene complex) refer respectively to the gene products and genes of this chromosomal region. Numerous minor histocompatibility antigens, on the contrary, are encoded by multiple regions of the genome. They correspond to weaker alloantigenic differences between molecules that perform various functions. Structures carrying MHC determinants play a significant role in immunity and self-recognition during cell and tissue differentiation. Information about the MHC-control of the immune response was obtained in experiments on animals, when the immune response genes were mapped inside the MHC-in mice (H-2), rats (RT1), guinea pigs (GPLA). In humans, the MHC is named HLA. The individual letters of the abbreviation HLA are given different meanings, and with international agreement, HLA serves to designate the human MHC complex.
Several generalizations can be made about the MHC. First, in a small region (less than 2 centimorgan) MHC encodes three classes of gene products. Class I molecules, expressed by almost all cells, contain one heavy and one light polypeptide chain and are products of three reduplicated loci - HLA-A, HLA-B and HLA-C. Class II molecules, whose expression is limited to B-lymphocytes, monocytes and activated T-lymphocytes, contain two polypeptide chains (a and b) of unequal size and are products of several closely linked genes, collectively referred to as the HLA-D zone. Class III molecules are complement components C4, C2 and Bf. Second, class I and II molecules form a complex with the pseudoantigen, or the histocompatibility antigen and the pseudoantigen are recognized together by T-lymphocytes that have an appropriate receptor for the antigen. Recognition of self and non-self at the start and in the effector phase of the immune response is directly directed by molecules of classes I and II. Thirdly, there are no clear restrictions on intercellular interactions involving suppressor T-lymphocytes in humans, but the role of HLA genes is quite important for some manifestations of suppressor T-cell activity. Fourth, the MHC region contains genes for enzyme systems that are not directly related to immunity, but are important for the growth and development of the skeleton. Known HLA loci on the short arm of chromosome 6 are shown at 63-1.
Loci of the HLA system. Class I antigens. HLA class I antigens are determined serologically using human sera, mainly from multiparous women, and to a lesser extent using monoclonal antibodies. Class I antigens travel at varying densities in many body tissues, including B cells, T cells, and platelets, but not on mature erythrocytes. The number of serologically detectable specificities is large, and the HLA system is the most polymorphic of the known human genetic systems. Within the HLA complex, three loci are clearly defined for serologically detectable HLA class I antigens. Each class 1 antigen contains a b 2 -microglobulin subunit (mol. wt. 11500) and a heavy chain (mol. wt. 44000) carrying antigenic specificity (63-2). There are 70 well-defined A and B specificities and eight C locus specificities. The designation HLA is commonly used in naming major histocompatibility complex antigens, but may be omitted when the context permits. Antigens classified by the WHO inconclusively are designated with a w after the locus name. The number following the locus designation serves as the antigen's own name. The HLA antigens of the populations of Africa, Asia and Oceania are currently not well defined, although they include some of the common antigens common to people of Western European origin. The distribution of HLA antigens is different in different racial groups, and they can be used as anthropological markers in the study of diseases and migration processes.
63-1. Schematic representation of chromosome 6.
The localization of the HLA zone in region 21 of the short arm is shown. The HLA-A, HLA-B, and HLA-C loci encode class I heavy chains (44,000), while the b 2 -microglobulin light chain (11,500) of class I molecules is encoded by the gene on chromosome 15. The HLA-D zone (class II) is located centromere in relation to loci A, B and C with closely linked genes for complement components C4A, C4B, Bf and C2 in the B-D region. The order of the complement genes has not been established. Each class II molecule of the D-region is formed by a- and b-chains. They travel on the cell surface in different areas (DP, DQ and DR). The number preceding the characters a and b means that there are different genes for this type of chain, for example, for DR there are three b-chain genes, so the expressed molecules can be 1ba, 2ba or 3ba. The DRw52(MT2) and DRw53(MT3) antigens are on the 2b chain, while DR is on the lb chain. DR is non-polymorphic, while DQ antigen molecules are polymorphic in both a- and b-chains (2a2b). Other DQ types (1a1b) have limited polymorphism. DP polymorphism is associated with b-chains. The total length of the HLA region is about 3 cm.
Because the chromosomes are paired, each individual has up to six serologically detectable HLA-A, HLA-B, and HLA-C antigens, three from each parent. Each of these sets is designated as a haplotype, and according to simple Mendelian inheritance, a quarter of the offspring have identical haplotypes, half are part of the common haplotypes, and the remaining quarter are completely incompatible (63-3). The significance of the role of this gene complex in the transplant response is confirmed by the fact that haplotype selection of donor-recipient pairs among the offspring of one generation provides the best results in kidney transplantation - about 85-90% of long-term survival (chapter 221).
class II antigens. The HLA-D zone is adjacent to the class I loci on the short arm of the 6th chromosome (63-1). This region encodes a series of class II molecules, each containing an a-chain (molecular weight 29,000) and a b-chain (molecular weight 34,000) (63-2). Incompatibility in this region, especially in DR antigens, determines the proliferative response of lymphocytes in vitro. Mixed lymphocytic reaction (MLR) is assessed by the level of proliferation in mixed lymphocyte culture (MLC) and may be positive even when identical for HLA-A, HLA-B and HLA-C antigens (63-3). HLA-D antigens are detected using standard stimulating lymphocytes homozygous for HLA-D and inactivated by x-rays or mitomycin C to impart a unidirectional response. There are 19 such antigens (HLA-Dwl-19) detected using homozygous typing cells.
Attempts to determine HLA-D by serological methods first made it possible to detect a series of D-linked (DR) antigens expressed on class II molecules of B lymphocytes, monocytes, and activated T lymphocytes. Then other closely linked antigenic systems were described, which received various names (MB, MT, DC, SB). The identity of individual groups of class II molecules has now been established, and the genes of the corresponding a - and b-chains are isolated and sequenced. The class II gene map shown in 63-1 reflects the minimum number of genes and molecular regions. Although the mass II molecule may contain DRa from the haplotype of one of the parents, and DRb from the other (transcomplementation), combinatorics outside of each of the DP, DQ, DR regions is rare, if not impossible. DR molecules, and to some extent DQ, can serve as stimuli for primary MLR. Secondary MLR is defined as a lymphocyte-primed test (PLT) and results in 24-36 hours instead of 6-7 days for a primary response. DP alloantigens were discovered due to their ability to induce PLT stimulation, although they do not confer primary MLR. Although B-lymphocytes and activated T-lymphocytes express all three sets of class II molecules, DQ antigens are not expressed on 60-90% of DP- and DR-positive monocytes.
63-2. Schematic representation of class I and II cell surface molecules.
Class I molecules consist of two polypeptide chains. Heavy chain with a pier. weighing 44,000 passes through the plasma membrane; its outer section consists of three domains (a 1 , a 2 and a 3) formed by disulfide bonds. Light chain with mol. with a mass of 11500 (b 2 -microglobulin, b2mu) is encoded by chromosome 15 and is non-covalently linked to the heavy chain. Amino acid homology between class I molecules is 80-85%, decreasing to 50% in the a 1 and a 2 regions, which probably correspond to the regions of alloantigenic polymorphism. Class II molecules are formed by two non-covalently linked polypstide chains, a-chain with a pier. with a mass of 34,000 and a b-chain with a mol mass of 29,000. Each chain contains two domains formed by disulfide bonds (from S. B. Carpenter, E. L. Milford, Renal Transplantation: Immunobiology in the Kidnev/Eds. B. Brenner, F. Rector, New York: Samiders, 1985).
63-3. HLA region of chromosome 6: inheritance of HLA haplotypes. Each chromosomal segment of linked genes is designated as a haplotype, and each individual inherits one haplotype from each parent. The diagram shows the antigens A, B and C of haplotypes a and b for this hypothetical individual; below, the designations of haplotypes are disclosed in accordance with the text. If a male with an ab haplotype marries a woman with a cd haplotype, the offspring can only be of four types (in terms of HLA). If during meiosis one of the parents undergoes recombination (marked with broken lines), then this leads to the formation of an altered haplotype. The frequency of altered haplotypes in children serves as a measure of distances on the genetic hag (1% recombination frequency == 1 cM; 63-1) (from H. W. Carpenter. Kidney International, D)78. 14.283).
Molecular genetics. Each polypeptide chain of class I and II molecules contains several polymorphic regions in addition to a "private" antigenic determinant determined using antisera. The cell mediated lympholysis (CML) assay determines the specificity of killer T cells (TK) that proliferate in MLR by testing on target cells from donors who have not provided MLR stimulating cells. The antigenic systems determined by this method show a close but incomplete correlation with "private" class 1 antigens. Cytotoxic cell cloning has allowed the detection of a set of polymorphic target determinants on HLA molecules, some of which cannot be detected using alloantisera and monoclonal antibodies obtained by immunization of mice human cells. Some of these reagents can be used to identify "particular" HLA determinants, while others target more "general" (sometimes called supertyping) determinants. One such system of "common" HLA-B antigens has two alleles, Bw4 and Bw6. Most "private" HLA-Bs are associated with either Bw4 or Bw6. Other systems are associated with subgroups of HLA antigens. For example, HLA-B positive heavy chains contain additional regions common to B7, B27, Bw22 and B40 or B5, B15, B18 and Bw35. There are other types of overlapping antigenic determinants, as evidenced by the reaction of monoclonal antibodies with a site common to the heavy chains of HLA-A and HLA-B. The study of the amino acid sequence and pstid maps of some HLA molecules showed that the hypervariable regions of class I antigens are concentrated in the outer a 1 -domain (63-2) and the adjacent region of the a 2 -domain. Variable sequences of class II molecules are different for different loci. It is remarkable that a 3 -domain of class I, a 2 -domain of class II and b 2 -domain, as well as a part of the membrane molecule T8 (Leu 2) involved in intercellular interactions (chap. 62), show significant amino acid sequence homology with constant areas of immunoglobulins. This confirms the hypothesis about the evolutionary formation of a family of gene products that carry the functions of immunological recognition. In the study of HLA genomic DNA for molecules of classes I and II, typical exon-intron sequences were found, and exons were identified for signal peptides (5) of each of the domains, the transmembrane hydrophobic segment and the cytoplasmic segment (3). cDNA probes are available for most HLA chains, and the use of enzymatic digests to assess restriction fragment length polymorphism (RFLP) status has yielded data that correlates with class 11 serologic assays in the MLR. However, the abundance (20-30) of class 1 genes makes the evaluation of polymorphism by RFLP difficult. Many of these genes are not expressed (pseudogenes), although some may correspond to additional class I loci that are only expressed on activated T cells; their functions are unknown. The development of specific tests for the HLA-A and HLA-B loci will help to understand this rather complex problem.
Complement (class III). Structural genes of the three complement components C4, C2 and Bf travel in the HLA-B-D zone (63-1). These are two C4 loci encoding C4A and C4B, originally described as the erythrocyte antigens Rodgers and Chido, respectively. These antigens were in fact absorbed from the plasma by C4 molecules. The other components of complement do not have a tight bond with HLA. No crossing over has been described between the C2, Bf, and C4 genes. All of them are encoded by a section between HLA-B and HLA-DR with a length of about 100 kb. There are two C2 alleles, four Bf, seven C4A and three C4B alleles, in addition, there are silent QO alleles at each locus. The exceptional polymorphism of complement histotypes (complotypes) makes this system suitable for genetic research.
Table 63-1. Most common HLA haplotins
In table. Figure 63-1 shows the four most common haplotypes found in individuals of Western European ancestry. MLR results in unrelated individuals selected for compatibility for these haplotypes are negative, while a reaction usually occurs if unrelated individuals are matched for HLA-DR and DQ compatibility only. Such identical common haplotypes may be descended unchanged from a single ancestor.
Other genes of the 6th chromosome. Deficiency of the steroid 21-hydroxylase, an autosomal recessive trait, causes the syndrome of congenital adrenal hyperplasia (chaps. 325 and 333). The gene for this enzyme is located in the HLA-B-D region. The 21-hydroxylase gene adjacent to the C4A gene is deleted in individuals suffering from the mentioned syndrome, along with C4A (C4AQO), and the HLA-B gene can be transformed with the conversion of B 13 into rare Bw47, found only in altered haplotypes. Unlike the late onset HLA-linked 21-hydroxylase deficiency, 21b-hydroxylase-deficient congenital adrenal hyperplasia is not HLA-linked. Several family studies have shown that idiopathic hemochromatosis, an autosomal recessive disease, is linked to HLA (chap. 310). Although the pathogenesis of disorders of iron absorption in the gastrointestinal tract is unknown, it has been established that the genes that modulate this process are located near the HLA-A region.
| Table 63-2. Linkage of genetic defects | ||
| Localization | discoverable |
|
| haplotypes |
||
| C2 deficiency | Aw25, B18, BfS, DR2 |
|
| 21-OH deficiency | A3, Bw47, BfF, DR7 |
|
| 21-OH deficiency (late manifestation) | ||
| Idiopathic hemochromatosis | ||
| Paget's disease | ||
| Spino-cerebellar ataxia | ||
| Hodgkin's disease | ||
63-4. Scheme of the relative role of HLA-A, HLA-B, HLA-C and HLA-D antigens in the initiation of the alloimmune response and in the formation of effector cells and antibodies.
Two main classes of T lymphocytes recognize antigens: Tk - precursors of cytotoxic "killer" cells and Tx helper cells that contribute to the development of a cytotoxic response. Tx also provide assistance to B-lymphocytes in the development of a "mature" IgG response. It is important to note that TK usually recognize class I antigens, while the signal for Th is generated predominantly by HLA-D, which is closely associated with class II antigens (from C. B. Carpenter. - Kidney International, 1978, 14, 283).
immune response genes. An in vitro study of the response to synthetic polypeptide antigens, hemocyanin, collagen, and tetanus toxoid revealed that the HLA-D zone is similar to the H-2 region. I in the mouse. Presentation of antigenic fragments on the surface of macrophages or other cells bearing class II molecules requires coupled recognition of the class II molecule + antigen complex by T-lymphocytes bearing the appropriate receptor(s) (chap. 62). The core of this “self-)-X” or “altered self” hypothesis is that the T-dependent immune response, the action of T-helpers / inducers (Tx) is carried out only if the corresponding class II determinants are synthesized. The genes of the latter are the Ir-genes. Because class I allogeneic determinants are recognized as already altered, allogeneic MLP is a model of the immune system in which pseudoantigen passage is optional (63-4). The effector phases of immunity require the recognition of a pseudoantigen in combination with its own structures. The latter in humans, as well as in mice, are molecules of class I histocompatibility antigens. Influenza-infected human cell lines are lysed by immune cytotoxic T-lymphocytes (TC) only if the responding and target cells are identical at the HLA-A and HLA-B loci. Allogeneic MLR also serves as a model for the formation of class I-restricted cytotoxic T-lymphocytes (63-4). Restriction details for various class I and II molecules and epitopes can be isolated using primed cells that have been expanded and cloned. For example, at the level of antigen-presenting cells, a given Th clone recognizes an antigenic fragment complexed with a specific region of a class II molecule via the Ti receptor. Restrictive elements for some microbial antigens are the DR and Dw alleles.
Suppression of the immune response (or, low level of response) to cedar pollen, streptococcal antigens and schistosome antigens is dominant and linked to HLA, which indicates the existence of immune suppression genes (Is). The presence of specific allelic associations of HLA with the level of the immune response was also shown, for example, for the castor bean antigen Ra5 - with DR2 and for collagen - with DR4.
Associations with diseases. If the major histocompatibility complex has an important biological function, what is that function? One hypothesis is that it plays a role in the immune surveillance of neoplastic cells that appear during an individual's lifetime. The importance of this system during pregnancy is great, since there is always tissue incompatibility between the mother and the fetus. A high degree of polymorphism may also contribute to the survival of species in the face of a huge number of microbial agents wandering in the environment. Tolerance to “self” (self-tolerance) can cross over to microbial antigens, resulting in high susceptibility leading to fatal infections, while polymorphism in the HLA system contributes to the fact that part of the population recognizes dangerous agents as foreign and includes an adequate response . These hypotheses link the role of HLA to the benefits of the system surviving under selection pressure. Each of these hypotheses has some support.
An important evidence of the role of the HLA complex in immunobiology was the discovery of a positive association of some pathological processes with HLA antigens. The study of these associations was stimulated by the discovery of immune response genes linked to the H-2 complex in mice. In table. 63-3 summarizes the most significant HLA and disease associations.
It has been established that the frequency of occurrence of HLA-B27 is increased in some rheumatic diseases, especially in ankylosing spondylitis, a disease of a clearly familial nature. The B27 antigen is present in only 7% of people of Western European origin, but it is found in 80-90% of patients with ankylosing spondylitis. In terms of relative to this means that this antigen is responsible for the susceptibility to the development of ankylosing spondylitis, which is 87 times higher in its carriers than in the general population. Similarly, a high degree of association with the B27 antigen in acute anterior uveitis, Reiter's syndrome, and reactive arthritis in at least three bacterial infections (yersiniosis, salmonellosis, and gonorrhea) has been shown. Although the common form of juvenile rheumatoid arthritis is also associated with B27, the type of disease with mild articular syndrome and iritis is associated with B27. In psoriatic arthritis of the central type, B27 is more common, while Bw38 is associated with both central and peripheral types. Psoriasis is associated with Cw6. Patients with degenerative arthritis or gout do not show any change in the frequency of antigens.
Most other associations with diseases are characteristic of HLA-D antigens. For example, gluten-sensitive enteropathy in children and adults is associated with the DR3 antigen (relative to 21) The actual percentage of patients with this antigen varies from 63 to 96% compared to 22-27% in controls . The same antigen is more often found in patients with active chronic hepatitis and dermatitis herpetiformis, who also suffer from gluten-sensitive enteropathy. Juvenile insulin-dependent diabetes mellitus (type I) is associated with DR3 and DR4 and negatively associated with DR2. In 17-25% of patients with type I diabetes, a rare allele Bf (M) was found. Diabetes with onset in adulthood (type II) has no association with HLA. Hyperthyroidism in the US is associated with B8 and Dw3, while in the Japanese population it is associated with Bw35. A broader survey of healthy and sick representatives of various races will help clarify the issue of universal HLA markers. For example, the B27 antigen, which is rare in healthy Japanese individuals, is common in patients with ankylosing spondylitis. Similarly, DR4 is a marker for aphid type I diabetes in all races. Sometimes the HLA marker is clearly associated with only a part of the symptoms within the syndrome. For example, myasthenia gravis is significantly more strongly associated with B8 and DR3 antigens in patients without thymoma, and multiple sclerosis is associated with DR2 antigen in individuals with a rapidly progressive course of the disease. Goodpasture's syndrome associated with autoimmune damage to the glomerular basement membranes, idiopathic membranous glomerulonephritis, reflecting autoimmune processes with the formation of antibodies to glomerular antigens, as well as gold-induced membranous nephritis, are largely associated with HLA-DR.
Table 63-3. Diseases associated with HLA antigens
| Diseases | Relative to | |||
| Rheumatoid | ||||
| Ankylosing spondylitis | ||||
| Reiter's syndrome | ||||
| Acute anterior uveitis | ||||
| Reactive arthritis (Yersinia, Salmonella, Gonococcus) | ||||
| Psoriatic arthritis (central) | ||||
| Psoriatic arthritis (peripheral) | ||||
| Juvenile rheumatoid arthritis | ||||
| Juvenile arthritis with mild articular syndrome | ||||
| Rheumatoid arthritis | ||||
| Sjögren's syndrome | ||||
| Systemic lupus erythematosus | ||||
| Systemic lupus erythematosus (as a result of | ||||
| taking apressin) | ||||
| Gastrointestinal | ||||
| Gluten sensitive enteropathy | ||||
| Chronic active hepatitis | ||||
| Ulcerative colitis | ||||
| Hematological | ||||
| Idiopathic hemochromatosis | ||||
| pernicious anemia | ||||
| Dermatitis herpetiformis | ||||
| Psoriasis vulgaris | ||||
| Psoriasis vulgaris (in the Japanese population) | ||||
| Pemphigus vulgaris (in the European population) | ||||
| Behçet's disease | ||||
| Endocrine | ||||
| Type I diabetes | ||||
| Hyperthyroidism | ||||
| Ginerthyroidism (in the Japanese population) | ||||
| Diseases | Most closely associated antigens | Relative to |
||
| Adrenal insufficiency | ||||
| Subacute thyroiditis (de Quervain) | ||||
| Hashimoto's thyroiditis | ||||
| H eurological | ||||
| myasthenia gravis | ||||
| Multiple sclerosis | ||||
| Manic depressive disorder | ||||
| Schizophrenia | ||||
| Renal | ||||
| Idiopathic membranous glomerulo- | ||||
| Goodpasture's disease (anti-GMB) | ||||
| Minimal change disease (steroid | ||||
| Polycystic kidney disease | ||||
| IgA nephropathy | ||||
| Nephropathy Caused by Gold | ||||
| infectious | ||||
| Tuberculoid leprosy (in Asian ass | ||||
| full paralysis | ||||
| Poor response to virus vaccine | ||||
| immunodeficiency | ||||
| IgA deficiency (blood donors) | ||||
Unbalanced grip. Although the distribution of HLA alleles varies in racial and ethnic populations, the most characteristic feature of the population genetics of HLA antigens is the presence of linkage disequilibrium for some A and B, B and C, B, D antigens and complement loci. Linkage disequilibrium means that antigens from closely linked loci are found together more often than would be expected from the assumption of random association. A classic example of linkage disequilibrium is the association of the AHLA-A1 locus antigen with the HLA-B8 B locus antigen in individuals of Western European origin. The simultaneous presence of A1 and B8, calculated on the basis of the frequencies of their genes, should be observed with a frequency of 0.17. 0.11, i.e. approximately 0.02. Whereas the observed frequency of their coexistence is 0.08, i.e., 4 times higher than expected, and the difference between these values is 0.06. The last value is denoted delta (D) and serves as a measure of non-equilibrium. Linkage disequilibrium was also found for other A- and B-locus haplotypes: A3 and B7, A2 and B12, A29 and B12, A11 and Bw35. AT 8); as well as for antigens of B and C loci. Serologically detectable HLA antigens serve as markers for whole haplotype genes within a family and as markers for specific genes in a population, but only in the presence of linkage disequilibrium.
Linkage disequilibrium is significant because such gene associations can generate certain functions. Selection pressure during evolution may be a major factor in the maintenance of certain gene combinations in genotypes. For example, there is a theory that A1 and B8, as well as some determinants of D and other regions, provide a selective advantage in the face of epidemics of diseases such as plague or smallpox. However, it is also possible that the descendants of people who survived such epidemics remain susceptible to other diseases, because their unique gene complex does not provide an adequate response to other environmental factors. The main difficulty of this hypothesis lies in the assumption that selection acts on several genes simultaneously and thereby ensures the occurrence of the observed values of P, however, the need for complex interactions between the products of different loci of the MHC complex is only the initial link for the observed phenomena, and selection can enhance multiple linkage disequilibrium. . The retention of some common haplotypes named above supports this view.
On the other hand, the selection hypothesis need not explain linkage disequilibrium. When a population lacking some antigens is crossed with another that has a high frequency of these antigens in equilibrium, D may appear after several generations. For example, the increase in D for A1 and B8 found in populations in an east-west direction from India to Western Europe can be explained on the basis of population migration and assimilation. In small groups, disequilibrium can be due to compatibility, founder effects, and genetic drift. Finally, some cases of linkage disequilibrium are the result of non-random crossing over during meiosis, as chromosome segments can be more or less brittle. Whether it is selection pressure or crossover constraints, linkage disequilibrium can disappear within a few generations. A large number of non-random associations exist in the HLA gene complex, and determining their causes can provide insight into the mechanisms underlying disease susceptibility.
Clutch and associations. In table. 63-2 lists diseases that serve as an example of HLA linkage, when hereditary traits are marked within the family with the corresponding haplotypes. For example, deficiency of C2, 21-hydroxylase, idiopathic hemochromatosis are inherited in a recessive manner with partial deficiency in heterozygotes. These genetic disorders are also HLA-associated and are caused by an excess of certain HLA alleles in unrelated affected people. C2 deficiency is usually linked to the HLA-Aw 25, B 18, B55, D / DR2 haplotypes, and in idiopathic hemochromatosis, both linkage and a strong association between HLA-A3 and B 14 are manifested. A high degree of linkage disequilibrium in this case is caused by mutations in the person who served as its source; in addition, the period of time required for the return of the gene pool to a state of equilibrium was insufficient. From this point of view, HLA genes are simple markers of linked genes. On the other hand, interaction with specific HLA alleles may be required to manifest a particular disorder. The latter hypothesis would require the recognition of a higher rate of mutations with the expression of defective genes, which occurs only under the condition of linkage with some HLA genes.
Paget's disease and spinal ataxia are HLA-linked, autosomal dominant hereditary disorders; they are found in several family members at once. Hodgkin's disease is a manifestation of an HLA-linked recessive hereditary defect. No HLA associations have been found in these diseases, suggesting an initial multiplicity of originators of these diseases with mutations associated with different HLA alleles.
Linkage to HLA is easily determined when the dominance and recessiveness of traits are easy to distinguish, i.e., when expressivity is high and the process is determined by a defect in single genes. In most associations, HLA markers reflect the factors involved in the implementation and modulation of the immune response under the influence of multiple genes. An example of a polygenic immune disease is atonic allergy, in which association with HLA may only be apparent in individuals with low genetically controlled (not due to HLA) levels of IgE production. Another example of this kind is the IgA deficiency (Table 63-3) associated with HLA-DR3.
Clinical significance of the HLA system. The clinical significance of HLA typing for diagnosis is limited to the determination of B27 in the diagnosis of ankylosing spondylitis; however, in this case, there are 10% of false positive and false negative results. The study of HLA is also of value in the practice of genetic counseling for the early detection of diseases in families with idiopathic hemochromatosis, congenital adrenal hyperplasia associated with steroid hydroxylase deficiency, especially if HLA typing is performed on cells obtained by amniocentesis. The high degree of polymorphism in the HLA system makes it a valuable tool for testing various cell preparations, especially in forensic medicine. Some diseases, such as type I diabetes mellitus and others, for which HLA associations are indicated, require further study of the role of the components of the HLA system in the pathogenesis of these diseases.
During the first human heart transplant performed in 1967 by C. Barnard, and hundreds of subsequent transplants, surgeons faced the problem of transplant rejection. It turned out that the main difficulty lies not in the technique of the operation, which is now well developed, but in the incompatibility of tissues due to immunological mechanisms. Thus, in humans, the survival of transplant recipients taken from a random donor is 10.5 days, while transplants exchanged between identical twins (isografts), take root. This is due to the presence of antigens on the surface of cells, called transplantation antigens or histocompatibility antigens. Most transplantation antigens are located on leukocytes, but they are also found on all other nucleated cells (cells of the skin, lungs, liver, kidneys, intestines, heart, etc.). The genes encoding these antigens are called tissue compatibility genes. The system of genes that controls the transplantation antigens of leukocytes is called the Major Histocompatibility Complex (MHC). Histocompatibility genes are codominant.
The efficiency of transplantation depends not only on leukocyte and erythrocyte antigens, but also on minor histocompatibility system. Transplants between monozygotic twins take root. However, in brothers and sisters, if the MHC haplotypes match, but the minor histocompatibility systems do not match, skin grafts are rejected.
After immunoglobulins and T-cell receptors, major histocompatibility complex proteins are the most diverse of all proteins. There are two classes of MHC proteins. Class I proteins are found on the surface of almost all cells. A protein molecule consists of two polypeptide chains: a large and a small one. Squirrels
Class II MHCs are present on the surface of some cells (B-" lymphocytes, macrophages, specialized epithelial cells), and their molecule consists of approximately equal polypeptide-* chains. MHC proteins have some similarities with immunoglobulins. The main role of MHC proteins is not in the rejection of foreign tissue, but in the direction of the reaction of T cells to the antigen. Cytotoxic T cells can recognize the antigen if it is located together with MHC class I proteins on the surface of one cell. Helper T cells recognize the antigen in combination with MHC class II proteins. Such double stimulation is called MHC-o restriction.For the first time, the main system of tissue compatibility of mouse H-2 was discovered by P. Gorer in 1936. In addition to H-2, many tissue compatibility loci located in all chromosomes were found.
In 1980, D. Snell, J. Dosset and B. Benatzeraff received the Nobel Prize for "various aspects of research leading to the modern understanding of the human histocompatibility gene system." D. Snell formulated the basic genetic laws of tissue compatibility and obtained data on the fine structure of the H-2 locus in mice.
The H-2 system is fairly well understood and therefore serves as a good model for studying MHC in other animal species. The H-2 complex includes several closely linked loci 0.35 cm long located on the 17th chromosome. The H-2 complex is divided into five regions: K, I, S, G, D (Fig. 56).
