Lakhasly

Relevance of the topic under study: The protection of the body from infectious agents, the performance of the immune system tasks of maintaining tissue homeostasis of the body depend on the adequacy of the immune response, which is impossible without adequate recognition of the antigen by T-lymphocytes.Each allelic variant of the MHC molecule binds peptides to certain "anchor" amino acid residues. Natural selection. Each individual is potentially able to develop a response only to those peptides that are able to bind the MHC glycoproteins of this individual. Specific variants of MHC are fixed in evolution by natural selection, and each individual is adapted to the regional species and strains of microorganisms, which were protected from the selection of MHC in the ancestors. Non-classical MHC genes are not polymorphic or not as polymorphic as classical MHC genes. The value of MHC polymorphism. Genetic polymorphism reflects the adaptive potential of a population and a species. The wider it is, the more likely it is that there are individuals within the species that can survive extreme changes in environmental conditions. Microorganisms, having a high rate of reproduction and the ability to change, represent a potential danger to the existence of highly organized living beings, whose MHC molecules are the main structures that present infectious antigens. Their ability to bind foreign peptides and activate T-lymphocytes largely determines the level of response of the adaptive immune system to an infectious agent. It is no coincidence that the pathogenic properties of viruses are due to the ability to inhibit the expression of MHC molecules. It was the diversity of microorganisms that led to the polymorphism of MHC, but the amount of hereditary information is limited by the capacity of the cell nucleus, and an individual is not able to have the entire possible spectrum of allelic diversity in the genome. Nature has distributed it among individuals within the species. Thus, the polymorphism of the HLA genes protects all of humanity from extinction, but not its individual representatives. Antigenic peptide - MHC complexes. The formation of complexes of antigenic peptides with MHC of different classes occurs in different cell compartments. MHC-I "serve" the zone of the cytosol communicating through the nuclear pores with the contents of the nucleus.MHC molecules are polymorphic products of genes of the major histocompatibility complex of classes I and II. HLA molecules encoded by MHC genes are divided into MHC class I glycoproteins (HLA-A, HLA-B, and HLA-C), which are present on the surface of all somatic cells except for the cells of the villous trophoblast and red blood cells, and HLA molecules encoded by MHC class II genes (HLA-DP, HLA-DQ, and HLA-DR) are expressed mainly on the membrane of antigen-presenting cells (DC, activated macrophages and B-lymphocytes), as well as on some T-helper cells.In addition to the role of leukocyte antigens in protecting against diseases, they can cause organ rejection after transplantation, can protect against cancer or increase its likelihood (if unregulated due to frequent infections); can affect the development of autoimmune diseases (e.g., type 1 diabetes, SLE, Bekhterev's disease).There are many variants of MHC class II membrane molecules, which is due, on the one hand, to the polygenism of the ?- and ?-chains, on the other hand, to their ability to combine not only within the haplotype, but also to form combinations of parent chains encoded within the same regions.The ?1 and ?2 domains form a groove for binding antigenic peptides with a length of 9-11 amino acids, presented for recognition to T-lymphocytes.Moreover, it was found that T-cells recognize the antigen only in combination with MHC molecules, in contrast to B-lymphocytes and immunoglobulins, which recognize epitopes in the composition of any protein molecules.T-lymphocytes with the help of antigen-recognizing receptors are able to recognize antigens only in combination with MHC-I or MHC-II molecules on the cell surface of their body - the phenomenon of double recognition.In the immune system, these glycoproteins perform an important function: they are involved in the presentation of antigen-presenting cells (APC) of peptide antigens to T-lymphocytes.Initially, they were divided by the induction of their products mainly humoral (class II) or cellular (class I) immunity.Initially, human leukocyte antigen (HLA) genes were identified in successful organ transplants between people with similar HLA.Human leukocyte antigens (HLA) are glycoproteins encoded by the genes of the major histocompatibility complex - MHC.Unlike MHC-I, the peptide-binding cleft is open on both sides, which allows the binding of longer peptides (15-30 amino acids).The mechanism of their adaptation to an unlimited set of antigens lies in their genetic polymorphism (co-dominance, multiplicity of alleles, natural selection).The polymorphism of the classical MHC genes means that the population has many alleles-variants of the same gene in different individuals.HLA diversity in the human population is an aspect of disease defense, and therefore the chances of all HLA genes matching at all loci are very small.MHC-II class molecules are heterodimers of 2 transmembrane glycoproteins: ?-and ?-chains.The MHC I genes occupy a distal and MHC II genes occupy a proximal position with respect to the centromere.Both classical MHC molecules and non-classical structures are encoded in MHC class II and I clusters.Genes that carry information about the structure of classical MHC molecules are characterized by polymorphism and polygenism.Class I and II antigen products are involved in the rejection of incompatible implants and the presentation of antigen to T-cells.and ?) encoding the corresponding polypeptide chains of the molecules are directly involved in the presentation of the antigen.The MHC-I have 3 genes (A, B, C) in each of the homologous chromosomes, and the MHC-II genes have also 3 of them (DP, DQ, DR).In addition to the genes encoding the 6 main antigens, there are many other genes involved in the functioning of the immune system, which are also found in the HLA complex.MHC-I class molecules consist of 2 polypeptide chains - ?-chain and ?2-microglobulin.A light molecular chain, ?2-microglobulin, is non-covalently associated with extracellular ?-domains.There are 3 sites in the MHC:

a cluster encoding I class MHC, a cluster encoding II class MHC, a cluster encoding III class MHC.MHC I genes carry information about the structure of the ?-chains of MHC I molecules, MHC II genes - about the structure of the ?- and ?-chains of MHC II proteins.The expression of histocompatibility genes occurs co-dominantly, i.e. both alleles are realized in the phenotype.As a result, 6 variants of classical MHC class I molecules can be simultaneously represented on the surface of a particular cell.MHC class III genes are not the part of histocompatibility molecules and their presentation.They encode some complement components, TNF-family cytokines, heat shock proteins.The genes of MHC complex (unlike the TCR or Ig genes) do not undergo recombination.Co-dominance is the simultaneous expression of the genes of the maternal and paternal chromosomes.The peptide-binding groove is formed together by the ?1-and ?1-domains.The first is formed by the genes A, B, and C, which are characterized by high polymorphism -- several hundred of their allelic forms are known.Another group is formed by non-classical genes E, F, G, H (genes with limited polymorphism).There can be more than 100 allelic variants of individual MHC loci.HLA may be associated with some individual odors that play a role in the selection of sexual partners.Somatic cells do not express MHC-II molecules under normal conditions.The ?-chain has 3 extracellular domains (?1, ?2, ?3), a transmembrane site, and a cytoplasmic site.Genes of the major histocompatibility complex

The complex is localized in the short arm of human chromosome 6.Polygenism is the coding of one characteristic by several genes.MHC class II genes also include several variants.Thus, if the mother and father do not have the same alleles, each person has 12 different alleles of the MHC genes.Therefore, the student needs to know the structure and functions of histocompatibility molecules.Transmembrane MHC molecules.Between them is a MHC class III cluster.The extracellular part of each chain has 2 domains.There are 2 groups of class I genes.The products of the genes DR (?Genes of the major histocompatibility complex.Multiplicity of alleles.They determine the biological identity of each person.Pic.These are classic class I genes.and ?), DP (? and ?), and DQ (?Pic.Genetic polymorphism.1.2.

Relevance of the topic under study: The protection of the body from infectious agents, the performance of the immune system tasks of maintaining tissue homeostasis of the body depend on the adequacy of the immune response, which is impossible without adequate recognition of the antigen by T-lymphocytes. Moreover, it was found that T-cells recognize the antigen only in combination with MHC molecules, in contrast to B-lymphocytes and immunoglobulins, which recognize epitopes in the composition of any protein molecules. Therefore, the student needs to know the structure and functions of histocompatibility molecules.

Initially, human leukocyte antigen (HLA) genes were identified in successful organ transplants between people with similar HLA.

HLA diversity in the human population is an aspect of disease defense, and therefore the chances of all HLA genes matching at all loci are very small.

In addition to the role of leukocyte antigens in protecting against diseases, they can cause organ rejection after transplantation, can protect against cancer or increase its likelihood (if unregulated due to frequent infections); can affect the development of autoimmune diseases (e.g., type 1 diabetes, SLE, Bekhterev's disease). HLA may be associated with some individual odors that play a role in the selection of sexual partners. In addition to the genes encoding the 6 main antigens, there are many other genes involved in the functioning of the immune system, which are also found in the HLA complex.

Human leukocyte antigens (HLA) are glycoproteins encoded by the genes of the major histocompatibility complex - MHC. They determine the biological identity of each person. In the immune system, these glycoproteins perform an important function: they are involved in the presentation of antigen-presenting cells (APC) of peptide antigens to T-lymphocytes.

MHC molecules are polymorphic products of genes of the major histocompatibility complex of classes I and II. HLA molecules encoded by MHC genes are divided into MHC class I glycoproteins (HLA-A, HLA-B, and HLA-C), which are present on the surface of all somatic cells except for the cells of the villous trophoblast and red blood cells, and HLA molecules encoded by MHC class II genes (HLA-DP, HLA-DQ, and HLA-DR) are expressed mainly on the membrane of antigen-presenting cells (DC, activated macrophages and B-lymphocytes), as well as on some T-helper cells. Somatic cells do not express MHC-II molecules under normal conditions.

T-lymphocytes with the help of antigen-recognizing receptors are able to recognize antigens only in combination with MHC-I or MHC-II molecules on the cell surface of their body - the phenomenon of double recognition.

MHC-I class molecules consist of 2 polypeptide chains - α-chain and β2-microglobulin. The α-chain has 3 extracellular domains (α1, α2, α3), a transmembrane site, and a cytoplasmic site. The α1 and α2 domains form a groove for binding antigenic peptides with a length of 9-11 amino acids, presented for recognition to T-lymphocytes. A light molecular chain, β2-microglobulin, is non-covalently associated with extracellular α-domains.

MHC-II class molecules are heterodimers of 2 transmembrane glycoproteins: α-and β-chains. The extracellular part of each chain has 2 domains. The peptide-binding groove is formed together by the α1-and β1-domains. Unlike MHC-I, the peptide-binding cleft is open on both sides, which allows the binding of longer peptides (15-30 amino acids).
Pic. 1. Transmembrane MHC molecules.

Genes of the major histocompatibility complex

The complex is localized in the short arm of human chromosome 6.

There are 3 sites in the MHC:

a cluster encoding I class MHC,
a cluster encoding II class MHC,
a cluster encoding III class MHC.
The MHC I genes occupy a distal and MHC II genes occupy a proximal position with respect to the centromere. Between them is a MHC class III cluster. MHC I genes carry information about the structure of the α-chains of MHC I molecules, MHC II genes - about the structure of the α- and β-chains of MHC II proteins. Both classical MHC molecules and non-classical structures are encoded in MHC class II and I clusters.

Genes that carry information about the structure of classical MHC molecules are characterized by polymorphism and polygenism.

Polygenism is the coding of one characteristic by several genes. The expression of histocompatibility genes occurs co-dominantly, i.e. both alleles are realized in the phenotype. As a result, 6 variants of classical MHC class I molecules can be simultaneously represented on the surface of a particular cell. There are many variants of MHC class II membrane molecules, which is due, on the one hand, to the polygenism of the α- and β-chains, on the other hand, to their ability to combine not only within the haplotype, but also to form combinations of parent chains encoded within the same regions.

Class I and II antigen products are involved in the rejection of incompatible implants and the presentation of antigen to T-cells. Initially, they were divided by the induction of their products mainly humoral (class II) or cellular (class I) immunity.

There are 2 groups of class I genes. The first is formed by the genes A, B, and C, which are characterized by high polymorphism — several hundred of their allelic forms are known. These are classic class I genes. Another group is formed by non-classical genes E, F, G, H (genes with limited polymorphism).

MHC class II genes also include several variants. The products of the genes DR (α and β), DP (α and β), and DQ (α and β) encoding the corresponding polypeptide chains of the molecules are directly involved in the presentation of the antigen.

MHC class III genes are not the part of histocompatibility molecules and their presentation. They encode some complement components, TNF-family cytokines, heat shock proteins.
Pic. 2. Genes of the major histocompatibility complex.

Genetic polymorphism.

The genes of MHC complex (unlike the TCR or Ig genes) do not undergo recombination. The mechanism of their adaptation to an unlimited set of antigens lies in their genetic polymorphism (co-dominance, multiplicity of alleles, natural selection).

Co-dominance is the simultaneous expression of the genes of the maternal and paternal chromosomes. The MHC-I have 3 genes (A, B, C) in each of the homologous chromosomes, and the MHC-II genes have also 3 of them (DP, DQ, DR). Thus, if the mother and father do not have the same alleles, each person has 12 different alleles of the MHC genes.

Multiplicity of alleles. The polymorphism of the classical MHC genes means that the population has many alleles-variants of the same gene in different individuals. There can be more than 100 allelic variants of individual MHC loci. Each allelic variant of the MHC molecule binds peptides to certain "anchor" amino acid residues.

Natural selection. Each individual is potentially able to develop a response only to those peptides that are able to bind the MHC glycoproteins of this individual. Specific variants of MHC are fixed in evolution by natural selection, and each individual is adapted to the regional species and strains of microorganisms, which were protected from the selection of MHC in the ancestors.

Non-classical MHC genes are not polymorphic or not as polymorphic as classical MHC genes.

The value of MHC polymorphism.

Genetic polymorphism reflects the adaptive potential of a population and a species. The wider it is, the more likely it is that there are individuals within the species that can survive extreme changes in environmental conditions. Microorganisms, having a high rate of reproduction and the ability to change, represent a potential danger to the existence of highly organized living beings, whose MHC molecules are the main structures that present infectious antigens. Their ability to bind foreign peptides and activate T-lymphocytes largely determines the level of response of the adaptive immune system to an infectious agent. It is no coincidence that the pathogenic properties of viruses are due to the ability to inhibit the expression of MHC molecules. It was the diversity of microorganisms that led to the polymorphism of MHC, but the amount of hereditary information is limited by the capacity of the cell nucleus, and an individual is not able to have the entire possible spectrum of allelic diversity in the genome. Nature has distributed it among individuals within the species. Thus, the polymorphism of the HLA genes protects all of humanity from extinction, but not its individual representatives.

Antigenic peptide - MHC complexes.

The formation of complexes of antigenic peptides with MHC of different classes occurs in different cell compartments.

MHC-I "serve" the zone of the cytosol communicating through the nuclear pores with the contents of the nucleus. This is where the "folding" (assuming the correct conformation) of the synthesized protein molecules takes place. When errors occur, including during the synthesis of viral proteins, protein products are broken down in multiprotease complexes (proteosomes). The resulting peptides bind to MHC-I molecules. As a result, MHC-I molecules present peptide antigens (AG) formed inside the cell to T-lymphocytes, that is why CD8+ T-lymphocytes, which recognize antigen complexes with MHC-I, are primarily involved in protecting against viral as well as intracellular bacterial infectious diseases.

МНС-II. The area of MHC-II is associated with the extracellular environment, as well as with cellular organelles (Golgi apparatus, endoplasmic reticulum, lysosomes, endosomes, phagosomes). Peptides, formed in this zone are of extracellular origin, are the products of proteolysis of proteins captured by the cell by endocytosis or phagocytosis. The newly synthesized molecules of the α-and β-chains of MHC-II with the help of the invariant polypeptide chain Ii and calnexin are exposed inside the vesicles and only here, having bound to the peptide antigen, take the necessary conformation for further representation on the cell membrane. MHC-II molecules represent antigen in the development of immune response on extracellular pathogens. The main role in this response is played by CD4+ T-lymphocytes, which recognize antigen in combination with MHC-II
Pic. 3. Antigen processing and presenatation.

Superantigens

Infectious superantigens are the most powerful of all known T-cell mitogens. They cause uncontrolled activation of T-lymphocytes, which is accompanied by fever, shock, and sometimes death. Their feature is that they interact with MHC Class II molecules without affecting the peptide-binding cavity. At the moment when the MHC structure is recognized by Th, another part of the superantigen molecule is fixed on a variable fragment of the TCR β-chain. As a result, the APC and T-lymphocyte receive activation signals and begin to produce pro-inflammatory cytokines: TNFa, IL-1, IFNγ, IL-2, etc. However, superantigens activate not 1 clone of T-lymphocytes, but up to 30% of all T-lymphocytes, and the cytokine volume produced by them increases many times, initiating systemic reactions. The consequence of total activation of T-cells is the development of delayed immunosuppression, since activated lymphocytes later undergo apoptosis. As a result, lymphopenia and areactivity are formed.

Staf.aureus, Str.pyogenes, Yersinia pseudotuberculosis, Mycobacterium tuberculosis, rabies virus, HIV, EBV, etc. include superantigens. G+ microorganisms secrete exotoxins - these are exogenous superantigens, and intracellular bacteria and viruses form endogenous superantigens, these toxins are usually fixed on the cell membrane and interact with the MHC or TCR of the same cell inside which they were produced.

Antigen-presenting CD1 molecules.

There are genes encoding antigen-presenting molecules (e.g., CD1 cluster genes encoding CD1a, CD1b, CD1c, CD1d, CD1e) outside of the MHC system. The products of these genes are heterodimers (consisting of α-chain and β-microglobulin). They are able to bind and present non-protein AG to T-lymphocytes. These heterodimer molecules are constitutively expressed on DC and B-lymphocytes, as well as on thymocytes and enterocytes. The antigen in combination with CD1 is recognized by γδT lymphocytes and NKT cells.

MHC molecules control the immune response.

Thus, MHC-II are involved in the presentation of AG to T-cells and in the interaction of T- and B-lymphocytes. MHC-I and MHC-II antigens bind to the surface markers of T-cells: MHC-I with CD8+, MHC-II with CD4+.

MHC-II molecules are expressed only on professional antigen-presenting cells (APC) - these are dendritic cells (DC) of bone marrow origin, B-lymphocytes and macrophages. All the co-receptor molecules necessary for the presentation of antigen to T-cells are located on their membrane, in addition to MHC-I class and MHC-II class molecules. They produce cytokines for the activation of T-lymphocytes and the launch of immune response.

The endothelium can also express MHC molecules.

The association of HLA with diseases.

HLA molecules can form the resistance and predisposition of the body to the development of various diseases, because they determine the tissue identity and levels of immune responses to a wide range of antigens.

Hereditary predisposition to certain diseases is caused not only by HLA genes, but also by genes of cytokines and their receptors, heat shock proteins, proteins involved in the processing of AGs and their transport, NK-lymphocyte receptors, etc. Many autoimmune diseases have associations with different alleles of MHC I or MHC II classes.

The functioning of a large number of genes is obligatory for the implementation of the immune response. Depending on the allelic forms of certain genes, the severity of the reactions of different parts of the immune response varies. The main stage in the immune response is the presentation of the antigenic epitope to the T-helper. The effectiveness of the presentation depends on the degree of correspondence between the epitope configurations and the antigen-binding cavity of the MHC-II molecule. In cases where the conformational features of the antigen-recognizing region of MHC class II molecules correspond to the structure of the antigen (more precisely, the antigenic epitopes), an immunogenic complex is formed, expressed on the surface of the antigen-presenting cells, which ensures the development of the immune response. On the contrary, the inability of MHC class II molecules of individuals of a certain genotype to interact with antigenic peptides will cause immune areactivity.

The genes of the immune response include genes that control:

antigen processing,
affinity of peptides to the antigen-binding cleft of the MHC molecule
Thus, the association of genetic control of the immune response with MHC class II genes (HLA-DR, HLA-DQ, HLA-DP) is clearly manifested in autoimmune diseases. In people with a certain genotype, the relative risk of developing autoimmune diseases is increased. For instance, in ankylosing spondylitis, a link with the HLA-B27 allele was found. And the predominant incorporation of autoantigenic peptides from thyroid and pancreatic proteins into HLA-B8 and HLA-DR3 molecules leads to a positive correlation between the incidence of Graves' disease, Hashimoto's thyroiditis, and juvenile diabetes mellitus with the presence of these alleles.

MHC-dependent genetic control of the immune response level also extends to the regulation of resistance to infections. Thus, the influenza virus peptides with the greatest affinity are embedded in the HLA-B27 and HLA-A2 molecules, as a result the carriers of these alleles, and especially the A2B27 haplotype, are resistant to influenza.