Major histocompatibility complex………………………………………...3

The structure of the major histocompatibility complex………………………………6

Molecules of the major histocompatibility complex…………………………..8

Functions of the Major Histocompatibility Complex…………………………..14

MHC antigens: research history……………………………………………………………………………………………………………………16

List of used literature…………………………………………...18
Major histocompatibility complex.

The major histocompatibility complex is a group of genes and the cell surface antigens they encode that play a critical role in foreign recognition and the development of an immune response.

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.

The discovery of MHC occurred in the study of issues of intraspecific tissue grafting.

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

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

The high polymorphism of MHC molecules, as well as the ability of each antigen-presenting cell (APC) to express several different MHC molecules, allows the presentation of many different antigenic peptides to T cells.

It should be noted that although MHC molecules are usually called antigens, they exhibit antigenicity only when they are recognized by the immune system of a genetically different organism rather than one's own, for example, during organ allotransplantation.

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

There are also MHC class III molecules, but MHC class I molecules and MHC class II molecules are the most important immunologically.

major histocompatibility complex characterized by extremely pronounced polymorphism. No other genetic system in the body has as many allelic forms as the MHC genes.

For a long time, the biological meaning of such a pronounced polymorphism remained incomprehensible, although some selective significance of such allelic variability was obvious. Subsequently, it was proved that such polymorphism is directly related to the process of presentation of antigenic determinants to T cells.

The phenomenon of genetic control of the immune response is associated with the polymorphism of MHC antigens. In cases where the amino acid residues that form the antigen-binding cleft at class II molecules, unable to bind the peptide fragment of the foreign antigen, T-helpers remain unreactive, and their assistance to B-cells is not realized. This circumstance is the cause of a genetically determined defect in the immune response.

The main events that led to the formation of MHC gene diversity in the course of evolution are associated with tandem duplications, point mutations, recombinations, and conversion of genetic material. Tandem duplications (the process of repeating an original gene on the same chromosome) are well known for many genetic systems that control protein synthesis, for example, immunoglobulins. It is as a result of this process that several polygenic forms of MHC molecules have arisen. Spontaneous substitutions of individual nucleotides during DNA replication (point mutations) are also well known; they lead to the formation of allelic genes, which also determine protein polymorphism. Recombinations between individual sections of homologous chromosomes during meiosis can lead to the exchange of both entire sections of these chromosomes, as well as individual genes and even parts of genes. In the latter case, the process is called gene conversion. Mutations, recombinations and conversion of genes create a variety of their allelic forms and determine the polymorphism of MHC antigens.

Such a high degree of polymorphism is of potential value for the survival of the species, and it is thanks to it that the entire species does not become a victim of microbial mimicry, in which they express structures close in conformation to MHC products. T-cells, capable of recognizing the unique individual combination of the specificities of their own organism, are able to respond to the products of such mimicry as if they were foreign. In addition, it is possible that such a high balanced polymorphism of MHC products provides a wider variety of antigens recognized by the immune system of a given species, as well as heterosis (hybrid strength), since maximum allele combinatorics occurs in heterozygotes. Siblings have a one in four chance of being identical for MHC antigens.
The structure of the major histocompatibility complex.

Chromosomal hybridization has established that the MHC system is localized on the short arm of the 6th human autosomal chromosome, while in mice it is located on the 17th chromosome.

R
is. 1. Schematic representation of chromosome 6.
The major histocompatibility complex occupies a significant stretch of DNA, including up to 4 * 106 base pairs or about 50 genes. The main feature of the complex is significant polygenicity (the presence of several non-allelic closely linked genes, the protein products of which are structurally similar and perform identical functions) and pronounced polymorphism - the presence of many allelic forms of the same gene. All genes of the complex are inherited according to co-dominant type.

Polygenicity and polymorphism (structural variability) determine the antigenic individuality of individuals of a given species.

All MHC genes are divided into three groups. Each group includes genes that control the synthesis of polypeptides of one of the three MHC classes (I, II, and III) (Fig. 3.5). Between the molecules of the first two classes there are pronounced structural differences, but at the same time, according to the general plan of the structure, they are all of the same type. At the same time, no functional or structural similarity was found between the gene products of class III, on the one hand, and classes I and II, on the other hand. A group of more than 20 class III genes is generally functionally isolated - some of these genes encode, for example, proteins complement systems( C4 , C2 , factor B ) or molecules involved in antigen processing .

The area of ​​localization of the genes encoding the complex of mouse MHC molecules is designated as H-2, for humans - HLA.

HLA-A , HLA-B and HLA-C are chromosomal loci whose genes control the synthesis of "classical" molecules (antigens) of class I human MHC and encode the heavy chain (alpha chain). The region of these loci occupies a region longer than 1500 kb.

The synthesis of molecules (antigens) of class II human MHC is controlled by the genes of the HLA-D region, which encode at least six variants of alpha and ten variants of beta chains (Fig. 3.5). These genes occupy the three loci HLA-DP, HLA-DQ and HLA-DR. Most of the class II molecules belong to the products of their expression.

In addition, the HLA-D region includes the HLA-LMP and HLA-TAP genes. Small molecular weight proteins controlled by these genes are involved in the preparation of a foreign antigen for presentation to T cells.

The genes of the human loci HLA-A, HLA-B and HLA-C encode the heavy chain (alpha chain) of the "classic" MHC class I molecules. In addition, numerous additional genes have been found outside these loci, encoding "non-classical" MHC class I molecules and located in such HLA loci as HLA-X HLA-F, HLA-E, HLA-J, HLA-H, HLA-G, HLA-F.

Molecules of the major histocompatibility complex.

The spatial organization of MHC molecules has been elucidated by X-ray diffraction analysis:

Class I MHC molecules (HLA allelic variants: HLA-A, HLA-B, HLA-C) are expressed on the cell surface and are a heterodimer consisting of a single heavy alpha chain (45 kDa) non-covalently linked to a single domain beta2-microglobulin(12 kDa), which is also found in free form in the blood serum, they are called classic transplantation antigens .

The heavy chain consists of an extracellular portion (forming three domains: alpha1, alpha2 and alpha3 domains), a transmembrane segment, and a cytoplasmic tail domain. Each extracellular domain contains approximately 90 amino acid residues, and together they can be separated from the cell surface by treatment with papain.

The alpha2 and alpha3 domains each have one intrachain disulfide bond that loops 63 and 68 amino acid residues, respectively.

The alpha3 domain is homologous in amino acid sequence C-domains of immunoglobulins, and the conformation of the alpha3 domain resembles a folded structure immunoglobulin domains .

Beta2-microglobulin (beta2-m) necessary for the expression of all MHC class I molecules and has an unchanged sequence, but in the mouse it occurs in two forms, differing in the replacement of one amino acid at position 85. In structure, this protein corresponds to C-domain of immunoglobulins. Beta2-microglobulin can also non-covalently interact with nonclassical class I molecules, for example, with CD1 gene products.

Depending on the species and haplotype, the extracellular portion of class I MHC heavy chains is glycosylated to varying degrees.

The transmembrane segment of MHC class I consists of 25 predominantly hydrophobic amino acid residues and spans the lipid bilayer, most likely in an alpha-helical conformation.

The main property of class I molecules - binding peptides (antigens) and presenting them in an immunogenic form for T cells - depends on the alpha1 and alpha2 domains. These domains have significant alpha-helical regions, which, when interacting with each other, form an elongated cavity (slit) that serves as a binding site. processed antigen. The resulting antigen complex with alpha1 and alpha2 domains determines its immunogenicity and the ability to interact with antigen-recognizing receptors on T cells .

Class I includes A antigens, AB antigens, and AC antigens.

Class I antigens are present on the surface of all nucleated cells and platelets.

Class II MHC molecules are heterodimers built from non-covalently linked heavy alpha and light beta chains.

A number of facts indicate a close similarity of alpha and beta chains in terms of their general structure. The extracellular part of each of the chains is folded into two domains (alpha1, alpha2 and beta1, beta2, respectively) and connected by a short peptide to a transmembrane segment (approximately 30 amino acid residues long). The transmembrane segment transitions into a cytoplasmic domain containing approximately 10-15 residues.

The antigen-binding region of MHC class II molecules is formed by alpha helical regions of interacting chains like class I molecules, but with one significant difference: the antigen-binding cavity of MHC class II molecules is formed not by two domains of one alpha chain, but by two domains of different chains - alpha1 and beta1 domains.

The general structural similarity between the two classes of MHC molecules is evident. This is the uniformity of the spatial organization of the entire molecule, the number of domains (four), the conformational structure of the antigen-binding site.

In the structure of class II molecules, the antigen-binding cavity is more open than in class I molecules, so longer peptides can fit in it.

The most important function of MHC antigens (HLA) class II is to provide interactions between T-lymphocytes and macrophages during the course of the immune response. T-helpers recognize a foreign antigen only after it has been processed by macrophages, combined with HLA class II antigens, and the appearance of this complex on the surface of the macrophage.

Class II antigens are present on the surface of B lymphocytes, activated T lymphocytes, monocytes, macrophages, and dendritic cells.

MHC class II genes encode membrane-bound transmembrane peptides (glycoproteins). Molecules of class II histocompatibility antigens (DR, DP, DQ), as well as class I, are heterodimeric proteins consisting of a heavy alpha chain (33 kDa) and a light beta chain (26 kDa), encoded by the genes of the HLA complex. Both chains form two domains: alpha1 and alpha2, as well as beta1 and beta2.

MHC class II products are associated mainly with B-lymphocytes and macrophages and serve as recognition structures for T-helpers.

MHC class III genes, located within or closely linked to the MHC gene group, control several complement components: C4 and C2, as well as factor B, which are located in the blood plasma rather than on the cell surface. And unlike MHC class I and class II molecules, they are not involved in the control of the immune response.

The term MHC class IV is used to describe certain MHC-linked loci.

The study of the expression of MHC class I and II molecules on various cell types revealed a wider tissue distribution of class I molecules compared to class II molecules. While class I molecules are expressed on almost all studied cells, class II molecules are expressed mainly on immunocompetent cells or cells that are relatively nonspecifically involved in the formation of the immune response, such as epithelial cells.

In table. 1 presents data on the nature of the tissue distribution of MHC molecules in mice and humans.

tab. 1 Tissue distribution of MHC class I and II molecules in mice and humans

cell type	H-2 complex mice		human HLA complex
	Class I	Class II	Class I	Class II
B cells	+	+	+	+
T cells	+	(+)	+	(+)
thymocytes	+	(+)	+	(+)
macrophages	+	+	+	+
Granulocytes	.	.	+	-
Reticulocytes	+	.	+	.
red blood cells	+	-	-	-
platelets	+	-	+	-
fibroblasts	+	-	+	-
epithelial cells	+	.	+	+
epidermal cells	+	+	+	+
Liver	+	-	+	-
Bud	+	-	+	-
cardiac muscle	+	-	+	-
Skeletal muscle	+	-	+	-
Brain	+	-	(+)	.
Placenta	+	.	+	.
spermatozoa	+	+	+	+
Oocytes	(+)	.	.	.
trophoblast	-	.	(+)	.
Blastocytes	+	.	.	.
Embryonic tissue	+	.	+	.

The representation of class I molecules on almost all cell types correlates with the dominant role of these molecules in allogeneic graft rejection. Class II molecules are less active in the process of tissue rejection. Comparative data on the degree of participation of molecules of I and II classes of MHC in some immune responses demonstrate that some properties of MHC are more associated with one of the classes, while others are a characteristic feature of both classes (Table 2)

Tab. 2 Participation of MHC class I and II molecules in some immune responses

Functions of the major histocompatibility complex.

Although MHC molecules were originally identified by their ability to cause transplant rejection, they also serve other biologically important functions in the body. First, they are directly involved in initiating the immune response by controlling molecules that present the antigen in immunogenic form for recognition by cytotoxic T cells and helper T cells. Secondly, the MHC contains genes that control the synthesis of immunoregulatory and effector molecules - cytokines TNF-alpha, TNF-beta, and some complement components.

It should be noted their role as surface cell markers recognized by cytotoxic T-lymphocytes and T-helpers in complex with the antigen. Molecules encoded by the Tla complex (region of part of the MHC genes) are involved in differentiation processes, especially in the embryo, and possibly in the placenta. MHC is involved in a variety of non-immunological processes, many of which are hormone-mediated, such as the regulation of body weight in mice or egg production in chickens. MHC class I molecules can be part of hormone receptors. Thus, insulin binding is markedly reduced if MHC class I antigens, but not class II antigens, are removed from the cell surface. In addition, associations of MHC products with glucagon, epidermal growth factor, and gamma-endorphin receptors have been described. On fig. Table 3 presents the functions of MHC products, and the main immunological properties associated with MHC are listed in Table. 3 .

rice. 3 im MHC: functions

Tab. 3 Immunological properties associated with MHC

These facts make us think that MHC evolved and developed specifically for the implementation of immunological functions.

A special place is occupied by the question of the relationship of MHC molecules with diseases. In some forms of noncommunicable diseases, the frequency of individual antigens among patients is much higher than in the population of healthy people. Clear mechanisms for such a correlation could not be established. However, it is clear that the mechanisms are likely to be different in different forms of the disease. With the help of HLA typing, it was possible to confirm the commonality of some disorders or to approach the issue of their classification in a new way. An important conclusion was made that in the body there are various groups of MHC antigens associated with diseases. Some of them are associated with resistance or, conversely, with susceptibility, and others with the severity of their course, and, finally, others with the life expectancy of patients.

It has now become apparent that class II MHC products are critical in the pathogenesis autoimmune diseases. In this regard, inevitably arose the desire to associate autoimmune diseases with immunoreactivity genes that control the response to the corresponding autoantigen or to any probable etiological agent.

MHC antigens: a history of research.

In the history of the study of histocompatibility antigens, the following stages are the most significant:

1958 - the first human histocompatibility antigen Mac (HLA-A2, J. Dasse) was discovered;

1966 - the leading role of HLA antigens in the development of graft rejection was proved (J. van Ruud et al.);

1972 - a correlation was established between allelic variants of HLA antigens and certain diseases (Z. Falchuk et al.);

1973 - the structure of HLA class I antigens was established (K. Nakamura et al.);

1974 - the role of histocompatibility antigens in limiting the immune response was shown (double recognition, R. Zinkernagel, P. Doherty);

1981 - isolation and determination of the amino acid sequence of HLA class II antigens was carried out (G. Kratzin et al.);

1983 - demonstrated biochemical polymorphism of HLA antigens (R. Vasilov et al.);

1987 - the spatial structure of the HLA-A2 antigen was determined (P. Berkman et al.);

1991-1993 - the nature of the distribution of HLA antigens in most ethnic groups of the planet was established

List of used literature.

Immunology, ed. E. S. Voronina, M.: Kolos-Press, 2002
J. Kolman, K.- G. Rem, Visual biochemistry, M .: Mir 2000
Sochnev A.M. , Alekseev L.P. ,Tananov A.T. Antigens of the HLA system in various diseases and transplantation. – Riga, 1987
www.humbio.ru
www.rusmedserver.ru/med/haris/60.html

They provide the presentation (presentation) of fragments of antigens of microorganisms that enter the body to T-lymphocytes, which destroy infected cells or stimulate other cells (B-cells and macrophages), which ensures coordination of the actions of various cells of the immune system in suppressing infection. In humans, the major histocompatibility complex is located on chromosome 6 and is called the human leukocyte antigen.

MHC and sexual partner choice

A number of independent studies in the 1970s-1990s. showed that the choice of a sexual partner is influenced by the major histocompatibility complex. Experiments conducted initially on mice and fish, then on volunteer human participants, showed that women tended to choose partners with MHC different from their own, however, their choice was reversed in the case of using hormonal oral contraceptives - in this case, women were more likely to choose partner with a similar GKG

see also

Notes

Links

Literature

• Meil, D. Immunology / D. Meil, J. Brostoff, D. B. Roth, A. Reutt / Per. from English. – M.: Logosphere, 2007. – 568 p.
• Koiko, R. Immunology / R. Koiko, D. Sunshine, E. Benjamini; per. from English. A.V. Kamaeva, A.Yu. Kuznetsova, ed. N.B. Silver. -M: Publishing Center "Academy", 2008. - 368 p.

Wikimedia Foundation. 2010 .

See what the "Major Histocompatibility Complex" is in other dictionaries:

- (MHC major histocompability complex) fam. genes encoding molecules of 3 classes. In humans, this is the HLA complex located on the 6th chromosome. Provides somatic individuality and immunoreactivity of the individual. Genes/classes are expressed on... Dictionary of microbiology

major histocompatibility complex- - Biotechnology topics EN major histocompatibility complex ... Technical Translator's Handbook

Major histocompatibility complex, MHC major histocompatibility complex. Relatively small region of the genome, which contains numerous genes whose products perform functions associated with the immune response

MAIN HISTOCOMPATIBILITY COMPLEX (MHC)- A complex of genes encoding a group of proteins that provide recognition of foreign antigens in the body, i.e. substances that are not genetically characteristic of this organism. The designation of MHC of different animal species is as follows: human HLA; BoLA large… … Terms and definitions used in breeding, genetics and reproduction of farm animals

A number of genes located on chromosome No. 6 that code for several antigens, including HLA antigens; these genes play an important role in the process of determining histocompatibility in humans. Source: Medical Dictionary... medical terms

HISTO COMPATIBILITY COMPLEX MAIN- (major histocompatibility complex, MHC) a number of genes located on chromosome No. 6 that encode some antigens, including HLA antigens; these genes play an important role in the process of determining human histocompatibility... Explanatory Dictionary of Medicine

histocompatibility antigen- * histocompatibility antigen - a genetically encoded alloantigen located on the surface of cells that controls the response of the immune system to the transplant, as a result of which it is rejected or not (see). ... ...

Leukocyte antigen complex CLG- Leukocyte antigen complex, CLG * human leukocyte antigen complex or HLA c. the main gene histocompatibility complex (see) in humans, which occupies a 3500 kb section in DNA on the short arm of the 6th ... Genetics. encyclopedic Dictionary

H2-Complex- * H2 complex * H2 complex is the major histocompatibility complex in mice. Localized on chromosome 17. Represented by a large group of haplotypes ... Genetics. encyclopedic Dictionary

H2 complex H2 complex. major histocompatibility complex mice; localized on chromosome 17, represented by a large group of haplotypes among them, one of the most studied are t haplotypes Molecular biology and genetics. Dictionary.

Books

• , Khaitov Rakhim Musaevich , Organ, tissue, cellular and molecular aspects of the structure and functioning of the immune system are presented in the textbook, the components of the immune system, populations are considered ... Category: Anatomy and Physiology Publisher: GEOTAR-Media,
• Immunology. Structure and functions of the immune system. Textbook, Khaitov Rakhim Musaevich, The textbook presents modern immunological knowledge, acceptable for biologists who begin to study the subject, as well as for experienced professionals and teachers. Presented… Category:

1646 0

Molecule structure of class I major histocompatibility complex

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

Rice. 9.3. Different images of the major histocompatibility complex class I molecule

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

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

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

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

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

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

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

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

Molecule structure of major histocompatibility complex class II

The α and β MHC class II genes encode chains with a mass of about 35,000 and 28,000 Da, respectively. On fig. 9.4, A shows that class II MHC molecules, like class I, are transmembrane glycoproteins with cytoplasmic "tails" and extracellular domains similar to Ig; the domains are α1, α2, β1, and β2.

Major histocompatibility complex class II molecules are also members of the immunoglobulin superfamily. As with class I MHC molecules, class II MHC molecules include variable, or polymorphic (different for different alleles), and invariable, or non-polymorphic (common for all alleles) regions. The T-cell molecule CD4 is attached to the invariant part of all major histocompatibility complex class II molecules.

Rice. 9.4. Different images of the major histocompatibility complex moleculeII class

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

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

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

R. Koiko, D. Sunshine, E. Benjamini

GOU VPO Tver State Medical Academy of the Ministry of Health of Russia Department of Clinical Immunology with Allergology

MAIN HISTO COMPATIBILITY COMPLEX

Teaching aid for general immunology. Tver 2008.

Products

Educational and methodological development for practical classes in general immunology for 5th year students of the medical and pediatric faculties, as well as for clinical residents and doctors interested in immunology.

Compiled by Associate Professor Yu.I. Budchanov.

Head of the Department, Professor A.A. Mikhailenko

© Budchanov Yu.I. 2008

Motivation Immunogenetics is a new and important branch of immunology. Knowledge of the histocompatibility system

is necessary not only in transplantology, but also in understanding the regulation of the immune response, and the interaction of cells in the immune response. The determination of HLA antigens is used in forensic medicine, population genetic studies and in the study of the gene of predisposition to diseases.

1. The student must know: A. The structure of the human HLA system.

B. HLA antigens of classes I, II and their role in intercellular interactions. B. The concepts of genotype, phenotype, haplotype.

D. Significance of HLA typing in medicine.

E. Relationship between HLA antigens and a number of human diseases. 2. The student must be able to:

Apply the acquired knowledge of immunogenetics in clinical practice.

Questions for self-preparation on the topic of the lesson:

1. The concept of genes and antigens of histocompatibility. HLA human system. Nomenclature, gene organization (genes of classes I, II, III).

2. Antigens of classes I and III, their role in intercellular interactions, in antigen presentation T-lymphocytes, in the phenomenon of double recognition.

3. The concept of HLA phenotype, genotype, haplotype. Features of inheritance.

4. Methods for research and typing of the HLA system: serological, cell-mediated, gene (polymerase chain reaction, DNA probes).

5. Practical aspects of typing HLA antigens. HLA in populations, biological significance.

6. HLA and human diseases, association mechanisms.

LITERATURE FOR SELF-EDUCATION

1. Khaitov R.M., Ignatieva G.A., Sidorovich I.G. Immunology. Norm and pathology. Textbook. - 3rd

ed., M., Medicine, 2010. - 752 p. – [p.241 - 263].

2. Khaitov R.M. Immunology: a textbook for medical students. – M.: GEOTAR-Media, 2006. - 320p. - [With. 95-102].

3. Belozerov E.S. Clinical immunology and allergology. A-Ata., 1992, p. 31-34.

4. Zaretskaya Yu.M. Clinical immunogenetics. M., 1983.

5. Methodical development. 6. Lecture.

additional literature

Konenkov V.I. Medical and ecological immunogenetics. Novosibirsk, 1999 Yarilin A.A. Fundamentals of immunology. M., 1999, p. 213-226.

Alekseev L.P., Khaitov R.M. HLA and medicine. Sat. Modern problems of allergology, immunology and immunopharmacology. M., 2001, p. 240-260.

CAN YOU ANSWER?

(Enter at home. Self-control will identify difficult questions for discussion. In class, you will check the correctness of the answers, supplement them. Try to find answers on your own and show that you can do it.)

1. In which pair of chromosomes is the major histocompatibility complex located in humans? …………….

2. Cells of what organs and tissues contain transplant cells? …………antigens

……………………………………………………………………………….……………………. .

3. What does the abbreviation HLA stand for? …………………………………………………………………………….

………………………………………………………………………………………… .

4. On what cells are antigens of the HLA system not found? ……………………….…

…………………………………………………………………………………………. .

5. What loci, subloci does the MCGS consist of: Class I ……..……… Class II ………………………………

Grade III …………………………………….. .

6. Gene products of what class of MHCs are not expressed on the cell membrane? ……………………….

7. What cells should be isolated to detect HLA class II? ………………..…………………… .

8. How are HLA antigens detected? ………………………………………………………………

………………………………………………………………………………………….. .

9. Typed patient has 6 possible antigens HLA-A, HLA-B, HLA-C. What is the name of such a situation? …………………………….

10. What histocompatibility antigen is often found in patients with ankylosing spondylitis?

…………………….. .

11. What genes are included in HLA class III? ………………………………..……………………………

…………………………………………………………………………………………… .

12. What chains make up HLA class I antigens? ………………….

13. What chains do HLA class II antigens consist of? …………………

14. Cytotoxic lymphocyte (CD8) recognizes a foreign peptide in the complex with HLA of what class?

…………………………. .

15. Th (CD4+) recognizes a foreign antigen presented by a dendritic cell or a macrophage in combination with HLA of what class? …..………

What are the possible combinations of erythrocyte antigens in a child if the isoantigenic composition

erythrocytes
Father: AO, NM, ss, dd, Cc, Ee,		and mothers: AB, MM, SS, DD, Cc, EE.
Choose the correct answer.
	AO, MN, Ss, DD, CC, EE
	AA, MM, Ss, Dd, cc, ee
	OO, NN, Ss, Dd, CC, Ee
	AB, MN, Ss, Dd, cc, EE
	AO, NN, Ss, Dd, Cc, EE
	AB, MM, SS, Dd, cc, Ee
Write another correct answer ___, ___, ___, ___, ___, ___.			Can you do more?
How? …………. .

Reference and theoretical materials

The Major Histocompatibility Complex (MHC) is a system of genes that control the synthesis of antigens that determine tissue histocompatibility during organ transplants and induce reactions that cause transplant rejection. Surface structures of the cytomembrane of cells that induce reactions

rejection, got the name histocompatibility antigens, and the genes encoding them were called histocompatibility genes - H-genes (Histocompatibility). The discovery of histocompatibility antigens served as the basis for the development of transplantation immunology.

Subsequently, it was proved that the major histocompatibility complex is

the main genetic system that determines the functioning of the immune system,

especially the T-system of the immune system. GCGC regulates immune response,et encodes ability to recognize "one's own" and "alien", to reject foreign cells, the ability to synthesize a number of

The classical antigens of the HLA system are not detected at all in adipose tissue and on erythrocytes, as well as on neurons and trophoblast cells.

		LOCATION SCHEME OF THE HLA SYSTEM GENES
		ON CHROMOSOME 6
DP LMP TAP DQ DR		C2 Bf C4b C4a TNF

In humans, the main histocompatibility system is called the HLA system (Human Leukocyte Antigens). This is a system of genes that control the synthesis of histocompatibility antigens. It consists of three regions located on the short arm of the 6th chromosome. These regions are called: class 1, class 2, class 3 (class I, class II, class III). The region includes genes or loci. The name of each HLA gene contains the letter designation of the locus (A, B, C) and a serial number, for example: HLA-A3, HLA-B27, HLA-C2, etc. The antigens encoded by the gene also have the same designation.. At the D locus, 3 sublocuses (DP, DQ, DR) were identified. (See diagram above). There are 138 HLA antigens on the list approved by WHO. (However, the use of DNA typing, i.e. the ability to study the genes themselves, has led to the identification of more than 2000 alleles in just recent years).

Class I includes HLA - A, -B and -C loci. These three loci of the human major histocompatibility complex control the synthesis of transplantation antigens, which can be determined by serological methods (CD - Serological Determined). Molecules of HLA class I antigens consist of 2 subunits: α- and β-chains (see figure). The heavy or α-chain consists of 3 extracellular fragments - the α1, α2, and α3 domains (extracellular domains), a small region belonging to the cell membrane (transmembrane region) and an intracellular fragment (cytoplasmic region). The light chain is β2-microglobulin, non-covalently bound to the α-chain, and not bound to the cell membrane.

The α1 and α2 domains form a recess in which a peptide (antigen region) 8-10 amino acids long can be located. This depression is called peptide-binding cleft(from English cleft).

(New HLA class I antigens discovered recently include MIC and HLA-G antigens. Little is known about them at present. It should be noted that HLA-G, which is called non-classical, has only been identified

on the surface of trophoblast cells and it provides the mother with immunological tolerance to fetal antigens.)

Class 2 region (D-region) of the HLA system consists of 3 subloci: DR, DQ, DP, encoding transplantation antigens. These antigens belong to the category of antigens detected by cell-mediated methods, namely the reaction of a mixed lymphocyte culture (English mixed lymphocyte culture - MLC). More recently, the HLA-DM and -DN loci, as well as the TAP and LMP genes (not expressed on cells), have been isolated. The classic ones are DP, DQ, DR.

Presented peptide is shown in red.

Recently, antibodies have been obtained that can identify the DR and DQ antigens. Therefore, class 2 antigens are currently determined not only by cell-mediated methods, but also serologically, as well as class 1 HLA antigens.

Class 2 HLA molecules are heterodimeric glycoproteins consisting of two different α and β chains (see figure). Each chain contains 2 extracellular domains α1 and β1 at the N-terminal end, α2 and β2 (closer to the cell membrane). There are also transmembrane and cytoplasmic regions. The α1 and β1 domains form a recess that can bind peptides up to 30 amino acid residues long.

MHC-II proteins are not expressed on all cells. HLA class II molecules are present in large quantities on dendritic cells, macrophages and B-lymphocytes, i.e. on those cells that interact with helper T-lymphocytes during the immune response, using

HLA class II molecules

T-lymphocytes

significant amount

antigens of the 2nd class, but when stimulated with mitogens, IL-2

begin to express HLA class 2 molecules.

Necessary

Mark,

all 3 types of interferons

greatly enhance

expression

HLA molecules of the 1st

on the cell membrane of various cells. So

γ-interferon in

significantly enhances the expression of class 1 molecules on T- and B-lymphocytes, but also on malignant tumor cells (neuroblastoma and melanoma).

Sometimes a congenital disorder in the expression of HLA molecules of the 1st or 2nd class is found, which leads to the development of " naked lymphocyto syndrome in". Patients with such disorders suffer from insufficient immunity and often die in childhood.

The class III region contains genes whose products are directly involved in the immune response. It includes structural genes for complement components C2 and C4, Bf (properdin factor) and tumor necrosis factor-TNF (TNF) genes. This includes genes encoding the synthesis of 21hydroxylase. Thus, class 3 HLA gene products are not expressed on the cell membrane, but are in a free state.

The HLA-antigenic composition of human tissues is determined by allelic, genes related to each of the loci, i.e. one chromosome can have only one gene of each locus.

In accordance with the basic genetic patterns, each individual is a carrier no more than two alleles of each locuso and subloci (one on each of the paired autosomal chromosomes). The haplotype (a set of alleles on one chromosome) contains one allele of each of the HLA subloci. Moreover, if an individual is heterozygous for all alleles of the HLA complex, no more than twelve HLA antigens are detected in him during typing (A, B, C, DR, DQ, DP - subloci). If an individual is homozygous for some antigens, a smaller number of antigens is detected in him, but this number cannot be less than 6.

If the typed subject has the maximum possible number of HLA antigens, this is called a “full house” (“full house” of antigens).

The inheritance of HLA genes occurs according to the codominant type, in which the offspring in

The most rich in HLA antigens are lymphocytes. Therefore, the detection of these antigens is carried out on lymphocytes. ( Remember how to isolate lymphocytes from peripheral blood).

Molecules of antigens HLA-A, -B, -C make up about 1% of proteins on the surface of lymphocytes, which is approximately equal to 7 thousand molecules.

One of the most significant advances in immunology has been the discovery of the central role played by the MHC in mammals and humans in the regulation of the immune response. In strictly controlled experiments, it has been shown that the same antigen causes an immune response of different heights in organisms with different genotypes, and vice versa, the same organism can be reactive to varying degrees with respect to different antigens. The genes that control this highly specific immune response are called Ir-genes (Immune response genes). They are localized in the class 2 region of the human HLA system. Ir-gene control is realized through the -T system of lymphocytes.

Central			cellular		interactions			immune		you refuse
interaction			HLA molecules,			expressed					surfaces
antigen presenting cells			representing			for recognition		alien			antigenic
peptide, and antigen-recognizing receptor - TCR (T-cell receptor)							on the surface of the T-lymphocyte
helper. At		simultaneously			recognition		alien				going on

recognition of own HLA antigens.

T-lymphocyte helper (CD4+) recognizes a foreign antigen only in the complex with surface molecules of MHC class 2 antigen-presenting cells.

Cytotoxic lymphocytes (T-effectors, CD8+) recognize an antigen

for example, of a viral nature, in combination with an HLA molecule of class I of the target cell. Exogenous antigens are represented by class II HLA molecules,

endogenous - class I molecules.

(Thus, the process of foreign recognition is limited by self HLA antigens. This is the concept of "double recognition" or "altered self recognition".)

An important role of the HLA system is also that it controls the synthesis of complement factors involved in both the classical (C2 and C4) and alternative (Bf) pathways of complement activation. Genetically determined deficiency of these complement components can predispose to infectious and autoimmune diseases.

Practical value of HLA-typing. High polymorphism makes the HLA system an excellent marker in population genetic studies and the study of genetic predisposition to diseases, but at the same time creates problems in the selection of donor–recipient pairs in organ and tissue transplantation.

Population studies conducted in many countries of the world have revealed characteristic differences in the distribution of HLA antigens in different populations. Features of the distribution of HLA-

antigens are used in genetic research to study the structure, origin and evolution of different populations. For example, the Georgian population, belonging to the southern Caucasoids, has similar features of the HLA genetic profile with the Greek, Bulgarian, and Spanish populations, indicating a common origin.

Typing of HLA antigens is widely used in forensic practice to exclude or establish paternity or kinship.

Pay attention to the connection of some diseases with the presence of one or another HLA antigen in the genotype. This is because HLA is widely used to study the genetic basis predisposition to disease. If it was not previously assumed, for example, that the disease of multiple sclerosis has a hereditary basis, now, thanks to the study of the connection with the HLA system, the fact of a hereditary predisposition is firmly established. Using

	the HLA system, for some diseases, the mode of inheritance is also determined.
For example,	ankylosing		spondylitis		autosomal dominant			inheritance,
hemochromatosis and congenital adrenal hyperplasia - autosomal recessive. Thanks very much
	associations	ankylosing		spondylitis		HLA-B27 antigen, HLA typing

used in the diagnosis of early and unclear cases of this disease. Genetic markers of insulin-dependent diabetes mellitus have been identified.

PRACTICAL WORK

Determination of HLA antigens "in donors"

Typing of tissue antigens is performed using a set of sera, consisting of 50 or more antileukocyte sera (sera of multiparous women, giving from 10 to 80% positive reactions with fetal leukocytes, or sera of volunteers immunized

human	leukocytes containing				certain SD antigens.				Serums
multiparous women, as a result of natural immunization with husband's HLA antigens during
pregnancy, contain in some cases antibodies to HLA in a sufficiently high titer.).
Serologically		antigens			histocompatibility				define
lymphocytotoxic		test (English)		lymphocytotoxicity test).						called
micro lymphocytotoxic				use			staging			microvolume
ingredients.

Its principle is based on the interaction of HLA molecules on the surface of lymphocytes of the examined person with specific anti-HLA antibodies and complement, which leads to cell death. Cell death is determined by conventional light microscopy after staining with vital dyes.

Suspensions of lymphocytes are mixed with antiserum to a certain antigen (HLA-B8, HLA-B27, etc.), incubated for 1 hour at 25 C, complement is added and incubated again for 2 hours at 37 C, and then trypan blue or eosin is added. If an antigen corresponding to antibodies contained in the serum is present in lymphocytes, antibodies in the presence of complement damage the membrane of leukocytes, the dye penetrates into their cytoplasm and they stain blue or red (if eosin was used).

What cells will be stained with HLA typing?

Based on the results of typing, the degree of compatibility of the donor and recipient and the possibility of transplantation of an organ or tissue between them are established. The donor and recipient must be compatible in terms of erythrocyte antigens ABO and Rh, leukocyte antigens of the HLA system. However, in practice it is difficult to find completely compatible donor and recipient. Selection is reduced to the selection of the most suitable dono. Transplantation is possible with

incompatibility for one of the HLA antigens, but against the background of significant immunosuppression. Selection of the optimal ratio of histocompatibility antigens between the donor and the recipient significantly prolongs the life of the graft.

The lesson will demonstrate HLA plates for leukocyte typing. Recall how to obtain a pure suspension of lymphocytes from peripheral blood cells. Think about how to protect the contents of the wells from drying out during the reaction? How are serums for HLA typing obtained?

Currently, complement-fixing monoclonal antibodies (MAT) can be used for complement typing. They are used both in the microlymphocytotoxicity test and in the immunofluorescence test. Accounting for the reaction is possible both by luminescence microscopy and by using a flow cytometer.

		modern method		determination of HLA genes DNA typing. He
based on various variants of the polymerase chain reaction (PCR) and molecular hybridization.
	these methods		lies in	accumulation of necessary		analysis of significant
quantity			its polymerization and in use, complementary probes
analyzed sections of DNA. Moreover, one of the advantages of DNA typing is that it does not
the presence of viable lymphocytes is required, and the DNA of any cells is used. But
DNA can be stored for years or decades. Required for the reaction						expensive

oligonucleotide probes, primers.

The use of the molecular genetic method - DNA typing, made it possible to significantly expand the understanding of the polymorphism of the previously known genetic loci of the HLA-A, B, C, DR, DQ, DP system. In addition, new genes have been discovered, in particular TAP, DM, LMP and others. HLA class I - E, F, G, H genes have been discovered, but the function of their products is still unclear. As of December 1998, the number of identified alleles of the HLA complex genes was 942. And as of December 31, 2000, 1349 alleles were identified by molecular genetic DNA typing, and their detection continues to grow.

NEW HLA NOMENCLATURE. As already noted, HLA class 1 molecules consist of α- and β-chains. And is only polymorphicα-chain.piAllelic variants of coding genes received a four-digit name in the new nomenclature (for example, HLA-A0201 instead of the previously used designation HLA-A2, and 12 (!) New subtypes of this antigen (new allelic variants) were identified by molecular biology methods, which received the name A0201, A0202, A0203, ... to A0212). HLA-B27 has 9 allelic specificity variants, and only some of them are associated with ankylosing spondylitis (this, of course, increases their prognostic value).

Efficiency of allogeneic kidney transplantation (according to the results of annual survival in transplantation centers that have switched to donor selection based on molecular genetic

coordinating center for organ donation and the Institute of Immunology.

Even more impressive data obtained over the past 2-3 years in the course of national (primarily in the United States) and international programs for transplantation of allogeneic, "unrelated" bone marrow. Thanks to the transition of the selection of donor-recipient pairs to -DNA typing and the creation of a bank of HLA-genotyped donors, including 1.5 million people, the annual survival rate of transplanted bone marrow has been increased by 10s -20% to 70-80% (!). In turn, this led to number of bone marrow transplants from unrelated donors in the United States (which currently has the largest number of genotyped donors and recipients) from 1993 to 1997. increased more than 8 times. Stunning

The effect of unrelated bone marrow transplants is achieved solely through the selection of fully HLA compatible donor-recipient pairs by DNA typing.

The following is an excerpt from Academician R.V. Petrov's book "Me or not me: Immunological mobiles". M., 1983. - 272 p.

“... Receiving the Nobel Prize in 1930, in his solemn lecture on this subject, Karl Landsteiner said that the discovery of ever new antigens in human tissue cells would

theoretical interest. It has found, among other practical applications, forensic applications.

Imagine the following situation: it is necessary to determine the identity of a blood stain. Whose blood is it - human or animal? There is no need to explain that this situation is most often related to forensics. And the solution of the problem often becomes the answer to the main questions of the investigation. The only way to answer it is with the help of immune sera. By no means

other indicators to distinguish between the blood of a person and, for example, a dog is impossible. Microscopic or biochemical research methods are powerless.

Forensic doctors have in their arsenal a set of immune sera of various specificity: against human, horse, chicken, dog, cow, cat, etc. proteins. The spot under study is washed off, and then precipitation reactions are put. In this case, the entire set of immune sera is used. Which serum will cause precipitation, the type of animal or person belongs to the blood of the spot under study.

Let's say the forensic scientist concludes: "The knife is stained with human blood." And the murder suspect says, “Yes. But this is my blood. Not so long ago, I cut my finger with this knife. Then the examination continues. Antisera against blood groups and HLA antigens appear on the table of criminologists. And immunology again gives the exact answer: the blood belongs to the AB group, contains the M factor, Rh-negative, histocompatibility antigens such and such, etc. The situation is final

explained. The resulting characteristic completely coincides with the antigenic characteristics of the suspect's blood. Therefore, he told the truth, it is indeed his blood.

Let us dwell on one more situation, which has a great moral connotation. Imagine that a war or other disaster separated parents from their children. The children lost their names and surnames. Is it really impossible to find your child among others? After all, erythrocyte antigens and HLA are inherited. And if the father and mother do not have a factor, then the child cannot have it either. Conversely, if both parents belong to type A, then the child cannot have blood type B or AB. The same goes for HLA antigens. And with a very high degree of certainty.”

Establishing the authenticity of the remains of members of the royal family of Nicholas II was carried out in this way, using DNA typing.

for example, in England, questions of determining paternity are particularly scrupulous. But there it is most often associated not with the war. Strict laws on paternity are explained by strict laws on heirs and inheritance rights of capitals, titles, rights, privileges.

Imagine a lord declaring as his heir a young man who was not borne by his wife. Then it may be necessary to prove that the young man is his son. Or suddenly a gentleman appears, declaring himself the illegitimate son and, therefore, the heir of a millionaire. It may be true, but it may be that this gentleman is a swindler. The question is solved by the analysis of antigens of parents and children.

The distribution of HLA antigens turned out to be different in representatives of different races of nationalities. Since 1966, an intensive study of the structure of tissue compatibility antigens, initiated by WHO, has been carried out in all countries of the world. Soon the world map was covered with immunological hieroglyphs showing where and in what combination antigens are found.

HLA. Now there is perhaps no need, like Thor Heyerdahl, to equip an expedition on a reed boat to prove the migration of the population from South America to the islands of Polynesia. It is enough to look at a modern atlas of the distribution of HLA antigens and say with confidence that in both these geographical regions there are common genetic markers.

Polymorphism of classical HLA - antigens detected by serological and cell-mediated methods

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 MHC class II 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.