MHC Molecules: Definition, Properties, Class, Types, Signaling Pathways (2023)

The major histocompatibility complex can be defined as a group of closely linked genes whose products play an important role in intercellular recognition and the distinction between self and non-self. The term "histo" means tissue and "match" refers to "match or tolerability". On the other hand, the term "complex" refers to "genes located in a large genetic region containing multiple loci". These genes encode antigens that are used to determine the compatibility of the transplanted tissue. Compatible tissues are accepted in theimmune systemwhile histo-incompatible ones are rejected. Rejection of foreign tissue leads to an immune response to cell surface molecules. The concept was first identified by Peter Gorer and George Snell. The main function of MHC molecules is to carry antigen to the cell surface for recognition by T cells. In humans, the genes encoding MHC molecules are located on the short arm of chromosome 6.

Properties of Major Histocompatibility Complex (MHC) Molecules

• The major histocompatibility complex is a genetic locus that encodes the glycoprotein molecules (transplant antigens) responsible for the rejection of transplant tissue between genetically dissimilar individuals.
• It is also the molecule that binds to peptide antigens processed by antigen presenting cells and presents them to T cells, thus they are responsible for antigen recognition via T cell receptors.
• Unlike B cell receptors, which directly interact with antigens, T cell receptors have an intertwined relationship with the MHC molecule, in the sense that T cell receptors can only receive and bind processed antigens. in the form of peptides, which bind to the MHC molecule and therefore T cell receptors are specific for MHC molecules.
• In humans, the major histocompatibility complex is known as human leukocyte antigen (HLA). There are three common MHC molecules, namely class I, class II and class III MHC proteins.
• MHC genes exhibit genetic variability; and the MHC has multiple genes for each class, making it polygenic.
• The MHC is also polymorphic, which means that for each of the genes there are a large number of alleles in the population.
• Thus, there are a large number of alleles in the population for each of the genes. Each individual inherits a restricted set of alleles from its parent. MHC gene sets tend to be inherited as a block, or haplotype. There are relatively rare crossover events at this location.
• The structure of MHC class I has two closely spaced domains consisting of two parallel α-helices on a platform generated by a β-sheet. The general structure looks like a slit with sides formed by α helices and a β sheet at the bottom.
• In general, MHC molecules have a broad specificity for peptide antigens, and any MHC allele can present many different peptides, each binding to a single peptide.
• The α-helices that form the binding clefts are the location of amino acid residues that are polymorphic (different allelic forms) in MHC proteins, meaning that different alleles can bind and present different peptide antigens. For all these reasons, the MHC polymorphism has a great impact on antigen recognition.
• The role of T cells in the interaction with MHC molecules shows that the peptide antigens associated with MHC class I molecules are recognized by CD8+ cytotoxic T lymphocytes (Tc cells) and the peptide antigens associated with MHC class II molecules they are recognized by CD4+ T helper cells (Th cells). ).
• The MHC in humans is known asHuman Leukocyte Antigen (HLA) Complex.

HLA complex

In humans, the HLA gene complex is located on the short arm of chromosome 6, which contains several genes critical for immune function. The HLA gene complex is divided into three classes as follows:

1. Clase I:HLA-A, HLA-B and HLA-C.
2. Class II:HLA-DR, HLA-DQ and HLA-DP. All of these are present in the HLA-D region of the HLA complex.
3. Class III:Complement sites encoding C2, C4 and factor B of the complement system and TNF alpha and beta.

Gene products of the HLA complex

1. Genes MHC Clase IIt encodes glycoproteins expressed on the surface of almost all nucleated cells; the main function of class I gene products is the presentation of endogenous peptide antigens to CD8⁺T cells.
2. Genes make MHC class IIencode glycoproteins that are predominantly expressed in APCs (macrophages, dendritic cells, and B cells), where they present mainly foreign antigenic peptides for CD4⁺T cells.
3. Genes make MHC class IIIthey encode several different proteins, some with immunological functions, including components of the complement system and molecules involved in inflammation.

Major Histocompatibility Complex (MHC)-Typen

In humans, MHC molecules are classified into three types, class I, class II, and class III. MHC class I molecules are encoded by three different loci called A, B, and C, and these molecules are expressed in all nucleated cells. MHC class II genes are located in the D region and there are multiple loci such as DR, DQ and DP, and these molecules are expressed only on antigen presenting cells. MHC class III genes are encoded in the region between the class I and class II genes. MHC class III genes encode cytokines and complement proteins that play important roles in the immune response.

MHC class I molecule

• The structure of the MHC class I molecule consists of two polypeptide chains α and β. These two chains are connected to each other by non-covalent bonds. The α chain is characterized as an inner membrane glycoprotein with a molecular weight of 45,000 Da (in humans). The β chain is an extracellular microglobulin with a molecular mass of 12 kDa.
• The α chain consists of about 350 amino acids and is also divided into three globular α domains.₁, A₂it's a₃. Each of these domains contains about 90 amino acids. The N terminus of the α chain is the α site₁domain, while α₂it's a₃are present after α₁oA₂the domain is characterized by the formation of a loop of 63 amino acids; The loop is formed due to a disulfide bond within the chain. He₃it also contains a disulfide bond spanning 86 amino acids. the A₁it's a₂The domains interact to form peptide-binding portions of the MHC class I molecule.
• In addition, the α chain also consists of a stretch of 26 hydrophobic amino acids that supports the α chain in the plasma membrane. This transmembrane segment exists as an α helix in the hydrophobic region of the plasma membrane. An intracellular domain or the carboxy terminus of the α chain is located within the cell and contains approximately 30 to 40 amino acids.
• The β chain is non-polymorphic in humans and dimorphic in mice. He₃and the β chain are structurally similar to the immunoglobulin C domain and are also characterized as a disulfide loop. A peptide-binding platform is made up of β sheets of α₁it's a₂
• T_ZytThe cell (cytotoxic T cell) has specificity for cells containing MHC class I associated peptides due to the presence of the CD8 antigen on the surface of the Tcyt cells. CD8 antigen has affinity for α₃Dominance of MHC class I molecules.

MHC class II molecule

• MHC class II molecules are heterodimers and are characterized by two non-covalently linked polypeptide chains. The chains are called the heavy chain (α, 30 kDa) and light chain (β, 26 kDa).
• Like MHC class I molecules, MHC class II molecules are characterized by an extracellular amino-terminal domain, a transmembrane domain, and an intracellular carboxy-terminal tail.
• MHC class II molecules are expressed on the surface of antigen-presenting cells, such as B cells, dendritic cells, and macrophages.
• The α chain is divided into two α domains.₁it's a₂, while the β chain also splits into two β groups₁and ß₂. a ß₂The domain is responsible for binding to the CD4 T cell co-receptor. the A₁and ß₁Domains, on the other hand, are involved in the formation of antigen binding sites. Peptides containing 13 to 20 amino acids can bind to the MHC class II antigen-binding site.
• The presence of disulfide bridges in α_2,B_1,and ß₂Domains are also an important structural feature of MHC class II molecules.

MHC class III molecule

• There are several serum proteases involved in the complement system that fall into the MHC class III group of molecules.
• MHC class III molecules are not involved in antigen presentation.
• Complement components such as C2, C4A and C4B and factor B are the main compounds involved as MHC class III molecules. In addition to these tumor necrosis factors, α and β factors and some heat shock proteins also fall into this category.

distribution of MHC

Essentially all nucleated cells carry classical class I molecules. These are abundantly expressed in lymphoid cells, less so in liver, lung, and kidney, and only poorly in brain and skeletal muscle. In humans, the surface of the villous trophoblast lacks HLA-A and -B and has HLA G, which is not found on any other cell in the body. Class II molecules also have restricted expression, as they are only present on antigen-presenting cells (APCs), such as B cells, dendritic cells, and macrophages, and on thymic epithelium. When activated by drugs such as interferon g, capillary endothelium and many epithelial cells in tissues other than the thymus can develop a class II surface and increase expression of class I.

They act as cell surface markers, allowing infected cells to signal helper and cytotoxic T cells.

meaning of chm

1. The antibody molecules interact directly with the antigen, but the T cell receptor (TCR) only recognizes the antigen presented by the MHC molecules on another cell, the antigen presenting cell. The TCR is antigen-specific, but the antigen must be presented on a self-MHC molecule.
2. The TCR is also specific for the MHC molecule. When the antigen is presented by another allelic form of the MHC molecule in vitro (usually in an experimental setting), it is not recognized by the TCR. This phenomenon is known asMHC restriction.

Peptide antigens associated with MHC class I molecules are recognized by CD8⁺cytotoxic T lymphocytes, while class II-associated peptide antigens are recognized by CD4⁺helper T lymphocytes

antigen presentation and processing

T cells can recognize foreign antigens if the antigen is bound to MHC molecules, such as an MHC peptide complex. The formation of the MHC-peptide complex requires protein-antigen degradation in several steps. The degradation process is called antigen processing. These broken proteins then bind to MHC molecules inside the cell, and the MHC molecules are then transported to the membrane to present antigen to the T cell.

Antigen presentation pathway: MHC class I molecules (cytosolic pathway)

• MHC class I molecules are involved in the presentation of intracellular or endogenous pathogens or antigens. Intracellular pathogens refer to organisms that live and replicate within the host cell. An example of this type of pathogen is a virus.
• Under normal conditions, MHC class I molecules form a complex with self peptides or self antigens. In the case of viral infection, MHC class I molecules present the virus-derived peptide, which is subsequently recognized by T cells.
• Cellular components such as the nucleus, the endoplasmic reticulum, and the Golgi apparatus play important roles in antigen processing and presentation.
• When a virus infects a normal cell, the viral DNA travels into the cell and uses the host cell's machinery to make viral proteins. Viral proteins are synthesized in the cytosol.
• The cytoplasm also contains a cylindrical protein complex called the proteasome. The main function of the proteasome is to break down unwanted or damaged protein into smaller peptides. At the time of viral infection, the viral proteins interacted with proteasomes present in the cytoplasm. Processing took place in the cytosol, and as a result, proteins are broken down into smaller peptides (8 to 15 amino acids in length).
• In the next step, these fragmented peptides are transported to the endoplasmic reticulum. Transport was due to a peptide delivery system called the antigen-associated transporter (TAP). TAP consists of two domains or subunits called TAP 1 and TAP 2.
• Within the endoplasmic reticulum, the α and β chains of MHC class I molecules are synthesized and, with the help of a set of chaperone proteins, the MHC class I molecule is formed and translocated to the TAP. As a result, the peptides bind to the peptide binding site of the MHC class I molecule within the endoplasmic reticulum and form the MHC class I peptide complex.
• In the next step, the MHC class I peptide complex moves to the surface of the Golgi apparatus and, with the help of secretory vesicles, to the surface of the plasma membrane.
• Once the MHC class I peptide complex reaches the cell surface, T cell receptors recognize the antigen-peptide complex. In addition, the CD8 T-cell coreceptor binds to the α receptor.₃Domain of the MHC class I molecule. Therefore, the antigen is presented to the T cell.

Antigen presentation pathway: MHC class II molecules (endocytic pathway)

• MHC class II molecules are responsible for the presentation of exogenous or extracellular pathogens or antigens. Extracellular pathogen refers to organisms that can grow and reproduce outside of the host cell. Bacteria, exotoxins, and parasites are examples of extracellular antigens. These antigens are taken up by the cell by endocytosis or phagocytosis.
• Only antigen presenting cells are involved in the processing and presentation of antigens by MHC class II molecules. These cells include B cells, macrophages, and dendritic cells. The pathway occurred only after the antigen had been engulfed by the antigen-presenting cells.
• Inside the cell, the antigen is covered by a sheath called the endosome. The endosome fuses with the lysosome present in the cytoplasm, forming endolysosomes. As a result, the foreign protein is broken down by the proteolytic enzyme present within the lysosome and small peptides are formed.
• MHC class II molecules are synthesized and formed in the endoplasmic reticulum. The α and β chains of the molecule are also associated with the invariant chain. This association helps to restrict the binding of the autoantigen to the MHC class II molecule. The MHC invariant chain complex is then transported from the endoplasmic reticulum to the Golgi apparatus and from the Golgi apparatus to another vesicle. Inside the vesicle, the invariant chain is digested and only a small fragment (class II associated invariant chain polypeptide: CLIP) is bound to the molecule.
• In the next step, the vesicle containing the MHC class II molecule is fused with the vesicle containing the fragmented peptides. The cleaved peptide then binds to the MHC class II molecule displacing the CLIP. This newly formed MHC class II peptide complex is then transported to the cell surface.
• Once on the cell surface, the antigen is presented to the T cell. The T cell recognizes the peptide bound to the MHC class II molecule through the T cell receptor and the CD4 co-receptor binds to β₂Domain of the MHC class II molecule.

references

1. Fahim Halim Khan, The Elements of Immunology, Pearson Education.
2. Thomas J. Kindt, Barbara A. Osborne, Richard Goldsby, Inmunología de Kuby, 6^ºedition.

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