Major Histocompatibility Complex (MHC) encodes the MHC proteins present on the plasma membrane of all human tissue/cells. MHC is a tightly linked group of genes located on chromosome 6 in humans. MHC proteins are involved in intercellular recognition of foreign substance (antigen) to T-lymphocytes.

Haplotypes is the term used for a group of linked MHC genes inherited as a unit from parents. Human MHC molecules are termed as Human Leucocyte Antigens (HLA). MHC genes are polymorphic, many alleles are present for each gene and polygenic, many different MHC genes are present.

Classes

The classes I, II, and III of MHC genes express for molecules of classes I, II and III, respectively (table). Class I MHC genes have A, B and C gene loci. Glycoproteins (or class I MHC molecule) secreted by these genes are present on surface of nucleated cells. Class I MHC molecules present the peptide antigens to T_c cells.

The length of class I MHC gene in humans is ~2,000kb (about 20 genes) and is present at the telomeric terminus of the HLA complex. The length of class II MHC gene range is ~1,000kb and is present at the centromeric terminus of HLA. The length of class III genes is ~10,000kb and is present between the class I and II genes.

Table : Organisation of Major Histocompatibility Complex (MHC) HLA Genes in Chromosome 6 in Humans

In humans, the class II MHC genes have the DP, DQ and DR regions encoding the class II MHC molecules (glycoproteins) expressed on antigen presenting cells like macrophages, dendritic cells and B-cells. Class II genes present the processed antigenic peptides to T_H cells, and class II molecules provide immune response.

Class I and II molecules share the same structural features, and both function in antigen processing. Class III MHC gene is flanked by the Class I and II regions and encodes molecules important for immune function. The complement components of Class III MHC molecules are C₄, C₂, BF, inflammatory cytokines, Tunour Necrosis Factor (TNF), and heat shock proteins.

Structure

The Class I molecule acts as a trans-membrane glycoprotein. It has two chains, a-chain (or heavy chain) of molecular weight 42KD, associated non-covalently with a β₂,-microglobulin (or light chain) of molecular weight 12KD.

The a-chain has three extracellular domains (α₁, α₂, and α₃), a hydrophobic trans-membrane segment, and a short hydrophilic cytoplasmic tail (figure A). These are encoded by the A, B, and C regions of HLA complex, and are expressed on the plasma membrane of all cells (excluding erythrocytes).

Different chromosomes express the β₂-microglobulin molecule. The a-chain together with β₂-microglobulin is required for expressing class I molecules on the cell membrane. The α₁, and α₂ form the antigenic-binding cleft situated on the top of molecule surface.

Class II MHC molecules also serve as trans-membrane glycoprotein. Separate MHC genes encode them. They have two different α – (33KD) and β-chains (28KD) associated through non-covalent bond (figure B).

Two domains (β₁ and β₂ domains in other domain) are formed upon folding of the α- and β-chains. One domain is the membrane-proximal domain, and the other is membrane distal domain. Similar to class I MHC molecules, trans-segment and a cytoplasmic anchor segment are present in class II molecules also. The chains of class II molecule bear two external domains (α₁ and α₂ domains in one chain, and β₁ and β₂ domains in the other chain).

Functions

MHC provides cell mediated as well as humoral immune responses. The antibodies selectively bind with antigens. T-cells recognise only those antigens combined with MHC molecules; therefore, MHC molecules are antigen-presenting structure.

MHC partially ascertains how an individual responds to antigens of infectious microorganisms. Hence, MHC is associated to disease susceptibility and autoimmunity. The natural killer cells also express receptors for MHC class I antigens. The interaction of receptor with MHC may cause inhibition or activation.

Class I and II MHC molecules provide processed endogenous antigen to CD8 T-cells. Class II molecules provide exogenous antigen to CD4 T-cells. Class I molecules identifies all the body cells as ‘shelf’ and induce antibodies synthesis that enter the host having different class I molecules. This forms the base for MHC typing in patients undergoing antigen transplantation.

Class II molecules have D group of MHC responsible for stimulating antibody formation. They also participate in T-cell communication with macrophage and B- cells. An important step in immune response is that prior to cytokine secretion by T-cells, the class II molecules on the adjacent cell are identified by the T-cells receptor.

Microorganisms are identified by both class I and II molecules. These molecules engage in the susceptibility of an individual to specific non-infectious diseases, multiple sclerosis, acute glomerulonephritis, tuberculoid leprosy, paralytic poliomyelitis, etc. During immune responses the class III molecules (C₂, C_4a and C_4b) involve in the classical pathway and factor B (alternate pathway).