Major Histocompatibility Complex (MHC)
Major Histocompatibility Complex (MHC) is a tightly linked cluster of genes present in every vertebrate species, the products of which play important roles in intercellular recognition and in discrimination between self and non-self. MHC is located on chromosome 6 in humans and on chromosome 17 in mice and referred to as the HLA (human leukocyte antigen) complex and H-2 (histocompatibility-2) complex, respectively. Major Histocompatibility Complex (MHC) is highly polymorphic i.e. many alternative forms of the gene, or alleles, exist at each locus.
Different individuals within a species have different alleles of MHC gene– that is, at a single MHC locus, different individuals have different types of a prototypical gene. The phenomenon of having multiple stable forms of one gene in the population is known as genetic polymorphism. MHC genes are co-dominantly expressed – that is, every cell that expresses MHC molecules expresses proteins transcribed from both the maternal and the paternal chromosome.
The genes of the Major Histocompatibility Complex (MHC) loci lie close together. A set of linked MHC genes is generally inherited as a unit from parents; these linked groups are called haplotypes. An individual inherits one haplotype from the mother and one haplotype from the father. Each individual expresses a distinct array of MHC molecules. This diversity comes about because different individuals within a species have a range of slightly different forms (alleles) of MHC genes (genetic polymorphism). Because of the extensive polymorphism of MHC genes, every individual has an almost unique array of inherited MHC genes.
The MHC genes are traditionally divided into three classes:
- Class I MHC genes,
- Class II MHC genes and
- Class III MHC genes.
MHC class I and class II genes encode the antigen-presenting MHC molecules. The peptide antigen-presenting MHC molecules are known as classical MHC molecules. Both classes also encode proteins that do not function in the presentation of peptide antigens to T-cells: these are known as non-classical MHC molecules. The concept of classical and nonclassical does not apply to class III.
Class I MHC genes
- Class I MHC genes express glycoproteins called MHC molecules, sometimes referred to as MHC antigens on nearly all nucleated cells.
- Each MHC class I gene codes for a transmembrane glycoprotein of approximate molecular weight 43 kDa, which is referred to as the α, or heavy chain.
- It comprises three extracellular domains: α1, α2 and α3.
- The α3 domain is highly conserved and interacts with the CD8 membrane molecule present on TC cells. Every MHC class I molecule is expressed on the surface of a cell in noncovalent association with a small invariant polypeptide called β2-microglobulin (β2m; molecular weight 12 kDa), which is coded from another chromosome (human chromosome 15).
- In the absence of β2m; the class I MHC chain is not expressed on the cell membrane.
- The hydrophobic protein anchors the molecule on the cell membrane and a short hydrophilic sequence carries the COOH protein into the cytoplasm.
- In general, class I MHC molecules are expressed on most nucleated cells, but the level of expression differs among different cell types.
- The highest levels of class I molecules are expressed by lymphocytes whereas fibroblasts, liver hepatocytes, and neural cells express very low levels of class I MHC molecules. A few cell types (e.g. neurons and sperm cells at certain stages of differentiation) appear to lack class I MHC molecules altogether.
- Class I molecules are virtually present in all cells except the villous trophoblasts.
- The three independent genes that code for the human MHC class I molecules; the genes and molecules are known as HLA-A, HLA-B, and HLA-C.
Class II MHC genes
- Class II MHC genes code for α and β-chains of approximate molecular weight 35,000 and 28,000Da, respectively.
- MHC class II molecules, like MHC class I molecules, are transmembrane glycoprotein molecules with cytoplasmic tails and extracellular Ig-like domains; the domains are referred to as α1, α2, β1 and β2.
- MHC class II molecules are also members of the Ig superfamily.
- The T-cell molecule CD4 binds to the invariant portion of all MHC class II molecules.
- Class II MHC genes express Major Histocompatibility Complex (MHC) molecule constitutively (i.e. under all conditions) only on antigen presenting cells (APCs). APCs are classified as professional and non-professional antigen-presenting cells.
- Professional antigen presenting cells are dendritic cells, macrophages, and B lymphocytes.
- Non-professional antigen-presenting cells like fibroblasts, thymic epithelial cells, glial cells can be induced to express class II MHC molecules or a co-stimulatory signal.
- The class II molecules are particularly associated with B cells and macrophages, but can be induced on capillary endothelial cells by γ-interferon.
- The human MHC class II region is made up of three sets of genes, known as HLA-DP,
HLA-DQ, and HLA-DR.
- Each MHC class II subregion contains A and B genes that codes for one chain, α or β,
respectively, of a two-chain MHC class II molecule.
Class III MHC genes
Class III genes are grouped together in a region between D and B. These genes code for number of complement components, TNF, heat shock protein (HSP), etc.
Human leukocyte antigen loci are multiallelic that is the gene occupying the locus can be any one of several alternative forms (alleles). As each allele determines a distinct product (antigen) HLA system is very pleomorphic. For example, at least 24 distinct alleles have been identified in HLA locus ‘A’ and 50 at B. The immune response (Ir) genes, which control immunological response are believed to be situated in HLA class II region, probably associated with direct repeat (DR) locus. HLA-DR antigens are known to generate strongest rejection reactions.
The MHC also contains many other genes that have no role in immunology, such as those encoding heat shock protein 2 or the steroidogenic enzyme 21-β hydroxylase. The functional significance of the latter’s association, if any, is unknown.