The MHC is a complex locus, composed of a large cluster of genes located on the short arm of chromosome 6 (see image). On the basis of structural and functional differences, these genes are categorized into three classes, each of which is highly complex and polymorphic. Two of the three classes, class I and class II, correspond to the human leukocyte antigen (HLA) genes, originally discovered by virtue of their importance in tissue transplantation between unrelated individuals.
The class I genes (HLA-A, HLA-B, and HLA-C) encode antigens that are an integral part of the plasma membrane of nucleated cells. These antigens not only are involved in transplant rejection, but are also critical to immunocompetence, and are intricately involved in antigen recognition, lymphocyte interactions, and the development of self-tolerance. A class I antigen consists of two polypeptide subunits, a heavy chain encoded within the MHC and a nonpolymorphic polypeptide, β2-microglobulin, which is encoded by a gene outside the MHC, mapping to chromosome 15.
The class II locus is composed of several sub-regions that encode the HLA-DP, HLA-DQ, and HLA-DR antigens. These molecules are expressed primarily on B lymphocytes, macrophages, and activated T lymphocytes, but under certain conditions they may be expressed by other cell types as well. Each class II molecule is a heterodimer, composed of α and β subunits, both of which are encoded by the MHC. Like the class I antigens, they are integral to the cell membrane and to immune cellular interactions and function. The HLA class I and class II antigens play a critical role in the initiation of an immune response and specifically in the "presentation" of antigen to T lymphocytes, which cannot recognize and respond to antigen unless it is complexed with an HLA molecule.
The class III genes are not HLA genes but include genes for proteins such as properdin factors B, C2 and C4, which are part of the complement system, a series of polymorphic serum Proteins and membrane receptors closely involved in immune function. Also in this region are genes that when defective cause single-gene diseases, such as the gene for 21-hydroxylase; deficiency of 2l-hydroxylase is associated with one form of congenital adrenal hyperplasia. Thus class III genes appear to be functionally distinct from class I and class II genes, and they are not considered further here.
A number of other gene loci within the MHC are genetically linked to the HLA genes but are functionally unrelated to them. These include the genes for tumor necrosis factor and lymphotoxin, as well as other genes, more recently isolated, for which a function remains to be defined. There is a striking similarity, both in organization and in DNA sequence, between HLA class I and class II genes and between the HLA genes and the immunoglobulin and T-cell receptor genes described in the following sections. The similarity among these genes and a number of others has led to their classification into a gene family designated the immunoglobulin gene super family. The members of the family appear to be evolutionarily related genes, whose products serve a wide variety of functions beyond the immunological role of HLA molecules and immunoglobulins.