3.1.1 Major histocompatibility complex and its functional organization in mammals Major histocompatibility complex (MHC) is recognised as an important set of genes responsible for controlling whether grafts are accepted between individuals whose tissues are genetically similar (histocompatible) or rejected by individuals whose are not (histoincompatible). The MHC contains a set of genes located together on one chromosome as a complex. They encode several series of families of polymorphic glycoproteins, including two families of molecules that are expressed at the cell surface, the class I and class II molecules. These specialised membrane proteins act as a guidance system that allow T cells to recognise antigen.
3.1.1.1 Structure of class I and class II molecules Each class I molecule consists of a heavy chain, which is noncovalently associated with a light chain, the 2- microglobulin (Grey et al., 1973; Nakamuro et al., 1973). The chain is a polymorphic transmembrane glycoprotein of about 45 kilodaltons (KD) encoded by class I MHC loci, whereas the 2-microglobulin is an invariant protein of about 12 KD encoded by another gene located on a separate chromosome (reviewed in Ploegh et al., 1981). Although 2-microglobulin is not located in the MHC, its association with class I molecules is required for the expression of MHC on cell membranes (Goodfellow et al., 1975; Ploegh et al., 1979 and Rein et al., 1987). Recent experiments suggest that the binding of a peptide to a class I MHC chain may induce a conformational change in the molecule, enabling it to associate with 2-microglobulin and then be transported to the cell membrane.
The chain of class I MHC molecules is organized into three external domains (1, 2 and 3), each having approximately 90 amino acids, a transmembrane domain of about 40 amino acids and a cytoplasmic anchor segment of 30 amino acids. It is anchored in the plasma membrane by its hydrophobic transmembrane segment and hydrophilic cytoplasmic tail. According to size and organization, 2-microglobulin is similar to the external domains of the chain, and its sequence analysis shows that there is a considerable homology between the 3 domain, 2- microglobulin and the constant-region domains of immunoglobulins. Class I MHC molecules and 2 - microglobulin are therefore, classified as members of a immunoglobulin superfamily (Kuby, 1997; Williams and Barclay, 1988). The 3 domain appears to be highly conserved among class I MHC molecules and contains a sequence that is recognised by the CD8 (cluster determinant) T cell membrane molecule. The 2-microglobulin interacts extensively with the 3 domain and also interacts with amino acids of the 1 and 2 domains. The interaction of 2-microglobulin appears to be necessary for the proper conformation of the class I MHC molecules (Kuby, 1997).
The structure of class II MHC molecules is similar to that of class I molecules in that they are membrane-bound glycoproteins containing external domains, a transmembrane segment, and a cytoplasmic anchor segment. Each chain in a class II molecule contains two external domains : 1 and 2 domains, and 1 and 2 domains. The membrane proximal 2 and 2 domain, like the membrane-proximal 3 domain of class I MHC molecules, possess sequence homology to the immunoglobulin-fold domain structure and for that reason, class II MHC molecules are also classified in the immunoglobulin superfamily.
The chromosomal loci that encode class I and class II MHC molecules are the most polymorphic known in higher vertebrates, i.e. within a given species, there are extraordinarily large number of different alleles at each locus (Klein, 1986; Rothbard and Gefter, 1991). In mice, more than 55 alleles have been identified at the K locus and 60 alleles at the D locus.A comparison of the amino acid sequences of several allelic MHC molecules encoded at a single locus reveals a sequence divergence of between 5 and 10%. This degree of variation is unusually high. The sequence variation among MHC molecules is not randomly distributed along the entire polypeptide chain, but instead is clustered in short stretches, largely within the 1 and 2 domains of class I molecules and within the 1 and 1 domains of class II molecules. A number of researchers have suggested that the differences in these polymorphic amino acids in the class II MHC molecules expressed on antigen-presenting cells, might influence the cells’ ability to recognise a given peptide (Kuby, 1997).
