Most polymorphic genes encode proteins that vary by only one or a few amino acids, whereas the allelic variants of MHC proteins differ from each other by up to 20 amino acids. The extensive polymorphism of the MHC proteins has almost certainly evolved to outflank the evasive strategies of pathogens. The requirement that pathogen antigens must be presented by an MHC molecule provides two possible ways in which pathogens could evolve to evade detection. One is through mutations that eliminate from the pathogen’s proteins all peptides able to bind MHC molecules. The Epstein–Barr virus provides an example. There are small isolated populations in southeast China and Papua New Guinea in which about 60% of the people carry the HLA-A11 allele. Many isolates of the Epstein–Barr virus obtained from these populations have mutations in a dominant peptide epitope normally presented by HLA-A11; the mutant peptides no longer bind to HLA-A11 and cannot be recognized by HLA-A11-restricted T cells. This strategy is clearly much less successful if there are many different MHC molecules, and the polygeny of the MHC may have evolved in response.
In addition, in large outbred populations, polymorphism at each locus can potentially double the number of different MHC molecules expressed by an individual, as most individuals will be heterozygotes. Polymorphism has the additional advantage that individuals in a population will differ in the combinations of MHC molecules that they express and will therefore present different sets of peptides from each pathogen. This makes it unlikely that all individuals in a population will be equally susceptible to a given pathogen, and its spread will therefore be limited. The fact that exposure to pathogens over an evolutionary timescale can select for particular MHC alleles is indicated by the strong association of the HLA-B53 allele with recovery from a potentially lethal form of malaria. This allele is very common in people from West Africa, where malaria is endemic, and rare elsewhere, where lethal malaria is uncommon.
Similar arguments apply to a second strategy by which pathogens could evade recognition. Pathogens that can block the presentation of their peptides by MHC molecules can avoid the adaptive immune response. Adenoviruses encode a protein that binds to MHC class I molecules in the endoplasmic reticulum and prevents their transport to the cell surface, thus preventing the recognition of viral peptides by CD8 cytotoxic T cells. This viral MHC-binding protein interacts with a polymorphic region of the MHC class I molecule, as some allelic variants are retained in the endoplasmic reticulum by the adenoviral protein, whereas others are not. Increasing the variety of MHC molecules expressed reduces the likelihood that a pathogen will be able to block presentation by all of them and completely evade an immune response.
These arguments raise a question: if having three MHC class I loci is better than having one, why are there not far more? The probable explanation is that each time a distinct MHC molecule is added to the repertoire, all T cells that can respond to self peptides bound to that MHC molecule must be removed to maintain self tolerance. It seems that the number of MHC genes present in humans and mice is about optimal to balance the advantages of presenting an increased range of foreign peptides with the disadvantages of losing T cells from the repertoire.
Summary.