Genetic associations of the major histocompatibility complex (MHC) with infectious disease

Although the major histocompatibility complex (MHC) was originally discovered as a highly polymorphic genetic locus responsible for rapid allograft rejection, it seems clear that the true function of classical MHC molecules is to present peptides derived from infectious pathogens and tumors to T lymphocytes of the immune system. A molecular arms race with pathogens is believed to drive both the high allelic polymorphism and the high level of sequence variation found in the classical MHC molecules, with evidence for heterozygous advantage, rare allele advantage, and fluctuating selection. However, contrary to expectations, there are few genetic associations of the MHC of humans and other mammals with resistance and susceptibility to infectious pathogens, which are weak by comparison to associations with autoimmunity. The strongest and best studied associations are with persistent viruses that have small genome size. For human immunodeficiency virus (HIV), genome-wide association studies (GWAS) consistently identify the MHC as the most significant association, particularly human leukocyte antigens HLA-B and HLA-C, for which there are several mechanisms of resistance suggested. In contrast, there are very strong associations of the MHC of nonmammalian vertebrates with resistance and susceptibility to infectious pathogens, likely because there is only one class I locus and one class II locus expressed at a high level, as opposed to the multigene family typically found in mammals. Recently, the diversity of peptides presented by alleles of MHC molecules has come under scrutiny, with promiscuous class I molecules proposed to act as generalists.