Role of MHC-Linked Susceptibility Genes in the Pathogenesis of Human and Murine Lupus

Figure 3

Protective effect of MHC polymorphism on populations (simplified scheme). Evolution of MHC genes and alleles is driven by the need to maximize peptide binding diversity in order to recognize a maximum of potential pathogens. Thus, the extreme polymorphism of MHC molecules of vertebrates is thought to reflect a pathogen-driven selection. This insures that no germ can exterminate the whole population by developing peptides that cannot be bound by any MHC molecule. However, compared to the enormous diversity of MHC molecules within a population (outer circle), their heterogeneity within a single individual is restricted to a few different MHC polypeptides (individuals A–D). This can be attributed to a mechanism called “MHC restriction” (see MHC chapter) that limits polygeny of the MHC genes (in general to 3 genes per MHC class I and class II). As a consequence some agents may evolve polypeptides that evade the immune system of single individuals (individual C) and harm or even kill them. In consequence of these opposed requirements, the immune surveillance is a delicate balance between (self-)tolerance and immune response that ensures survival of a population and/or a species at the expense of single individuals.