The function of MHC molecules is to bind peptide fragments derived from pathogens and display them on the cell surface for recognition by the appropriate T cells. The consequences are almost always deleterious to the pathogen—virus-infected cells are killed, macrophages are activated to kill bacteria living in their intracellular vesicles, and B cells are activated to produce antibodies that eliminate or neutralize extracellular pathogens. Thus, there is strong selective pressure in favor of any pathogen that has mutated in such a way that it escapes presentation by an MHC molecule.
Two separate properties of the major histocompatibility complex (MHC) make it difficult for pathogens to evade immune responses in this way. First, the MHC is polygenic: it contains several different MHC class I and MHC class II genes, so that every individual possesses a set of MHC molecules with different ranges of peptide-binding specificities. Second, the MHC is highly polymorphic; that is, there are multiple variants, or alleles, of each gene within the population as a whole. The MHC genes are, in fact, the most polymorphic genes known. In this section we describe the organization of the genes in the MHC and discuss how the variation in MHC molecules arises. We also consider how the effect of polygeny and polymorphism on the range of peptides that can be bound contributes to the ability of the immune system to respond to the multitude of different and rapidly evolving pathogens.
6-10 Many proteins involved in antigen processing and presentation are encoded by genes within the MHC.
The MHC is located on chromosome 6 in humans and chromosome 17 in the mouse and extends over at least 4 million base pairs. In humans it contains more than 200 genes. As work continues to define the genes within and around the MHC, it becomes difficult to establish precise boundaries for this genetic region, which is now thought to span as many as 7 million base pairs. The genes encoding the α chains of MHC class I molecules and the αand βchains of MHC class II molecules are linked within the complex; the genes for β2-microglobulin and the invariant chain are on different chromosomes (chromosomes 15 and 5, respectively, in humans, and chromosomes 2 and 18 in the mouse). Figure 6.16 shows the general organization of the MHC class I and II genes in human and mouse. In humans these genes are called human leukocyte antigen or HLA genes, because they were first discovered through antigenic differences between white blood cells from different individuals; in the mouse they are known as the H-2 genes. The mouse MHC class II genes were in fact first identified as genes that controlled whether an immune response was made to a given antigen and were originally called Ir (immune response) genes. Because of this, the mouse MHC class II A and E genes were in the past referred to as I-A and I-E, but this terminology could be confused with MHC class I genes and it is no longer used.