Major Histocompatibility Complex: Human

Abstract

The major histocompatibility complex (MHC) is a large genetic region with hundreds of genes, among them the most polymorphic loci known in humans and other vertebrates. MHC genes are intensively studied because they influence so many important traits, including compatibility of transplants, autoimmunity, resistance to infectious diseases and reproduction. Key Concepts The human MHC (HLA) is a large genetic region with hundreds of genes, including the classical class I and class II MHC molecules that are responsible for tissue graft rejection. Human classical class I and class II MHC molecules have hundreds of alleles, are well‐expressed across many tissues and present peptides to T lymphocytes and natural killer (NK) cells, while nonclassical MHC molecules (some of which are encoded outside of the MHC) lack one or more of these properties. Human classical class I and class II MHC molecules are polymorphic due to a molecular arms race with pathogens, with MHC molecules selecting pathogens that no longer express the previously presented peptides, which then drives the appearance of new alleles of MHC molecules that bind the newly evolved pathogen peptides. Human classical class I and class II MHC molecules play key roles in resistance to infectious disease, susceptibility to autoimmune disease, allergy and asthma, and in reproduction. Human classical class I MHC molecules present peptides primarily derived from the cytoplasm and nucleus where viruses replicate, and are recognized by cytotoxic CD8‐bearing T lymphocytes (CTLs) and natural killer (NK) cells. Human classical class II MHC molecules present peptides primarily derived from intracellular vesicles and the extracellular space where many different kinds of pathogens are found, and are recognized by a variety of CD4‐bearing T cells with nuanced responses depending on the nature of the pathogen. Human nonclassical MHC molecules (particularly class I molecules encoded outside of the MHC) have a wide variety of functions, only some of which are involved with immunity. Not all genetic associations with the human MHC involve classical and nonclassical MHC genes, since other genes in the MHC have alleles which affect many biological functions.