The major histocompatibility complex (MHC) is a large genomic region or gene family found in most vertebrates containing many genes with important immune system roles. In humans, the MHC spans almost 4 megabases of chromosome 6 and includes more than 200 known genes, of which about half have known immmunological functions.
Certainly the best known genes in the MHC region are the subset that encodes cell-surface antigen-presenting proteins. In humans, these genes are referred to as human leukocyte antigen (HLA) genes, although people often use the abbreviation MHC to refer to HLA gene products. To disambiguate the usage, some of the biomedical literature uses Mhc to refer specifically to the HLA protein molecules and reserves MHC for the region of the genome that encodes for this molecule, however this convention is not consistently adhered to.
The most intensely studied HLA genes are the nine so-called classical Mhc genes: HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, and HLA-DRB1. In humans, the MHC is divided into three regions: Class I, II, and III. The A, B, and C genes belong to MHC class I while the six D genes belong to class II.
Besides being scrutinized by immunologists for its pivotal role in the immune system, the MHC has also attracted the attention of many evolutionary biologists, due to the high levels of allelic diversity found within many of its genes. Indeed, much theory has been devoted to explaining why this particular region of the genome harbors so much diversity, especially in light of its immunological importance.
Molecular biology of MHC proteins
The classical Mhc molecules (also referred to as HLA molecules in humans) have a vital role in the complex immunological dialog that must occur between T cells and other cells of the body. At maturity, Mhc molecules are anchored in the cell membrane, where they display short polypeptides to T cells, via the T cell receptors (TCRs). The polypeptides may be "self," that is, originating from a protein created by the organism itself, or they may be foreign, originating from bacteria, viruses, pollen, etc. The overarching design of the MHC_TCR interaction is that T cells should ignore self peptides while reacting appropriately to the foreign peptides. Foreign peptides that provoke an immune response are termed antigens.
Interestingly, the immune system has another, equally important method to identify antigen: B cells with their membrane_bound antibodies, also known as B cell receptors (BCRs). However, while the BCRs of B cells can bind to antigens without much outside help, the TCRs of T cells require "presentation" of the antigen: this is the job of Mhc. It is important to realize that the vast majority of the time, Mhc are kept busy presenting self-peptides, which the T cells should appropriately ignore. A full-force immune response usually requires the activation of B cells via BCRs and T cells via the Mhc-TCR interaction. This duplicity creates a system of "checks and balances" and underscores the immune system's potential for running amok and causing harm to the body (see autoimmune disorders.)
All Mhc molecules receive polypeptides from inside the cells they are part of and display them on the cell's exterior surface for recognition by T cells. However, there are major differences between MHC class I and II in the method and outcome of peptide presentation.
- Mhc Class I molecules are found on almost every nucleated cell of the body. Class I molecules are heterodimers, consisting of a single transmembrane polypeptide chain (the α_chain) and a β2 microglobulin (which is encoded elsewhere, not in the MHC). The α chain has two polymorphic domains, α1, α2, which present peptides derived from cytosolic proteins to the immune system. The peptides are short, consisting of 8-10 amino acid residues.
Because class I Mhc is loaded with proteins found in the cytosol, it is the primary way for a virus-infected cell to signal to T cells. It interacts exclusively with CD8+ T cells (also known as cytotoxic T cell lymphocytes or CTLs). The fate of a virus-infected cell is almost always apoptosis, or programmed cell death, initiated by the CD8+ T cell. This response seems like "killing the messenger," but the messenger in this case is virally infected and probably represents a risk of contagion for neighboring cells.
- Mhc Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells, activated T cells, and B cells, which may be referred to collectively as "antigen-presenting cells" (APCs). Class II molecules are also heterodimers, but in this case consist of two homologous peptides, an α and β chain, both of which are encoded in the MHC. The peptides presented by class II molecules are derived from extracellular proteins (not cytosolic as in class I). Loading of class II molecules must still occur inside the cell; extracellular proteins are endocytosed, digested in lysosomes, and bound by the class II MHC molecule prior to the molecule's migration to the plasma membrane. The peptides are longer, generally between 15-24 amino-acid residues.
Because class II Mhc is loaded with extracellular proteins, it is mainly concerned with presentation of extracellular pathogens (for example, bacteria that might be infecting a wound or the blood.) Class II molecules interact exclusively with CD4+ T cells (also known as helper T cell lymphocytes or HTLs). The helper T cells then help to trigger an appropriate immune response which may include localized inflammation and swelling due to recruitment of phagocytes or may lead to a full-force antibody immune response due to activation of B cells.
MHC evolution and allelic diversity
MHC gene families are found in essentially all vertebrates, though the gene composition and genomic arrangement varies widely. Chickens, for instance, have one of the smallest known MHC regions (19 genes), though most mammals have an MHC structure and composition fairly similar to that of humans. Gene duplication is almost certainly responsible for much of the genic diversity. In humans, the MHC is littered with many pseudogenes.
One of the most striking features of the MHC, particularly in humans, is the astounding allelic diversity found therein and especially among the nine classical genes. In humans, the most conspicuously diverse loci, HLA_A, HLA_B, and HLA_DRB1, have roughly 250, 500, and 300 known alleles respectively __ diversity which is truly exceptional in the human genome. And population surveys of the other classical loci routinely find tens to a hundred alleles __ still highly diverse. And perhaps even more remarkable is that many of these alleles are quite ancient: it is often the case that an allele from a particular HLA gene is more closely related to an allele found in chimpanzees than it is to another human allele from the same gene!
The allelic diversity of MHC genes has created fertile grounds for evolutionary biologists. The most important task for theoreticians is to explain the evolutionary forces that have created and maintained such diversity. Most explanations invoke balancing selection, a broad term which identifies any kind of natural selection in which no single allele is absolutely most fit. Frequency dependent selection and heterozygote advantage are two types of balancing selection that have been suggested to explain MHC allelic diversity.