Structural Biochemistry/Protein function/Major Histocompatibility Complex (MHC)

MHC, also known as the Major Histocompatibility Complex is attached to a host cell and it produces a protein that can basically present an antigen fragment to other cells (such as T cells), which will then take an appropriate action depending on what fragment is being presented. The interaction of the antigen fragment with the MHC molecule and T Cell receptor is an event that the acquired immunity (our immune system) uses in order to destroy pathogens that are not meant to be in the body. The MHC is a large genomic region or gene family that is found in most vertebrates. It is the region that most densely contains the genes of the mammalian genome and is important for the success of the immune system, autoimmunity, and reproduction. Proteins that have been encoded by the MHC are expressed on the surface of cells in all jawed vertebrates and display both self and nonself antigens to a type of white blood cell known as a T cell that has the ability to kill or coordinate the killing of pathogens, infected, or malfunctioning cells.

Variation of MHC proteins

Different forms of MHC proteins are present in different people. This variation aids in the prevention of a widespread epidemic, since if all people had the same MHC proteins and a pathogen mutated to avoid being presented by MHC proteins, the entire population would be susceptible to the pathogen. This variation is also why a "match" is needed for a successful organ transplant. That is, rejections of transplanted organs by the immune system are often caused by too much variation in the MHC genotypes of the organ donor and acceptor. The hereditary nature of MHC structure reveals why immediate family members are the best candidates for an organ donor.

Subgroups

The MHC region is divided into three subgroups: MHC class I, MHC class II, and MHC class III. MHC class I is responsible for encoding heterodimeric peptide-binding proteins, as well as antigen-processing molecules such as TAP and Tapasin. MHC class I can be found in all nucleated cells. the MHC class I proteins contain an α chain and β2-micro-globulin. They present antigen fragments to cytotoxic T-cells that will bind to the CD8 on cytotoxic T-cells. MHC class II is responsible for encoding hetrodimeric peptide-binding proteins and proteins that modulate antigen loading onto MHC class II proteins in the lysosomal compartment such as MHC II DM, MHC II DQ, MHC II DR, and MHC II DP. MHC class II can be found on antigen-presenting cells. MHC class II proteins contain α and β chains and they present antigen fragments to T-helper cells by binding to the CD4 receptor on the T-helper cells. The MHC class III region is responsible for encoding for other immune components, such as complement components (C2, C4, factor B) and some that encode cytokines (TNF-α) and also hsp. Class III has a very different function than do class I and II, but it has a locus between the other two, so they are frequently discussed together.

Responses

The MHC proteins act as "signposts" that show fragmented pieces of an antigen on the host cell's surface. These antigens can be either self or nonself. If they are nonself, there are two ways by which the foreign protein can be processed and recognized as being "nonself." The first method is when the phagocytic cells, such as macrophages, neutrophils, and monocytes, degrade foreign particles that are engulfed during a process known as phagocytosis. Degraded particles are then presented on MHC class II molecules. The other method involves the host cell first being infected by a bacterium or virus, or being diagnosed as cancerous, then it may be able to display the antigens on its surface with a Class I MHC molecule. Cancerous cells and cells infected by a virus usually display unusual, nonself antigens on their surface. These nonself antigens, despite which type of MHC molecule they are displayed on, will initiate the specific immunity of the host's body. It is important to remember that cells constantly process endogenous proteins and display them within the context of MHC I. Immune effector cells are then built up to be non-reactive to self peptides within MHC, and are then able to recognize when foreign peptides are being presented during infection or cancer.

HLA Genes

The most well known genes in the MHC region are the group that encodes cell surface antigen-presenting proteins. These genes are referred to as human leukocyte antigen genes in humans, though people often abbreviate MHC to mean the HLA gene products. Some of the biomedical literature uses HLA to refer to the HLA protein molecules and uses MHC for the region of the genome that encodes for this molecule, though this is not consistently adhered to. The most intensely studied HLA genes are the nine classical MHC genes: HLA-A, HLA-B, HLA-C. HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, and HLA-DRB1. The MHC is divided into three regions: Class I, II, and III. The A, B, and C genes belong to the first class, whereas the six D genes belong to the second class. 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 spent to explaining why this specific region of the genome harbors so much diversity, especially in light of its immunological importance.

Molecular Biology of MHC Proteins

The classical MHC molecules have a vital roles in the complex immunological dialogue that must occur between T-cells and other cells of the body. At the time of 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," meaning they originate from a protein created by the organism itself, or they may be foreign, "nonself," where they originate from bacteria, virus, 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. The immune system has another and equally important method for identifying an antigen. B-cells with their membrane-bound antibodies, also known as B-cell receptors (BCRs). BCRs of B-cells do not require much outside help in order to bind to antigens while TCRs of T-cells require "presentation" of the antigen, which is the job of the MHC. During the vast majority of the time, MHC are kept busy presenting self-peptides, which the T-cells should appropriately ignore. 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.

MHC Evolution and Allelic Diversity

MHC gene families are found in almost all vertebrates, though the gene composition and genomic arrangement vary widely. Gene duplication is almost certainly responsible for much of the genetic diversity. MHC is littered with many pseudogenes in humans. One of the most striking features of the MHC is the astounding allelic diversity found therein, and especially among the nine classical genes. The most conspicuously diverse loci, HLA-A, HLA-B, and HLA-DRB1, have roughly 250, 500, and 300 known alleles respectively, which is a truly exceptional exemplification of diversity. The MHC gene is the most polymorphic in the genome. Population surveys of the other classical loci routinely find tens to a hundred alleles, which is still relatively high in diversity. Many of these alleles are quite old, too. 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 that 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. However, recent models have suggested that a high number of alleles is not plausibly achievable through heterozygote advantage alone. Pathogenic co-evolution, a counter-hypothesis, has recently emerged. It theorizes that the most common alleles will be placed under the greatest pathogenic pressure, thus there will always be a tendency for the least common alleles to be positively selected for. This creates a "moving target" for pathogen evolution. As the pathogenic pressure decreases on the previously common alleles, their concentrations in the population will stabilize, and they will usually not go extinct if the population is large enough, and a large number of alleles will remain in the population as a whole. This explains the high degree of MHC polymorphism found in the population, although an individual can have a maximum of 18 MHC I or II alleles.

MHC and Natural Selection

It has been suggested that MHC plays a role in the selection of potential mates. MHC genes make molecules that enable the immune system to recognize invaders. Generally, the more diverse the MHC genes of the parents, the stronger the immune system of the offspring. It would obviously be beneficial, therefore, to have evolved systems of recognizing individuals with different MHC genes and preferentially selecting them to breed with.