The major histocompatibility complex (MHC) is a large cluster of genes found on the short arm of chromosome 6. The complex spans four million base pairs of DNA and contains 128 genes as well as 96 pseudogenes (non-functional gene remnants). Many, but by no means all of the genes in this complex play important roles in the immune system.
Traditionally, the MHC is divided into the class I, II and II regions, each containing groups of genes with related functions.
The class I and II MHC genes encode human leukocyte antigens (HLAs), proteins that are displayed on the cell surface and define an individual’s tissue type (see Tissue matching for transplants ). There are many possible tissue types in the population because each HLA exists as a large number of varieties. Everyone's immune system is tolerant of its own HLAs, but if foreign HLAs are detected then the cells displaying them are attacked and destroyed. This is why the body rejects grafts and transplants from donors that have not been matched for tissue type.
The class I and II MHC proteins also perform the important function of antigen presentation. This is how the immune system finds out what is happening inside our cells even though it can only survey them from the outside. Proteins inside the cell are broken into short fragments and displayed as peptide antigens by MHC proteins on the surface. This helps the immune system to discriminate between normal (self) antigens and those that are foreign and potentially dangerous.
Class I MHC proteins are found on virtually all cell types and their job is to present fragments of proteins that are synthesised inside the cell. The peptide antigens presented in this manner are checked by killer T-cells, which have receptors for the class I MHC proteins. The purpose of this surveillance system is to identify abnormal body cells, such as those infected with viruses or those that have turned malignant. Such cells will display unfamiliar peptide antigens, e.g. fragments of viral proteins, and are attacked and destroyed.
Class II MHC proteins are found only on immune cells such as phagocytes that engulf foreign particles such as bacteria. These cells are specially designed to present peptide antigens derived from such digested particles. The antigens are presented to helper T-cells, which have receptors for class II MHC proteins. The purpose of this surveillance system is to stop the immune system running out of control and attacking the body's own cells. Only if the presented antigen is recognised as foreign by the helper T-cell is the phagocyte allowed to survive.
Class III MHC genes encode several components of the complement system, a collection of soluble proteins found in the blood that targets foreign cells and breaks open their membranes. Adjacent to the class III region is a group of genes that control inflammation. Further genes with various immune and non-immune functions are dotted throughout the complex.
The MHC shows a high degree of polymorphism (100 times higher than the genome average, i.e. a 10 per cent difference between any two unrelated individuals). Many of these polymorphisms appear to be associated with either increased or decreased susceptibility to a range of infectious diseases including malaria, tuberculosis, leprosy, typhoid fever, hepatitis and HIV/AIDS.
Defects in certain MHC genes lead to autoimmune disorders in which the body fails to recognise self-antigens. Examples of such diseases include multiple sclerosis, some forms of arthritis and diabetes, and inflammatory bowel disease.
Image credit: T Blundell and N Campillo