The immune system has several ways of protecting your body against invasion by viruses, bacteria, parasites and any other foreign intruder or cancerous cell. The first line of defence is mounted by an innate immune response consisting of barriers such as skin, tears, saliva and mucus, as well as an inflammatory response. This is followed closely by defensive mechanisms mounted by adaptive immune responses that are more specific for the invading intruder. Adaptive immunity includes both a humoral response produced by antibodies, and a cell-mediated response produced by T cells that have the ability to destroy other cells. The cell-mediated adaptive immune response is regulated by the major histocompatibility complex (MHC), so named because it is responsible for graft rejection, or tissue compatibility. Individuals identical for this region can exchange grafts more successfully than those with different MHC combinations, which is not an easy task to find considering that the diversity of MHC combinations is extensive, such that there is on average roughly a 10% difference between any two unrelated individuals. However, this diversity in MHC proteins has a protective function, making it more difficult for an invading pathogen to elude the host immune system. A major role of the MHC is to bind small peptides and to present them to the cell surface where the antigen can be recognised by T cell receptors, the topic of next month’s Protein-of-the-Month.
In humans, the MHC genes encode the human leukocyte antigens (HLAs) on the cell surface. Proteins inside the cell are broken down into short fragments that can be displayed as peptide antigens by MHC molecules on the surface of the cell. MHC molecules display both ‘self’ peptides derived from their own proteins, and foreign peptides derived from invading pathogens. The immune system is constantly monitoring the surfaces of cells, and the MHC-presented peptides help immune cells to discriminate between normal antigens on the surface of all cells, and those that are foreign and potentially dangerous. The immune system also monitors the amount of MHC-presented antigens, which helps them to target and destroy cancerous cells that often display increased amounts of self-antigens. Defects in certain MHC genes lead to autoimmune disorders in which the body fails to recognize self-antigens, such as occurs in diseases like multiple sclerosis, inflammatory bowel disease, and in some forms of arthritis and diabetes.
MHC proteins have the ability to bind to several different peptides, which is necessary as there are a vast number of potential peptide targets, and only a limited number of MHC proteins. Furthermore, the different peptides that an MHC protein can bind are often structurally different from one another. This is an unusual property for a protein, and makes MHC molecules very different from other immune system proteins such as antibodies and T cell receptors, both of which show much greater specificity for their targets. MHC molecules are able to bind to such diverse peptides, because both the MHC binding pocket and the peptides are relatively flexible, the latter because of their small size. In addition, water molecules can fill in the gaps between the MHC molecule and its peptide to improve its fit.