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Histocompatibility, or tissue compatibility, is the property of having the same, or mostly the same, alleles of a set of genes called human leukocyte antigens (HLA). The presence of histocompatibility antigens is one of the major biological features of a mammalian cell surface membrane. The presence of these histocompatibilty antigens on the surface is well-known for their ability to mount an immune rejection that usually results due to an engraftment of tissues from another individual of the same species bearing different histocompatibility antigens from that of the receiver. HLA is the human form of the major histocompatibility complex genes found in all vertebrates. On a population level there is a great number of different alleles at each HLA loci on Chromosome 6 at 6p21.3 in humans with new ones being continuously discovered. Histocompatibility can be classified into the major histocompatibility complex and minor histocompatibility complex. Not much is known about the minor histocompatibility complexes. Each individual inherits two different HLA alleles. Each of these alleles contain six loci (location on the chromosome) which code for major histocompatibility complex (MHC) proteins. These genes are codominantly expressed meaning every individual expresses each of the inherited alleles, both paternal and maternal. This results in a mixture of different types of MHC proteins for every individual. The similarity of difference of one individual's HLA alleles, and therefore MHC proteins, to another person's is what makes the tissues compatible or incompatible. The immune response that arises due to a rejection by major histocompatibility antigens are more difficult to suppress. Although the histocompatibility antigen system due to transplants are viewed with more importance, it is possible that they have developed to meet other biological needs such as distinguishing fetal tissue from maternal tissue or, more importantly distinguishing between foreign microbial antigens from self antigens.

Major Histocompatibilty Complex (MHC)
Major histocompatibility complex (MHC) is a cell surface molecule that is encoded by a large gene family in the majority of vertebrates. MHC molecules are responsible for mediating interactions of leukocytes, also called white blood cells (WBCs), which are immune cells, with other leukocytes or body cells. MHC is also responsible for determining the compatibility of donors for organ transplant as well as one's susceptibility to an autoimmune disease via crossreacting immunization.

This family of cell membrane proteins are crucial in the adaptive immune response. MHC genetic encoding is polygenic and the genes are highly polymorphic and have several variants. MHC genes are expressed from both inherited alleles. There are two types or classes of MHC : 1) Major Histocompatibilty Complex I and 2) Major Histocompatibility Complex II. They differ in both their structure and in their expression pattern in the tissues of the body. MHC class I and class II differ in their subunit composition. They both have two paired protein domains nearest to the membrane that resemble immunoglobulin domains. The two other domains furthest away from the membrane fold together to create a cleft to which an antigen can bind to.

Major Histocompatibility Complex I
MHC class I molecules consist of two polypeptide chains. It is a dimer. One chain is the alpha chain (found on chromosome 6 in humans) and is noncovalently associated with a smaller beta-2 microglobulin (found on chromosome 15 in humans). About 8-10 amino acids long peptides can bind to the cleft in the MHC class I molecule. MHC I molecules are usually found in the lumen of endoplasmic reticulum where they bind to small fragments of foreign antigens (usually viruses) that are present in the cytoplasm of the cell. The antigens are usually chopped by a proteosome and taken up into the ER lumen by a TAP protein and transferred onto the cleft of an MHC class I molecule. The MHC class I molecule with the antigen is then released from the ER in a vesicle and is transported to the phospholipid membrane where it can display the antigen for the cells of the immune system to detect.

Major Histocompatibility Complex II
MHC class II molecules consist of a noncovalent complex of two chains, alpha and beta, both of which can span the membrane. The amino acids are usually longer than the binding site. MHC class II molecules act on foreign antigens (bacteria or other microbial bodies) that are extracellular. The antigen is taken up into the cell by endocytosis and a vacuole containing endosomal proteases cleave the antigen into small fragments. This vesicle then fuses with the vesicle containing MHC class II molecule and its components (invariant chain (li), CLIP, HLA-DM) and the antigen can bind with the cleft site of the MHC class II molecules. The MHC class II molecule with its antigen can then be expressed on the cell surface.

Histocompatibility and transplantation
When a patient receives an organ from a donor, the patients immune system cells will react to the new foreign tissue in a way as to destroy it since it may contain several cell surface markers i.e. antigens such as glycoproteins, glycolipids and most importantly the expressed MHC proteins. This reaction will continue and eventually the transplanted tissue would be destroyed if the MHC proteins expressed on its surface are not the same or in the very least some way similar to that of the recipient's. It can be said that the more similar the spread of the HLA alleles are between the two people, the more tolerant they would be to each other's tissue or organ tissue and its expressed MHC antigens. Practically organizing transplant operations means seeking out donors with similar tissue types, most often siblings, though due to the number of HLA loci involved it is rare to find a complete tissue type match even between siblings (unless they are identical twins). This is why most transplants will require post-operative immunosuppressant therapy to lessen the immune response to the transplant and prevent tissue rejection - unless the transplanted tissue enjoys immune privilege, such as with corneal transplants.

Histocompatibility testing
To test for histocompatibility between donor's and recipient's tissues medical laboratory professionals compare antibodies of the recipient and the donor. The presence of specific anti-HLA antibodies will be an indication of the presence of the corresponding MHC protein. A common technique utilized in the histocompatibility testing is microcytotoxicity assays. This involves adding a sample of the donor or recipient's cells containing MHC proteins to a serum containing known anti-HLA antibodies. The antibodies that bind to the cells activate a complement signaling cascade resulting in cell lysis. When a particular cell is lysed it will take up an added dye such as trypan blue allowing for identification. Histocompatibility testing has evolved greatly with the technological advances in DNA based molecular typing and solid phase immunoassays. With this technology is possible to detect very small amounts of HLA specific antibodies within and individual. This has produced a major challenge for transplant teams as is still unclear whether or not such small concentrations of antibodies are clinically relevant. Histocompatibility testing is only one of many criteria necessary for matching transplant donors to recipients. Currently certain MHC proteins, DR, HLA-B, and HLA-A are known to have more of a negative affect and must be the same between tissues in order for a transplant team to proceed. Blood type, age, as well as overall health is also taken into consideration. These criteria are different across the globe for instance in Europe the Histocompatibility threshold of older patients is different as the result of several studies stating that the immune response of older transplant patients towards MHC proteins is slower and therefore less compatibility is necessary to still have positive results.