Human leukocyte antigen
The human leukocyte antigen (HLA) system or complex of genes on chromosome 6 in humans which encode cell-surface proteins responsible for regulation of the immune system.[1] The HLA system is also known as the human version of the major histocompatibility complex (MHC) found in many animals.[2]
Mutations in HLA genes may be linked to autoimmune diseases such as type I diabetes, and celiac disease. The HLA gene complex resides on a 3 Mbp stretch within chromosome 6, p-arm at 21.3. HLA genes are highly polymorphic, which means that they have many different alleles, allowing them to fine-tune the adaptive immune system. The proteins encoded by certain genes are also known as antigens, as a result of their historic discovery as factors in organ transplants.[3]
HLAs corresponding to MHC class I (A, B, and C), all of which are the HLA Class1 group, present peptides from inside the cell. For example, if the cell is infected by a virus, the HLA system brings fragments of the virus to the surface of the cell so that the cell can be destroyed by the immune system. These peptides are produced from digested proteins that are broken down in the proteasomes. In general, these particular peptides are small polymers, of about 8-10 amino acids in length.[4] Foreign antigens presented by MHC class I attract T-lymphocytes called killer T-cells (also referred to as CD8-positive or cytotoxic T-cells) that destroy cells. Some new work has proposed that antigens longer than 10 amino acids, 11-14 amino acids, can be presented on MHC I, eliciting a cytotoxic T-cell response.[5] MHC class I proteins associate with β2-microglobulin, which, unlike the HLA proteins, is encoded by a gene on chromosome 15.
HLAs corresponding to MHC class II (DP, DM, DO, DQ, and DR) present antigens from outside of the cell to T-lymphocytes. These particular antigens stimulate multiplication of T-helper cells (also called CD4-positive T cells), which in turn stimulate antibody-producing B-cells to produce antibodies to that specific antigen. Self-antigens are suppressed by regulatory T cells. Predicting which (fragments of) antigens will be presented to the immune system by a certain HLA type is difficult, but the technology involved is improving.[6]
HLAs corresponding to MHC class III encode components of the complement system.
HLAs have other roles. They are important in disease defense. They are the major cause of organ transplant rejection. They may protect against cancers or fail to protect (if down-regulated by an infection).[7] HLA may also be related to people's perception of the odor of other people, and may be involved in mate selection, as at least one study found a lower-than-expected rate of HLA similarity between spouses in an isolated community.[8]
Aside from the genes encoding the six major antigen-presenting proteins, many other genes, many involved in immune function, are located on the HLA complex. Diversity of HLAs in the human population is one aspect of disease defense, and, as a result, the chance of two unrelated individuals with identical HLA molecules on all loci is extremely low. HLA genes have historically been identified as a result of the ability to successfully transplant organs between HLA-similar individuals.[9]
Role of allelic variation[edit]
Studies of humans and animals imply a heterozygous selection mechanism operating on these loci as an explanation for this variability.[39] One proposed mechanism is sexual selection in which females are able to detect males with different HLA relative to their own type.[40] While the DQ and DP encoding loci have fewer alleles, combinations of A1:B1 can produce a theoretical potential of 7,755 DQ and 5,270 DP αβ heterodimers, respectively. While nowhere near this number of isoforms exist in the human population, each individual can carry 4 variable DQ and DP isoforms, increasing the potential number of antigens that these receptors can present to the immune system.
Studies of the variable positions of DP, DR, and DQ reveal that peptide antigen contact residues on class II molecules are most frequently the site of variation in the protein primary structure. Therefore, through a combination of intense allelic variation and/or subunit pairing, the class II peptide receptors are capable of binding an almost endless variation of peptides of 9 amino acids or longer in length, protecting interbreeding subpopulations from nascent or epidemic diseases. Individuals in a population frequently have different haplotypes, and this results in many combinations, even in small groups. This diversity enhances the survival of such groups, and thwarts evolution of epitopes in pathogens, which would otherwise be able to be shielded from the immune system.
Antibodies[edit]
HLA antibodies are typically not naturally occurring, and with few exceptions are formed as a result of an immunologic challenge to a foreign material containing non-self HLAs via blood transfusion, pregnancy (paternally inherited antigens), or organ or tissue transplant.
Antibodies against disease-associated HLA haplotypes have been proposed as a treatment for severe autoimmune diseases.[41]
Donor-specific HLA antibodies have been found to be associated with graft failure in renal, heart, lung, and liver transplantation. These donor-specific HLA antibodies can exist pretransplant as consequence of sensitization to prior transplants or through pregnancies, but also occur de novo post-transplantation. There is a clear link between the risk of HLA antibody sensitisation and the donor-recipient HLA (molecular) mismatch.[42]