Human leukocyte antigen

frame|right|HLA region of Chromosome 6

The human leukocyte antigen (HLA) system is a complex of genes on chromosome 6 in humans that encode cell-surface proteins responsible for regulation of the immune system. The HLA system is also known as the human version of the major histocompatibility complex (MHC) found in many animals.

Specific 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.

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. 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. 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.

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). 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.

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.

Functions

The proteins encoded by HLAs are those on the outer part of body cells that are (in effect) unique to that person. The immune system uses the HLAs to differentiate self cells and non-self cells. Any cell displaying that person's HLA type belongs to that person and is therefore not an invader.

frame|left|DR protein (DRA:DRB1*0101 gene products) with bound Staphylococcal enterotoxin ligand (subunit I-C), view is top down showing all DR amino acid residues within 5 Angstroms of the SEI peptide.

In infectious diseases

When a foreign pathogen enters the body, specific cells called antigen-presenting cells (APCs) engulf the pathogen through a process called phagocytosis. Proteins from the pathogen are digested into small pieces (peptides) and loaded on to HLA antigens (to be specific, MHC class II). They are then displayed by the antigen-presenting cells to CD4+ helper T cells, which then produce a variety of effects and cell-to-cell interactions to eliminate the pathogen.

Through a similar process, proteins (both native and foreign, such as the proteins of viruses) produced inside most cells are displayed on HLAs (to be specific, MHC class I) on the cell surface. Infected cells can be recognized and destroyed by CD8+ T cells.

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! HLA allele !! Diseases with increased risk !! Relative risk

|rowspan=3| HLA-B27

| Ankylosing spondylitis || 12

|Reactive arthritis|| 14

|rowspan=4| HLA-DR3

| Autoimmune hepatitis || 14

In autoimmunity

HLA types are inherited, and some of them are connected with autoimmune disorders and other diseases. People with certain HLA antigens are more likely to develop certain autoimmune diseases, such as type I diabetes, ankylosing spondylitis, rheumatoid arthritis, celiac disease, SLE (systemic lupus erythematosus), myasthenia gravis, inclusion body myositis, Sjögren syndrome, and narcolepsy.

HLA typing has led to some improvement and acceleration in the diagnosis of celiac disease and type 1 diabetes; however, for DQ2 typing to be useful, it requires either high-resolution B1*typing (resolving *02:01 from *02:02), DQA1*typing, or DR serotyping. Current serotyping can resolve, in one step, DQ8. HLA typing in autoimmunity is being increasingly used as a tool in diagnosis. In celiac disease, it is the only effective means of discriminating between first-degree relatives that are at risk from those that are not at risk, prior to the appearance of sometimes-irreversible symptoms such as allergies and secondary autoimmune disease.

In cancer

Some HLA-mediated diseases are directly involved in the promotion of cancer. Gluten-sensitive enteropathy is associated with increased prevalence of enteropathy-associated T-cell lymphoma, and DR3-DQ2 homozygotes are within the highest risk group, with close to 80% of gluten-sensitive enteropathy-associated T-cell lymphoma cases. More often, however, HLA molecules play a protective role, recognizing increases in antigens that are not tolerated because of low levels in the normal state. Abnormal cells might be targeted for apoptosis, which is thought to mediate many cancers before diagnosis. Moreover, variations in the HLA repertoire can be important for anticancer immunity in cancer patients.

In mate selection

There is evidence for non-random mate choice with respect to certain genetic characteristics. This has led to a field known as genetic matchmaking.

Classification

MHC class I proteins form a functional receptor on most nucleated cells of the body.

Variability

thumb|right|300px|Codominant expression of HLA genes

MHC loci are some of the most genetically variable coding loci in mammals, and the human HLA loci are no exceptions. Despite the fact that the human population went through a constriction several times during its history that was capable of fixing many loci, the HLA loci appear to have survived such a constriction with a great deal of variation. Of the 9 loci mentioned above, most retained a dozen or more allele-groups for each locus, far more preserved variation than the vast majority of human loci. This is consistent with a heterozygous or balancing selection coefficient for these loci. In addition, some HLA loci are among the fastest-evolving coding regions in the human genome. One mechanism of diversification has been noted in the study of Amazonian tribes of South America that appear to have undergone intense gene conversion between variable alleles and loci within each HLA gene class. Less frequently, longer-range productive recombinations through HLA genes have been noted producing chimeric genes.

Six loci have over 100 alleles that have been detected in the human population. Of these, the most variable are HLA B and HLA DRB1. As of 2012, the number of alleles that have been determined are listed in the table below. To interpret this table, it is necessary to consider that an allele is a variant of the nucleotide (DNA) sequence at a locus, such that each allele differs from all other alleles in at least one (single nucleotide polymorphism, SNP) position. Most of these changes result in a change in the amino acid sequences that result in slight to major functional differences in the protein.

There are issues that limit this variation. Certain alleles like DQA1*05:01 and DQA1*05:05 encode proteins with identically processed products. Other alleles like DQB1*0201 and DQB1*0202 produce proteins that are functionally similar. For class II (DR, DP and DQ), amino acid variants within the receptor's peptide-binding cleft tend to produce molecules with different binding capability.

However, the gene frequencies of the most common alleles (>5%) of HLA-A, -B, -C and HLA-DPA1, -DPB1, -DQA1, -DQB1, and -DRB1 from South America have been reported from the typing and sequencing carried out in genetic diversity studies and cases and controls. In addition, information on the allele frequencies of HLA-I and HLA-II genes for the European population has been compiled. In both cases the distribution of allele frequencies reveals a regional variation related with the history of the populations.

Tables of variant alleles

Number of variant alleles at class I loci according to the IMGT-HLA database, last updated October 2018:

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! style = "height:30px" colspan="2" align="center" valign = "center" | MHC class I

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