HLA-A

HLA-A are a group of human leukocyte antigens (HLA) that are encoded by the HLA-A locus on human chromosome 6p. The HLA genes constitute a large subset of the Major histocompatibility complex (MHC) of humans. HLA-A is a component of certain MHC class I cell surface receptor isoforms that resides on the surface of all nucleated cells and platelets. The receptor is a heterodimer, and is composed of a heavy, alpha (α) chain and smaller beta (β) chain. The alpha chain is encoded by a variant HLA-A gene, and the beta chain (β₂-microglobulin) is composed by the invariant Beta-2 microglobulin gene.

MHC Class I molecules are part of a process that presents polypeptides from host of foreign derivation to the immune system. Under normal conditions, if a peptide of foreign, pathogenic, source is detected, it alerts the immune system that the cell may be infected with a virus, and, thus, target the cell for destruction.

For humans, as in most mammalian populations, MHC Class I molecules are extremely variable in their primary structure, and HLA-A is ranked among the genes in humans with the fastest-evolving coding sequence. After typing millions of individuals, hundreds of variant alleles and isoforms have been identified.^[1] This level of variation on MHC Class I is the primary cause of transplant rejection, as random transplantation between donor and host is unlikely to result in a matching of HLA-A, B or C antigens.

HLA-A gene

The HLA-A gene is part of the Human MHC complex on chromosome 6. The region is at the telomeric end of the HLA complex between the HLA-G and HLA-E genes. HLA-A gene encodes the larger, α-chain, constituent of HLA-A. Variation of HLA-A α-chain in certain ways is key to HLA function. This variation promotes diversity of class I recognition in the individual and also promotes genetic diversity in the population. This diversity allows more types of foreign, virus or cancer, antigens to be 'presented' on the cell surface, but also allows a subset of the population to survive if a new virus spreads rapidly through the population.

These changes are also key to inter-individual histocompatibility of organs and tissues. Difference in exposed structures of homologous proteins between individuals gives rise to antigen-antibody reactions when tissues are transplanted. This form of antigenicity gives rise to serotypes in tissue recipients. Refined serotypes are what scientists have used for grouping HLA.

There are many variant alleles of the gene. The HLA-A gene was discovered after a long process of determining MHC antigens. The original alleles discovered for MHC class I were not separated according to genes. The first 15 HL A1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 contained antigens from many HLA loci. HL A1, 2, 3, 9, 10, 11 were later found limited to a maximum of 2 in any given person. For example, a person could have A1, A2, A7, A8 but not A1, A2, A3, and A11 or A7, A8, A14, A15. Given the exclusion HLA-A alleles were sorted according A and B, creating HLA-A and HLA-B serotype groups, in late 1970s the first A and B isoforms were finally sequenced.^[2][3]

Alleles

There are many alleles, so that classification by serotype simplifies categorization. For example HLA-A*0101, *0102, *0103, . . . *0130 are assigned to the serotype A1.^[4] The A*01 prefix signifies that the gene products (expressed proteins) of the alleles are identified primarily by the A1 serotype or most similar to alleles recognized by the serotype. There is a useful logic in this classification: HLA alleles evolve by a process called 'gene conversion' in which a few (<50 nucleotides) are swapped between HLA haplotypes and often results in the change of 1 to 3 nucleotides on the converted chromosome. Infrequently, there are recombination events that cross-over a gene in the style of recombination we are familiar with in genetics. This can result in entirely new serotypes and alleles. Less frequently, single-nucleotide polymorphisms alter the gene (intro or exon) but can cause changes unseen at the protein level. These cryptic alleles are designated with further extension such as A*01010101 or A*01010102, but they are still A*0101 allele, also.

There are 673 gene alleles capable of producing 527 HLA-A isoforms and 46 nulls.^[1]

Assignment of alleles

HLA alleles and specificity are assigned as a consequence of workshops and working groups. Some Allele groups have been updated with recent information from the IMGT/HLA Database ^[5] Explanation - within each allele group there are alleles that are recognized by the serological typing for that group (e.g., A24-serotype) some within the group may also recognize the broad antigen typing (A9, A10, A19, A28) or only the broad antigen typing, some by alternative serological within the group (e.g., A2403), and some by no serological method. Some groups are more closely related than other groups, which is often reflected in broad antigen reactivity.

Function

Natural function

MHC Class I molecules present smaller peptides, in general, 9 amino acids in length, but somewhat longer molecules are tolerated, to the immune system. Several target cells include CD8⁺ T-lymphocytes. In response to signaling, these lymphocytes result in programmed cell death (apoptosis). This mechanism is the result of responses to viral infection or intracellular microbial infections in which, as a means of preventing propagation, affected cells are killed and the antigens are presented to the immune system for Class II presentation and antibody development. Over a short period of time, antibodies that can neutralize the ability of viruses and invasive bacteria to invade cells develop.

Other activities

One major activity of HLA-A receptors resulted from the era of organ transplantation initiated after WWII. By the 1960s, it became evident that factors on the donated organs and tissues resulted in an inflammatory destruction of those transplants by the host. The MHC class I receptors were a primary target on donor tissues. As a consequence, donated organs must be matched with regard to HLA between donor and recipient.

In disease

Associated Diseases

HLA often suffer a peculiar problem in genetics; many of the haplotypes associated with disease are very large, often millions of nucleotides. Therefore, associations with disease often mark a variable gene that is close to a susceptibility gene for a disease. Most of the susceptibility for inflammatory disease lies between HLA-B locus and HLA-DP locus, with a substantial fraction linked to DR-DQ haplotypes. There are a few diseases, however, that link to the region telomeric from HLA-B, which contains most of the Class I loci, HLA-F, HLA-G, and HLA-E, as well as other genes.

Diseases by Haplotype

A*02:Cw*16 : higher viral load in HIV^[7]
A*23:B*14 : higher viral load in HIV^[7]
A*23:Cw*07 : higher viral load in HIV^[7]
A*30:Cw*03 : higher viral load in HIV^[7]

Interactions

HLA-A has been shown to interact with CD8A,^[8][9] Tapasin^[10] and TAP1.^[10]

References

External links

• Molecular Anthropology Yahoo Group
• HLA Allele and Haplotype Frequency Database
• HLA Nomenclature Full List of Class I Proteins