HLA-A
Encyclopedia
HLA-A are a group of human leukocyte antigen
s (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 allele
s and isoforms have been identified. 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.
ic 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.
|+ Serotypes of HLA-A gene products
|- align = "center"
| antigen > -
Broadantigen
Split antigens
|- align="center"
| A1
A9
A23
A24
|- align="center"
| A2
A10
A25
A26
A34
>- align="center"
| A3
A43
A66
>- align="center"
| A11
A19
A29
A30
A31
>- align="center"
| A36
A32
A33
A74
>- align="center"
| A80
A28
A68
A69
>- align="center"
| colspan = "6" align="center"| "HLA-" prefix trimmed from serotype names.
For example HLA-A, , , . . . are assigned to the serotype A1
.
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 or A, but they are still A*0101 allele, also.
There are 673 gene alleles capable of producing 527 HLA-A isoforms and 46 nulls.
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.
|+ HLA-A associated diseases
|-
| Associated disease > Serotypes
|-
| Ankylosing spondylitis
A24
|-
| Diabetes, type-I A1
A24
|-
| Hemochromatosis (lower CD8+ cells)
A3
| myasthenia gravis
A3
A24
A30
|-
| Leukemia, T-cell, Adult
A26
A68
| Multiple sclerosis A3
| Papilloma virus susept. A11
| Spontaneous abortion A2
A*23:B*14 : higher viral load in HIV
A*23:Cw*07 : higher viral load in HIV
A*30:Cw*03 : higher viral load in HIV
with CD8A
, Tapasin
and TAP1
.
Human leukocyte antigen
The human leukocyte antigen system is the name of the major histocompatibility complex in humans. The super locus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and...
s (HLA) that are encoded by the HLA-A locus
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
on human chromosome 6p. The HLA genes constitute a large subset of the Major histocompatibility complex
Major histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
(MHC) of humans. HLA-A is a component of certain MHC class I
MHC class I
MHC class I molecules are one of two primary classes of major histocompatibility complex molecules and are found on every nucleated cell of the body...
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
Beta-2 microglobulin
β2 microglobulin also known as B2M is a component of MHC class I molecules, which are present on all nucleated cells . In humans, the β2 microglobulin protein is encoded by the B2M gene.-Structure and function:...
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
Primary structure
The primary structure of peptides and proteins refers to the linear sequence of its amino acid structural units. The term "primary structure" was first coined by Linderstrøm-Lang in 1951...
, and HLA-A is ranked among the genes in humans with the fastest-evolving coding sequence. After typing millions of individuals, hundreds of variant allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
s and isoforms have been identified. 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 telomerTelomer
The word telomer has two distinct, yet related meanings.*Its original meaning is in polymer science, when telomerization results in an extremely small polymer—one whose degree of polymerization is generally between 2 and 5....
ic end of the HLA complex between the HLA-G
HLA-G
HLA-G histocompatibility antigen, class I, G, also known as human leukocyte antigen G , is a protein that in humans is encoded by the HLA-G gene....
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.
|- align = "center"
| antigen >
|- align="center"
| A1
HLA-A1
HLA-A1 is a human leukocyte antigen serotype within HLA-A "A" serotype group. The serotype is determined by the antibody recognition of α1 subset of HLA-A α-chains. For A1, the alpha "A" chain are encoded by the HLA-A*01 allele group and the β-chain are encoded by B2M locus. This group...
HLA-A9
HLA-A9 is a broad antigen HLA-A serotype that recognized the HLA-A23 and HLA-A24 serotypes. A*2402 appears to have evolved from A*23 alleles by a process of gene conversion. The A23 is more common in Africa and regions proximal to Africa. A24 is at very high frequencies in Austronesia and certain...
HLA-A23
HLA-A23 is a human leukocyte antigen serotype within HLA-A serotype group. The serotype is determined by the antibody recognition of α23 subset of HLA-A α-chains. For A23, the alpha, "A", chain are encoded by the HLA-A*23 allele group and the β-chain are encoded by B2M locus. This group currently...
HLA-A24
HLA-A24 is a human leukocyte antigen serotype within HLA-A serotype group. The serotype is determined by the antibody recognition of α24 subset of HLA-A α-chains. For A24, the alpha, "A", chain are encoded by the HLA-A*24 allele group and the β-chain are encoded by B2M locus. This group currently...
|- align="center"
| A2
HLA-A2
HLA-A2 is a human leukocyte antigen serotype within HLA-A "A" serotype group. The serotype is determined by the antibody recognition of α2 subset of HLA-A α-chains. For A2, the alpha "A" chain are encoded by the HLA-A*02 allele group and the β-chain are encoded by B2M locus. A2 and A*02 are...
HLA-A10
HLA-A10 is a broad antigen HLA-A serotype. The ancestral A10 type is believed to be A*2601, which via gene conversion with other HLA-A alleles produced A*2501, A*3401, A*4301 and A*6601. A10 serotypes in general show a pattern of more recent expansion...
HLA-A25
-A25 frequencies:A*2501 distribution is primarily located in Western Eurasia. Frequency tends to be highest in the populations that underwent later neolithization suggesting A*2501 spread in Europe. The high frequency in Saudi Arabia is suggestive of a source....
HLA-A26
-Distribution:-Disease associations:A26 Serotype is associated with adult T-cell leukemia in Japanese....
HLA-A34
-A*3401:A*3401 when found outside of Africa is primarily found in the South Asia, Austronesia and the South/Central part of the West Pacific Rim . It appears to have made it to Eastern Taiwan's indigenous tribes but not more north of this region. It has not been detected in any sampling of Japan...
>- align="center"
| A3
HLA-A3
HLA-A3 is a human leukocyte antigen serotype within HLA-A serotype group. The serotype is determined by the antibody recognition of α3 subset of HLA-A α-chains. For A3, the alpha, "A", chain are encoded by the HLA-A*03 allele group and the β-chain are encoded by B2M locus. This group currently is...
HLA-A43
-Distribution:...
HLA-A66
-A*6601 Frequencies:...
>- align="center"
| A11
HLA-A11
HLA-A11 is a human leukocyte antigen serotype within HLA-A "A" serotype group. The serotype is determined by the antibody recognition of α11 subset of HLA-A α-chains. For A11, the alpha "A" chain are encoded by the HLA-A*11 allele group and the β-chain are encoded by B2M locus. This group...
HLA-A19
HLA-A19 is a broad antigen HLA-A serotype that may recognize the A29, A30, A31, A32, A33, and A74 serotypes. While these haplotypes are found all over the globe their combined frequencies are higher in Sub Saharan Africa, frequencies tend to decline away from Africa....
HLA-A29
-Allele distribution:-Haplotypes:For A29-Cw*16-B44 haplotype see Cw*16...
HLA-A30
-Alleles:...
HLA-A31
There is substantive false reaction of A30 with A*3101, otherwise serological identification is good.-Distribution:-Haplotypes:Examination of A31 haplotypes reveals a probable connection across northern Eurasia during the prehistoric period. Frequencies of the more 'tale-tell' haplotypes fall...
>- align="center"
| A36
HLA-A36
-Distribution:A36 is largely limited to Africa. Outside of Africa more than half of the populations have no A36 and the majority that do, have only trace levels. The exception is in Central/East Central Asia. This appears not to be coincidental...
HLA-A32
-Distribution:A32 is most common around the Persian Gulf and the Mediterranean Basin. It has a consistent presence in Europe. The A32 frequenceies in the more isolated peoples of Europe suggests that the A32 rise in the Mediterranean may only be partially attributable to recent migrations from...
HLA-A33
-A33 frequencies:A33 shows two different distributions that can be discriminated by subtyping capability of SSP-PCR.-A*3301 distribution:...
HLA-A74
-Disease associations:A significant association has been found between A74 and nasal polyposis.-Allele distribution:...
>- align="center"
| A80
HLA-A80
-Distribution:...
HLA-A28
HLA-A28 is a broad antigen HLA-A serotype that recognized the A68 and A69 serotypes. These haplotypes are most common in the middle eastern region and NE Africa but can be found along central Asia to eastern siberia and within the New World....
HLA-A68
-By allele:A*68 is associated with higher viral load in HIV. A68 may be protectiveagainst symptomatic heart disease in Chaga's cardiomyopathy.-Allele freqeuncies:A68 can be subdivided into 3 alleles, *6801, *6802, *6803...
HLA-A69
-Distribution:Distribution of A69 places nodal center in the Levant, but high levels in West Africa. The model of human genetic origin places first migrations from Eastern Africa. However in many east African populations the frequency of A69 is zero. A more consistent model of A69 distribution is...
>- align="center"
| colspan = "6" align="center"| "HLA-" prefix trimmed from serotype names.
Alleles
There are many alleles, so that classification by serotype simplifies categorization.For example HLA-A, , , . . . are assigned to the serotype A1
HLA-A1
HLA-A1 is a human leukocyte antigen serotype within HLA-A "A" serotype group. The serotype is determined by the antibody recognition of α1 subset of HLA-A α-chains. For A1, the alpha "A" chain are encoded by the HLA-A*01 allele group and the β-chain are encoded by B2M locus. This group...
.
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 or A, but they are still A*0101 allele, also.
There are 673 gene alleles capable of producing 527 HLA-A isoforms and 46 nulls.
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 DatabaseExplanation - 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.
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 disease >
|-
| Ankylosing spondylitis
HLA-A24
HLA-A24 is a human leukocyte antigen serotype within HLA-A serotype group. The serotype is determined by the antibody recognition of α24 subset of HLA-A α-chains. For A24, the alpha, "A", chain are encoded by the HLA-A*24 allele group and the β-chain are encoded by B2M locus. This group currently...
|-
| Diabetes, type-I
HLA-A1
HLA-A1 is a human leukocyte antigen serotype within HLA-A "A" serotype group. The serotype is determined by the antibody recognition of α1 subset of HLA-A α-chains. For A1, the alpha "A" chain are encoded by the HLA-A*01 allele group and the β-chain are encoded by B2M locus. This group...
HLA-A24
HLA-A24 is a human leukocyte antigen serotype within HLA-A serotype group. The serotype is determined by the antibody recognition of α24 subset of HLA-A α-chains. For A24, the alpha, "A", chain are encoded by the HLA-A*24 allele group and the β-chain are encoded by B2M locus. This group currently...
|-
| Hemochromatosis (lower CD8+ cells)
HLA-A3
HLA-A3 is a human leukocyte antigen serotype within HLA-A serotype group. The serotype is determined by the antibody recognition of α3 subset of HLA-A α-chains. For A3, the alpha, "A", chain are encoded by the HLA-A*03 allele group and the β-chain are encoded by B2M locus. This group currently is...
| myasthenia gravis
Myasthenia gravis
Myasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability...
HLA-A3
HLA-A3 is a human leukocyte antigen serotype within HLA-A serotype group. The serotype is determined by the antibody recognition of α3 subset of HLA-A α-chains. For A3, the alpha, "A", chain are encoded by the HLA-A*03 allele group and the β-chain are encoded by B2M locus. This group currently is...
HLA-A24
HLA-A24 is a human leukocyte antigen serotype within HLA-A serotype group. The serotype is determined by the antibody recognition of α24 subset of HLA-A α-chains. For A24, the alpha, "A", chain are encoded by the HLA-A*24 allele group and the β-chain are encoded by B2M locus. This group currently...
HLA-A30
-Alleles:...
|-
| Leukemia, T-cell, Adult
HLA-A26
-Distribution:-Disease associations:A26 Serotype is associated with adult T-cell leukemia in Japanese....
HLA-A68
-By allele:A*68 is associated with higher viral load in HIV. A68 may be protectiveagainst symptomatic heart disease in Chaga's cardiomyopathy.-Allele freqeuncies:A68 can be subdivided into 3 alleles, *6801, *6802, *6803...
| Multiple sclerosis
HLA-A3
HLA-A3 is a human leukocyte antigen serotype within HLA-A serotype group. The serotype is determined by the antibody recognition of α3 subset of HLA-A α-chains. For A3, the alpha, "A", chain are encoded by the HLA-A*03 allele group and the β-chain are encoded by B2M locus. This group currently is...
| Papilloma virus susept.
HLA-A11
HLA-A11 is a human leukocyte antigen serotype within HLA-A "A" serotype group. The serotype is determined by the antibody recognition of α11 subset of HLA-A α-chains. For A11, the alpha "A" chain are encoded by the HLA-A*11 allele group and the β-chain are encoded by B2M locus. This group...
| Spontaneous abortion
HLA-A2
HLA-A2 is a human leukocyte antigen serotype within HLA-A "A" serotype group. The serotype is determined by the antibody recognition of α2 subset of HLA-A α-chains. For A2, the alpha "A" chain are encoded by the HLA-A*02 allele group and the β-chain are encoded by B2M locus. A2 and A*02 are...
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 HIVA*23:B*14 : higher viral load in HIV
A*23:Cw*07 : higher viral load in HIV
A*30:Cw*03 : higher viral load in HIV
Interactions
HLA-A has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with CD8A
CD8A
CD8a , is a human gene.-Interactions:CD8A has been shown to interact with CD3D, HLA-G and HLA-A.-Further reading:...
, Tapasin
Tapasin
TAP-associated glycoprotein also known as tapasin or TAPBP is a protein that in humans is encoded by the TAPBP gene.- Function :...
and TAP1
TAP1
Antigen peptide transporter 1 is a protein that in humans is encoded by the TAP1 gene.-Interactions:TAP1 has been shown to interact with Tapasin and HLA-A.-Further reading:...
.