HLA region of Chromosome 6

The human leukocyte antigen system (HLA) is the name of the major histocompatibility complex (MHC) in humans. The superlocus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6, and encode cell-surface antigen-presenting proteins and many other genes. The proteins encoded by certain genes are also known as antigens, as a result of their historic discovery as factors in organ transplantations. The major major HLA antigens are essential elements in immune function. Different classes have different functions.

HLA class I antigens (A, B & C) present peptides from inside the cell (including viral peptides if present). These peptides are produced from digested proteins that are broken down in the lysozomes. The peptides are generally small polymers, about 9 amino acids in length. Foreign antigens attract killer T-cells (also called CD8 positive cells) that destroy cells.

HLA class II antigens (DR, DP, & DQ) present antigens from outside of the cell to T-lymphocytes. These particular antigens stimulate T-helper cells to reproduce and these T-helper cells then stimulate antibody producing B-cells, self-antigens are suppressed by suppressor T-cells.

HLA have other roles. They are sometimes involved in mate selection. They may protect against or allow cancer. They may mediate autoimmune disease (examples: juvenile diabetes, coeliac disease).

Aside from the genes encoding the 6 major antigens, there are a large number of other genes, many involved in immune function located on the HLA complex. Diversity of HLA in human population is one aspect of disease defense, and, as a result, the chance of two unrelated individuals having identical HLA molecules on all loci is very low. Historically, HLA genes were identified as a result of the ability to successfully transplant organs between HLA similar individuals.

HLA functions

The proteins encoded by HLAs are the proteins on the outer part of body cells that are (effectively) 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 therefore is not an invader).

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. PDB 2G9H

In infectious disease. 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 onto HLA antigens (specifically MHC class II). They are then displayed by the antigen presenting cells for certain cells of the immune system called T cells, which then produce a variety of effects 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 HLA antigens (specifically MHC class I) on the cell surface. Infected cells can be recognized and destroyed by components of the immune system (specifically CD8+ T cells).

The image off to the side shows a piece of a poisonous bacterial protein (SEI peptide) bound within the binding cleft portion of the HLA-DR1 molecule. In the illustration far below, a different view, one can see an entire DQ with a bound peptide in a similar cleft, as view from the side. Disease-related peptides fit into these 'slots' much like a hand fits into a glove or a key fits into a lock. In these configurations peptides are presented to T-cells. The T-cells are restricted by the HLA molecules when certain peptides are within the binding cleft. These cells have receptors that are like antibodies and each cell only recognizes a few class II-peptide combinations. Once a T-cell recognizes a peptide within an MHC class II molecule it can stimulate B-cells that also recognize the same molecule in their sIgM antibodies. Therefore these T-cells help B-cells make antibodies to proteins they both recognize. There are billions of different T-cells in each person that can be made to recognize antigens, many are removed because they recognize self antigens. Each HLA can bind many peptides, and each person has 3 HLA types and can have 4 isoforms of DP, 4 isoforms of DQ and 4 Isoforms of DR (2 of DRB1, and 2 of DRB3,DRB4, or DRB5) for a total of 12 isoforms. In such heterozygotes it is difficult for disease related proteins to escape detection.

In graft rejection. Any cell displaying some other HLA type is "non-self" and is an invader, resulting in the rejection of the tissue bearing those cells. Because of the importance of HLA in transplantation, the HLA loci are among of the most frequently typed by serology or PCR relative to any other autosomal alleles.

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, Celiac Disease, SLE (Systemic Lupus Erythematosus), Myasthenia Gravis, inclusion body myositis and Sjögren's syndrome. 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 *0201 from *0202), 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 1st degree relatives who are at risk from those who 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 EATL cases. More often; however, HLA molecules play a protective role, recognizing the increase in antigens that were not tolerated because of low levels in the normal state. Abnormal cells may be targeted for apoptosis mediating many cancers before clinical diagnosis. Prevention of cancer may be a portion of heterozygous selection acting on HLA.

Classification of HLAs/alleles

Schematic representation of MHC class I

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

There are 3 major and 3 minor MHC class I genes in HLA:

• HLA-A
• HLA-B
• HLA-C
• minor genes are HLA-E, HLA-F and HLA-G
• β₂-microglobulin binds with major and minor gene subunits to produce a heterodimer

Illustration of an HLA-DQ molecule (magenta and blue) with a bound ligand (yellow) floating on the plasma membrane of the cell

There are 3 major and 2 minor MHC class II Proteins encoded by the HLA. The genes of the class II combine to form heterodimeric (αβ) protein receptors that are typically expressed on the surface of antigen presenting cells. Major MHC class II

• HLA-DP
  • α-chain encoded by HLA-DPA1 locus
  • β-chain encoded by HLA-DPB1 locus
• HLA-DQ
  • α-chain encoded by HLA-DQA1 locus
  • β-chain encoded by HLA-DQB1 locus
• HLA-DR
  • α-chain encoded by HLA-DRA locus
  • 4 β-chains (only 3 possible per person), encoded by HLA-DRB1, DRB3, DRB4, DRB5 loci

The Other MHC class II proteins, DM and DO are used in the internal processing of antigens, loading the antigenic peptides generated from pathogens onto the HLA molecules of antigen-presenting cell.

HLA Nomenclature

Modern HLA alleles are typically noted with a variety of levels of detail. Most designations begin with HLA- and the locus name, then * and some (even) number of digits specifying the allele. The first two digits specify a group of alleles. Older typing methodologies often could not completely distinguish alleles and so stopped at this level. The third through fourth digits specify a synonymous allele. Digits five through six denote any synonymous mutations within the coding frame of the gene. The seventh and eighth digits distinguish mutations outside the coding region. Letters such as L, N, Q, or S may follow an allele's designation to specify an expression level or other non-genomic data known about it. Thus, a completely described allele may be up to 9 digits long, not including the HLA- prefix and locus notation.

Historical Guide to Understanding HLA Nomenclature

The naming of HLA "antigens" is rooted in the history of their definition as serotypes and alleles. The system originated clinically as to explain illness for transplant recipients. The common cause of rejections was found to be antigens. In the same way bacterial antigens can cause inflammatory response, allotypic proteins from the donor of the organ caused an inflammatory response when placed in a recipient. But HLA gene products (i.e., antigen-presenting, cell-surface receptors) likely did not evolve to protect against organ transplantation, as the practice was unknown until 1960. The HLA genes are much older. The scientific problem has been to explain the such a molecule is involved in immunity and how variation developed and persists.

A simple example of HLA antigen causing rejection
A1, B7, B8, DR2 and DR3 do not cause reaction because they are in both donor and recipient, but A3 is recognized as foreign by the recipient's immune system

Origin of HLA science in organ transplantation. In the early 1960s, before PCR based gene sequencing and gene identification were available, some physicians began experimenting with organ transplantation^[1]. Knowing little about compatibility factors, they attempted transplantation between humans and even between non-humans and humans. Immunosuppressive drugs worked for a time, but the transplanted organs often failed or the patients died from infections. The rejection response was found to be accompanied by an antibody mediated agglutination of red blood cells (See figure).^[2] The search began for cell surface antigens that might trigger this process. These antigens were recognized as factors interfering with or, occasionally, permitting successful transplantion. Donor organs transplanted into recipients elicit antibodies against the donor's tissues which recognize the donor's HLA receptors as antigens, hence the name 'human leukocyte antigens'. The receptors could be classified based on the antibodies that they induced. These antibodies, particularly to donors who were homozygotes of a particular class II haplotype could be used to identify different receptor types and isoforms. Antibodies were identified which could attract lymphocytes and cause them to lyse cells via the immune system's complement pathway. Simiarly, Cytokine responses were identified which caused systemic inflammation.

Identifying Specific Antigens

In the late 1960's, scientist began reacting sera from transplant patients with donor or third party tissues. Their serum was alloreactive because its antibodies react with specific, previously recognized antigens in the foreign tissue. These sera are disignated an antiserum. An alloreactive antiserum could have strong reaction with the cells from one person (e.g., the transplant donor), mild reaction to another's cells, and no reaction to a third's cells (e.g., a close relative).

As a result of this complex reactivity, scientists were able to identify 15 antigens which determined reactivity. These were assigned, a simple number, from 1 to 15. At first these 15 antigens were called the Hu-1 antigens^[3] and tentatively tagged as gene products of the Human equivalent of the mouse histocompatibility locus (MHC). In 1968, it was discovered that matching these antigens between kidney donor and recipient improved the likelihood of kidney survival in the recipient.^[4] The antigen list still exists, although it has been reorganized to fit what we have since learned about genetics, refined, and greatly expanded.

Lymphocyte bearing antigens recognized

As the study of these 'rejection' sera and "allo"-antigens progressed, certain patterns in the antibody recognition were recognized. The first major observation, in 1969, was that allotypic antibodies to "4" ("Four") was only found on lymphocytes, while most of the antigens, termed "LA", were found on most cells in the body.^[5] This group "4" antigen on lymphocytes would later expand into "4a", "4b" and so on, becoming the "D" series (HLA-D (Class II) antigens) DP, DQ, and DR.

The Hu-1 antigens were renamed the Human-lymphoid (HL) allo-antigens (HL-As). Allo-antigen comes from the observation that a tolerated protein in the donor becomes antigenic in the recipient. This can be compared with an autoantigen, in which a person develops antibodies to one or more of their own proteins. This also suggested the donor and recipient have a different genetic makeup for these antigens. The "LA" group thereafter was composed of HL-A1, A2, A3, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14 and A15 until further divisions and renaming were necessary. Some of the antigens above, for example HL-A1, are similar to HLA-A1, as they are the same serotype. Some of the above, like A5, are not mentioned within the last few years, as they have been renamed.

Subclassification of lymphoid antigens

A series of tests on cultured cells revealed that, within the "LA" group, a donor tissue might have some antigens but not others. For example, an antiserum may react with patterns (on a given tissue):

• A1, A2, A7, A12
• A1, A3, A7, A8
• A1, A11, A8, A5
• A1, A8
• A2, A3, A7, A12
• A2, A11, A
• A2, A7, A12
• A3, A11, A7, B5
• A3, A7
• A11, A5

But fail to react in the following patterns:

• A1, A2, A3, ...
• A1, A2, A11
• A2, A3, A11
• . . . A7, A8, A12

The HLA serotype series

Series "A"

If 2 members of the series (A1, 2, 3, 9, 10, 11) were typed, a reaction with a third member of the series to the donor was not observed. This 'exclusivity' identified series "A".^[6] One might notice the similarities of this numeric series with the HLA-A series, as series "A" antigens are the first six members of HLA-A. Inadvertently, the scientist had discovered an antibody set that recognized only gene products from one locus,HLA-A the "antigens" being the gene products. The implication is that an alloreactive anti-sera can be a tool for genetic identification.

Series "B"

Not long after the series A antigens were separated from the (rapidly expanding) list of antigens, it was determined another group also could be separated along the same logical lines. This group included HL-A5, A7, A8, A12. This became the series "B". Note the similarity of Series "B" to the first few members HLA-B serotypes. The names of these antigens were necessarily changed to fit the new putative series they were assigned to. From HL-A# to HLA-B#. The problem was that the literature was using "A7" and would soon be using "B7" as short hand for HLA-B7.

Pseudo-series "w"

Since it was now certain, by the early 1970s, that the "antigens" were encoded by different series, implicit loci, numeric lists became somewhat cumbersome. Many groups were discovering antigens. In these instances an antigen was assigned a temporary name, like "RoMa2" and after discussion, the next open numeric slot could be assigned, but not to an "A" or "B" series until proper testing had been done. To work around this problem a 'workshop' number "w#" was often assigned while testing continued to determined which series the antigen belonged to.

Series "C"

Before too long, a series "C" was uncovered. Series C has proved difficult to serotype, and the alleles in the series still carry the "w" tag signifying that status; in addition, it reminds us that Series C were not assigned names the same way as Series A and B, it has its own numeric list Cw1, Cw2, Cw3.

Serotype group expansion and refinement

By the mid 1970s, genetic research was finally beginning to make sense of the simple list of antigens, a new series "C" had been discovered and, in turn genetic research had determined the order of HLA-A, C, B and D encoding loci on the human 6p.^[7] With new series came new antigens; Cw1 and 2 were quickly populated, although Cw typing lagged. Almost half of the antigens could not be resolved by serotyping in the early 90's. Currently genetics defines 18 groups.

At this point, Dw was still being used to identify DR, DQ, and DP antigens. The ability to identify new antigens far exceeded the ability to characterize those new antigens.

As technology for transplantation was deployed around the world, it became clear that these antigens were far from a complete set, and in fact hardly useful in some areas of the world (eg, Africa, or those descended from Africans). Some serotyping antibodies proved to be poor, with broad specificities, and new serotypes were found that identified a smaller set of antigens more precisely. These broad antigen groups, like A9 and B5, were subdivided into "split" antigen groups, A23 & A24 and B51 & B52, respectively. As the HL-A serotyping developed, so did identification of new antigens.

Genetic identification

In the early 1980's, it was discovered that a restriction fragment segregates with individuals who bear the HLA-B8 serotype. By 1990, it was discovered that a single amino acid sequence difference between HLA-B44 (B*4401 versus B*4402) could result in allograft rejection. This revelation appeared to make serotyping based matching strategies problematic if many such differences existed. In the case of B44, the antigen had already been split from the B12 broad antigen group. In 1983, the cDNA sequences of HLA-A3 and Cw3^[8] All three sequences compared well with mouse MHC class I antigens. The Western European HLA-B7 antigen had been sequenced (although the first sequence had errors and was replaced). In short order, many HLA class I alleles were sequenced including 2 Cw1 alleles.^[9]

By 1990, the full complexity of the HLA class I antigens was beginning to be understood. At the time new serotypes were being determined, the problem with multiple alleles for each serotype was becoming apparent by nucleotide sequencing. RFLP analysis helped determine new alleles, but sequencing was more thorough. Throughout the 1990s, PCR kits, called SSP-PCR kits were developed that allowed, at least under optimal conditions, the purification of DNA, PCR and Agarose Gel identification of alleles within an 8 hour day. Alleles that could not be clearly identified by serotype and PCR could be sequenced, allowing for the refinement of new PCR kits.

Serotypes like B*4401, B*4402, B*4403, each abundant within those with B44 serotypes could be determined with unambiguous accuracy. The molecular genetics has advanced HLA technology markedly over serotyping technology, but serotyping still survives. Serotyping can help to reveal which primers for sequencing may best work for new sequences. Serotyping had identified the most similar antigens that now form the HLA subgroups.

HLA are extremely variable loci

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 more than 150 000 years ago that was capable of fixing many loci, the HLA loci appear to have survived such a constriction with a great deal of variation.^[10] 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.^[11] Less frequently, longer range productive recombinations through HLA genes have been noted producing chimeric genes.

Five 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 2004, 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 a 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*0501 and DQA1*0505 encode proteins with identically processed products. Other proteins 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.

Tables of variant alleles

Number of variant alleles at class I loci according to the IMGT-HLA database, last updated August 2007:

Number of variant alleles at class II loci (DP and DQ):

Examining HLA types

HLA serotype and allele names

There are two parallel systems of nomenclature that are applied to HLA. The, first, and oldest system is based on serological (antibody based) recognition. In this system antigens were eventually assigned letters and numbers (e.g. HLA-B27 or, shortened, B27). A parallel system was developed that allowed more refined definition of alleles, in this system a "HLA" is used in conjunction with a letter * and four or more digit number (e.g. HLA-B*0801, A*68011, A*240201N N=Null) to designate a specific allele at a given HLA locus. HLA loci can be further classified into MHC class I and MHC class II (or rarely, D locus). Every two years a nomenclature is put forth to aid researchers in interpreting serotypes to alleles.^[12]

HLA serotyping

Further information: Serotype

In order to create a typing reagent, blood from animals or humans would be taken, the blood cells allowed to separate from the serum, and the serum diluted to its optimal sensitivity and used to type cells from other individuals or animals. Thus serotyping became a way of crudely identifying HLA receptors and receptor isoforms. Over the years serotyping antibodies became more refined as techniques for increasing sensitivity improved and new serotyping antibodies continue to appear. One of the goals of serotype analysis is to fill gaps in the analysis. It is possible to predict based on 'square root','maximum-likelihood' method, or analysis of familial haplotypes to account for adequately typed alleles. These studies using serotyping techniques frequently revealed, particularly for non-European or north East Asian populations a large number of null or blank serotypes. This was particularly problematic for the Cw locus until recently, and almost half of the Cw serotypes went untyped in the 1991 survey of the human population.

There are several types of serotypes. A broad antigen serotype is a crude measure of identity of cells. For example HLA A9 serotype recognizes cells of A23 and A24 bearing individuals, it may also recognize cells that A23 and A24 miss because of small variations. A23 and A24 are split antigens, but antibodies specific to either are typically used more often than antibodies to broad antigens.

HLA Gene sequencing

Minor reactions to subregions that show similarity to other types can be observed to the gene products of alleles of a serotype group. The sequence of the antigens determines the antibody reactivities and so having a good sequencing capability (or sequence based typing) obviates then need for serological reactions. Therefore different serotype reactions may indicate the need to sequence a persons HLA to determine a new gene sequence. Broad antigen types are still useful, such as typing very diverse populations with many unidentified HLA alleles (Africa, Arabia,^[14] Southeastern Iran^[15] and Pakistan, India^[16]). Africa, Southern Iran and Arabia shows the difficulty in typing areas that were settled earlier, allelic diversity makes it necessary to use broad antigen typing followed by gene sequencing because there is an increased risk of misidentifying by serotyping techniques.

In the end, a workshop, based on sequence, decides which new allele goes into which serogroup either by sequence or reactivity. Once the sequence is verified it is assigned a number. For example, a new allele of B44 may get a serotype B*4465 as it is the 65th B44 allele discovered. Marsh et al. (2005)^[12] can be considered a code book for HLA serotypes and genotypes and a new book biannually with monthly updates in Tissue Antigens.

HLA Phenotyping

Gene typing is different from gene sequencing and serotyping. With this strategy PCR primers specific to a variant region of DNA are used (called SSP-PCR), if a product of the right size is found, the assumption is that the HLA allele has been identified. New gene sequences often result in an increasing appearance of ambiguity. Because gene typing is based on SSP-PCR it is possible that new variants, particularly in the class I and DRB1 loci may be missed.

For SSP-PCR within the clinical situation is often used for identifying HLA phenotypes. An example of an extended phenotype for a person might be:

A*0101/*0301, Cw*0701/*0702, B*0702/*0801, DRB1*0301/*1501, DQA1*0501/*0102, DQB1*0201/*0602

This is generally identical to the extended serotype: A1,A3,B7,B8,DR3,DR15(2), DQ2,DQ6(1)

For many populations such as the Japanese or European populations so many patients have been typed that new alleles are relatively rare, and thus SSP-PCR is more than adequate for allele resolution. Haplotypes can be obtained by typing family members. In areas of world where SSP-PCR is unable to recognize alleles and typing requires the sequencing of new alleles. Areas of the world were SSP-PCR or serotyping may be inadequate include Central Africa, Eastern Africa, parts of southern Africa, Arabia and S. Iran, Pakistan and India.

HLA Haplotypes

A HLA Haplotype is a series of HLA "genes" (loci-alleles) by chromosome, one passed from the mother and father

The phenotype exampled above is one of the more common in Ireland and is the result of two common genetic haplotypes:

A*0101 : Cw*0701 : B*0801 : DRB1*0301 : DQA1*0501 : DQB1*0201 (By serotyping A1-Cw7-B8-DR3-DQ2)

which is called ' 'super B8' ' or ' 'ancestral haplotype' ' and

A*0301 : Cw*0702 : B*0702 : DRB1*1501 : DQA1*0102 : DQB1*0602 (By serotyping A3-Cw7-B7-DR15-DQ6 or the older version "A3-B7-DR2-DQ1")

These haplotypes can be used to trace migrations in the human population because they are often much like a fingerprint of an event that has occurred in evolution. The Super-B8 haplotype is enriched in the Western Irish, declines along gradients away from that region and is only found in areas of the world where Western Europeans have migrated. The "A3-B7-DR2-DQ1" is more widely spread, from Eastern Asia to Iberia. The Super-B8 haplotype is associated with a number of diet associated autoimmune diseases. There are 100000s of extended haplotypes but only a few show a visible and nodal character in the human population.

Importance of HLA allelic variation

Studies of humans and other animals infer a heterozygous selection mechanism operating on these loci as an explanation for this exceptional variability.^[17] One credible mechanism is sexual selection in which females are able to detect males with different HLA relative to their own type.^[18] While the DQ and DP encoding loci have fewer alleles combinations of A1:B1 can produce a theoretical potential of 1586 DQ and 2552 DP αβ heterodimers, respectively. While certainly 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 in individual 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 have frequently different haplotypes and as a result many combinations, even in small groups, affords the survival of the groups and thwarts evolution of epitopes in pathogens to hide from the immune system.

HLA antibodies

HLA antibodies are typically not naturally occurring, with few exceptions are formed as a result of an immunologic challenge of 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.^[19]

Donor-specific HLA antibodies have been found to be associated with graft failure in kidney, heart, lung and liver transplantation.

External links

• HLA Informatics Group at The Anthony Nolan Trust
• IMGT/HLA Sequence Database at European Bioinformatics Institute
• American Society for Histocompatibility and Immunogenetics
• European Federation for Immunogenetics
• HistoCheck HLA matching tool for organ and stem cell transplantation
• Allele Frequencies at Variable Immune related loci
• MeSH Human+leukocyte+antigens

References