History and naming of human leukocyte antigens

571:, eight years to ferret out the structure of the HLA protein. They worked specifically with HLA-A*02. Bjorkman did the majority of the leg work and in the seven years managed to piece together the structure of 90% of the protein. That last 10% was elusive though. It took another year of work to finally unveil the complete structure of HLA-A*02. They completed their work in the spring of 1987, discovering that the final 10% made a "cup" (of sorts) located on top of the molecule. It was the perfect size to hold peptides. Other researchers had previously determined that T-Cells can recognize cells infected with a virus, cells injected with a single protein from a virus, and even cells injected with pieces of protein from a virus. The discovery of the HLA protein structure made it starkly clear that the HLA proteins hold viral peptides in their binding groove. But the research team from Harvard wasn't done. They also observed that there was clearly a peptide in the binding groove of the HLA molecules they used to determine the shape. However, the cells they had extracted the protein from were definitely not infected by any disease causing viruses. The conclusion they made and the conclusion that has stuck to this day, is that HLA molecules can bind both self, and non-self peptides. 500:(WHO) decided that the HLA research needed an official naming system. This in turn would aid in organization and would more easily facilitate the unification of data being collected at numerous laboratories across the world. This committee is still in existence today and vastly accelerated the rate of HLA research. The first meeting of this committee in 1968 set forth guidelines and rules that govern HLAs. First, compatibility genes were divided into two types, class I and class II. Class I molecules were identified via reactions between blood serum and cells. Class II molecules were identified by mixtures of white blood cells. Second, the compatibility genes were renamed Human Leukocyte Antigens (HLA). Despite this clarification and the ever-increasing number of identified HLAs, nobody knew how they worked. 409:

of leukemic mice early in life, he found that the mice had a drastically weakened immune system. Taking inspiration from Medawar's skin transplant work, he performed a series of skin-graft experiments that showed that these immunocompromised mice didn't reject skin grafts from non-genetically identical mice. Miller then hypothesized that the thymus was essential in the construction and maintenance of the immune system. At this point Burnet came back into the picture, extending the hypothesis to specify that the dead cells found in the thymus are not any old immune cells, but instead the cells that are activated by self molecules. In other words, any cell that binds to and hence "recognizes" a self molecule is killed before exiting the thymus. These cells were later found to be one of the three types of

1901:. By testing different anti-sera from recipients they were able to uncover some with unique reactivities. As a result, scientists were able to identify a few antigens. At first the first antigens were called the Hu-1 antigens and tentatively tagged as gene products of the Human equivalent of the mouse histocompatibility locus (H2). In 1968, it was discovered that matching these antigens between kidney donor and recipient improved the likelihood of kidney survival in the recipient. The antigen list still exists, although it has been reorganized to fit what we have since learned about genetics, refined, and greatly expanded. 347:

Glasgow Royal Infirmary. The first insight came when the pair decided to experiment, and grafted part of a wound with the patient's skin, and another part with skin from the patient's brother. Within days the skin grafts from the brother were completely destroyed. Successive skin grafts from the brother were destroyed even faster, a fact that gave them the evidence they needed to implicate the immune system. Medawar later repeated this experiment on rabbits and 625 surgeries later validated their initial conclusions. Medawar then set out in search of the reason why rabbits rejected non-self grafts.

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always prevent the same infection in other mice. After looking at the MHCs present in the mice, they realized that cytotoxic T-cells could only identify virus infections in cells with the right Class I compatibility gene. Traditional thinking was that the immune system identified infections directly but this discovery turned that theory on its head. Compatibility genes were essential in immune system mediated viral clearing. The pair coined the term "MHC Restriction" to describe this relationship between T-cells, specific MHC proteins, and viral detection. In 1975, in an article in the journal

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the time however these were all grouped together as HL-Antigens. On the left the "B" and "cw" antigens are matched (B and C are close together so if B matches then C likely also matches), but A antigens are not matched. The antisera that is produced by the recipient is most likely to be A3, but if the direction of transplant is reversed A2 is the likely alloantigen. Two of the first three alloantigens are thus readily easy to detect because of the similarity and frequency of the A2-B7 and A3-B7 haplotypes (see example 1).

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antigens that now form the HLA subgroups. Serotyping can reveal whether an antigen coded by the relevant HLA gene is expressed. An HLA allele coding non-expressed gene is termed "Null Allele", for example: HLA-B*15:01:01:02N. The expression level can also detected by serotyping, an HLA gene coding for antigens which has low protein expression on the cell surface is termed "Low Expresser", for example: HLA-A*02:01:01:02L.

39: 1932:, 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 1255: 138: 80: 1205:

DRw antigens were the first to be split, a process made easy by the virtue of having an invariant alpha chain, but complicated by 4 beta chain loci (DRB1, DRB3, DRB4, and DRB5). Serotypes to DQ reacted with alpha and beta chains, or both of certain isoforms. The proper classification was greatly aided by gene sequencing and PCR. Classification and description of DP antigens is ongoing.

322:. The pilot sustained severe burns requiring skin grafts; however, skin grafts were a risky business at the time, often being rejected for unknown reasons. Numerous theories were proposed and it wasn't until 1958 that the first of these "identifying" proteins was found. The first standardized naming system was established in 1968 by the 1197:, these new antigens were called "W" antigens, and as they were reassigned to new groups, for example "A" serotypes, they became Aw or Bw antigens. It was found that some antigens that behaved like A and B antigens but could be excluded based on '2-type max' exclusion. Thus a new group, "C" was created. Classification of 2182:

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.

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Once it was determined that a tissue with two antigens of a series (such as "A") excluded the possibility of a third antigen of the same series, HLA serotypes began to clarify the genetic alleles present in humans. HL-Series "A" antigens became the HLA-A locus gene products, but with exceptions. Some

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assays, depicted on the right. IgM has 10 antigen binding regions per molecule, allowing cross-linking of cells. An antiserum specific for HLA-A3 will then agglutinate HLA-A3 bearing red blood cells if the concentration of IgM in the antiserum is sufficiently high. Alternatively, a second antibody to

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Historical perspective is important to an understanding of how the HLA were systematized. In organ transplant the goal was to explain graft rejection for recipients, and of course, to prevent future rejection. From this perspective, the cause of rejections were found to be "antigens". In the same way

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The classification of the "A4" antigens was complicated. The "A4" subset evolved to become D-region antigens, which was a large cluster of genes that encoded MHC class II. Several renamings occurred. The D-region has 8 major coding loci that combine to form 3 different protein groups; DP, DQ, and DR.

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A person can have 2 antigen proteins per genetic-locus (one gene from each parent). When first discovered, identified antigens were clustered, creating groups in which no more than two antigens per cluster were found in a given person. Serotype group "A" consisted HL-A1, A2, A3, A9, A10, A11. Another

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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

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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,

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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

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Madura, Florian, Pierre J. Rizkallah, Kim M. Miles, Christopher J. Holland, Anna M. Bulek, Anna Fuller, Andrea J. A. Schauenburg, John J. Miles, Nathaniel Liddy, Malkit Sami, Yi Li, Moushumi Hossain, Brian M. Baker, Bent K. Jakobsen, Andrew K. Sewell, and David K. Cole. "T-cell Receptor Specificity

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published a paper offering an explanation. Miller was a PhD student at the Chester Beatty Research Institute in London. His discovery centered on the thymus. The thymus had long been regarded as nothing more than a repository for dead cells. Miller didn't buy this hypothesis. By removing the thymus

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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

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In the tables a fortuitous transplant between two unrelated individual has resulted in an antiserum to single alloantigen. By discovering these close-but-non-identical matches, the process with somewhat related haplotypes surface antigens were identified for HLA A, and in the table below, HLA B at

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Late in 1973 a pair of researchers in Australia, Rolf Zinkernagel and Peter Doherty made a revelatory discovery that altered the thinking of immunologists forever. The pair was doing research on viral infections in mice and noticed that T-cells that prevented viral infections in some mice wouldn't

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At this point the researchers all realized that the sheer quantity of data they were capable of obtaining was vastly greater than that of any previous study and so collaboration would be essential. The first international meeting, in 1964, highlighted the difficulties of such massive collaborative

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published a paper that modified and revolutionized antibody theory. "Burnet speculated that one cell makes one particular shape of antibody and that all our antibody-making immune cells together make an unimaginably vast repertoire of 10 billion antibodies, each having a slightly different shape".

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Nomenclature Committee for Factors of the HLA System. HLA research didn't heat up until the 1980s when a group of researchers finally elucidated the shape of the HLA-A*02 protein (just one of many specific HLA proteins). Even more recently, in 2010, the WHO committee responsible for naming all HLA

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This linkage disequilibrium in Europeans explains why A1, A2, A3, "A7", and "A8" were identified, first. It would have taken substantially longer to identify other alleles because frequencies were lower, and haplotypes that migrated into the European population had undergone equilibration or were

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was a zoologist turned clinician, who specialized in burn trauma. A plane crash near his home changed the path of his career, turning his work with burns from mere academia to a full on quest to save lives. Medawar and a Scottish surgeon, Tom Gibson, were tasked with working the Burns Unit of the

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that attack self proteins are not allowed to live. In essence, every individual's immune system is tuned to the specific set of HLA and self proteins produced by that individual; where this goes awry is when tissues are transferred to another person. Since individuals almost always have different

991:) indicates what protein the allele codes for, and these are numbered sequentially in the order they are discovered. Any HLA that has a different number here produces a different protein (AKA has a nucleotide change that replaces an amino acid with another). The third set of numbers (HLA-A*02:101 2219:

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 had identified the most similar

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To explain rejection in a nutshell, certain immune system components are highly variable, the agents are called the Major histocompatibility (MHC) antigens. MHC antigens cause rejection of improperly matched organ transplants. The variability stems from genetics. From the perspective of human

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The use of the word alloantigen actually masks the fact that HLA are infrequently autoantigens in the donor, and therefore their function is not as antigens, but something else. But the naming of these antigens is not borne out of function but the need to match organ donors with recipients.

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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 (e.g., Africa, or those descended from Africans). Some serotyping antibodies proved to be poor, with broad

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and "allo"-antigens progressed, certain patterns in the antibody recognition were recognized. The first major observation, in 1969, was that an allotypic antibodies to "4" ("Four") was only found on lymphocytes, while most of the antigens, termed "LA", recognized most cells in the body.

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Burnet, independently of Medawar, came to the conclusion that the immune system must learn to tolerate any self cells, and hypothesized that this must occur during fetal development. For this, he jointly was awarded the Nobel Prize in 1960. Burnet's work continued and in 1957 along with

987:) signifies what antigen type that particular allele is, which typically signifies the serological antigen present. In other words, HLAs with the same antigen type (HLA-A*02:101 and HLA-A*02:102) will not react with each other in serological tests. The next set of digits (HLA-A*02 373:

Abstract diagram of the clonal selection of B and T lymphocytes. Legend: 1. Hematopoietic stem cell 2. Immature lymphocytes with various receptors 3. "Self"-antigens from the body's tissues 4. Mature, inactive lymphocytes 5. Foreign antigen 6. Cloned activated

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building blocks) long. This chunk has avoided recombination for thousands of years. When the A1 serotype is found with B8 (i.e., the 'old' HL-A8) serotype in Europe, there is an even greater chance the HL-A1 antiserum has detected the A1*0101 allele's gene product.

529:, they introduced the idea of "altered self", meaning that viruses alter the MHC proteins and this alteration is detected by T-cells. For their work they won the 1996 Nobel Prize. It took the work of many others to determine how T-cells made this identification. 1873:

In these instances, the A1/A2, A2/A3, A1/A3 are matched, decreasing the probability of a rejection because many are linked to a given haplotype. Occasionally the 'recombinant' A1-Cw7-B7(rare), B7 becomes the alloantigen in a recipient with A1-Cw7-B8(common).

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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 determine which series the antigen belonged to.

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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". One might notice the similarities of this numeric series with the

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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

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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.

1470:. This assay measures the release of (biological) radioactive chromium from cells as a result of killer cell activity. These cells are attracted to class I antigens that either carry foreign antigens, or are foreign to the immune system. 1177:

In 1968 the WHO Nomenclature Committee for Factors of the HLA System first met. They established a system that divided the HLAs into HLA-A and HLA-B, A and B corresponding to a group of reactive serotypes. For example, "HL-A2" became

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The most recent HLA naming system was developed in 2010 by the WHO Committee for Factors of the HLA System. There are two types of MHCs, Class I and Class II. Both are named using the same system. Currently there are 7,678 Class I

2140:. 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 shorthand for 1681:. This means there are much higher frequencies of certain haplotypes relative to the expectation based on random sorting of gene-alleles. This aided the discovery of HLA antigens, but was unknown to the pioneering researchers. 277:

identified as a result of transplant rejection. The antigens were initially identified by categorizing and performing massive statistical analyses on interactions between blood types. This process is based upon the principle of

2091:). Sensitivity can be improved by knowing the haplotype. In Europe, HLA-A1 is strongly linked to a 'chunk of chromosome' called a 'haplotype'. This haplotype, Super-B8, is A1-Cw7-B8-DR3-DQ2, about 2 million DNA codons (the 1927:

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

2175:. 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 90s. Currently genetics defines 18 groups. 1966:

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):

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cluster, "B", contained A7, A8, A12, A13, A14, A15. HL-A4 antigen was found to occur on lymphoid cells. Since the "HL-Antigens" no longer belonged to a single group, a new naming system was needed.

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evolution, why are antigens of the MHC so variable when many other human proteins lack variability? The cause of host-versus-graft-disease may actually stem from the functions of the system.

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bacterial antigens can cause inflammatory response, HLA antigens from the donor of the organ caused an inflammatory response when placed in a recipient. This is called allograft rejection.

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work. Different experimental methods and inconsistency in the execution of the same tests and a non-homogeneity of naming systems added together to make collaboration incredibly difficult.

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This group "4" antigen on lymphocytes would expand into "4a", "4b" and so on, becoming the "D" series (HLA-D (Class II) antigens) DP, DQ, and DR. This is an interesting history in itself.

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system of two leucocyte antigens which he called 4a and 4b (later known as HLA-Bw4 and HLA-Bw6), while Payne with collaborators in 1964 detected two leucocyte antigen LA1 and LA2 (later

516:) at the top of the image are the edges of the binding groove. The red line between them signifies a peptide (in this case an E1A heteroclitic variant of melanoma peptide). The arrows ( 358:, Medawar's first graduate student at Oxford several years prior. Through carefully planned experimentation, the trio showed that mice exposed to cells of unrelated mice as fetuses did 331: 1960: 401:

completely rejected the idea, but repeated experimentation intended to disprove the theory actually served to build up a large body of evidence supporting Burnet and Jerne's theory.

2062:- 0.016%. The frequency of *0101 is 1000 times more abundant than *0103, or 99.9% of the time you have identified the correct allele with the serotype. The false negative rate for 968: 1279: 1089: 52: 2178:

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.

1234:. There is no doubt that HLA terminology can be bewildering, this terminology is a consequence of the complex genetics as well as the way these antigens were characterized. 1910: 2132:

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

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Everything from this point onward has some overlap with the two big sections above, but also provides some good historical detail. Should they be integrated to the above?

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Thus, whenever a non-self molecule appears in the human body, one of these antibodies will have an accurate enough shape to bind to that molecule. This idea is known as

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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.

999:) is used to designate a single or multiple nucleotide polymorphism in a non-coding region of the gene. The final aspect of HLA naming is a letter (HLA-A*02:101:01:01 464:

and identified more leucocyte antigens. Namely, in 1962 van Rood analyzed reaction patterns of 60 sera against leucocytes from 100 donors and detected a seemingly

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Medawar, P. B. "A second study of the behaviour and fate of skin homografts in rabbits: a report to the War Wounds Committee of the Medical Research Council.

1136: 1108: 995:) indicates an allele variant that has a different DNA sequence but produces the same protein as the normal gene. The final set of numbers (HLA-A*02:101:01 404:

The biggest weakness in Burnet's theory was that he had no explanation for how the body selected for immune cells that only identified non-self. In 1961,

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of red blood cells (See figure). The search for these cell surface antigens began. There are several processes by which antibodies can reduce function:

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on human leucocytes which he subsequently named MAC after the initials of three important volunteers for his experiments. Antigen MAC (later known as

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Davis, Daniel M. The Compatibility Gene. How Our Bodies Fight Disease, Attract Others, and Define Our Selves. Oxford: Oxford UP, 2014. Print. pg 34

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were frequently found co-linked to disease. This linkage is not necessarily a function of either gene, but a consequence of the way AH8.1 evolved.

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and found seven sera that had a very similar behavior, in that they agglutinated leucocytes from 11 of 19 tested individuals. Thus he detected an

2054:, a cell surface antigen, the similar cell surface antigens are found on almost all cells in the body. The frequency of HLA-A1 alleles is: HLA-A1 1122: 975:

HLA Naming can be quite confusing at first. All alleles start with "HLA", signifying they are part of the human MHC genes. The next portion (HLA

101: 302:"banks" of HLAs, the immune system of the recipient recognizes the transplanted tissue as non-self and destroys the foreign tissue, leading to 2257:

Davis, Daniel M. The Compatibility Gene. How Our Bodies Fight Disease, Attract Others, and Define Our Selves. Oxford: Oxford UP, 2014. Print.

2291:"HLA Nomenclature @ Hla.alleles.org." HLA Nomenclature @ Hla.alleles.org. Anthony Nolan Research Institute, 10 Nov. 2013. Web. 08 Dec. 2013. 1104: 2313:

Billingham, R.E., Brent, L. and Medawar, P.B. "Quantitative studies on tissue transplantation immunity. iii. Actively acquired tolerance.

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serotypes, such as HL-A1 were so homogeneous in nature that mistaking that serotyped allele (HLA-A*0101) for another allele was unlikely.

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Patel R, Mickey MR, Terasaki PI (1968). "Serotyping for homotransplantation. XVI. Analysis of kidney transplants from unrelated donors".

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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

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worked for a time, but transplanted organs would either always fail or the patients would die from infections. Patients received skin,

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Medawar continued his work, this time with a team of three at the University College London during the 1950s. Medawar's coworkers were

2200: 1936:, 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. 2124:

the "antigens" being the gene products. The implication is that an alloreactive anti-sera can be a tool for genetic identification.

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Irene Park, Paul Terasaki, Origins of the first HLA specificities, Human Immunology, Volume 61, Issue 3, March 2000, Pages 185-189

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from many but not all other tested individuals. In particular, Jean Dausset studied sera from patients who had received multiple

480:, and suggested the existence of at least one additional antigen which would be controlled by an additional allele at the same 2763: 454: 1129: 1323:

A1, A2, B7, B8 do not cause reaction because they are in both donor and recipient, DR2 and DR3 are found on lymphoid cells

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This is the genetic background against which scientists tried to uncover and understand the histocompatibility antigens.

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Reemtsma K, Mccracken BH, Schlegel JU, Pearl M (1964). "Heterotransplantation of the kidney: two clinical experiences".

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Mann DL, Rogentine GN, Fahey JL, Nathenson SG (1969). "Molecular heterogeneity of human lymphoid (HL-A) alloantigens".

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producing IgG. Graft recipients who generate an immune response have both IgM and IgG. The IgM can be used directly in

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and a specific shape. Determining the order of amino acids is relatively simple. Finding the shape requires the use of

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in the top haplotype. The transplant may not be rejected, but if rejection does occur that allotypic protein, the allo

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Antibodies could bind to and alter function (e.g., flow of a fluid, or prevention of binding of ligands to receptors)

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Peter Medawar- The first to truly explore immune rejection and the man who got the ball rolling for modern immunology

257: 239: 217: 177: 119: 66: 2789:"Complete nucleotide sequence of a functional class I HLA gene, HLA-A3: implications for the evolution of HLA genes" 2083:

Sensitivity is lower, particularly in the study of non-caucasians as the HL-A1 can cross-react to similar sites on

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The thought that the mammalian body must have some way of identifying introduced foreign tissues first arose during

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not be clearly identified by serotype and PCR could be sequenced, allowing for the refinement of new PCR kits.

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During these early studies it became known that there were associations with many autoimmune diseases. And the

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go through a process of maturation, from surface IgM production, to serum IgM production, to maturation into a

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proteins revised their standards for naming to introduce more clarity and specificity in the naming system.

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In the early 1980s, it was discovered that a restriction fragment segregates with individuals who bear the

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In the follow-up research, Jon van Rood and Rose Payne continued studying sera from multiple women who had

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antigens is still ongoing, and they have retained the name Cw as many serotypes have not been developed.

1677:, a cassette of genes passed on from each parent. The haplotype frequencies in Europeans are in strong 1270: 497: 24: 2446:

Maintained by Altered Thermodynamics." Journal of Biological Chemistry 288 (June 2013): 18766-18775.

1454:) region of the IgG can be used to cross-link antibodies on different cells, causing agglutination. 2137: 2109: 1461: 1219: 484:. Also, multiple other investigators started identifying more leucocyte antigens around that time. 204: 155: 293:, they vary from individual to individual as a result of genetic differences. An organ called the 94:

that states a Knowledge editor's personal feelings or presents an original argument about a topic.

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Doherty, P.C. and Zinkernagel, R.M. A biological role for the major histocompatibility antigens.

1897:(the liquid part of the blood when blood clots) was sensitized to the cells from donors - it was 1356: 1336: 1082: 363: 270: 2195:

antigen had already been split from the B12 broad antigen group. In 1983, the cDNA sequences of

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reject skin grafts from those same mice. For this discovery, Medawar and Australian scientist

2084: 1401:, in the donor tissue may have induced the dominant allo-reactive antibody in the recipient. 1328: 556: 2849: 2687: 2601: 2501: 461: 425:

In 1958 Jean Dausset, Jon van Rood and Rose Payne published papers in which they described

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All three sequences compared well with mouse MHC class I antigens. The Western European

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Yunis EJ, Dupont B, Hansen J (1976). "Immunogenetic Aspects of Allotransplantation".

2703: 2660: 2617: 2574: 2517: 2482:"Statistics." IPD- IMGT/HLA. European Molecular Biology Lab, 2013. Web. 13 Dec. 2013. 2428: 2410: 2370: 2362: 2357: 2340: 1944: 1265: 983:) identifies which gene the allele is a modification of. The first two numbers (HLA-A 438: 355: 2715: 2629: 2529: 2867: 2857: 2808: 2800: 2751: 2695: 2652: 2609: 2564: 2556: 2509: 2418: 2402: 2352: 2267: 2116:. Inadvertently, the scientist had discovered an antibody set that recognized only 1446: 1340: 1335:, they attempted transplantation between humans and between non-humans and humans. 481: 434: 390: 283: 28: 2699: 2613: 1893:

from patients with rejecting transplants to donor or 'third party' tissues. Their

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were rejected, it was found that the 'rejection' response was accompanied by an

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The references used may be made clearer with a different or consistent style of

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Alberts, Bruce. Essential Cell Biology. New York: Garland Science, 2009. Print.

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Philosophical Transactions of the Royal Society of London B Biological Sciences

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could attract lymphocytes and cause them to lyse cells via the immune system's

405: 159: 2895: 2414: 2366: 1917: 1894: 508: 430: 394: 343: 2862: 2391:"HLA Bw4 and Bw6 Epitopes Recognized by Antibodies and Natural Killer Cells" 1409: 1096: in this point onward. Unsourced material may be challenged and removed. 2521: 2432: 2374: 2172: 2117: 2051: 745: 442: 398: 351: 315: 287: 2881: 2822: 2707: 2664: 2621: 2578: 559:

and is anything but easy. It took a team of three researchers at Harvard,

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Bach FH, Amos DB (1967). "Hu-1: Major histocompatibility locus in man".

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is linked to a very long piece of conserved chromosome 6 variant called

1315: 517: 2092: 683: 2560: 1327:

In the early 1960s, some physicians began more aggressive attempts at

967: 330: 1674: 1388: 1348: 1344: 560: 319: 279: 1959: 1071: 306:. It was through the realization of this that HLAs were discovered. 1424: 1375: 1352: 1227: 548: 473: 446: 426: 369: 1193:

In this arrangement there were cells that were 'blank' or had new

520:) serve as the anchor that holds the protein in the cell membrane. 1473: 1397: 1223: 586: 414: 298: 274: 1391:(unknown to early clinicians) are identical, except for the one 2204: 2196: 2191: 2141: 2048: 1933: 1438: 1415: 1231: 1187: 1183: 1179: 533: 477: 469: 465: 450: 294: 282:. HLA are not typical antigens, like those found on surface of 2491: 2113: 1198: 2786: 2677: 2212: 1310: 91:

personal reflection, personal essay, or argumentative essay

2165: 1052:

Protein that is present in cytoplasm but not cell surface

1954: 1909: 1904: 1428: 1003:). There are six letters, each with a different meaning. 323: 1060:

Aberrant expression (uncertain if protein is expressed)

2838:"Nature of polymorphism in HLA-A, -B, and -C molecules" 1382: 2112:, as series "A" antigens are the first six members of 1437:. In generating an immune response to an antigen, the 551:. Proteins work by each having a specific sequence of 1226:" is deeply rooted in the discovery history of their 491: 318:. It started with a plane crash in the height of the 2787:

Strachan T, Sodoyer R, Damotte M, Jordan BR (1984).

2748:

The Reticuloendothelial System in Health and Disease

1464:

was modified to assay Antiserum mediated RBC lysis.

1347:, meaning 'of different genetics' grafts). If these 512:

The structure of the HLA-A*02 protein. The spirals (

453:

population. For his discovery, Dausset received the

2836:Parham P, Lomen CE, Lawlor DA, et al. (1988). 2642: 2542: 1044:Questionable (allele may affect normal expression) 420: 2287: 2285: 2283: 2281: 2279: 1213: 2835: 2745: 2545:"Heterophile antibodies in human transplantation" 1320:A simple example of HLA antigen causing rejection 393:. At the time, many leading scientists including 2893: 1105:"History and naming of human leukocyte antigens" 1020:Null allele (produces a non-functional protein) 542: 2276: 547:Nearly all important molecules in the body are 2147: 1474:The role of haplotypes in identifying antigens 1343:or kidney donations from other donors (called 2478: 2476: 2474: 2066:is 1% and the giving the HLA-A1 serotyping a 1983:But fail to react in the following patterns: 1884: 338: 2485: 2462: 1889:In the late 1960s, scientist began reacting 579: 2829: 2780: 2671: 2636: 2585: 2536: 67:Learn how and when to remove these messages 2739: 2471: 2000: 1168: 1036:Soluble protein not found on cell surface 1028:Lower than normal cell surface expression 2871: 2861: 2812: 2568: 2422: 2356: 2185: 1298:Learn how and when to remove this message 1156:Learn how and when to remove this message 378: 258:Learn how and when to remove this message 240:Learn how and when to remove this message 178:Learn how and when to remove this message 120:Learn how and when to remove this message 2591: 2395:Current Opinion in Organ Transplantation 2253: 1408: 1387:In the accompanying figure, two similar 1378:responses that cause systemic responses. 1314: 1311:Transplantation and transplant rejection 966: 507: 368: 329: 203:This article includes a list of general 2543:Rapaport FT, Kano K, Milgrom F (1968). 2338: 2251: 2249: 2247: 2245: 2243: 2241: 2239: 2237: 2235: 2233: 2166:Serotype group expansion and refinement 2156: 2127: 2077:Increasing confidence of Interpretation 2005: 2894: 1955:Subclassification of lymphoid antigens 1905:Lymphocyte bearing antigens recognized 1795: 1589: 449:) was present in approximately 60% of 417:(named for their origin, the thymus). 1404: 297:is responsible for ensuring that any 2388: 2334: 2332: 2230: 1383:Different antigens can be identified 1248: 1094:adding citations to reliable sources 1065: 189: 131: 73: 32: 16:Classification of leukocyte antigens 13: 2805:10.1002/j.1460-2075.1984.tb01901.x 2730:The genetics of histocompatibility 1958: 1916:As the study of these 'rejection' 1908: 503: 492:World Health Organization steps in 209:it lacks sufficient corresponding 14: 2913: 2329: 2041:Interpreting Serotypes as Alleles 1423:(RBCs) with anti-A3 alloreactive 48:This article has multiple issues. 2389:Lutz, Charles T. (August 2014). 2358:10.1111/j.1399-0039.2009.01291.x 2070:of 98.9% for the A1*0101 allele. 2027:Effects of intraseries exclusion 1253: 1070: 421:Identification of the first HLAs 194: 136: 78: 37: 2722: 2449: 1214:Genetic complexity typifies HLA 1081:needs additional citations for 574: 56:or discuss these issues on the 2439: 2381: 2320: 2307: 2294: 2260: 2009: 1687: 598:allele and protein quantities 1: 2700:10.1126/science.163.3874.1460 2614:10.1126/science.156.3781.1506 2272:10.1016/S0198-8859(99)00154-8 2223: 1477: 543:Discovering the protein shape 366:earned the 1960 Nobel Prize. 2842:Proc. Natl. Acad. Sci. U.S.A 2756:10.1007/978-1-4684-3300-5_20 2514:10.1126/science.143.3607.700 2407:10.1097/MOT.0000000000000103 2015: 1368:classical complement pathway 1364:Acute rejection - Antibodies 930: 896: 862: 825: 788: 751: 714: 689: 680: 651: 626: 601: 589:and 2,268 Class II alleles. 309: 7: 2657:10.1056/NEJM196809052791001 2082: 2046: 2032: 1273:. The specific problem is: 1208: 476:), seemingly controlled by 10: 2918: 2047:HL-A1 antiserum reacts to 1885:A list of antigens created 531: 462:given birth multiple times 339:Identification of non-self 18: 2728:Bach ML, Bach FH. (1970) 1697: 1692: 1487: 1482: 1458:Complement fixation assay 580:Current HLA naming system 498:World Health Organization 273:(HLA) began as a list of 25:Graft-versus-host disease 2341:"A short history of HLA" 1724: 1721: 1718: 1715: 1712: 1709: 1673:Each person has two HLA 1512: 1509: 1506: 1503: 1500: 1497: 1494: 1462:complement fixation test 1220:human leukocyte antigens 271:Human leukocyte antigens 2863:10.1073/pnas.85.11.4005 2001:The HLA serotype series 1878:from multiple sources. 1337:Immunosuppressive drugs 1331:. Knowing little about 1169:Establishing the system 391:clonal selection theory 224:more precise citations. 2902:Scientific terminology 2186:Genetic identification 2019:Genetics of Serotyping 1963: 1913: 1679:linkage disequilibrium 1468:Chromium release assay 1435:Hemagglutination assay 1431: 1324: 972: 521: 433:that reacted with the 379:Learned self-tolerance 375: 335: 100:by rewriting it in an 1962: 1912: 1412: 1333:compatibility factors 1329:organ transplantation 1318: 970: 748:alleles and proteins 557:x-ray crystallography 532:Further information: 511: 372: 354:, a PhD student, and 333: 19:Further information: 2339:Thorsby, E. (2009). 2085:genetic recombinants 1280:improve this section 1269:to meet Knowledge's 1090:improve this article 304:transplant rejection 21:Transplant rejection 2854:1988PNAS...85.4005P 2692:1969Sci...163.1460M 2606:1967Sci...156.1506B 2506:1964Sci...143..700R 1947:. In these studies 1941:HLA A1-B8 haplotype 1427:containing Anti-A3 1186:and "HL-A8" became 971:HLA naming protocol 2317:1956; 239, 357-414 2302:Journal of Anatomy 1964: 1914: 1432: 1405:Assaying antiserum 1325: 1079:This point onward 973: 522: 439:blood transfusions 376: 336: 102:encyclopedic style 89:is written like a 2765:978-1-4684-3302-9 2561:10.1172/JCI105759 2459:I, 1406-9 (1975). 2148:Pseudo-series "w" 2105: 2104: 2101: 2100: 1993:A2, A3, A11, .... 1990:A1, A2, A11, .... 1871: 1870: 1671: 1670: 1450:the invariable (F 1414:Agglutination of 1308: 1307: 1300: 1271:quality standards 1262:This section may 1182:, "HL-A7" became 1166: 1165: 1158: 1140: 1064: 1063: 965: 964: 740: 739: 677: 676: 364:Macfarlane Burnet 356:Rupert Billingham 284:infectious agents 268: 267: 260: 250: 249: 242: 188: 187: 180: 130: 129: 122: 71: 2909: 2886: 2885: 2875: 2865: 2833: 2827: 2826: 2816: 2784: 2778: 2777: 2743: 2737: 2726: 2720: 2719: 2686:(3874): 1460–2. 2675: 2669: 2668: 2640: 2634: 2633: 2600:(3781): 1506–8. 2589: 2583: 2582: 2572: 2540: 2534: 2533: 2489: 2483: 2480: 2469: 2466: 2460: 2453: 2447: 2443: 2437: 2436: 2426: 2385: 2379: 2378: 2360: 2336: 2327: 2324: 2318: 2311: 2305: 2304:1945; 79, 157-76 2298: 2292: 2289: 2274: 2264: 2258: 2255: 2120:from one locus, 2014: 2013: 2010: 1867: 1801: 1791: 1688: 1663: 1595: 1581: 1478: 1447:hemagglutination 1341:white blood cell 1303: 1296: 1292: 1289: 1283: 1257: 1256: 1249: 1161: 1154: 1150: 1147: 1141: 1139: 1098: 1074: 1066: 1006: 1005: 742: 741: 679: 678: 592: 591: 263: 256: 245: 238: 234: 231: 225: 220:this article by 211:inline citations 198: 197: 190: 183: 176: 172: 169: 163: 140: 139: 132: 125: 118: 114: 111: 105: 82: 81: 74: 63: 41: 40: 33: 29:Immune tolerance 2917: 2916: 2912: 2911: 2910: 2908: 2907: 2906: 2892: 2891: 2890: 2889: 2834: 2830: 2785: 2781: 2766: 2744: 2740: 2727: 2723: 2676: 2672: 2645:N. Engl. J. Med 2641: 2637: 2590: 2586: 2549:J. Clin. Invest 2541: 2537: 2500:(3607): 700–2. 2490: 2486: 2481: 2472: 2467: 2463: 2454: 2450: 2444: 2440: 2386: 2382: 2345:Tissue Antigens 2337: 2330: 2325: 2321: 2312: 2308: 2299: 2295: 2290: 2277: 2265: 2261: 2256: 2231: 2226: 2188: 2168: 2159: 2150: 2138:HLA-B serotypes 2130: 2097: 2089:gene conversion 2071: 2064:HLA-A1 serotype 2035: 2021: 2008: 2003: 1996:... A7, A8, A12 1987:A1, A2, A3, ... 1976:A1, A11, A8, A5 1970:A1, A2, A7, A12 1957: 1945:AH8.1 haplotype 1907: 1887: 1865: 1796: 1789: 1659: 1590: 1577: 1476: 1453: 1420:red blood cells 1407: 1385: 1322: 1313: 1304: 1293: 1287: 1284: 1277: 1258: 1254: 1216: 1211: 1171: 1162: 1151: 1145: 1142: 1099: 1097: 1087: 1075: 582: 577: 569:Pamela Bjorkman 565:Jack Strominger 545: 540: 538:MHC Restriction 506: 504:MHC restriction 494: 423: 381: 341: 312: 264: 253: 252: 251: 246: 235: 229: 226: 216:Please help to 215: 199: 195: 184: 173: 167: 164: 153: 147:has an unclear 141: 137: 126: 115: 109: 106: 98:help improve it 95: 83: 79: 42: 38: 31: 17: 12: 11: 5: 2915: 2905: 2904: 2888: 2887: 2848:(11): 4005–9. 2828: 2779: 2764: 2738: 2734:Hosp. Practice 2721: 2670: 2635: 2584: 2535: 2484: 2470: 2461: 2448: 2438: 2401:(4): 436–441. 2380: 2351:(2): 101–116. 2328: 2319: 2306: 2293: 2275: 2259: 2228: 2227: 2225: 2222: 2187: 2184: 2167: 2164: 2158: 2155: 2149: 2146: 2129: 2126: 2103: 2102: 2099: 2098: 2080: 2079: 2073: 2072: 2044: 2043: 2037: 2036: 2030: 2029: 2023: 2022: 2017: 2007: 2004: 2002: 1999: 1998: 1997: 1994: 1991: 1988: 1981: 1980: 1977: 1974: 1973:A1, A3, A7, A8 1971: 1956: 1953: 1906: 1903: 1886: 1883: 1869: 1868: 1863: 1861: 1859: 1857: 1855: 1853: 1852:Alloreactivity 1849: 1848: 1845: 1842: 1839: 1836: 1833: 1830: 1826: 1825: 1822: 1819: 1816: 1813: 1810: 1807: 1803: 1802: 1793: 1792: 1787: 1785: 1783: 1781: 1779: 1777: 1776:Alloreactivity 1773: 1772: 1769: 1766: 1763: 1760: 1757: 1754: 1750: 1749: 1746: 1743: 1740: 1737: 1734: 1731: 1727: 1726: 1723: 1720: 1717: 1714: 1711: 1708: 1702: 1701: 1696: 1691: 1669: 1668: 1666: 1664: 1657: 1655: 1653: 1651: 1650:Alloreactivity 1647: 1646: 1643: 1640: 1635: 1632: 1629: 1626: 1622: 1621: 1618: 1615: 1610: 1607: 1604: 1601: 1597: 1596: 1587: 1586: 1584: 1582: 1575: 1573: 1571: 1569: 1568:Alloreactivity 1565: 1564: 1561: 1558: 1553: 1550: 1547: 1544: 1540: 1539: 1536: 1533: 1528: 1525: 1522: 1519: 1515: 1514: 1511: 1508: 1505: 1502: 1499: 1496: 1492: 1491: 1486: 1481: 1475: 1472: 1451: 1406: 1403: 1384: 1381: 1380: 1379: 1373: 1370: 1312: 1309: 1306: 1305: 1261: 1259: 1252: 1218:The naming of 1215: 1212: 1210: 1207: 1170: 1167: 1164: 1163: 1078: 1076: 1069: 1062: 1061: 1058: 1054: 1053: 1050: 1046: 1045: 1042: 1038: 1037: 1034: 1030: 1029: 1026: 1022: 1021: 1018: 1014: 1013: 1010: 963: 962: 959: 956: 953: 950: 947: 944: 941: 938: 935: 929: 928: 925: 922: 919: 916: 913: 910: 907: 904: 901: 895: 894: 891: 888: 885: 882: 879: 876: 873: 870: 867: 861: 860: 857: 854: 851: 848: 845: 842: 839: 836: 833: 830: 824: 823: 820: 817: 814: 811: 808: 805: 802: 799: 796: 793: 787: 786: 783: 780: 777: 774: 771: 768: 765: 762: 759: 756: 750: 749: 738: 737: 734: 731: 728: 725: 722: 719: 713: 712: 709: 706: 703: 700: 697: 694: 688: 687: 675: 674: 671: 668: 665: 662: 659: 656: 650: 649: 646: 643: 640: 637: 634: 631: 625: 624: 621: 618: 615: 612: 609: 606: 600: 599: 581: 578: 576: 573: 544: 541: 505: 502: 493: 490: 422: 419: 406:Jacques Miller 380: 377: 340: 337: 311: 308: 266: 265: 248: 247: 202: 200: 193: 186: 185: 149:citation style 144: 142: 135: 128: 127: 86: 84: 77: 72: 46: 45: 43: 36: 15: 9: 6: 4: 3: 2: 2914: 2903: 2900: 2899: 2897: 2883: 2879: 2874: 2869: 2864: 2859: 2855: 2851: 2847: 2843: 2839: 2832: 2824: 2820: 2815: 2810: 2806: 2802: 2799:(4): 887–94. 2798: 2794: 2790: 2783: 2775: 2771: 2767: 2761: 2757: 2753: 2749: 2742: 2735: 2731: 2725: 2717: 2713: 2709: 2705: 2701: 2697: 2693: 2689: 2685: 2681: 2674: 2666: 2662: 2658: 2654: 2651:(10): 501–6. 2650: 2646: 2639: 2631: 2627: 2623: 2619: 2615: 2611: 2607: 2603: 2599: 2595: 2588: 2580: 2576: 2571: 2566: 2562: 2558: 2555:(3): 633–42. 2554: 2550: 2546: 2539: 2531: 2527: 2523: 2519: 2515: 2511: 2507: 2503: 2499: 2495: 2488: 2479: 2477: 2475: 2465: 2458: 2452: 2442: 2434: 2430: 2425: 2420: 2416: 2412: 2408: 2404: 2400: 2396: 2392: 2384: 2376: 2372: 2368: 2364: 2359: 2354: 2350: 2346: 2342: 2335: 2333: 2323: 2316: 2310: 2303: 2297: 2288: 2286: 2284: 2282: 2280: 2273: 2269: 2263: 2254: 2252: 2250: 2248: 2246: 2244: 2242: 2240: 2238: 2236: 2234: 2229: 2221: 2217: 2214: 2208: 2206: 2202: 2198: 2193: 2183: 2179: 2176: 2174: 2163: 2154: 2145: 2143: 2139: 2135: 2125: 2123: 2119: 2118:gene products 2115: 2111: 2094: 2090: 2086: 2081: 2078: 2075: 2074: 2069: 2065: 2061: 2057: 2053: 2050: 2045: 2042: 2039: 2038: 2031: 2028: 2025: 2024: 2020: 2016: 2012: 2011: 1995: 1992: 1989: 1986: 1985: 1984: 1978: 1975: 1972: 1969: 1968: 1967: 1961: 1952: 1950: 1946: 1942: 1937: 1935: 1931: 1925: 1922: 1919: 1911: 1902: 1900: 1896: 1892: 1882: 1879: 1875: 1864: 1862: 1860: 1858: 1856: 1854: 1851: 1850: 1846: 1843: 1840: 1837: 1834: 1831: 1828: 1827: 1823: 1820: 1817: 1814: 1811: 1808: 1805: 1804: 1800: 1794: 1788: 1786: 1784: 1782: 1780: 1778: 1775: 1774: 1770: 1767: 1764: 1761: 1758: 1755: 1752: 1751: 1747: 1744: 1741: 1738: 1735: 1732: 1729: 1728: 1707: 1704: 1703: 1700: 1695: 1690: 1689: 1686: 1682: 1680: 1676: 1667: 1665: 1662: 1658: 1656: 1654: 1652: 1649: 1648: 1644: 1641: 1639: 1636: 1633: 1630: 1627: 1624: 1623: 1619: 1616: 1614: 1611: 1608: 1605: 1602: 1599: 1598: 1594: 1588: 1585: 1583: 1580: 1576: 1574: 1572: 1570: 1567: 1566: 1562: 1559: 1557: 1554: 1551: 1548: 1545: 1542: 1541: 1537: 1534: 1532: 1529: 1526: 1523: 1520: 1517: 1516: 1493: 1490: 1485: 1480: 1479: 1471: 1469: 1465: 1463: 1459: 1455: 1448: 1444: 1440: 1436: 1430: 1426: 1422: 1421: 1417: 1411: 1402: 1400: 1399: 1394: 1390: 1377: 1374: 1371: 1369: 1365: 1362: 1361: 1360: 1358: 1357:agglutination 1354: 1350: 1346: 1342: 1338: 1334: 1330: 1321: 1317: 1302: 1299: 1291: 1288:December 2023 1281: 1276: 1272: 1268: 1267: 1260: 1251: 1250: 1247: 1243: 1239: 1235: 1233: 1229: 1225: 1221: 1206: 1202: 1200: 1196: 1195:specificities 1191: 1189: 1185: 1181: 1175: 1160: 1157: 1149: 1146:December 2013 1138: 1135: 1131: 1128: 1124: 1121: 1117: 1114: 1110: 1107: – 1106: 1102: 1101:Find sources: 1095: 1091: 1085: 1084: 1077: 1073: 1068: 1067: 1059: 1056: 1055: 1051: 1048: 1047: 1043: 1040: 1039: 1035: 1032: 1031: 1027: 1024: 1023: 1019: 1016: 1015: 1012:Significance 1011: 1008: 1007: 1004: 1002: 998: 994: 990: 986: 982: 978: 969: 960: 957: 954: 951: 948: 945: 942: 939: 936: 934: 931: 926: 923: 920: 917: 914: 911: 908: 905: 902: 900: 897: 892: 889: 886: 883: 880: 877: 874: 871: 868: 866: 863: 858: 855: 852: 849: 846: 843: 840: 837: 834: 831: 829: 826: 821: 818: 815: 812: 809: 806: 803: 800: 797: 794: 792: 789: 784: 781: 778: 775: 772: 769: 766: 763: 760: 757: 755: 752: 747: 744: 743: 735: 732: 729: 726: 723: 720: 718: 715: 710: 707: 704: 701: 698: 695: 693: 690: 685: 681: 672: 669: 666: 663: 660: 657: 655: 652: 647: 644: 641: 638: 635: 632: 630: 627: 622: 619: 616: 613: 610: 607: 605: 602: 597: 594: 593: 590: 588: 572: 570: 566: 562: 558: 554: 550: 539: 535: 530: 528: 519: 515: 510: 501: 499: 489: 485: 483: 479: 475: 471: 467: 463: 458: 456: 452: 448: 444: 440: 436: 432: 428: 418: 416: 412: 407: 402: 400: 396: 395:Linus Pauling 392: 387: 371: 367: 365: 361: 357: 353: 348: 345: 344:Peter Medawar 332: 328: 325: 321: 317: 307: 305: 300: 296: 292: 290: 285: 281: 276: 272: 262: 259: 244: 241: 233: 230:February 2020 223: 219: 213: 212: 206: 201: 192: 191: 182: 179: 171: 168:February 2020 161: 157: 151: 150: 145:This article 143: 134: 133: 124: 121: 113: 110:February 2020 103: 99: 93: 92: 87:This article 85: 76: 75: 70: 68: 61: 60: 55: 54: 49: 44: 35: 34: 30: 26: 22: 2845: 2841: 2831: 2796: 2792: 2782: 2747: 2741: 2733: 2729: 2724: 2683: 2679: 2673: 2648: 2644: 2638: 2597: 2593: 2587: 2552: 2548: 2538: 2497: 2493: 2487: 2464: 2456: 2451: 2441: 2398: 2394: 2383: 2348: 2344: 2322: 2314: 2309: 2301: 2296: 2262: 2218: 2209: 2189: 2180: 2177: 2169: 2160: 2151: 2133: 2131: 2110:HLA-A series 2106: 2087:(most often 2076: 2059: 2055: 2052:gene product 2040: 2026: 2018: 1982: 1965: 1948: 1938: 1926: 1923: 1915: 1899:alloreactive 1898: 1888: 1880: 1876: 1872: 1798: 1705: 1698: 1693: 1683: 1672: 1660: 1637: 1612: 1592: 1578: 1555: 1530: 1488: 1483: 1467: 1466: 1457: 1456: 1434: 1433: 1413: 1396: 1392: 1386: 1332: 1326: 1319: 1294: 1285: 1278:Please help 1274: 1263: 1244: 1240: 1236: 1217: 1203: 1192: 1176: 1172: 1152: 1143: 1133: 1126: 1119: 1112: 1100: 1088:Please help 1083:verification 1080: 1000: 996: 992: 988: 984: 980: 976: 974: 932: 898: 864: 827: 790: 753: 746:HLA class II 716: 691: 682:HLA Class I 653: 628: 603: 583: 575:Nomenclature 546: 526: 523: 496:In 1967 the 495: 486: 459: 424: 403: 399:James Watson 382: 359: 352:Leslie Brent 349: 342: 320:London Blitz 316:World War II 313: 288: 269: 254: 236: 227: 208: 174: 165: 146: 116: 107: 88: 64: 57: 51: 50:Please help 47: 2736:5(8): 33-44 2068:specificity 1930:autoantigen 1699:Haplotype 2 1694:Haplotype 1 1489:Haplotype 2 1484:Haplotype 1 1443:plasma cell 1282:if you can. 596:HLA class I 553:amino acids 455:Nobel Prize 443:alloantigen 411:Lymphocytes 386:Niels Jerne 374:lymphocytes 286:. HLAs are 222:introducing 2224:References 2157:Series "C" 2128:Series "B" 2122:HLA-A gene 2093:nucleotide 2006:Series "A" 1675:haplotypes 1389:haplotypes 1349:allografts 1345:allografts 1116:newspapers 684:pseudogene 482:gene locus 435:leucocytes 427:antibodies 205:references 160:footnoting 53:improve it 2415:1087-2418 2387:see also 2367:1399-0039 2058:- 17.3%, 1829:Recipient 1799:Example 4 1753:Recipient 1706:Example 3 1625:Recipient 1593:Example 2 1543:Recipient 1495:Example 1 1418:positive 1355:mediated 1228:serotypes 561:Don Wiley 514:α-helices 466:diallelic 457:in 1980. 429:in human 310:Discovery 280:serotypes 59:talk page 2896:Category 2716:45562235 2630:85394705 2530:35869420 2522:14081245 2433:24977435 2375:19523022 1425:antisera 1376:Cytokine 1353:antibody 1264:require 1224:antigens 1209:Genetics 933:Proteins 828:Proteins 686:alleles 654:Proteins 549:proteins 518:β-sheets 291:antigens 275:antigens 156:citation 2882:3375250 2850:Bibcode 2823:6609814 2708:5773111 2688:Bibcode 2680:Science 2665:4876470 2622:4887739 2602:Bibcode 2594:Science 2579:4866325 2502:Bibcode 2494:Science 2424:5742561 2134:logical 1949:HL-A1,8 1439:B-cells 1398:antigen 1393:antigen 1266:cleanup 1232:alleles 1130:scholar 899:Alleles 791:Alleles 717:Alleles 629:Alleles 587:alleles 478:alleles 415:T-cells 299:T-cells 218:improve 96:Please 2880: 2873:280349 2870: 2821: 2814:557443 2811: 2793:EMBO J 2774:136874 2772: 2762: 2714: 2706: 2663: 2628: 2620: 2577: 2570:297209 2567: 2528: 2520: 2457:Lancet 2431: 2421: 2413: 2373: 2365: 2205:HLA-B7 2197:HLA-A3 2192:HLA-B8 2142:HLA-B7 2049:HLA-A1 1979:A1, A8 1934:HLA-A1 1797: 1591: 1460:. The 1416:HLA-A3 1188:HLA-B8 1184:HLA-B7 1180:HLA-A2 1132: 1125: 1118: 1111: 1103: 1009:Letter 979:or HLA 567:, and 534:T cell 527:Lancet 474:HLA-A2 470:HLA-A1 451:French 447:HLA-A2 413:, the 295:thymus 207:, but 27:, and 2712:S2CID 2626:S2CID 2526:S2CID 2162:Cw3. 2114:HLA-A 2060:*0103 2056:*0101 1806:Donor 1730:Donor 1600:Donor 1518:Donor 1222:HLA " 1137:JSTOR 1123:books 893:DRB9 2878:PMID 2819:PMID 2770:PMID 2760:ISBN 2704:PMID 2661:PMID 2618:PMID 2575:PMID 2518:PMID 2429:PMID 2411:ISSN 2371:PMID 2363:ISSN 2213:RFLP 2199:and 1918:sera 1895:sera 1891:sera 1230:and 1109:news 989::101 937:1020 903:1375 890:DRB8 887:DRB7 884:DRB6 881:DRB5 878:DRB4 875:DRB3 872:DRB2 869:DRB1 865:Gene 835:1091 798:1476 785:DOB 773:DPB1 770:DPA1 767:DQB1 764:DQA1 754:Gene 692:Gene 664:1445 661:2329 658:1740 639:2035 636:3086 633:2432 604:Gene 536:and 472:and 431:sera 397:and 289:allo 158:and 2868:PMC 2858:doi 2809:PMC 2801:doi 2752:doi 2732:. 2696:doi 2684:163 2653:doi 2649:279 2610:doi 2598:156 2565:PMC 2557:doi 2510:doi 2498:143 2419:PMC 2403:doi 2353:doi 2268:doi 2201:Cw3 1429:IgM 1092:by 997::01 993::01 985:*02 847:160 841:303 822:13 810:193 804:459 782:DOA 779:DMB 776:DMA 761:DRB 758:DRA 673:16 648:50 360:not 324:WHO 2898:: 2876:. 2866:. 2856:. 2846:85 2844:. 2840:. 2817:. 2807:. 2795:. 2791:. 2768:. 2758:. 2710:. 2702:. 2694:. 2682:. 2659:. 2647:. 2624:. 2616:. 2608:. 2596:. 2573:. 2563:. 2553:47 2551:. 2547:. 2524:. 2516:. 2508:. 2496:. 2473:^ 2427:. 2417:. 2409:. 2399:19 2397:. 2393:. 2369:. 2361:. 2349:74 2347:. 2343:. 2331:^ 2278:^ 2232:^ 2173:6p 2144:. 1847:7 1824:8 1771:8 1748:7 1725:B 1722:Cw 1713:Cw 1645:8 1620:8 1563:7 1538:7 1513:B 1510:Cw 1501:Cw 1190:. 981:-B 977:-A 961:0 949:17 943:46 927:1 915:20 912:15 909:58 859:5 844:19 838:32 819:12 816:13 807:37 801:51 736:3 721:12 711:V 645:22 642:13 623:G 563:, 62:. 23:, 2884:. 2860:: 2852:: 2825:. 2803:: 2797:3 2776:. 2754:: 2718:. 2698:: 2690:: 2667:. 2655:: 2632:. 2612:: 2604:: 2581:. 2559:: 2532:. 2512:: 2504:: 2435:. 2405:: 2377:. 2355:: 2270:: 1866:8 1844:7 1841:1 1838:7 1835:7 1832:3 1821:7 1818:1 1815:7 1812:7 1809:3 1790:7 1768:7 1765:1 1762:8 1759:7 1756:1 1745:7 1742:1 1739:8 1736:7 1733:1 1719:A 1716:B 1710:A 1661:2 1642:7 1638:3 1634:8 1631:7 1628:1 1617:7 1613:2 1609:8 1606:7 1603:1 1579:3 1560:7 1556:2 1552:8 1549:7 1546:1 1535:7 1531:3 1527:8 1524:7 1521:1 1507:A 1504:B 1498:A 1452:c 1301:) 1295:( 1290:) 1286:( 1199:C 1159:) 1153:( 1148:) 1144:( 1134:· 1127:· 1120:· 1113:· 1086:. 1057:A 1049:C 1041:Q 1033:S 1025:L 1017:N 1001:L 958:0 955:0 952:0 946:8 940:0 924:1 921:2 918:3 906:1 856:3 853:7 850:4 832:2 813:7 795:7 733:5 730:5 727:6 724:9 708:P 705:L 702:K 699:J 696:H 670:4 667:5 620:F 617:E 614:C 611:B 608:A 261:) 255:( 243:) 237:( 232:) 228:( 214:. 181:) 175:( 170:) 166:( 162:. 152:. 123:) 117:( 112:) 108:( 104:. 69:) 65:(

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