| Major histocompatibility complex molecule | |
|---|---|
 | |
| Identifiers | |
| Symbol | HLA |
| InterPro | IPR001039 |
| Membranome | 63 |
Themajor histocompatibility complex (MHC) is a largelocus on vertebrate DNA containing a set of closely linkedpolymorphic genes that code forcell surface proteins essential for theadaptive immune system. These cell surface proteins are calledMHC molecules.
Its name comes from its discovery during the study of transplanted tissue compatibility.[1] Later studies revealed that tissue rejection due to incompatibility is only a facet of the full function of MHC molecules, which is to bind anantigen derived from self-proteins, or from pathogens, and bring the antigen presentation to the cell surface for recognition by the appropriateT-cells.[2] MHC molecules mediate the interactions ofleukocytes, also calledwhite blood cells (WBCs), with other leukocytes or with body cells. The MHC determines donor compatibility fororgan transplant, as well as one's susceptibility toautoimmune diseases.
In a cell,protein molecules of the host's ownphenotype or of other biologic entities are continually synthesized and degraded. Each MHC molecule on the cell surface displays a small peptide (a molecular fraction of a protein) called anepitope.[3] The presentedself-antigens prevent anorganism'simmune system from targeting its own cells. The presentation of pathogen-derived proteins results in the elimination of the infected cell by the immune system.
Diversity of an individual'sself-antigen presentation, mediated by MHC self-antigens, is attained in at least three ways: (1) an organism's MHC repertoire ispolygenic (via multiple, interacting genes); (2) MHC expression iscodominant (from both sets of inheritedalleles); (3) MHCgene variants are highlypolymorphic (diversely varying from organism to organism within aspecies).[4]Sexual selection has been observed in male micechoosing to mate with females with different MHCs.[5] Also, at least for MHC I presentation, there has been evidence of antigenic peptidesplicing, which can combine peptides from different proteins, vastly increasing antigen diversity.[6]
The first descriptions of the MHC were made by BritishimmunologistPeter Gorer in 1936.[7] MHC genes were first identified in inbred mice strains.Clarence Little transplanted tumors across different strains and found rejection of transplanted tumors according to strains of host versus donor.[8]George Snell selectively bred two mouse strains, attained a new strain nearly identical to one of the progenitor strains, but differing crucially inhistocompatibility—that is, tissue compatibility upon transplantation—and thereupon identified an MHClocus.[9] LaterJean Dausset demonstrated the existence of MHC genes in humans and described the first human leucocyte antigen, the protein which we call now HLA-A2. Some years later Baruj Benacerraf showed that polymorphic MHC genes not only determine an individual's unique constitution of antigens but also regulate the interaction among the various cells of the immunological system. These three scientists have been awarded the 1980 Nobel Prize in Physiology or Medicine[10] for their discoveries concerning "genetically determined structures on the cell surface that regulate immunological reactions".
The first fully sequenced and annotated MHC was published for humans in 1999 by a consortium of sequencing centers from the UK, USA and Japan inNature.[11] It was a "virtual MHC" since it was a mosaic from different individuals. A much shorter MHC locus from chickens was published in the same issue ofNature.[12] Many other species have been sequenced and the evolution of the MHC was studied, e.g. in the gray short-tailedopossum (Monodelphis domestica), amarsupial, MHC spans 3.95 Mb, yielding 114 genes, 87 shared with humans.[13] Marsupial MHCgenotypic variation lies betweeneutherian mammals andbirds, taken as the minimal MHC encoding, but is closer in organization to that of nonmammals. The IPD-MHC Database[14] was created which provides a centralised repository for sequences of the Major Histocompatibility Complex (MHC) from a number of different species. As of the release on December 19, 2019, the database contains information on 77 species.[citation needed]
The MHC locus is present in alljawed vertebrates; it is assumed to have arisen about 450 million years ago.[15] Despite the difference in the number of genes included in the MHC of different species, the overall organization of the locus is rather similar. Usual MHC contains about a hundred genes and pseudogenes, not all of which are involved in immunity. Inhumans, the MHC region occurs onchromosome 6, between the flankinggenetic markersMOG andCOL11A2 (from 6p22.1 to 6p21.3 about 29Mb to 33Mb on the hg38 assembly), and contains 224 genes spanning 3.6 megabase pairs (3 600 000 bases).[11] About half have known immune functions. Thehuman MHC is also called the HLA (human leukocyte antigen) complex (often just the HLA). Similarly, there is SLA (Swine leukocyte antigens), BoLA (Bovine leukocyte antigens), DLA for dogs, etc. However, historically, the MHC inmice is called the Histocompatibility system 2 or just the H-2, whereas it has been referred to as the RT1 complex in rats, and the B locus in chickens.[citation needed]
The MHC gene family is divided into three subgroups:MHC class I,MHC class II, andMHC class III. Among all those genes present in MHC, there are two types of genes coding for the proteinsMHC class I molecules andMHC class II molecules that are directly involved in theantigen presentation. These genes are highly polymorphic, 19031 alleles of class I HLA, and 7183 of class II HLA are deposited for human in the IMGT database.[16]
| Class | Encoding | Expression |
|---|---|---|
| I | (1) peptide-binding proteins, which select short sequences of amino acids forantigen presentation, as well as (2) molecules aidingantigen-processing (such asTAP andtapasin). | One chain, called α, whose ligands are theCD8 receptor—borne notably by cytotoxic T cells—and inhibitory receptors borne by NK cells |
| II | (1) peptide-binding proteins and (2) proteins assisting antigen loading onto MHC class II's peptide-binding proteins (such asMHC II DM,MHC II DQ,MHC II DR, andMHC II DP). | Two chains, called α & β, whose ligands are theCD4 receptors borne by helper T cells. |
| III | Other immune proteins, outside antigen processing and presentation, such as components of thecomplement cascade (e.g.,C2,C4,factor B), thecytokines of immune signaling (e.g.,TNF-α), andheat shock proteins buffering cells from stresses | Various |
MHC class I molecules are expressed in allnucleated cells and also inplatelets—in essence all cells butred blood cells. It presents epitopes to killerT cells, also calledcytotoxic T lymphocytes (CTLs). A CTL expresses CD8 receptors, in addition toT-cell receptors (TCRs). When a CTL's CD8 receptor docks to a MHC class I molecule, if the CTL's TCR fits the epitope within the MHC class I molecule, the CTL triggers the cell to undergo programmed cell death byapoptosis. Thus, MHC class I helps mediatecellular immunity, a primary means to addressintracellular pathogens, such asviruses and somebacteria, including bacterialL forms, bacterialgenusMycoplasma, and bacterial genusRickettsia. In humans, MHC class I comprisesHLA-A,HLA-B, andHLA-C molecules.[citation needed]
The first crystal structure of Class I MHC molecule, human HLA-A2, was published in 1989.[17] The structure revealed that MHC-I molecules areheterodimers. They have a polymorphic heavy α-subunit whose gene occurs inside the MHC locus and small invariantβ2 microglobulin subunit whose gene is usually located outside of it. Polymorphic heavy chain of MHC-I molecule contains N-terminal extra-cellular region composed by three domains, α1, α2, and α3, transmembrane helix to hold MHC-I molecule on the cell surface and short cytoplasmic tail. Two domains, α1 and α2, form deep peptide-binding groove between two long α-helices and the floor of the groove formed by eight β-strands. Immunoglobulin-like domain α3 involved in the interaction withCD8 co-receptor.β2 microglobulin provides stability of the complex and participates in the recognition of peptide-MHC class I complex byCD8 co-receptor.[18] The peptide is non-covalently bound to MHC-I, it is held by the several pockets on the floor of thepeptide-binding groove. Amino acid side-chains that are most polymorphic in human alleles fill the central and widest portion of the binding groove, while conserved side-chains are clustered at the narrower ends of the groove.[citation needed]
Classical MHC molecules present epitopes to the TCRs of CD8+ T lymphocytes.Nonclassical molecules (MHC class IB) exhibit limited polymorphism, expression patterns, and presented antigens; this group is subdivided into a group encoded within MHC loci (e.g., HLA-E, -F, -G), as well as those not (e.g.,stress ligands such as ULBPs, Rae1, and H60); the antigen/ligand for many of these molecules remain unknown, but they can interact with each of CD8+ T cells, NKT cells, and NK cells. The oldest evolutionary nonclassical MHC class I lineage in humans was deduced to be the lineage that includes the CD1 and PROCR (also known asEPCR) molecules. This lineage may have been established before the origin of tetrapod species.[19] However, the only nonclassical MHC class I lineage for which evidence exists that it was established before the evolutionary separation of Actinopterygii (ray-finned fish) and Sarcopterygii (lobe-finned fish plus tetrapods) is lineage Z of which members are found, together in each species with classical MHC class I, in lungfish and throughout ray-finned fishes;[20] why the Z lineage was well conserved in ray-finned fish but lost in tetrapods is not understood.
MHC class II can be conditionally expressed by all cell types, but normally occurs only on "professional"antigen-presenting cells (APCs):macrophages,B cells, and especiallydendritic cells (DCs). An APC takes up anantigenic protein, performsantigen processing, and returns a molecular fraction of it—a fraction termed theepitope—and displays it on the APC's surface coupled within an MHC class II molecule (antigen presentation). On the cell's surface, the epitope can be recognized by immunologic structures likeT-cell receptors (TCRs). The molecular region which binds to the epitope is theparatope.[citation needed]
On surfaces of helper T cells are CD4 receptors, as well as TCRs. When a naive helper T cell's CD4 molecule docks to an APC's MHC class II molecule, its TCR can meet and bind the epitope coupled within the MHC class II. This event primes thenaive T cell. According to the local milieu, that is, the balance ofcytokines secreted by APCs in the microenvironment, the naivehelper T cell (Th0) polarizes into either a memory Th cell or an effector Th cell ofphenotype either type 1 (Th1), type 2 (Th2), type 17 (Th17), or regulatory/suppressor (Treg), as so far identified, the Th cell's terminal differentiation.[citation needed]
MHC class II thus mediates immunization to—or, if APCs polarize Th0 cells principally to Treg cells,immune tolerance of—anantigen. The polarization during primary exposure to an antigen is key in determining a number ofchronic diseases, such asinflammatory bowel diseases andasthma, by skewing the immune response that memory Th cells coordinate when their memory recall is triggered upon secondary exposure to similar antigens. B cells express MHC class II to present antigens to Th0, but when theirB cell receptors bind matching epitopes, interactions which are not mediated by MHC, theseactivated B cells secrete soluble immunoglobulins:antibody molecules mediatinghumoral immunity.[citation needed]
Class II MHC molecules are also heterodimers, genes for both α and β subunits are polymorphic and located within MHC class II subregion. The peptide-binding groove of MHC-II molecules is formed by the N-terminal domains of both subunits of the heterodimer, α1 and β1, unlike MHC-I molecules, where two domains of the same chain are involved. In addition, both subunits of MHC-II contain transmembrane helix and immunoglobulin domains α2 or β2 that can be recognized byCD4 co-receptors.[21] In this way, MHC molecules guide the type of lymphocytes that may bind to the given antigen with high affinity, as different lymphocytes express different T-Cell Receptor (TCR) co-receptors.[citation needed]
MHC class II molecules in humans have five to sixisotypes.Classical molecules present peptides to CD4+ lymphocytes.Nonclassical molecules, also known as accessories, have intracellular functions. They are not exposed on cell membranes, but are found in internal membranes, where they assist with the loading of antigenic peptides onto classic MHC class II molecules. The important nonclassical MHC class II molecule DM is only found from the evolutionary level of lungfish,[22] although also in more primitive fishes both classical and nonclassical MHC class II are found.[23][24]
| Sr.No | Feature[25] | Class I MHC | Class II MHC |
|---|---|---|---|
| 1 | Constituting polypeptide chains | α chain (45KDa in humans) β2 chain (12 KDa in humans) | α chain (30–34 KDa in humans) β chain (26–29 KDa in humans) |
| 2 | Antigen binding domain | α1and α2 domains | α1 and β1 domains |
| 3 | Binds protein antigens of | 8–10 amino acids residues | 13–18 amino acids residues |
| 4 | Peptide bending cleft | Floor formed by β sheets and sides by α helices, blocked at both the ends | Floor formed by β sheets and sides by α helices, opened at both the ends |
| 5 | Antigenic peptide motifs involved in binding | Anchor residues located at amino and carbon terminal ends | Anchor residues located almost uniformly along the peptide |
| 6 | Presents antigenic peptide to | CD8+ T cells | CD4+ T cells |
Unlike classes I and II, Class III molecules have physiological roles and are encoded between classes I and II on the short arm of human chromosome 6. Class III molecules include several secreted proteins with immune functions: components of thecomplement system (such asC2,C4, andB factor), cytokines (such asTNF-α,LTA, andLTB), andheat shock proteins.[citation needed]
MHC is the tissue-antigen that allows the immune system (more specifically T cells) to bind to, recognize, and tolerate itself (autorecognition). MHC is also the chaperone for intracellular peptides that are complexed with MHCs and presented toT cell receptors (TCRs) as potential foreign antigens. MHC interacts with TCR and its co-receptors to optimize binding conditions for the TCR-antigen interaction, in terms of antigen binding affinity and specificity, and signal transduction effectiveness.[citation needed]
Essentially, the MHC-peptide complex is a complex of auto-antigen/allo-antigen. Upon binding, T cells should in principle tolerate the auto-antigen, but activate when exposed to the allo-antigen. Disease states occur when this principle is disrupted.[citation needed]
Antigen presentation: MHC molecules bind to bothT cell receptor andCD4/CD8 co-receptors onT lymphocytes, and the antigenepitope held in the peptide-binding groove of the MHC molecule interacts with thevariable Ig-Like domain of the TCR to trigger T-cell activation[26]
Autoimmune reaction: The presence of certain MHC molecules can increase the risk of autoimmune diseases more than others.HLA-B27 is an example. It is unclear how exactly having the HLA-B27 tissue type increases the risk ofankylosing spondylitis and other associated inflammatory diseases, but mechanisms involving aberrant antigen presentation or T cell activation have been hypothesized.[citation needed]
Tissueallorecognition: MHC molecules in complex with peptide epitopes are essentially ligands for TCRs. T cells become activated by binding to the peptide-binding grooves of any MHC molecule that they were not trained to recognize duringpositive selection in thethymus.[citation needed]
Peptides are processed and presented by two classical pathways:
| Characteristic | MHC-I pathway | MHC-II pathway |
|---|---|---|
| Composition of the stable peptide-MHC complex | Polymorphic chain α and β2 microglobulin, peptide bound to α chain | Polymorphic chains α and β, peptide binds to both |
| Types ofantigen-presenting cells (APC) | All nucleated cells | Dendritic cells, mononuclear phagocytes,B lymphocytes, some endothelial cells, epithelium ofthymus |
| T lymphocytes able to respond | Cytotoxic T lymphocytes (CD8+) | Helper T lymphocytes (CD4+) |
| Origin of antigenic proteins | cytosolic proteins (mostly synthesized by the cell; may also enter from the extracellular medium viaphagosomes) | Proteins present inendosomes orlysosomes (mostly internalized from extracellular medium) |
| Enzymes responsible for peptide generation | Cytosolicproteasome | Proteases from endosomes and lysosomes (for instance,cathepsin) |
| Location of loading the peptide on the MHC molecule | Endoplasmic reticulum | Specialized vesicular compartment |
| Molecules implicated in transporting the peptides and loading them on the MHC molecules | TAP (transporter associated with antigen processing) | DM, invariant chain |
In their development in thethymus, T lymphocytes are selected to recognize the host's own MHC molecules, but not other self antigens. Following selection, each T lymphocyte shows dual specificity: The TCR recognizes self MHC, but only non-self antigens.[citation needed]
MHC restriction occurs during lymphocyte development in the thymus through a process known aspositive selection. T cells that do not receive a positive survival signal — mediated mainly by thymic epithelial cells presenting self peptides bound to MHC molecules — to their TCR undergo apoptosis. Positive selection ensures that mature T cells can functionally recognize MHC molecules in the periphery (i.e. elsewhere in the body).[citation needed]
The TCRs of T lymphocytes recognise onlysequential epitopes, also calledlinear epitopes, of only peptides and only if coupled within an MHC molecule. (Antibody molecules secreted byactivated B cells, though, recognize diverse epitopes—peptide,lipid,carbohydrate, andnucleic acid—and recognizeconformational epitopes, which havethree-dimensional structure.)[citation needed]
MHC molecules enable immune system surveillance of the population of protein molecules in a host cell, and greater MHC diversity permits greater diversity ofantigen presentation. In 1976, Yamazakiet al demonstrated asexual selectionmate choice by male mice for females of a different MHC. Similar results have been obtained withfish.[29] Some data find lower rates ofearly pregnancy loss in human couples of dissimilar MHC genes.[30]
MHC may be related to mate choice in some human populations, a theory that found support by studies by Ober and colleagues in 1997,[31] as well as by Chaix and colleagues in 2008.[32] However, the latter findings have been controversial.[33] If it exists, the phenomenon might be mediated byolfaction, as MHC phenotype appears strongly involved in the strength and pleasantness of perceived odour of compounds fromsweat. Fatty acidesters—such asmethyl undecanoate,methyl decanoate,methyl nonanoate,methyl octanoate, andmethyl hexanoate—show strong connection to MHC.[34]
In 1995,Claus Wedekind found that in a group of female college students who smelled T-shirts worn by male students for two nights (without deodorant, cologne, or scented soaps), the majority of women chose shirts worn by men of dissimilar MHCs, a preference reversed if the women were on oral contraceptives.[35] In 2005 in a group of 58 subjects, women were more indecisive when presented with MHCs like their own,[36] although with oral contraceptives, the women showed no particular preference.[37] No studies show the extent to which odor preference determines mate selection (or vice versa).
Mostmammals have MHC variants similar to those of humans, who bear greatallelic diversity, especially among the nine classical genes—seemingly due largely togene duplication—though human MHC regions have manypseudogenes.[38] The most diverse loci, namely HLA-A, HLA-B, and HLA-C, have roughly 6000, 7200, and 5800 known alleles, respectively.[39] Many HLA alleles are ancient, sometimes of closerhomology to a chimpanzee MHC alleles than to some other human alleles of the same gene.[citation needed]
MHC allelic diversity has challengedevolutionary biologists for explanation. Most positbalancing selection (seepolymorphism (biology)), which is anynatural selection process whereby no single allele is absolutely most fit, such asfrequency-dependent selection[40] andheterozygote advantage. Pathogenic coevolution, as a type of balancing selection, posits that common alleles are under greatest pathogenic pressure, driving positive selection of uncommon alleles—moving targets, so to say, for pathogens. As pathogenic pressure on the previously common alleles decreases, their frequency in the population stabilizes, and remain circulating in a large population.[41]Genetic drift is also a major driving force in some species.[42][43] It is possible that the combined effects of some or all of these factors cause the genetic diversity.[44]
MHC diversity has also been suggested as a possible indicator for conservation, because large, stable populations tend to display greater MHC diversity than smaller, isolated populations.[45][46] Small, fragmented populations that have experienced apopulation bottleneck typically have lower MHC diversity. For example, relatively low MHC diversity has been observed in thecheetah (Acinonyx jubatus),[47]Eurasian beaver (Castor fiber),[48] andgiant panda (Ailuropoda melanoleuca).[49] In 2007 low MHC diversity was attributed a role in disease susceptibility in theTasmanian devil (Sarcophilus harrisii), native to the isolated island ofTasmania, such that an antigen of a transmissible tumor, involved indevil facial tumour disease, appears to be recognized as aself antigen.[50] To offsetinbreeding, efforts to sustain genetic diversity in populations of endangered species and of captive animals have been suggested.
In ray-finned fish like rainbow trout, allelic polymorphism in MHC class II is reminiscent of that in mammals and predominantly maps to the peptide binding groove.[51] However, in MHC class I of many teleost fishes, the allelic polymorphism is much more extreme than in mammals in the sense that the sequence identity levels between alleles can be very low and the variation extends far beyond the peptide binding groove.[51][52][20] It has been speculated that this type of MHC class I allelic variation contributes to allograft rejection, which may be especially important in fish to avoid grafting of cancer cells through their mucosal skin.[53]
The MHC locus (6p21.3) has 3 other paralogous loci in the human genome, namely 19pl3.1, 9q33–q34, and 1q21–q25. It is believed that the loci arouse from the two-round duplications invertebrates of a single ProtoMHC locus, and the new domain organizations of the MHC genes were a result of later cis-duplication and exon shuffling in a process termed "the MHC Big Bang."[54] Genes in this locus are apparently linked to intracellularintrinsic immunity in the basalMetazoanTrichoplax adhaerens.[55]
In a transplant procedure, as of an organ orstem cells, MHC molecules themselves act asantigens and can provoke immune response in the recipient, thus causing transplant rejection. MHC molecules were identified and named after their role intransplant rejection between mice of different strains, though it took over 20 years to clarify MHC's role in presenting peptide antigens tocytotoxic T lymphocytes (CTLs).[56]
Each human cell expresses six MHC class I alleles (one HLA-A, -B, and -C allele from each parent) and six to eight MHC class II alleles (one HLA-DP and -DQ, and one or two HLA-DR from each parent, and combinations of these). The MHC variation in the human population is high, at least 350 alleles for HLA-A genes, 620 alleles for HLA-B, 400 alleles for DR, and 90 alleles for DQ. Any two individuals who are not identical twins, triplets, or higher order multiple births, will express differing MHC molecules. All MHC molecules can mediate transplant rejection, but HLA-C and HLA-DP, showing low polymorphism, seem least important.[clarification needed]
When maturing in the thymus, T lymphocytes are selected for their TCR incapacity to recognize self antigens, yet T lymphocytes can react against the donor MHC'speptide-binding groove, the variable region of MHC holding the presented antigen's epitope for recognition by TCR, the matchingparatope. T lymphocytes of the recipient take the incompatible peptide-binding groove as nonself antigen.[clarification needed]
There are various types of transplant rejection that are known to be mediated by MHC (HLA):[citation needed]
In all of the above situations, immunity is directed at the transplanted organ, sustaining lesions. A cross-reaction test between potential donor cells and recipient serum seeks to detect presence of preformed anti-HLA antibodies in the potential recipient that recognize donor HLA molecules, so as to prevent hyperacute rejection. In normal circumstances, compatibility between HLA-A, -B, and -DR molecules is assessed. The higher the number of incompatibilities, the lower the five-year survival rate. Global databases of donor information enhance the search for compatible donors.
The involvement in allogeneic transplant rejection appears to be an ancient feature of MHC molecules, because also in fish associations between transplant rejections and (mis-)matching of MHC class I[57][58] and MHC class II[59] were observed.
Human MHC class I and II are also calledhuman leukocyte antigen (HLA). To clarify the usage, some of the biomedical literature uses HLA to refer specifically to the HLA protein molecules and reserves MHC for the region of the genome that encodes for this molecule, but this is not a consistent convention.[citation needed]
The most studied HLA genes are the nine classical MHC genes:HLA-A,HLA-B,HLA-C,HLA-DPA1,HLA-DPB1,HLA-DQA1,HLA-DQB1,HLA-DRA, andHLA-DRB1. In humans, the MHC gene cluster is divided into three regions: classes I, II, and III. The A, B and C genes belong to MHC class I, whereas the six D genes belong to class II.[citation needed]
MHC alleles are expressed in codominant fashion.[60] This means thealleles (variants) inherited from both parents are expressed equally:
The set of alleles that is present in each chromosome is called the MHChaplotype. In humans, each HLA allele is named with a number. For instance, for a given individual, his haplotype might be HLA-A2, HLA-B5, HLA-DR3, etc... Each heterozygous individual will have two MHC haplotypes, one each from the paternal and maternal chromosomes.
The MHC genes are highly polymorphic; many different alleles exist in the different individuals inside a population. The polymorphism is so high, in a mixed population (nonendogamic), no two individuals have exactly the same set of MHC molecules, with the exception ofidentical twins.
The polymorphic regions in each allele are located in the region for peptide contact. Of all the peptides that could be displayed by MHC, only a subset will bind strongly enough to any given HLA allele, so by carrying two alleles for each gene, each encoding specificity for unique antigens, a much larger set of peptides can be presented.
On the other hand, inside a population, the presence of many different alleles ensures there will always be an individual with a specific MHC molecule able to load the correct peptide to recognize a specific microbe. The evolution of the MHC polymorphism ensures that a population will not succumb to a new pathogen or a mutated one, because at least some individuals will be able to develop an adequate immune response to win over the pathogen. The variations in the MHC molecules (responsible for the polymorphism) are the result of the inheritance of different MHC molecules, and they are not induced byrecombination, as it is the case for the antigenreceptors.
Because of the high levels ofallelic diversity found within its genes, MHC has also attracted the attention of manyevolutionary biologists,[61] as well as disease specialists.[62]
The Nobel Assembly of Karolinska Institutet has decided today to award the Nobel Prize in Physiology or Medicine for 1980 jointly to Baruj Benacerraf, Jean Dausset and George Snell
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