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72-444: MHC class I molecules are one of two primary classes of major histocompatibility complex (MHC) molecules (the other being MHC class II ) and are found on the cell surface of all nucleated cells in the bodies of vertebrates . They also occur on platelets , but not on red blood cells . Their function is to display peptide fragments of proteins from within the cell to cytotoxic T cells ; this will trigger an immediate response from

144-570: A disulfide bond between the MHC I and B2M, named "open MHC-I". The peptides are generated mainly in the cytosol by the proteasome . The proteasome is a macromolecule that consists of 28 subunits, of which half affect proteolytic activity. The proteasome degrades intracellular proteins into small peptides that are then released into the cytosol. Proteasomes can also ligate distinct peptide fragments (termed spliced peptides), producing sequences that are noncontiguous and therefore not linearly templated in

216-400: A self antigen . To offset inbreeding , 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. However, in MHC class I of many teleost fishes, the allelic polymorphism

288-668: A species ). Sexual selection has been observed in male mice choosing to mate with females with different MHCs. Also, at least for MHC I presentation, there has been evidence of antigenic peptide splicing , which can combine peptides from different proteins, vastly increasing antigen diversity. The first descriptions of the MHC were made by British immunologist Peter Gorer in 1936. 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. George Snell selectively bred two mouse strains, attained

360-454: A MHC class I molecule. For example, an interaction of sec61 with bovine albumin has been observed. MHC class I molecules are loaded with peptides generated from the degradation of ubiquitinated cytosolic proteins in proteasomes . As viruses induce cellular expression of viral proteins, some of these products are tagged for degradation, with the resulting peptide fragments entering the endoplasmic reticulum and binding to MHC I molecules. It

432-407: A cell, protein molecules of the host's own phenotype 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 an epitope . The presented self-antigens prevent an organism 's immune system from targeting its own cells. The presentation of pathogen-derived proteins results in

504-410: A chimpanzee MHC alleles than to some other human alleles of the same gene. MHC allelic diversity has challenged evolutionary biologists for explanation. Most posit balancing selection (see polymorphism (biology) ), which is any natural selection process whereby no single allele is absolutely most fit, such as frequency-dependent selection and heterozygote advantage . Pathogenic coevolution, as

576-501: A gene which can then undergo separate evolutionary processes. Sometimes these processes result in pseudogenization (death) of one copy of the gene, though sometimes this process results in two new genes with divergent function. It is likely that human MHC class Ib loci (HLA-E, -F, and -G) as well as MHC class I pseudogenes arose from MHC class Ia loci (HLA-A, -B, and -C) in this birth-and-death process. Major histocompatibility complex The major histocompatibility complex ( MHC )

648-573: A groove for peptides to bind. MHC class I molecules bind peptides that are predominantly 8-10 amino acid in length (Parham 87), but the binding of longer peptides have also been reported. While a high-affinity peptide and the B2M subunit are normally required to maintain a stable ternary complex between the peptide, MHC I, and B2M, under subphysiological temperatures, stable, peptide-deficient MHC I/B2M heterodimers have been observed. Synthetic stable, peptide-receptive MHC I molecules have been generated using

720-411: 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. In 2005 in a group of 58 subjects, women were more indecisive when presented with MHCs like their own, although with oral contraceptives,

792-523: A new strain nearly identical to one of the progenitor strains, but differing crucially in histocompatibility —that is, tissue compatibility upon transplantation—and thereupon identified an MHC locus . Later Jean 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

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864-421: A particular allele in an evolutionary related MHC class I gene remains in two species, likely due to strong pathogen-mediated balancing selection by pathogens that can infect both species. Birth-and-death evolution is one of the mechanistic explanations for the size of the MHC class I gene family. Birth-and-death evolution asserts that gene duplication events cause the genome to contain multiple copies of

936-421: A process known as cross-presentation . A normal cell will display peptides from normal cellular protein turnover on its class I MHC, and CTLs will not be activated in response to them due to central and peripheral tolerance mechanisms. When a cell expresses foreign proteins, such as after viral infection, a fraction of the class I MHC will display these peptides on the cell surface. Consequently, CTLs specific for

1008-563: A theory that found support by studies by Ober and colleagues in 1997, as well as by Chaix and colleagues in 2008. However, the latter findings have been controversial. If it exists, the phenomenon might be mediated by olfaction , as MHC phenotype appears strongly involved in the strength and pleasantness of perceived odour of compounds from sweat . Fatty acid esters —such as methyl undecanoate , methyl decanoate , methyl nonanoate , methyl octanoate , and methyl hexanoate —show strong connection to MHC. In 1995, Claus Wedekind found that in

1080-414: 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. Genetic drift is also a major driving force in some species. It

1152-404: Is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system . These cell surface proteins are called MHC molecules . The name of this locus comes from its discovery through the study of transplanted tissue compatibility. Later studies revealed that tissue rejection due to incompatibility

1224-862: 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 by CD4 co-receptors. 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. MHC class II molecules in humans have five to six isotypes . 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

1296-478: Is in this way, the MHC class I-dependent pathway of antigen presentation, that the virus infected cells signal T-cells that abnormal proteins are being produced as a result of infection. The fate of the virus-infected cell is almost always induction of apoptosis through cell-mediated immunity , reducing the risk of infecting neighboring cells. As an evolutionary response to this method of immune surveillance, many viruses are able to down-regulate or otherwise prevent

1368-435: Is involved in the regulation of visual plasticity . PirB is expressed in the central nervous system and diminishes ocular dominance plasticity in the developmental critical period and adulthood. When the function of PirB was abolished in mutant mice, ocular dominance plasticity became more pronounced at all ages. PirB loss of function mutant mice also exhibited enhanced plasticity after monocular deprivation during

1440-453: 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. 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. The MHC locus (6p21.3) has 3 other paralogous loci in

1512-573: Is non-covalently bound to MHC-I, it is held by the several pockets on the floor of the peptide-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. 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

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1584-497: Is only a facet of the full function of MHC molecules, which is to bind an antigen derived from self-proteins, or from pathogens, and bring the antigen presentation to the cell surface for recognition by the appropriate T-cells . MHC molecules mediate the interactions of leukocytes , also called white blood cells (WBCs), with other leukocytes or with body cells. The MHC determines donor compatibility for organ transplant , as well as one's susceptibility to autoimmune diseases . In

1656-468: Is possible that the combined effects of some or all of these factors cause the genetic diversity. 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. Small, fragmented populations that have experienced a population bottleneck typically have lower MHC diversity. For example, relatively low MHC diversity has been observed in

1728-544: 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 as EPCR ) molecules. This lineage may have been established before

1800-573: 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 to T 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. Essentially,

1872-517: Is triggered upon secondary exposure to similar antigens. B cells express MHC class II to present antigens to Th 0 , but when their B cell receptors bind matching epitopes, interactions which are not mediated by MHC, these activated B cells secrete soluble immunoglobulins: antibody molecules mediating humoral immunity . 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

1944-464: The cheetah ( Acinonyx jubatus ), Eurasian beaver ( Castor fiber ), and giant panda ( Ailuropoda melanoleuca ). In 2007 low MHC diversity was attributed a role in disease susceptibility in the Tasmanian devil ( Sarcophilus harrisii ), native to the isolated island of Tasmania , such that an antigen of a transmissible tumor, involved in devil facial tumour disease , appears to be recognized as

2016-407: The critical period . These results suggest that PirB may be involved in the modulation of synaptic plasticity in the visual cortex . MHC class I molecules are heterodimers that consist of two polypeptide chains, α and β 2 -microglobulin (B2M). The two chains are linked noncovalently via interaction of B2M and the α 3 domain. Only the α chain is polymorphic and encoded by a HLA gene , while

2088-520: The epitope —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 like T-cell receptors (TCRs). The molecular region which binds to the epitope is the paratope . 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

2160-556: The B2M subunit is not polymorphic and encoded by the Beta-2 microglobulin gene. The α 3 domain is plasma membrane-spanning and interacts with the CD8 co-receptor of T-cells . The α 3 -CD8 interaction holds the MHC I molecule in place while the T cell receptor (TCR) on the surface of the cytotoxic T cell binds its α 1 -α 2 heterodimer ligand, and checks the coupled peptide for antigenicity. The α 1 and α 2 domains fold to make up

2232-623: The H-2, whereas it has been referred to as the RT1 complex in rats, and the B locus in chickens. The MHC gene family is divided into three subgroups: MHC class I , MHC class II , and MHC class III . Among all those genes present in MHC, there are two types of genes coding for the proteins MHC class I molecules and MHC class II molecules that are directly involved in the antigen presentation . These genes are highly polymorphic, 19031 alleles of class I HLA, and 7183 of class II HLA are deposited for human in

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2304-514: The IMGT database. MHC class I molecules are expressed in some nucleated cells and also in platelets —in essence all cells but red blood cells . It presents epitopes to killer T cells , also called cytotoxic T lymphocytes (CTLs). A CTL expresses CD8 receptors, in addition to T-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

2376-491: The MHC class I molecule, the CTL triggers the cell to undergo programmed cell death by apoptosis . Thus, MHC class I helps mediate cellular immunity , a primary means to address intracellular pathogens , such as viruses and some bacteria , including bacterial L forms , bacterial genus Mycoplasma , and bacterial genus Rickettsia . In humans, MHC class I comprises HLA-A , HLA-B , and HLA-C molecules. The first crystal structure of Class I MHC molecule, human HLA-A2,

2448-453: 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. Ternary complex The term ternary complex can also refer to a polymer formed by electrostatic interactions. Trevor Palmer (Enzymes, 2nd edition) This protein -related article is a stub . You can help Misplaced Pages by expanding it . This biochemistry article

2520-753: The MHC molecule interacts with the variable Ig-Like domain of the TCR to trigger T-cell activation 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 of ankylosing spondylitis and other associated inflammatory diseases, but mechanisms involving aberrant antigen presentation or T cell activation have been hypothesized. Tissue allorecognition : MHC molecules in complex with peptide epitopes are essentially ligands for TCRs. T cells become activated by binding to

2592-468: The MHC molecule, calnexin dissociates. The MHC molecule lacking a bound peptide is inherently unstable and requires the binding of the chaperones calreticulin and Erp57. Additionally, tapasin binds to the MHC molecule and serves to link it to the TAP proteins and facilitates the selection of peptide in an iterative process called peptide editing, thus facilitating enhanced peptide loading and colocalization. Once

2664-481: 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. Antigen presentation : MHC molecules bind to both T cell receptor and CD4 / CD8 co-receptors on T lymphocytes , and the antigen epitope held in the peptide-binding groove of

2736-465: The MHC:peptide complex will recognize and kill presenting cells. Alternatively, class I MHC itself can serve as an inhibitory ligand for natural killer cells (NKs). Reduction in the normal levels of surface class I MHC, a mechanism employed by some viruses and certain tumors to evade CTL responses, activates NK cell killing. Paired-immunoglobulin-like receptor B (PirB), an MHCI-binding receptor,

2808-483: The Th cell's terminal differentiation. MHC class II thus mediates immunization to—or, if APCs polarize Th 0 cells principally to T reg cells, immune tolerance of—an antigen . The polarization during primary exposure to an antigen is key in determining a number of chronic diseases , such as inflammatory bowel diseases and asthma , by skewing the immune response that memory Th cells coordinate when their memory recall

2880-614: The UK, USA and Japan in Nature . 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 of Nature . Many other species have been sequenced and the evolution of the MHC was studied, e.g. in the gray short-tailed opossum ( Monodelphis domestica ), a marsupial , MHC spans 3.95 Mb, yielding 114 genes, 87 shared with humans. Marsupial MHC genotypic variation lies between eutherian mammals and birds , taken as

2952-431: 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 especially dendritic cells (DCs). An APC takes up an antigenic protein, performs antigen processing , and returns a molecular fraction of it—a fraction termed

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3024-421: 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

3096-722: The basal Metazoan Trichoplax adhaerens . In a transplant procedure, as of an organ or stem cells , MHC molecules themselves act as antigens and can provoke immune response in the recipient, thus causing transplant rejection. MHC molecules were identified and named after their role in transplant rejection between mice of different strains, though it took over 20 years to clarify MHC's role in presenting peptide antigens to cytotoxic T lymphocytes (CTLs). 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

3168-425: 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 with CD8 co-receptor. β 2 microglobulin provides stability of the complex and participates in the recognition of peptide-MHC class I complex by CD8 co-receptor. The peptide

3240-451: The degradation of cytosolic proteins by the proteasome . The MHC I: peptide complex is then inserted via the endoplasmic reticulum into the external plasma membrane of the cell. The epitope peptide is bound on extracellular parts of the class I MHC molecule. Thus, the function of the class I MHC is to display intracellular proteins to cytotoxic T cells (CTLs). However, class I MHC can also present peptides generated from exogenous proteins, in

3312-399: 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. In humans , the MHC region occurs on chromosome 6 , between the flanking genetic markers MOG and COL11A2 (from 6p22.1 to 6p21.3 about 29Mb to 33Mb on

3384-445: The elimination of the infected cell by the immune system. Diversity of an individual's self-antigen presentation , mediated by MHC self-antigens, is attained in at least three ways: (1) an organism's MHC repertoire is polygenic (via multiple, interacting genes); (2) MHC expression is codominant (from both sets of inherited alleles ); (3) MHC gene variants are highly polymorphic (diversely varying from organism to organism within

3456-459: The ends involved in binding carbon terminal ends along the peptide 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 the complement system (such as C2 , C4 , and B factor ), cytokines (such as TNF-α , LTA , and LTB ), and heat shock proteins . MHC

3528-426: The epitope coupled within the MHC class II. This event primes the naive T cell . According to the local milieu, that is, the balance of cytokines secreted by APCs in the microenvironment, the naive helper T cell (Th 0 ) polarizes into either a memory Th cell or an effector Th cell of phenotype either type 1 (Th 1 ), type 2 (Th 2 ), type 17 (Th 17 ), or regulatory/suppressor (T reg ), as so far identified,

3600-452: The genome. The origin of spliced peptide segments can be from the same protein (cis-splicing) or different proteins (trans-splicing). The peptides have to be translocated from the cytosol into the endoplasmic reticulum (ER) to meet the MHC class I molecule, whose peptide-binding site is in the lumen of the ER. They have membrane proximal Ig fold The peptide translocation from the cytosol into

3672-593: The hg38 assembly), and contains 224 genes spanning 3.6 mega base pairs (3 600 000 bases). About half have known immune functions. The human 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 in mice is called the Histocompatibility system 2 or just

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3744-463: The human genome, namely 19pl3.1, 9q33–q34, and 1q21–q25. It is believed that the loci arouse from the two-round duplications in vertebrates 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." Genes in this locus are apparently linked to intracellular intrinsic immunity in

3816-405: 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. When maturing in

3888-483: The immune system against a particular non-self antigen displayed with the help of an MHC class I protein. Because MHC class I molecules present peptides derived from cytosolic proteins, the pathway of MHC class I presentation is often called cytosolic or endogenous pathway . In humans, the HLAs corresponding to MHC class I are HLA-A , HLA-B , and HLA-C . Class I MHC molecules bind peptides generated mainly from

3960-466: The interaction among the various cells of the immunological system. These three scientists have been awarded the 1980 Nobel Prize in Physiology or Medicine 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

4032-403: 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, although also in more primitive fishes both classical and nonclassical MHC class II are found. β 2 chain (12 KDa in humans) β chain (26–29 KDa in humans) helices, blocked at both the ends helices, opened at both

4104-473: The lumen of the ER is accomplished by the transporter associated with antigen processing (TAP). TAP is a member of the ABC transporter family and is a heterodimeric multimembrane-spanning polypeptide consisting of TAP1 and TAP2 . The two subunits form a peptide binding site and two ATP binding sites that face the cytosol. TAP binds peptides on the cytoplasmic side and translocates them under ATP consumption into

4176-485: The lumen of the ER. The MHC class I molecule is then, in turn, loaded with peptides in the lumen of the ER. The peptide-loading process involves several other molecules that form a large multimeric complex called the Peptide loading complex consisting of TAP, tapasin , calreticulin , calnexin , and Erp57 ( PDIA3 ). Calnexin acts to stabilize the class I MHC α chains prior to β2m binding. Following complete assembly of

4248-549: The minimal MHC encoding, but is closer in organization to that of non mammals . The IPD-MHC Database 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. The MHC locus is present in all jawed vertebrates ; it is assumed to have arisen about 450 million years ago. Despite

4320-475: 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 and MHC class II were observed. Human MHC class I and II are also called human leukocyte antigen (HLA). To clarify

4392-401: The origin of tetrapod species. 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; why

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4464-464: The peptide is loaded onto the MHC class I molecule, the complex dissociates and it leaves the ER through the secretory pathway to reach the cell surface. The transport of the MHC class I molecules through the secretory pathway involves several posttranslational modifications of the MHC molecule. Some of the posttranslational modifications occur in the ER and involve change to the N-glycan regions of

4536-515: The peptide-binding grooves of any MHC molecule that they were not trained to recognize during positive selection in the thymus . Peptides are processed and presented by two classical pathways: In their development in the thymus , 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. MHC restriction occurs during lymphocyte development in

4608-457: The population of protein molecules in a host cell, and greater MHC diversity permits greater diversity of antigen presentation . In 1976, Yamazaki et al demonstrated a sexual selection mate choice by male mice for females of a different MHC. Similar results have been obtained with fish . Some data find lower rates of early pregnancy loss in human couples of dissimilar MHC genes. MHC may be related to mate choice in some human populations,

4680-487: The presentation of MHC class I molecules on the cell surface. In contrast to cytotoxic T lymphocytes, natural killer (NK) cells are normally inactivated upon recognizing MHC I molecules on the surface of cells. Therefore, in the absence of MHC I molecules, NK cells are activated and recognize the cell as aberrant, suggesting that it may be infected by viruses attempting to evade immune destruction. Several human cancers also show down-regulation of MHC I, giving transformed cells

4752-532: The protein, followed by extensive changes to the N-glycans in the Golgi apparatus . The N-glycans mature fully before they reach the cell surface. Peptides that fail to bind MHC class I molecules in the lumen of the endoplasmic reticulum (ER) are removed from the ER via the sec61 channel into the cytosol, where they might undergo further trimming in size, and might be translocated by TAP back into ER for binding to

4824-573: The same survival advantage of being able to avoid normal immune surveillance designed to destroy any infected or transformed cells. The MHC class I genes originated in the most recent common ancestor of all jawed vertebrates , and have been found in all living jawed vertebrates that have been studied thus far. Since their emergence in jawed vertebrates, this gene family has been subjected to many divergent evolutionary paths as speciation events have taken place. There are, however, documented cases of trans-species polymorphisms in MHC class I genes, where

4896-814: The thymus through a process known as positive 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). The TCRs of T lymphocytes recognise only sequential epitopes , also called linear epitopes , of only peptides and only if coupled within an MHC molecule. (Antibody molecules secreted by activated B cells , though, recognize diverse epitopes— peptide , lipid , carbohydrate , and nucleic acid —and recognize conformational epitopes , which have three-dimensional structure.) MHC molecules enable immune system surveillance of

4968-489: The thymus, T lymphocytes are selected for their TCR incapacity to recognize self antigens, yet T lymphocytes can react against the donor MHC's peptide-binding groove , the variable region of MHC holding the presented antigen's epitope for recognition by TCR, the matching paratope . T lymphocytes of the recipient take the incompatible peptide-binding groove as nonself antigen. There are various types of transplant rejection that are known to be mediated by MHC (HLA): In all of

5040-403: 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. 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 , and HLA-DRB1 . In humans,

5112-557: The women showed no particular preference. No studies show the extent to which odor preference determines mate selection (or vice versa). Most mammals have MHC variants similar to those of humans, who bear great allelic diversity , especially among the nine classical genes—seemingly due largely to gene duplication —though human MHC regions have many pseudogenes . The most diverse loci, namely HLA-A, HLA-B, and HLA-C, have roughly 6000, 7200, and 5800 known alleles, respectively. Many HLA alleles are ancient, sometimes of closer homology to

5184-436: Was published in 1989. The structure revealed that MHC-I molecules are heterodimers . They have a polymorphic heavy α-subunit whose gene occurs inside the MHC locus and small invariant β 2 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

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