Editing Major histocompatibility complex

{{short description|Cell surface proteins, part of the acquired immune system}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox protein family
| Symbol = HLA
| Name = Major histocompatibility complex molecule
| image =62-MajorHistocompatibilityComplex-1hsa.tif
| width =
| caption =Major histocompatibility complex protein (class I) in orange and pink, with a presented peptide in red. Membrane in grey. The transmembrane and cytoplasmic domains are shown in cartoon form. ({{PDB|1hsa}})
| InterPro= IPR001039
| SMART=
| PROSITE =
| SCOP =
| TCDB =
| OPM family=
| OPM protein=
| Pfam=
| PDB=
| Membranome superfamily= 63
}}
The '''major histocompatibility complex''' ('''MHC''') is a large [[Locus (genetics)|locus]] on vertebrate DNA containing a set of closely linked [[polymorphic genes]] that code for [[Cell (biology)|cell]] surface proteins essential for the [[adaptive immune system]]. These cell surface proteins are called '''MHC molecules'''.

Its name comes from its discovery during the study of transplanted tissue compatibility.<ref>{{cite journal | vauthors = Hull P | title = Notes on Dr Snell's observations concerning the H-2 locus polymorphism | journal = Heredity | volume = 25 | issue = 3 | pages = 461–5 | date = August 1970 | pmid = 5275401 | doi = 10.1038/hdy.1970.47 | doi-access = free }}</ref> Later studies revealed that tissue rejection due to incompatibility 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 cell|T-cells]].<ref>{{cite book | vauthors = Janeway Jr CA, Travers P, Walport M, etal | title = Immunobiology: The Immune System in Health and Disease.| edition = 5th | location = New York | publisher = Garland Science | date = 2001 | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK27156 | chapter = The Major Histocompatibility Complex and Its Functions }}</ref> 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 disease]]s.

In 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]].<ref>{{cite web | vauthors = Kimball JW | url = http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/H/HLA.html | archive-url = https://web.archive.org/web/20160204135034/http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/H/HLA.html | archive-date = 4 February 2016 | date = 11 February 2011 | work = Kimball's Biology Pages | title = Histocompatibility Molecules }}</ref> The presented [[Immune tolerance|self-antigens]] prevent an [[organism]]'s [[immune 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's [[antigen presentation|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 [[alleles|gene variants]] are highly [[polymorphism (biology)|polymorphic]] (diversely varying from organism to organism within a [[species]]).<ref>{{cite book | vauthors = Janeway Jr CA, Travers P, Walport M, etal | title = Immunobiology: The Immune System in Health and Disease.| edition = 5th | location = New York | publisher = Garland Science | date = 2001 | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK27156 | chapter = The Major Histocompatibility Complex and Its Functions }}</ref> [[Major histocompatibility complex and sexual selection|Sexual selection]] has been observed in male mice [[mate choice|choosing to mate]] with females with different MHCs.<ref>{{cite journal | vauthors = Yamazaki K, Boyse EA, Miké V, Thaler HT, Mathieson BJ, Abbott J, Boyse J, Zayas ZA, Thomas L | title = Control of mating preferences in mice by genes in the major histocompatibility complex | journal = The Journal of Experimental Medicine | volume = 144 | issue = 5 | pages = 1324–35 | date = November 1976 | pmid = 1032893 | pmc = 2190468 | doi = 10.1084/jem.144.5.1324 }}</ref> Also, at least for MHC I presentation, there has been evidence of antigenic peptide [[Protein splicing|splicing]], which can combine peptides from different proteins, vastly increasing antigen diversity.<ref>{{cite journal | vauthors = Vigneron N, Stroobant V, Chapiro J, Ooms A, Degiovanni G, Morel S, van der Bruggen P, Boon T, Van den Eynde BJ | title = An antigenic peptide produced by peptide splicing in the proteasome | journal = Science | volume = 304 | issue = 5670 | pages = 587–90 | date = April 2004 | pmid = 15001714 | doi = 10.1126/science.1095522 | bibcode = 2004Sci...304..587V | s2cid = 33796351 }}</ref>

==Discovery==

The first descriptions of the MHC were made by British [[immunology|immunologist]] [[Peter Alfred Gorer|Peter Gorer]] in 1936.<ref>{{cite journal | vauthors = Klein J | title = Seeds of time: fifty years ago Peter A. Gorer discovered the H-2 complex | journal = Immunogenetics | volume = 24 | issue = 6 | pages = 331–8 | year = 1986 | pmid = 3539775 | doi = 10.1007/bf00377947 | s2cid = 28211127 }}</ref>   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.<ref>Little CC 1941, "The genetics of tumor transplantation", pp 279–309, in ''Biology of the Laboratory Mouse'', ed by Snell GD, New York: Dover.</ref> [[George Davis Snell|George Snell]] selectively bred two mouse strains, attained 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 (genetics)|locus]].<ref>{{cite journal | vauthors = Snell GD, Higgins GF | title = Alleles at the histocompatibility-2 locus in the mouse as determined by tumor transplantation | journal = Genetics | volume = 36 | issue = 3 | pages = 306–10 | date = May 1951 | doi = 10.1093/genetics/36.3.306 | pmid = 14840651 | pmc = 1209522 }}</ref>  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&nbsp;[[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<ref>{{cite web | url = https://www.nobelprize.org/prizes/medicine/1980/press-release/ | title = The Nobel Prize in Physiology or Medicine 1980 | date = 10 October 1980 | quote = 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 }}</ref> 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 in ''Nature''.<ref name="MHCsc2">{{cite journal | title = Complete sequence and gene map of a human major histocompatibility complex. The MHC sequencing consortium | journal = Nature | volume = 401 | issue = 6756 | pages = 921–3 | date = October 1999 | pmid = 10553908 | doi = 10.1038/44853 | bibcode = 1999Natur.401..921T | author1 = The Mhc Sequencing Consortium | s2cid = 186243515 }}</ref> 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''.<ref>{{cite journal | vauthors = Kaufman J, Milne S, Göbel TW, Walker BA, Jacob JP, Auffray C, Zoorob R, Beck S | title = The chicken B locus is a minimal essential major histocompatibility complex | journal = Nature | volume = 401 | issue = 6756 | pages = 923–5 | date = October 1999 | pmid = 10553909 | doi = 10.1038/44856 | bibcode = 1999Natur.401..923K | s2cid = 4387040 }}</ref>  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.<ref name="belov2">{{cite journal | vauthors = Belov K, Deakin JE, Papenfuss AT, Baker ML, Melman SD, Siddle HV, Gouin N, Goode DL, Sargeant TJ, Robinson MD, Wakefield MJ, Mahony S, Cross JG, Benos PV, Samollow PB, Speed TP, Graves JA, Miller RD | title = Reconstructing an ancestral mammalian immune supercomplex from a marsupial major histocompatibility complex | journal = PLOS Biology | volume = 4 | issue = 3 | pages = e46 | date = March 2006 | pmid = 16435885 | pmc = 1351924 | doi = 10.1371/journal.pbio.0040046 | doi-access = free }}</ref>  Marsupial MHC [[Genotype|genotypic]] variation lies between [[Eutheria|eutherian mammals]] and [[bird]]s, taken as the minimal MHC encoding, but is closer in organization to that of non[[mammals]]. The IPD-MHC Database<ref>{{cite web | url = https://www.ebi.ac.uk/ipd/mhc/ | title = IPD-MHC Database | work = EMBL-EBI }}</ref> 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.

==Genes==

The MHC locus is present in all [[Gnathostomata|jawed vertebrates]]; it is assumed to have arisen about 450 million years ago.<ref>{{cite journal | vauthors = Kulski JK, Shiina T, Anzai T, Kohara S, Inoko H | title = Comparative genomic analysis of the MHC: the evolution of class I duplication blocks, diversity and complexity from shark to man | journal = Immunological Reviews | volume = 190 | pages = 95–122 | date = December 2002 | pmid = 12493009 | doi = 10.1034/j.1600-065x.2002.19008.x | s2cid = 41765680 }}</ref> 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. In [[human]]s, the MHC region occurs on [[chromosome 6]], between the flanking [[genetic marker]]s ''[[Myelin oligodendrocyte glycoprotein|MOG]]'' and ''[[COL11A2]]'' (from 6p22.1 to 6p21.3 about 29Mb to 33Mb on the hg38 assembly), and contains 224 genes spanning 3.6 mega[[base pairs]] (3 600 000 bases).<ref name="MHCsc2" /> 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  [[Mouse|mice]] 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|date=March 2023}}

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 the IMGT database.<ref>{{cite web | title = The International ImMunoGeneTics Information System | url = http://www.imgt.org/ | access-date = 2020-03-11 | archive-date = 2012-07-17 | archive-url = https://web.archive.org/web/20120717023051/http://www.imgt.org/ | url-status = dead }}</ref>
{| class="wikitable"
! Class
! Encoding
! Expression
|-
|'''[[MHC class I|I]]'''
|(1) peptide-binding proteins, which select short sequences of amino acids for [[antigen presentation]], as well as (2) molecules aiding [[Antigen processing|antigen-processing]] (such as [[Transporter associated with antigen processing|TAP]] and [[tapasin]]).
|One chain, called α, whose ligands are the [[CD8]] receptor—borne notably by cytotoxic T cells—and inhibitory receptors borne by NK cells
|-
|'''[[MHC class II|II]]'''
|(1) peptide-binding proteins and (2) proteins assisting antigen loading onto MHC class II's peptide-binding proteins (such as [[MHC II DM]], [[MHC II DQ]], [[MHC II DR]], and [[MHC II DP]]).
|Two chains, called α & β, whose ligands are the [[CD4]] receptors borne by helper T cells.
|-
|'''[[MHC class III|III]]'''
|Other immune proteins, outside antigen processing and presentation, such as components of the [[Complement system|complement cascade]] (e.g., [[Complement component 2|C2]], [[Complement component 4|C4]], [[Complement factor B|factor B]]), the [[cytokine]]s of immune signaling (e.g., [[TNF-α]]), and [[heat shock proteins]] buffering cells from stresses
|Various
|}

== Proteins ==
[[Image:063-T-CellReceptor-MHC.tiff|thumb|[[T-cell receptor]] complexed with [[MHC-I]] and [[MHC-II]]]]

===MHC class I===
{{Main|MHC class I}}

[[MHC class I]] molecules are expressed in all [[nucleated]] cells and also in [[platelet]]s—in essence all cells but [[red blood cell]]s. It presents epitopes to killer [[T cell]]s, also called [[cytotoxic T lymphocyte]]s (CTLs). A CTL expresses CD8 receptors, in addition to [[T-cell receptor]]s (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 by [[apoptosis]]. Thus, MHC class I helps mediate [[cellular immunity]], a primary means to address [[intracellular pathogen]]s, such as [[virus]]es and some [[bacteria]], including bacterial [[L-form bacteria|L forms]], bacterial [[genus]] ''[[Mycoplasma]]'', and bacterial genus ''[[Rickettsia]]''. In humans, MHC class I comprises [[HLA-A]], [[HLA-B]], and [[HLA-C]] molecules.{{citation needed|date=March 2023}}

The first crystal structure of Class I MHC molecule, human HLA-A2, was published in 1989.<ref>{{cite journal | vauthors = Saper MA, Bjorkman PJ, Wiley DC | title = Refined structure of the human histocompatibility antigen HLA-A2 at 2.6 A resolution | journal = Journal of Molecular Biology | volume = 219 | issue = 2 | pages = 277–319 | date = May 1991 | pmid = 2038058 | doi = 10.1016/0022-2836(91)90567-p }}</ref> 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 [[Beta-2 microglobulin|β<sub>2</sub> 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 with [[CD8]] co-receptor. [[Beta-2 microglobulin|β<sub>2</sub> microglobulin]] provides stability of the complex and participates in the recognition of peptide-MHC class I complex by [[CD8]] co-receptor.<ref>{{cite journal | vauthors = Gao GF, Tormo J, Gerth UC, Wyer JR, McMichael AJ, Stuart DI, Bell JI, Jones EY, Jakobsen BK | title = Crystal structure of the complex between human CD8alpha(alpha) and HLA-A2 | journal = Nature | volume = 387 | issue = 6633 | pages = 630–4 | date = June 1997 | pmid = 9177355 | doi = 10.1038/42523 | bibcode = 1997Natur.387..630G | s2cid = 4267617 }}</ref>  The peptide 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.
[[File:MHC classe 1 i 2.jpg|thumb|Schematic view of MHC class I and MHC class II molecules]]

'''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., [[induced-self antigen|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 [[Endothelial protein C receptor|EPCR]]) molecules. This lineage may have been established before the origin of tetrapod species.<ref name="Dijkstra-2018">{{cite journal | vauthors = Dijkstra JM, Yamaguchi T, Grimholt U | title = Conservation of sequence motifs suggests that the nonclassical MHC class I lineages CD1/PROCR and UT were established before the emergence of tetrapod species | journal = Immunogenetics | volume = 70 | issue = 7 | pages = 459–476 | date = July 2018 | pmid = 29270774 | doi = 10.1007/s00251-017-1050-2 | s2cid = 24591879 }}</ref> 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;<ref name="Grimholt-2015">{{cite journal | vauthors = Grimholt U, Tsukamoto K, Azuma T, Leong J, Koop BF, Dijkstra JM | title = A comprehensive analysis of teleost MHC class I sequences | journal = BMC Evolutionary Biology | volume = 15 | pages = 32 | date = March 2015 | issue = 1 | pmid = 25888517 | pmc = 4364491 | doi = 10.1186/s12862-015-0309-1 | doi-access = free | bibcode = 2015BMCEE..15...32G }}</ref> why the Z lineage was well conserved in ray-finned fish but lost in tetrapods is not understood.

=== MHC class II ===
{{Main|MHC class II}}

[[MHC class II]] can be conditionally expressed by all cell types, but normally occurs only on "professional" [[antigen-presenting cells]] (APCs): [[macrophage]]s, [[B cell]]s, 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 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 receptor]]s (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 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 [[cytokine]]s secreted by APCs in the microenvironment, the naive [[helper T cell]] (Th<sub>0</sub>) polarizes into either a memory Th cell or an effector Th cell of [[phenotype]] either type 1 (Th<sub>1</sub>), type 2 (Th<sub>2</sub>), type 17 (Th<sub>17</sub>), or regulatory/suppressor (T<sub>reg</sub>), as so far identified, the Th cell's terminal differentiation.

MHC class II thus mediates immunization to—or, if APCs polarize Th<sub>0</sub> cells principally to T<sub>reg</sub> cells, [[immune tolerance]] of—an [[antigen]]. The polarization during primary exposure to an antigen is key in determining a number of [[chronic disease]]s, such as [[inflammatory bowel diseases]] and [[asthma]], 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 Th<sub>0</sub>, but when their [[B cell receptor]]s bind matching epitopes, interactions which are not mediated by MHC, these [[Plasma cell|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 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.<ref>{{cite journal | vauthors = Wang XX, Li Y, Yin Y, Mo M, Wang Q, Gao W, Wang L, Mariuzza RA | title = Affinity maturation of human CD4 by yeast surface display and crystal structure of a CD4-HLA-DR1 complex | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 38 | pages = 15960–5 | date = September 2011 | pmid = 21900604 | pmc = 3179091 | doi = 10.1073/pnas.1109438108 | bibcode = 2011PNAS..10815960W | doi-access = free }}</ref> 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 [[Isotype (immunology)|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 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,<ref name="Dijkstra-2019">{{cite journal | vauthors = Dijkstra JM, Yamaguchi T | title = Ancient features of the MHC class II presentation pathway, and a model for the possible origin of MHC molecules | journal = Immunogenetics | volume = 71 | issue = 3 | pages = 233–249 | date = March 2019 | pmid = 30377750 | doi = 10.1007/s00251-018-1090-2 | s2cid = 53110357 }}</ref> although also in more primitive fishes both classical and nonclassical MHC class II are found.<ref name="Dijkstra-2013">{{cite journal | vauthors = Dijkstra JM, Grimholt U, Leong J, Koop BF, Hashimoto K | title = Comprehensive analysis of MHC class II genes in teleost fish genomes reveals dispensability of the peptide-loading DM system in a large part of vertebrates | journal = BMC Evolutionary Biology | volume = 13 | pages = 260 | date = November 2013 | issue = 1 | pmid = 24279922 | doi = 10.1186/1471-2148-13-260 | pmc = 4219347 | doi-access = free | bibcode = 2013BMCEE..13..260D }}</ref><ref name="Almeida-2020">{{cite journal | vauthors = Almeida T, Gaigher A, Muñoz-Mérida A, Neves F, Castro LF, Flajnik MF, Ohta Y, Esteves PJ, Veríssimo A | title = Cartilaginous fish class II genes reveal unprecedented old allelic lineages and confirm the late evolutionary emergence of DM | journal = Molecular Immunology | volume = 128 | pages = 125–138 | date = October 2020 | pmid = 33126081 | doi = 10.1016/j.molimm.2020.10.003 | pmc = 8010645 | doi-access = free }}</ref>
{| class="wikitable"
!Sr.No
!Feature<ref>{{Cite book|last=Khan|first=Fahim Halim|title=The elements of immunology|date=2009|publisher=Pearson Education|isbn=978-81-317-1158-3|location=Delhi|oclc=276274663}}</ref>
!Class I MHC
!Class II MHC
|-
|1
|Constituting polypeptide chains
|α chain (45KDa in humans)
β<sub>2</sub> 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
|α<sub>1</sub> and β<sub>1</sub> 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
|}

=== MHC class III ===
{{Main|MHC class III}}
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 [[Complement component 2|C2]], [[Complement component 4|C4]], and [[Complement factor B|B factor]]), cytokines (such as [[TNF-alpha|TNF-α]], [[Lymphotoxin alpha|LTA]], and [[Lymphotoxin beta|LTB]]), and [[heat shock protein]]s.

=== Function ===
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 to [[T cell receptor]]s (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, 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 the MHC molecule interacts with the [[Immunoglobulin superfamily|variable Ig-Like domain]] of the TCR to trigger T-cell activation<ref name="KindtGoldsby20072">{{cite book| vauthors = Kindt TJ, Goldsby RA, Osborne BA, Kuby J |url=https://books.google.com/books?id=oOsFf2WfE5wC&pg=PA223|title=Kuby immunology |publisher=Macmillan|year=2007|isbn=978-1-4292-0211-4|access-date=28 November 2010}}</ref>

[[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 the peptide-binding grooves of any MHC molecule that they were not trained to recognize during [[MHC restriction|positive selection]] in the [[thymus]].

== Antigen processing and presentation ==
[[File:MHC Class I processing.svg|left|350px|thumb|'''MHC class I pathway''': Proteins in the [[cytosol]] are degraded by the [[proteasome]], liberating peptides internalized by [[transporter associated with antigen processing|TAP]] channel in the [[endoplasmic reticulum]], there associating with MHC-I molecules freshly synthesized. MHC-I/peptide complexes enter [[Golgi apparatus]], are [[glycosylation|glycosylated]], enter secretory vesicles, fuse with the [[cell membrane]], and externalize on the cell membrane interacting with T lymphocytes.]]

Peptides are processed and presented by two classical pathways:
* In '''MHC class II''', [[phagocytes]] such as [[macrophages]] and immature [[dendritic cells]] take up entities by [[phagocytosis]] into [[phagosomes]]—though [[B cells]] exhibit the more general [[endocytosis]] into [[endosomes]]—which fuse with [[lysosomes]] whose acidic enzymes cleave the uptaken protein into many different peptides. Via [[physicochemical dynamics]] in molecular interaction with the particular MHC class II variants borne by the host, encoded in the host's genome, a particular peptide exhibits [[immunodominance]] and loads onto MHC class II molecules. These are trafficked to and externalized on the cell surface.<ref name="aderem">{{cite journal|last=Nesmiyanov|first=Pavel|year=2020|title=Antigen Presentation and Major Histocompatibility Complex|url=https://www.sciencedirect.com/science/article/pii/B978012818731900029X|journal=Reference Module in Biomedical Sciences|pages=90–98|doi=10.1016/B978-0-12-818731-9.00029-X|pmid=|isbn=978-0-12-801238-3|s2cid=234948691|via=Elsevier|url-access=subscription}}</ref>
* In '''MHC class I''', any nucleated cell normally presents cytosolic peptides, mostly self peptides derived from protein turnover and defective ribosomal products. During viral infection, intracellular microorganism infection, or cancerous transformation, such proteins degraded in the [[proteosome]] are as well loaded onto MHC class I molecules and displayed on the cell surface. T lymphocytes can detect a peptide displayed at 0.1–1% of the MHC molecules.

[[File:MHC Binding Diagram.png|left|350px|thumb|'''Peptide binding for Class I and Class II MHC molecules''', showing the binding of peptides between the alpha-helix walls, upon a beta-sheet base. The difference in binding positions is shown. Class I primarily  makes contact with backbone residues at the Carboxy and amino terminal regions, while Class II primarily makes contacts along the length of the residue backbone. The precise location of binding residues is determined by the MHC allele.<ref>{{cite book | vauthors = Murphy | chapter = Antigen recognition by T cells | title = Janeway's Immunobiology | edition = 8th | publisher = Garland Science | date = 2012 | pages = 138–153 }}</ref>]]

{| class="wikitable" style="text-align:center"
|+ '''Table 2.''' Characteristics of the antigen processing pathways
|-
! Characteristic !! MHC-I pathway !! MHC-II pathway
|-
! Composition of the stable peptide-MHC complex
| Polymorphic chain α and β<sub>2</sub> microglobulin, peptide bound to α chain || Polymorphic chains α and β, peptide binds to both
|-
! Types of [[antigen-presenting cell]]s (APC)
| All nucleated cells || [[Dendritic cell]]s, mononuclear phagocytes, [[B lymphocytes]], some endothelial cells, epithelium of [[thymus]]
|-
! T lymphocytes able to respond
| [[Cytotoxic T lymphocytes]] (CD8+) || [[Helper T cells|Helper T lymphocytes]] (CD4+)
|-
! Origin of antigenic proteins
| [[cytosol]]ic proteins (mostly synthesized by the cell; may also enter from the extracellular medium via [[phagosome]]s) || Proteins present in [[endosome]]s or [[lysosome]]s (mostly internalized from extracellular medium)
|-
! Enzymes responsible for peptide generation
| Cytosolic [[proteasome]] || [[Protease]]s 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
| [[Transporter associated with antigen processing|TAP]] (transporter associated with antigen processing) || DM, invariant chain
|}

==T lymphocyte recognition restrictions==
{{Main|MHC restriction}}

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 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 epitope]]s, also called [[linear epitope]]s, of only peptides and only if coupled within an MHC molecule. (Antibody molecules secreted by [[plasma cell|activated B cells]], though, recognize diverse epitopes—[[peptide]], [[lipid]], [[carbohydrate]], and [[nucleic acid]]—and recognize [[conformational epitope]]s, which have [[three-dimensional]] structure.)

==In sexual mate selection==
{{main|Major histocompatibility complex and sexual selection}}
{{See also|Interpersonal compatibility}}
MHC molecules enable immune system surveillance of 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]].<ref name="boehm">{{cite journal | vauthors = Boehm T, Zufall F | title = MHC peptides and the sensory evaluation of genotype | journal = Trends in Neurosciences | volume = 29 | issue = 2 | pages = 100–7 | date = February 2006 | pmid = 16337283 | doi = 10.1016/j.tins.2005.11.006 | s2cid = 15621496 }}</ref> Some data find lower rates of [[early pregnancy loss]] in human couples of dissimilar MHC genes.<ref name="Haig">{{cite journal | vauthors = Haig D | title = Maternal-fetal interactions and MHC polymorphism | journal = Journal of Reproductive Immunology | volume = 35 | issue = 2 | pages = 101–9 | date = November 1997 | pmid = 9421795 | doi = 10.1016/s0165-0378(97)00056-9 }}</ref>

MHC may be related to mate choice in some human populations, a theory that found support by studies by Ober and colleagues in 1997,<ref name="ober">{{cite journal | vauthors = Ober C, Weitkamp LR, Cox N, Dytch H, Kostyu D, Elias S | title = HLA and mate choice in humans | journal = American Journal of Human Genetics | volume = 61 | issue = 3 | pages = 497–504 | date = September 1997 | pmid = 9326314 | pmc = 1715964 | doi = 10.1086/515511 }}</ref> as well as by Chaix and colleagues in 2008.<ref name="chaix">{{cite journal | vauthors = Chaix R, Cao C, Donnelly P | title = Is mate choice in humans MHC-dependent? | journal = PLOS Genetics | volume = 4 | issue = 9 | pages = e1000184 | date = September 2008 | pmid = 18787687 | pmc = 2519788 | doi = 10.1371/journal.pgen.1000184 | doi-access = free }}</ref> However, the latter findings have been controversial.<ref name="Derti2010">{{cite journal | vauthors = Derti A, Cenik C, Kraft P, Roth FP | title = Absence of evidence for MHC-dependent mate selection within HapMap populations | journal = PLOS Genetics | volume = 6 | issue = 4 | pages = e1000925 | date = April 2010 | pmid = 20442868 | pmc = 2861700 | doi = 10.1371/journal.pgen.1000925 | doi-access = free }}</ref> 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.<ref name="krefts">{{cite journal |vauthors=Janeš D, Klun I, Vidan-Jeras B, Jeras M, Kreft S | title = Influence of MHC on odour perception of 43 chemicals and body odor | journal = Central European Journal of Biology | volume = 5 | issue = 3 | pages = 324–330 | year = 2010 | doi = 10.2478/s11535-010-0020-6 | doi-access = free }}</ref>

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.<ref name="wedekind">{{cite journal | vauthors = Wedekind C, Seebeck T, Bettens F, Paepke AJ | title = MHC-dependent mate preferences in humans | journal = Proceedings. Biological Sciences | volume = 260 | issue = 1359 | pages = 245–9 | date = June 1995 | pmid = 7630893 | doi = 10.1098/rspb.1995.0087 | bibcode = 1995RSPSB.260..245W | s2cid = 34971350 }}</ref> In 2005 in a group of 58 subjects, women were more indecisive when presented with MHCs like their own,<ref name="santos">{{cite journal | vauthors = Santos PS, Schinemann JA, Gabardo J, Bicalho MD | title = New evidence that the MHC influences odor perception in humans: a study with 58 Southern Brazilian students | journal = Hormones and Behavior | volume = 47 | issue = 4 | pages = 384–8 | date = April 2005 | pmid = 15777804 | doi = 10.1016/j.yhbeh.2004.11.005 | s2cid = 8568275 }}</ref> although with oral contraceptives, the women showed no particular preference.<ref>{{cite web | vauthors = Bryner J | date = 12 August 2008 | work = Live Science | publisher = Future US Inc | url = http://www.livescience.com/culture/080812-contraceptive-smell.html | title = The pill makes women pick bad mates }}</ref> No studies show the extent to which odor preference determines mate selection (or vice versa).

==Evolutionary diversity==
Most [[mammal]]s have MHC variants similar to those of humans, who bear great [[gene pool|allelic diversity]], especially among the nine classical genes—seemingly due largely to [[gene duplication]]—though human MHC regions have many [[pseudogene]]s.<ref>{{cite journal | vauthors = Sznarkowska A, Mikac S, Pilch M | title = MHC Class I Regulation: The Origin Perspective | journal = Cancers | volume = 12 | issue = 5 | page = 1155 | date = May 2020 | pmid = 32375397 | doi = 10.3390/cancers12051155 | pmc = 7281430 | doi-access = free }}</ref> The most diverse loci, namely HLA-A, HLA-B, and HLA-C, have roughly 6000, 7200, and 5800 known alleles, respectively.<ref>{{cite web | url = http://hla.alleles.org/nomenclature/stats.html | title = HLA Alleles Numbers | work = hla.alleles.org }}</ref> Many HLA alleles are ancient, sometimes of closer [[Sequence homology|homology]] to a chimpanzee MHC alleles than to some other human alleles of the same gene.

MHC allelic diversity has challenged [[Evolutionary biology|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]]<ref>{{cite journal | vauthors = van Oosterhout C | title = A new theory of MHC evolution: beyond selection on the immune genes | journal = Proceedings. Biological Sciences | volume = 276 | issue = 1657 | pages = 657–65 | date = February 2009 | pmid = 18986972 | pmc = 2660941 | doi = 10.1098/rspb.2008.1299 }}</ref> and [[heterozygote 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.<ref>{{cite journal | vauthors = Manczinger M, Boross G, Kemény L, Müller V, Lenz TL, Papp B, Pál C | title = Pathogen diversity drives the evolution of generalist MHC-II alleles in human populations | journal = PLOS Biology | volume = 17 | issue = 1 | pages = e3000131 | date = January 2019 | pmid = 30703088 | pmc = 6372212 | doi = 10.1371/journal.pbio.3000131 | doi-access = free }}</ref> [[Genetic drift]] is also a major driving force in some species.<ref>{{cite journal | vauthors = Zeisset I, Beebee TJ | title = Drift rather than selection dominates MHC class II allelic diversity patterns at the biogeographical range scale in natterjack toads Bufo calamita | journal = PLOS ONE | volume = 9 | issue = 6 | pages = e100176 | date = 2014 | pmid = 24937211 | pmc = 4061088 | doi = 10.1371/journal.pone.0100176 | bibcode = 2014PLoSO...9j0176Z | doi-access = free }}</ref><ref>{{cite journal | vauthors = Cortázar-Chinarro M, Lattenkamp EZ, Meyer-Lucht Y, Luquet E, Laurila A, Höglund J | title = Drift, selection, or migration? Processes affecting genetic differentiation and variation along a latitudinal gradient in an amphibian | journal = BMC Evolutionary Biology | volume = 17 | issue = 1 | pages = 189 | date = August 2017 | pmid = 28806900 | pmc = 5557520 | doi = 10.1186/s12862-017-1022-z | doi-access = free | bibcode = 2017BMCEE..17..189C }}</ref> It is possible that the combined effects of some or all of these factors cause the genetic diversity.<ref>{{cite journal | vauthors = Apanius V, Penn D, Slev PR, Ruff LR, Potts WK | title = The Nature of Selection on the Major Histocompatibility Complex | journal = Critical Reviews in Immunology | volume = 37 | issue = 2–6 | pages = 75–120 | date = 2017 | pmid = 29773018 | doi = 10.1615/CritRevImmunol.v37.i2-6.10 }}</ref>

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.<ref name="Sommer">{{cite journal | vauthors = Sommer S | title = The importance of immune gene variability (MHC) in evolutionary ecology and conservation | journal = Frontiers in Zoology | volume = 2 | issue = 16 | pages = 16 | date = October 2005 | pmid = 16242022 | pmc = 1282567 | doi = 10.1186/1742-9994-2-16 | doi-access = free }}</ref><ref name="Manlik">{{cite journal | vauthors = Manlik O, Krützen M, Kopps AM, Mann J, Bejder L, Allen SJ, Frère C, Connor RC, Sherwin WB | title = Is MHC diversity a better marker for conservation than neutral genetic diversity? A case study of two contrasting dolphin populations | journal = Ecology and Evolution | volume = 9 | issue = 12 | pages = 6986–6998 | date = June 2019 | pmid = 31380027 | pmc = 6662329 | doi = 10.1002/ece3.5265 | bibcode = 2019EcoEv...9.6986M }}</ref> Small, fragmented populations that have experienced a [[population bottleneck]] typically have lower MHC diversity. For example, relatively low MHC diversity has been observed in the [[cheetah]] (''Acinonyx jubatus''),<ref name="Castro-Prieto">{{cite journal | vauthors = Castro-Prieto A, Wachter B, Sommer S | title = Cheetah paradigm revisited: MHC diversity in the world's largest free-ranging population | journal = Molecular Biology and Evolution | volume = 28 | issue = 4 | pages = 1455–68 | date = April 2011 | pmid = 21183613 | doi = 10.1093/molbev/msq330 | pmc = 7187558 | doi-access = free }}</ref> [[Eurasian beaver]] (''Castor fiber''),<ref name="Babik">{{cite journal | vauthors = Babik W, Durka W, Radwan J | title = Sequence diversity of the MHC DRB gene in the Eurasian beaver (Castor fiber) | journal = Molecular Ecology | volume = 14 | issue = 14 | pages = 4249–57 | date = December 2005 | pmid = 16313590 | doi = 10.1111/j.1365-294X.2005.02751.x | s2cid = 22260395 | doi-access = free | bibcode = 2005MolEc..14.4249B }}</ref> and [[giant panda]] (''Ailuropoda melanoleuca'').<ref name="pmid17555583">{{cite journal | vauthors = Zhu L, Ruan XD, Ge YF, Wan QH, Fang SG | title = Low major histocompatibility complex class II DQA diversity in the Giant Panda (Ailuropoda melanoleuca) | journal = BMC Genetics | volume = 8 | pages = 29 | date = June 2007 | pmid = 17555583 | pmc = 1904234 | doi = 10.1186/1471-2156-8-29 | doi-access = free }}</ref> 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 a ''self antigen''.<ref name="Siddle">{{cite journal | vauthors = Siddle HV, Kreiss A, Eldridge MD, Noonan E, Clarke CJ, Pyecroft S, Woods GM, Belov K | title = Transmission of a fatal clonal tumor by biting occurs due to depleted MHC diversity in a threatened carnivorous marsupial | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 41 | pages = 16221–6 | date = October 2007 | pmid = 17911263 | pmc = 1999395 | doi = 10.1073/pnas.0704580104 | doi-access = free }}</ref> 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.<ref name="Shum-2001">{{cite journal | vauthors = Shum BP, Guethlein L, Flodin LR, Adkison MA, Hedrick RP, Nehring RB, Stet RJ, Secombes C, Parham P | title = Modes of salmonid MHC class I and II evolution differ from the primate paradigm | journal = Journal of Immunology | volume = 166 | issue = 5 | pages = 3297–308 | date = March 2001 | pmid = 11207285 | doi = 10.4049/jimmunol.166.5.3297 | s2cid = 5725603 | doi-access = free }}</ref> 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.<ref name="Shum-2001" /><ref name="Aoyagi-2002">{{cite journal | vauthors = Aoyagi K, Dijkstra JM, Xia C, Denda I, Ototake M, Hashimoto K, Nakanishi T | title = Classical MHC class I genes composed of highly divergent sequence lineages share a single locus in rainbow trout (Oncorhynchus mykiss) | journal = Journal of Immunology | volume = 168 | issue = 1 | pages = 260–73 | date = January 2002 | pmid = 11751970 | doi = 10.4049/jimmunol.168.1.260 | s2cid = 36838421 | doi-access = free }}</ref><ref name="Grimholt-2015" /> 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.<ref name="Yamaguchi-2019">{{cite journal | vauthors = Yamaguchi T, Dijkstra JM | title = Major Histocompatibility Complex (MHC) Genes and Disease Resistance in Fish | journal = Cells | volume = 8 | issue = 4 | page = 378 | date = April 2019 | pmid = 31027287 | doi = 10.3390/cells8040378 | pmc = 6523485 | doi-access = free }}</ref>

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 in [[vertebrate]]s 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."<ref>{{cite journal | vauthors = Abi Rached L, McDermott MF, Pontarotti P | title = The MHC big bang | journal = Immunological Reviews | volume = 167 | issue = 1 | pages = 33–44 | date = February 1999 | pmid = 10319249 | doi = 10.1111/j.1600-065X.1999.tb01380.x | s2cid = 29886370 }}</ref> Genes in this locus are apparently linked to intracellular [[intrinsic immunity]] in the basal [[Metazoan]] ''[[Trichoplax adhaerens]]''.<ref>{{cite journal | vauthors = Suurväli J, Jouneau L, Thépot D, Grusea S, Pontarotti P, Du Pasquier L, Rüütel Boudinot S, Boudinot P | title = The proto-MHC of placozoans, a region specialized in cellular stress and ubiquitination/proteasome pathways | journal = Journal of Immunology | volume = 193 | issue = 6 | pages = 2891–901 | date = September 2014 | pmid = 25114105 | doi = 10.4049/jimmunol.1401177 | doi-access = free }}</ref>

== In transplant rejection ==
In a transplant procedure, as of an organ or [[stem cells]], MHC molecules themselves act as [[antigen]]s and can provoke immune response in the recipient, thus causing transplant rejection. MHC molecules were identified and named after their role in [[organ transplant|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).<ref name="ABBAS Ch.10">{{cite book | vauthors = Abbas AB, Lichtman AH | title = Basic Immunology. Functions and disorders of the immune system | edition = 3rd | year = 2009| isbn = 978-1-4160-4688-2 | chapter = Ch.10 Immune responses against tumors and transplant | publisher = Saunders (Elsevier) }}</ref>

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.{{Clarify|date=August 2013}}

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'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. {{Clarify|date=August 2013}}

There are various types of transplant rejection that are known to be mediated by MHC (HLA):
* '''Hyperacute rejection''' occurs when, before the transplantation, the recipient has preformed anti-HLA antibodies, perhaps by previous blood transfusions (donor tissue that includes lymphocytes expressing HLA molecules), by anti-HLA generated during pregnancy (directed at the father's HLA displayed by the fetus), or by previous transplantation;
* '''Acute cellular rejection''' occurs when the recipient's T lymphocytes are activated by the donor tissue, causing damage via mechanisms such as direct cytotoxicity from CD8 cells.
* '''Acute humoral rejection and chronic disfunction''' occurs when the recipient's anti-HLA antibodies form directed at HLA molecules present on [[endothelial cells]] of the transplanted tissue.

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<ref name="Sarder-2003">{{cite journal | vauthors = Sarder MR, Fischer U, Dijkstra JM, Kiryu I, Yoshiura Y, Azuma T, Köllner B, Ototake M | title = The MHC class I linkage group is a major determinant in the in vivo rejection of allogeneic erythrocytes in rainbow trout (Oncorhynchus mykiss) | journal = Immunogenetics | volume = 55 | issue = 5 | pages = 315–24 | date = August 2003 | pmid = 12879308 | doi = 10.1007/s00251-003-0587-4 | s2cid = 21437633 }}</ref><ref name="Quiniou-2005">{{cite journal | vauthors = Quiniou SM, Wilson M, Bengtén E, Waldbieser GC, Clem LW, Miller NW | title = MHC RFLP analyses in channel catfish full-sibling families: identification of the role of MHC molecules in spontaneous allogeneic cytotoxic responses | journal = Developmental and Comparative Immunology | volume = 29 | issue = 5 | pages = 457–67 | date = 2005 | pmid = 15707666 | doi = 10.1016/j.dci.2004.08.008 }}</ref> and MHC class II<ref name="Cardwell-2001">{{cite journal | vauthors = Cardwell TN, Sheffer RJ, Hedrick PW | title = MHC variation and tissue transplantation in fish | journal = The Journal of Heredity | volume = 92 | issue = 4 | pages = 305–8 | date = August 2001 | pmid = 11535641 | doi = 10.1093/jhered/92.4.305 | doi-access =}}</ref> were observed.

==HLA biology==
[[File:MHC expression.svg|thumb|right|300px|Codominant expression of HLA genes]]
{{Main|Human leukocyte antigen}}
Human MHC class I and II are also called [[human 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.

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, 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.

MHC alleles are expressed in codominant fashion.<ref name="ABBAS">{{cite book | vauthors = Abbas AB, Lichtman AH | title = Basic Immunology. Functions and disorders of the immune system | edition = 3rd | year = 2009| isbn = 978-1-4160-4688-2 | chapter = Ch.3 Antigen capture and presentation to lymphocytes | publisher = Saunders (Elsevier) }}</ref> This means the [[allele]]s (variants) inherited from both parents are expressed equally:
* Each person carries 2 alleles of each of the 3 class-I genes, (''HLA-A, HLA-B'' and ''HLA-C''), and so can express six different types of MHC-I (see figure).
* In the class-II locus, each person inherits a pair of HLA-DP genes (DPA1 and DPB1, which encode α and β chains), a couple of genes'' HLA-DQ'' (''DQA1'' and ''DQB1'', for α and β chains), one gene ''HLA-DRα'' (''DRA1''), and one or more genes ''HLA-DRβ'' (''DRB1'' and ''DRB3, -4'' or ''-5''). That means that one [[heterozygous]] individual can inherit six or eight functioning class-II alleles, three or more from each parent. The role of ''DQA2'' or ''DQB2'' is not verified. The ''DRB2, DRB6, DRB7, DRB8'' and ''DRB9'' are pseudogenes.

The set of alleles that is present in each chromosome is called the MHC [[haplotype]]. 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 (non[[endogamy|endogamic]]), no two individuals have exactly the same set of MHC molecules, with the exception of [[twin|identical 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 by [[Genetic recombination|recombination]], as it is the case for the antigen [[Immune receptor|receptors]].

Because of the high levels of [[allele|allelic]] diversity found within its genes, MHC has also attracted the attention of many [[evolution]]ary biologists.<ref>{{cite journal | vauthors = Spurgin LG, Richardson DS | title = How pathogens drive genetic diversity: MHC, mechanisms and misunderstandings | journal = Proceedings. Biological Sciences | volume = 277 | issue = 1684 | pages = 979–88 | date = April 2010 | pmid = 20071384 | pmc = 2842774 | doi = 10.1098/rspb.2009.2084 }}</ref>

== See also ==
* [[Cell-mediated immunity]]
* [[Disassortative sexual selection]]
* [[Humoral immunity]]
* [[MHC multimer]]
* [[Pheromone]]
* [[Streptamer]]
* [[Transplant rejection]]

== Notes and references ==
{{Reflist|2}}

== Bibliography ==
{{refbegin}}
* {{cite book | vauthors = Davis DN | title = [[The Compatibility Gene]] | location = London | publisher = [[Penguin Books]] | date = 2014 | isbn = 978-0-241-95675-5}}
{{refend}}

== External links ==
* {{MeshName|Major+Histocompatibility+Complex}}
* [http://www.meine-molekuele.de/polymorphismus ''Molecular Individuality''] {{Webarchive|url=https://web.archive.org/web/20130129073807/http://www.meine-molekuele.de/polymorphismus/ |date=2013-01-29 }}—German online book (2012)
* [http://www.cbs.dtu.dk/services/NetMHC/ NetMHC 3.0 server]—predicts binding of peptides to a number of different MHC (HLA) alleles
* [https://web.archive.org/web/20090905031057/http://www.tcells.org/pMHCI.html T-cell Group]—Cardiff University
* [https://archive.today/20130802040609/http://www.pdbe.org/quips?story=MHCstory The story of 2YF6: A Chicken MHC]
* [http://pdb101.rcsb.org/motm/62 RCSB Protein Data Bank: Molecule of the Month—Major Histocompatibility Complex]
* [https://www.ncbi.nlm.nih.gov/gv/mhc/ dbMHC Home, NCBI's database of the Major Histocompatibility Complex]

{{Immune system}}
{{Surface antigens}}
{{T cell receptor}}
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{{Authority control}}

[[Category:Gene families]]
[[Category:Glycoproteins]]
[[Category:Immune system]]
[[Category:Single-pass transmembrane proteins]]