Changes: Major histocompatibility complex

Latest revision as of 07:42, 7 October 2013

Biological: Behavioural genetics · Evolutionary psychology · Neuroanatomy · Neurochemistry · Neuroendocrinology · Neuroscience · Psychoneuroimmunology · Physiological Psychology · Psychopharmacology (Index, Outline)

The major histocompatibility complex (MHC) is a set of cell surface molecules encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells (WBCs), which are immune cells, with other leukocytes or body cells. MHC determines compatibility of donors for organ transplant as well as one's susceptibility to an autoimmune disease via crossreacting immunization. In humans, MHC is also called human leukocyte antigen (HLA).

File:MHC

Protein molecules—either of the host's own phenotype or of other biologic entities—are continually synthesized and degraded in a cell. Occurring on the cell surface, each MHC molecule displays a molecular fraction, called epitope, of a protein.^[1] The presented antigen can be either self or nonself. On the cell membrane, the MHC population in its entirety is like a meter indicating the balance of proteins within the cell.

The MHC gene family is divided into three subgroups: class I, class II and class III. Diversity of antigen presentation, mediated by MHC classes I and II, 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); (2) MHC gene variants are highly polymorphic (diversely varying from organism to organism within a species).^[2]

Discovery of MHC loci

MHC genes were first identified in inbred mice strains. Clarence Little transplanted tumors across differing strains and found rejection of transplanted tumors according to strains of host versus donor.^[3] 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.^[4] For this work, Snell was awarded the 1980 Nobel Prize in Physiology or Medicine.

MHC in immunity

Of the three MHC classes identified, human attention commonly goes to classes I and II. MHC class II mediates immunization to an antigen—that is, specific immunity, aka acquired immunity or adaptive immunity—and MHC class I thereafter mediates destruction of host cells displaying that antigen. Thus cellular immunity occurs. (The other arm of specific immunity is humoral immunity, whose relation to MHC is more indirect.)

Lymphocytes

As a lineage of leukocytes, lymphocytes reside in peripheral lymphoid tissues, including lymphoid follicles and lymph nodes, and include B cells, T cells, and natural killer cells (NK cells). B cells, which act specifically, secrete antibody molecules, but do not bind MHC. T cells, which act specifically, as well as NK cells, which act innately, interact with MHC. When MHC class I expression is low, as typically reflects abnormal cell function, NK cells trigger programmed cell death of the cell. NK cell thus help prevent progress of cancerous cells by contributing to tumor surveillance.

MHC class II

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 uptakes an antigen, performs antigen processing, and returns a molecular fraction of it—a fraction termed epitope—to the APC's surface, coupled within an MHC class II molecule mediating antigen presentation by displaying this epitope. On the cell's surface, the epitope can contact its cognate, that is, matching, molecular region on immunologic structures recognizing that epitope. That molecular region which docks to—that is, binds or in jargon ligates—the epitope is the paratope.

On surfaces of helper T cells are CD4 receptors as well as T cell receptors (TCRs). When a naive helper T cell's CD4 molecule docks to an APC's MHC class II molecule, its TCR can meet and be imprinted by the epitope coupled within the MHC class II. This event primes the naive helper T cell. According to the local milieu, that is, the balance of cytokines secreted by APCs in the microenvironment, the naive helper T cell (Th₀) polarizes into either a memory Th cell or an effector Th cell of phenotype either type 1 (Th₁), type 2 (Th₂), type 17 (Th₁₇), or regulatory/suppressor (T_reg), as so far identified, the Th cell's terminal differentiation.

MHC class II thus mediates immunization to—or, if APCs polarize Th₀ 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 chronic diseases, 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 antigen to Th₀, but when their B cell receptors bind matching epitopes, which interactions are not mediated by MHC, these activated B cells secrete soluble immunoglobulins: antibody molecules mediating humoral immunity.)

MHC class I

MHC class I occurs on all nucleated cells—in essence all cells but red blood cells—and 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 the MHC class I molecule, the CTL trigger's 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 a viruses and some bacteria, including bacterial L forms, bacterial genus Mycoplasma, and bacterial genus Rickettsia.

MHC genes

MHC gene families are found in all vertebrates, though they vary widely. In humans the MHC region occurs on chromosome 6, between the flanking genetic markers MOG and COL11A2 (from 6p22.1 to 6p21.3 ~29Mb to 33Mb on the hg19 assembly), and contains 140 genes spanning 3.6 mega base pairs (3.6 Mb or 3 600 000 bases).^[5] About half have known immune functions.

The same markers in the gray short-tailed opossum (Monodelphis domestica), a marsupial, span 3.95 Mb yielding 114 genes, 87 shared with humans.^[6] Marsupial MHC genotypic variation lies between eutherian mammals and birds—taken as minimal MHC encoding—but is closer in organization to that of nonmammals, and MHC class I genes of marsupials have amplified within the class II region, yielding a unique class I/II region.^[6]

Class III function very differently from class I and class II, but its locus occurs between the other two classes—on chromosome 6 in humans—and are frequently discussed together.

Class	Encoding	Expression
I	(1) peptide-binding proteins, which select short sequences of amino acids for antigen presentation, as well as (2) molecules aiding antigen-processing (such as 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.
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.
III	Other immune proteins, outside antigen processing and presentation, such as components of the complement cascade (e.g., C2, C4, factor B), the cytokines of immune signaling (e.g., TNF-α), and heat shock proteins buffering cells from stresses.	Various.

MHC proteins

MHC proteins have immunoglobulin-like structure.

File:MHC Class 1.svg

MHC class I protein molecule

Class I

Main article: MHC class I

MHC I occurs as an α chain composed of three domains—α1, α2, α3. The α1 rests upon a unit of the non-MHC molecule β2 microglobulin (encoded on human chromosome 15). The α3 subunit is transmembrane, anchoring the MHC class I molecule to the cell membrane. The peptide being presented is held by the floor of the peptide-binding groove, in the central region of the α1/α2 heterodimer (a molecule composed of two nonidentical subunits). The genetically encoded and expressed sequence of amino acids, the sequence of residues, of the peptide-binding groove's floor determines which particular peptide residues it binds.^[7]

File:MHC Class 2.svg

MHC class II protein molecule

Classical MHC molecules present epitopes to the TCRs of CD8+ T lymphocytes. Nonclassical molecules (MHC class IB) exhibit limited polymorphism, expression patterns, and presented antigens; this group is subdivided into a group encoded within MHC loci (e.g., HLA-E, -F, -G) as well as those not (e.g., stress ligands such as ULBPs, Rae1, 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.

Class II

Main article: MHC class II

MHC class two is formed of two chains, α and β, each having two domains—α1 and α2 and β1 and β2—each chain having a transmembrane domain, α2 and β2, respectively, anchoring the MHC class II molecule to the cell membrane.^[8] The peptide-binding groove is formed of the heterodimer of α1 and β1.

MHC class II molecules in humans have five to six isotypes. Classic molecules present peptides to CD4+ lymphocytes. Nonclassic molecules, accessories, with intracellular functions, are not exposed on cell membranes, but in internal membranes in lysosomes, normally loading the antigenic peptides onto classic MHC class II molecules.

Class III

Class III molecules have physiologic roles unlike classes I and class II, but are encoded between them in 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, LTB), and heat shock proteins (hsp).

Antigen processing and presentation

File:MHC Class I processing.svg

MHC class I pathway: Proteins in the cytosol are degraded by the proteasome, liberating peptides internalized by TAP channel in the endoplasmic reticulum, there associating with MHC-I molecules freshly synthesized. MHC-I/peptide complexes enter Golgi apparatus, are glycosylated, enter secratory 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 uptake 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.^[9]
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.

**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 β2 microglobulin, peptide bound to α chain	Polymorphic chains α and β, peptide binds to both
Types of antigen presenting cells (APC)	All nucleated cells	Dendritic cells, mononuclear phagocytes, B lymphocytes, some endothelial cells, epithelium of thymus
T lymphocytes able to respond	Cytotoxic T lymphocytes (CD8+)	Helper T lymphocytes (CD4+)
Origin of antigenic proteins	cytosolic proteins (mostly synthetized by the cell; may also enter from the extracellular medium via phagosomes)	Proteins present in endosomes or lysosomes (mostly internalized from extracellular medium)
Enzymes responsible for peptide generation	Cytosolic proteasome	Proteases from endosomes and lysosomes (for instance, cathepsin)
Location of loading the peptide on the MHC molecule	Endoplasmic reticulum	Specialized vesicular compartment
Molecules implicated in transporting the peptides and loading them on the MHC molecules	TAP (transporter associated with antigen processing)	DM, invariant chain

T lymphocyte recognition restrictions

Main article: MHC restriction

In their development in the thymus, T lymphocytes are selected to recognize MHC molecules of the host but not recognize other self antigens. Following selection each T lymphocyte shows dual specificity: The T cell receptor (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 epitopes, also called linear epitopes, of only peptides and only if coupled within an MHC molecule. (Antibody molecules secreted by activated B cells, on the other hand, ligate diverse epitopes—peptide, lipid, carbohydrate, and nucleic acid—and recognize conformational epitopes, which have 3D structure.)

MHC in sexual mate selection

Main article: 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 preference by male mice for females of different MHC. Similar results have been obtained with fish^[10] and birds (e.g. the black-throated blue warblers).^[11] Some data find lower rates of early pregnancy loss in human couples of dissimilar MHC genes.^[12]

It has been proposed that MHC is related to mate choice in some human populations, a theory that has found support by studies by Ober and colleagues in 1997,^[13] as well as by Chaix and colleagues in 2008.^[14] However, the latter findings have been controversial.^[15] If it exists, the phenomena 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.^[16]

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), by far most women chose shirts worn by men of dissimilar MHCs, a preference reversed if the women were on oral contraceptives.^[17] Results of a 2002 experiment likewise suggest HLA-associated odors influence odor preference and may mediate social cues.^[18] In 2005 in a group of 58 subjects, women were more indecisive when presented with MHCs alike their own,^[19] although without oral contraceptives, the women showed no particular preference.^[20] There are no studies on the extent to which odor preference determines mate selection (or vice versa).

MHC evolutionary diversity

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-DRB1, have roughly 1000, 1600, and 870 known alleles, respectively. Many HLA alleles are ancient, sometimes of greater homology to 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. Recent models suggest that a high number of alleles is implausible via heterozygote advantage alone.^{[citation needed]}

Pathogenic co-evolution, a counter-hypothesis, 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. Despite great MHC polymorphism at the population level, an individual bears at most 18 MHC I or II alleles.

Relatively low MHC diversity has been observed in the cheetah (Acinonyx jubatus),^[21] Eurasian beaver (Castor fiber),^[22] and giant panda (Ailuropoda melanoleuca).^[23] 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.^[24] To offset inbreeding, efforts to sustain genetic diversity in populations of endangered species and of captive animals have been suggested.

MHC in transplant rejection

In a transplant procedure, as of an organ or stem cells, MHC molecules act themselves as antigens and can provoke immune response in the recipient—thus 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).^[25]

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 2 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 not identical twins express differing MHC molecules. All MHC molecules can mediate transplant rejection, but HLA-C and HLA-DP, showing low polymorphism, seem least important.

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When maturing in the thymus, T lymphocytes are selected for their T cell receptors (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. The T lymphocytes' recognition of the foreign MHC as self is allorecognition.

This article or section may be confusing or unclear for some readers, and should be edited to rectify this.
Please improve the article, or discuss the issue on the talk page.

Transplant rejection has two types known as mediated by MHC (HLA):

Hyperacute rejection occurs when, before the trasplantation, 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 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 either situation, 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.

HLA biology

File:MHC expression.svg

Codominant expression of HLA genes.

Main article: 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 intensely studied HLA genes are the nine so-called 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 is divided into three regions: classes I, II, and III. The A, B, C, E, F, and G genes belong to MHC class I, whereas the six D genes belong to class II.

MHC genes are expressed in codominant fashion.^[8] This means that the alleles (variants) inherited from both progenitors are expressed in equivalent way:

As there are 3 Class-I genes, named in humans HLA-A, HLA-B and HLA-C, and as each person inherits a set of genes from each progenitor, that means that any cell in an individual can express 6 different types of MHC-I molecules (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 6 or 8 functioning Class-II alleles, three or more from each progenitor. The role of DQA2, 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 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 in each chromosome (one of paternal origin and the other of maternal origin).

The MHC genes are highly polymorphic; this means that there are many different alleles in the different individuals inside a population. The polymorphism is so high that in a mixed population (non-endogamic) there are not two individuals with exactly the same set of MHC genes and molecules, with the exception of identical twins.

The polymorphic regions in each allele are located in the region for peptide contact, which is going to be displayed to the lymphocyte. For this reason, the contact region for each allele of MHC molecule is highly variable, as the polymorphic residues of the MHC will create specific clefts in which only certain types of residues of the peptide can enter. This imposes a very specific link between the MHC molecule and the peptide, and it implies that each MHC variant will be able to bind specifically only those peptides that are able to properly enter in the cleft of the MHC molecule, which is variable for each allele. In this way, the MHC molecules have a broad specificity, because they can bind many, but not all types of possible peptides. This is an essential characteristic of MHC molecules: In a given individual, it is enough to have a few different molecules to be able to display a high variety of peptides.

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 recombination, as it is the case for the antigen receptors.

Because of the high levels of allelic diversity found within its genes, MHC has also attracted the attention of many evolutionary biologists.^{[citation needed]}

References

↑ Kimball's Biology, Histocompatibility Molecules
↑ Janeway CA Jr, Travers P, Walport M, et al, Immunobiology: The Immune System in Health and Disease, 5^th edn (New York: Garland Science, 2001), "The major histocompatibility complex and its functions".
↑ Little CC 1941, "The genetics of tumor transplantation", pp 279–309, in Biology of the Laboratory Mouse, ed by Snell GD, New York: Dover.
↑ Snell GD & Higgins GF 1951, "Alleles at the histocompatibility-2 locus in the mouse as determined by tumor transplantation", Genetics 36:306–310
↑ MHC Sequencing Consortium (1999). Complete sequence and gene map of a human major histocompatibility complex. Nature 401 (6756): 921–923.
↑ ^6.0 ^6.1 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 (March 2006). Reconstructing an ancestral mammalian immune supercomplex from a marsupial major histocompatibility complex. PLoS Biol. 4 (3): e46.
↑ Toh H, Savoie CJ, Kamikawaji N, Muta S, Sasazuki T, Kuhara S (October 2000). Changes at the floor of the peptide-binding groove induce a strong preference for proline at position 3 of the bound peptide: molecular dynamics simulations of HLA-A*0217. Biopolymers 54 (5): 318–27.
↑ ^8.0 ^8.1 Abbas; Lichtman A.H. (2009). "Ch.3 Antigen capture and presentation to lymphocytes" Basic Immunology. Functions and disorders of the immune system, 3rd.
↑ Aderem A, Underhill DM (1999). Mechanisms of phagocytosis in macrophages. Annu. Rev. Immunol. 17: 593–623.
↑ Boehm T, Zufall F (2006). MHC peptides and the sensory evaluation of genotype. Trends Neurosci 29 (2): 100–107.
↑ Smith, S.B., Webster, M.S.; Holmes, R.T. (2005). The heterozygosity theory of extra-pair mate choice in birds: a test and a cautionary note. Journal of Avian Biology 36: 146–154.Template:Paywall
↑ Haig D (November 1997). Maternal-fetal interactions and MHC polymorphism. J. Reprod. Immunol. 35 (2): 101–9.
↑ Ober C, Weitkamp LR, Cox N, Dytch H, Kostyu D, Elias S (September 1997). HLA and mate choice in humans.. Am. J. Hum. Genet. 61 (3): 497–504.
↑ Chaix R, Chen C, Donnelly P (September 2008). Is Mate Choice in Humans MHC-Dependent?. PLoS Genetics 4 (9): e1000184.
↑ Derti A, Cenik C, Kraft P, Roth FP (April 2010). Absence of evidence for MHC-dependent mate selection within HapMap populations. PLoS Genetics 6 (4): e1000925.
↑ Janeš D, Klun I, Vidan-Jeras B, Jeras M, Kreft S (2010). Influence of MHC on odour perception of 43 chemicals and body odor. Central European Journal of Biology 5 (3): 324–330.
↑ Wedekind C, Seebeck T, Bettens F, Paepke AJ (June 1995). MHC-dependent mate preferences in humans. Proc. Biol. Sci. 260 (1359): 245–9.
↑ Jacob S, McClintock MK, Zelano B, Ober C (February 2002). Paternally inherited HLA alleles are associated with women's choice of male odor. Nat. Genet. 30 (2): 175–9.
↑ Santos, P S, Schinemann JA, Gabardo J, Bicalho MG (April 2005). New evidence that the MHC influences odor perception in humans: A study with 58 southern Brazilian students. Horm Behav. 47 (4): 384–388.
↑ "The pill makes women pick bad mates"
↑ Castro-Prieto A, Wachter B, Sommer S (April 2011). Cheetah paradigm revisited: MHC diversity in the world's largest free-ranging population. Mol. Biol. Evol. 28 (4): 1455–68.
↑ Babik W, Durka W, Radwan J (December 2005). Sequence diversity of the MHC DRB gene in the Eurasian beaver (Castor fiber). Mol. Ecol. 14 (14): 4249–57.
↑ Zhu L, Ruan XD, Ge YF, Wan QH, Fang SG (2007). Low major histocompatibility complex class II DQA diversity in the Giant Panda (Ailuropoda melanoleuca). BMC Genet. 8: 29.
↑ Siddle HV, Kreiss A, Eldridge MD, Noonan E, Clarke CJ, Pyecroft S, Woods GM, Belov K (October 2007). Transmission of a fatal clonal tumor by biting occurs due to depleted MHC diversity in a threatened carnivorous marsupial. Proc. Natl. Acad. Sci. U.S.A. 104 (41): 16221–6.
↑ Abbas; Lichtman A.H. (2009). "Ch.10 Immune responses against tumors and transplant" Basic Immunology. Functions and disorders of the immune system, 3rd.

External links

MeSH Major+Histocompatibility+Complex
Molecular individuality (German online-book 2012)
Sexual attraction is linked to MHC compatibility
NetMHC 3.0 server — predicts binding of peptides to a number of different MHC (HLA) alleles
T-cell Group - Cardiff University
The story of 2YF6: A Chicken MHC
RCSB Protein Data Bank: Molecule of the Month - Major Histocompatibility Complex
dbMHC Home, NCBI's database of the Major Histocompatibility Complex

This page uses Creative Commons Licensed content from Wikipedia (view authors).

[1] Kimball's Biology, Histocompatibility Molecules

[Janeway-etal-2005-2] Janeway CA Jr, Travers P, Walport M, et al, Immunobiology: The Immune System in Health and Disease, 5^th edn (New York: Garland Science, 2001), "The major histocompatibility complex and its functions".

[3] Little CC 1941, "The genetics of tumor transplantation", pp 279–309, in Biology of the Laboratory Mouse, ed by Snell GD, New York: Dover.

[4] Snell GD & Higgins GF 1951, "Alleles at the histocompatibility-2 locus in the mouse as determined by tumor transplantation", Genetics 36:306–310

[MHCsc-5] MHC Sequencing Consortium (1999). Complete sequence and gene map of a human major histocompatibility complex. Nature 401 (6756): 921–923.

[belov-6] 6.0 ^6.1 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 (March 2006). Reconstructing an ancestral mammalian immune supercomplex from a marsupial major histocompatibility complex. PLoS Biol. 4 (3): e46.

[pmid10935972-7] Toh H, Savoie CJ, Kamikawaji N, Muta S, Sasazuki T, Kuhara S (October 2000). Changes at the floor of the peptide-binding groove induce a strong preference for proline at position 3 of the bound peptide: molecular dynamics simulations of HLA-A*0217. Biopolymers 54 (5): 318–27.

[ABBAS-8] 8.0 ^8.1 Abbas; Lichtman A.H. (2009). "Ch.3 Antigen capture and presentation to lymphocytes" Basic Immunology. Functions and disorders of the immune system, 3rd.

[aderem-9] Aderem A, Underhill DM (1999). Mechanisms of phagocytosis in macrophages. Annu. Rev. Immunol. 17: 593–623.

[boehm-10] Boehm T, Zufall F (2006). MHC peptides and the sensory evaluation of genotype. Trends Neurosci 29 (2): 100–107.

[11] Smith, S.B., Webster, M.S.; Holmes, R.T. (2005). The heterozygosity theory of extra-pair mate choice in birds: a test and a cautionary note. Journal of Avian Biology 36: 146–154.Template:Paywall

[Haig-12] Haig D (November 1997). Maternal-fetal interactions and MHC polymorphism. J. Reprod. Immunol. 35 (2): 101–9.

[ober-13] Ober C, Weitkamp LR, Cox N, Dytch H, Kostyu D, Elias S (September 1997). HLA and mate choice in humans.. Am. J. Hum. Genet. 61 (3): 497–504.

[chaix-14] Chaix R, Chen C, Donnelly P (September 2008). Is Mate Choice in Humans MHC-Dependent?. PLoS Genetics 4 (9): e1000184.

[Derti2010-15] Derti A, Cenik C, Kraft P, Roth FP (April 2010). Absence of evidence for MHC-dependent mate selection within HapMap populations. PLoS Genetics 6 (4): e1000925.

[krefts-16] Janeš D, Klun I, Vidan-Jeras B, Jeras M, Kreft S (2010). Influence of MHC on odour perception of 43 chemicals and body odor. Central European Journal of Biology 5 (3): 324–330.

[wedekind-17] Wedekind C, Seebeck T, Bettens F, Paepke AJ (June 1995). MHC-dependent mate preferences in humans. Proc. Biol. Sci. 260 (1359): 245–9.

[jacob-18] Jacob S, McClintock MK, Zelano B, Ober C (February 2002). Paternally inherited HLA alleles are associated with women's choice of male odor. Nat. Genet. 30 (2): 175–9.

[santos-19] Santos, P S, Schinemann JA, Gabardo J, Bicalho MG (April 2005). New evidence that the MHC influences odor perception in humans: A study with 58 southern Brazilian students. Horm Behav. 47 (4): 384–388.

[20] "The pill makes women pick bad mates"

[Castro-Prieto-21] Castro-Prieto A, Wachter B, Sommer S (April 2011). Cheetah paradigm revisited: MHC diversity in the world's largest free-ranging population. Mol. Biol. Evol. 28 (4): 1455–68.

[Babik-22] Babik W, Durka W, Radwan J (December 2005). Sequence diversity of the MHC DRB gene in the Eurasian beaver (Castor fiber). Mol. Ecol. 14 (14): 4249–57.

[pmid17555583-23] Zhu L, Ruan XD, Ge YF, Wan QH, Fang SG (2007). Low major histocompatibility complex class II DQA diversity in the Giant Panda (Ailuropoda melanoleuca). BMC Genet. 8: 29.

[Siddle-24] Siddle HV, Kreiss A, Eldridge MD, Noonan E, Clarke CJ, Pyecroft S, Woods GM, Belov K (October 2007). Transmission of a fatal clonal tumor by biting occurs due to depleted MHC diversity in a threatened carnivorous marsupial. Proc. Natl. Acad. Sci. U.S.A. 104 (41): 16221–6.

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This box: view • talk • edit Immune system / Immunology / Psychoneuroimmunology
Systems	Adaptive immune system vs. Innate immune system • Humoral immune system vs. Cellular immune system • Complement system (Anaphylatoxins)
Antibodies and antigens	Antibody (Monoclonal antibodies, Polyclonal antibodies, Autoantibody) • Allotype • Isotype • Idiotype • Antigen (Superantigen)
Immune cells	White blood cells (T cell, B cell, NK cell, Mast cell, Basophil, Eosinophil) • Phagocyte (Neutrophil, Macrophage, Dendritic cell) • Antigen-presenting cell • Reticuloendothelial system
Immunity vs. tolerance	Immunity • Autoimmunity • Allergy • Tolerance (Central) • Immunodeficiency
Immunogenetics	Somatic hypermutation • V(D)J recombination • Immunoglobulin class switching • MHC / HLA
Other	Cytokines • Inflammation • Opsonin

v·d·e Surface antigens
Histocompatibility/Human leukocyte antigen	MHC - MHC class I (HLA-A, HLA-B, HLA-C, HLA-E) MHC class II (HLA-DP, HLA-DQ, HLA-DR) - Minor histocompatibility antigen
Other	Arrestin - Calgranulin - Blood group antigens - Cell adhesion molecules - Differentiation antigens

v·d·e The T cell receptor complex
The antigen receptor	TCR \| TCRα \| TCRβ \| TCRγ \| TCRδ
Accessory molecules	CD3 \| CD3γ \| CD3δ \| CD3ε \| ζ-chain (also called CD3ζ and TCRζ)
Co-receptors	CD8 (with two glycoprotein chains CD8α and CD8β) \| CD4
Ligands	MHC (MHC class I and MHC class II)

@@ Line 1: / Line 1: @@
 {{Biopsy}}
+The '''major [[histocompatibility]] complex''' ('''MHC''') is a set of cell surface molecules encoded by a large [[gene family]] in all [[vertebrate]]s. MHC molecules mediate interactions of [[leukocytes]], also called [[white blood cells]] (WBCs), which are [[immune cells]], with other leukocytes or body cells. MHC determines compatibility of donors for [[organ transplant]] as well as one's susceptibility to an [[autoimmune disease]] via crossreacting immunization. In humans, MHC is also called [[human leukocyte antigen]] (HLA).
-[[Image:MHC I vs MHC II.png|thumb|Right|300px|Protein images comparing the MHC I (1hsa) and MHC II (1dlh) molecules.
+[[File:MHC|thumbnail]]
-([http://www.pdb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb62_1.html more details...])]]
+[[Protein]] molecules—either of the host's own [[phenotype]] or of other biologic entities—are continually synthesized and degraded in a [[Cell (biology)|cell]]. Occurring on the cell surface, each MHC molecule displays a molecular fraction, called [[epitope]], of a protein.<ref>[http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/H/HLA.html Kimball's Biology], Histocompatibility Molecules</ref> The presented antigen can be either ''self'' or ''nonself''. On the cell membrane, the MHC population in its entirety is like a meter indicating the balance of proteins within the cell.
-The '''major histocompatibility complex''' ('''MHC''') is a large [[genome|genomic]] region or [[gene family]] found in most [[vertebrate]]s. It is the most gene-dense region of the mammalian [[genome]] and plays an important role in the [[immune system]], [[autoimmunity]], and [[reproduction|reproductive]] success. The proteins encoded by the MHC are expressed on the surface of [[Cell (biology)|cells]] in all [[Gnathostomata|jawed vertebrate]]s, and display fragments of molecules from invading [[microbe]]s or dysfunctional cells (e.g. [[tumor cell]]s) to a particular type of [[white blood cell]] called a [[T cell]] that has the capacity to kill or co-ordinate the killing of the microbe, infected cell or malfunctioning cell.
+The MHC gene family is divided into three subgroups: [[MHC class I|class I]], [[MHC class II|class II]] and class III. Diversity of [[antigen presentation]], mediated by MHC classes I and II, 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]]); (2) MHC [[alleles|gene variants]] are highly [[polymorphism (biology)|polymorphic]] (diversely varying from organism to organism within a [[species]]).<ref name=Janeway-etal-2005>Janeway CA Jr, Travers P, Walport M, ''et al'', ''Immunobiology: The Immune System in Health and Disease'', 5<sup>th</sup> edn (New York: Garland Science, 2001), [http://www.ncbi.nlm.nih.gov/books/NBK27156 "The major histocompatibility complex and its functions"].</ref>
-==Classification==
+==Discovery of MHC loci==
-In [[human]]s, the 3.6 Mb (3 600 000 [[base pair]]s) MHC region on Chromosome 6 contains 140 genes between flanking [[genetic marker]]s MOG and COL11A2.<ref>{{cite journal | title=Complete sequence and gene map of a human major histocompatibility complex | last=MHC Sequencing Consortium | year=1999 | journal=Nature | volume=401 | pages=921–923}}</ref>  About half have known immunological functions (see [[human leukocyte antigen]]). The same markers in the marsupial ''[[Monodelphis domestica]]'' (gray short-tailed [[opossum]]) span 3.95 Mb and contain 114 genes, 87 shared with humans.<ref name="belov">{{cite journal | title=Reconstructing an Ancestral Mammalian Immune Supercomplex from a Marsupial Major Histocompatibility Complex | last=Belov | first=Katherine  | coauthors=Janine E. Deakin, Anthony T. Papenfuss, et. al | year=March 2006 | journal=PLoS Biol | volume=4(3) | issue=e46 | url=http://biology.plosjournals.org/perlserv/?request=get-document&doi=10%2E1371%2Fjournal%2Epbio%2E0040046 }}</ref>
+MHC genes were first identified in inbred mice strains. [[Clarence Little]] transplanted tumors across differing 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 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>Snell GD & Higgins GF 1951, "Alleles at the histocompatibility-2 locus in the mouse as determined by tumor transplantation", ''Genetics'' '''36''':306–310</ref> For this work, Snell was awarded the 1980 [[Nobel Prize in Physiology or Medicine]].
-===Subgroups===
-The MHC region is divided into three subgroups called MHC class I, MHC class II, and MHC class III.
+==MHC in immunity==
+Of the three MHC classes identified, human attention commonly goes to classes I and II. MHC class II mediates immunization to an antigen—that is, [[specific immunity]], [[aka]] acquired immunity or adaptive immunity—and MHC class I thereafter mediates destruction of host cells displaying that antigen.  Thus [[cellular immunity]] occurs.  (The other arm of specific immunity is [[humoral immunity]], whose relation to MHC is more indirect.)
+===Lymphocytes===
+As a lineage of [[leukocytes]], [[lymphocyte]]s reside in peripheral [[lymphoid tissue]]s, including [[lymphoid follicles]] and [[lymph nodes]], and include [[B cell]]s, [[T cell]]s, and [[natural killer cell]]s (NK cells).  [[B cells]], which act [[specific immunity|specifically]], secrete antibody molecules, but do not bind MHC.  T cells, which act [[specific immunity|specifically]], as well as NK cells, which act [[innate immunity|innately]], interact with MHC.  When MHC class I expression is low, as typically reflects abnormal cell function, NK cells trigger [[programmed cell death]] of the cell.  NK cell thus help prevent progress of [[cancerous]] cells by contributing to ''tumor surveillance''.
+===MHC class II===
+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 uptakes an [[antigen]], performs [[antigen processing]], and returns a molecular fraction of it—a fraction termed ''[[epitope]]''—to the APC's surface, coupled within an MHC class II molecule mediating [[antigen presentation]] by displaying this epitope.  On the cell's surface, the epitope can contact its ''cognate'', that is, matching, molecular region on immunologic structures recognizing that epitope.  That molecular region which ''docks'' to—that is, ''binds'' or in [[jargon]] ''ligates''—the epitope is the ''[[paratope]]''.
+On surfaces of [[helper T cells]] are [[CD4]] receptors as well as [[T cell receptor]]s (TCRs).  When a ''naive'' helper T cell's CD4 molecule docks to an APC's MHC class II molecule, its TCR can meet and be imprinted by the [[epitope]] coupled within the MHC class II.  This event ''primes'' the naive helper 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 [[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 antigen to Th<sub>0</sub>, but when their [[B cell receptor]]s bind matching [[epitope]]s, which interactions are not mediated by MHC, these [[plasma cell|activated B cell]]s secrete soluble [[immunoglobulins]]: [[antibody]] molecules mediating [[humoral immunity]].)
+===MHC class I===
+MHC class I occurs on all [[nucleated]] cells—in essence all cells but [[red blood cells]]—and presents epitopes to killer T cells, 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 trigger's 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 a [[virus]]es and some [[bacteria]], including bacterial [[L-form bacteria|L forms]], bacterial [[genus]] ''[[Mycoplasma]]'', and bacterial genus ''[[Rickettsia]]''.
+==MHC genes==
+MHC gene families are found in all [[vertebrate]]s, though they vary widely. In [[human]]s the MHC region occurs on chromosome 6, between the flanking [[genetic marker]]s MOG and COL11A2 (from 6p22.1 to 6p21.3 ~29Mb to 33Mb on the hg19 assembly), and contains 140 genes spanning 3.6 mega [[base pairs]] (3.6 Mb or 3 600 000 bases).<ref name="MHCsc">{{cite journal | title=Complete sequence and gene map of a human major histocompatibility complex | last=MHC Sequencing Consortium | year=1999 | journal=Nature | volume=401 | pages=921–923 | doi=10.1038/44853 | pmid=10553908 | issue=6756}}</ref> About half have known immune functions.
+The same markers in the gray short-tailed [[opossum]] (''[[Monodelphis domestica]]''), a [[marsupial]], span 3.95 Mb yielding 114 genes, 87 shared with humans.<ref name="belov">{{cite journal | author = 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 Biol. | volume = 4 | issue = 3 | pages = e46 | year = 2006 | month = March | pmid = 16435885 | pmc = 1351924 | doi = 10.1371/journal.pbio.0040046 }}</ref> Marsupial MHC [[genotype|genotypic]] variation lies between [[Eutheria|eutherian mammals]] and [[bird]]s—taken as minimal MHC encoding—but is closer in organization to that of non[[mammals]], and MHC class I genes of marsupials have amplified within the class II region, yielding a unique class I/II region.<ref name="belov" />
+Class III function very differently from class I and class II, but its [[locus (genetics)|locus]] occurs between the other two classes—on [[chromosome 6]] in humans—and are frequently discussed together.
 {| class="wikitable"
-| '''Name''' || '''Function''' || '''Expression'''
+| '''Class''' || '''Encoding''' || '''Expression'''
  |-
- | ''[[MHC class I]]''  || Encodes [[heterodimer]]ic peptide binding proteins, as well as [[antigen processing]] molecules such as [[Transporter associated with antigen processing|TAP]] and [[Tapasin]].  || All nucleated cells
+ | '''[[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]]'' || Encodes heterodimeric peptide binding proteins and proteins that modulate peptide loading onto MHC class II proteins in the [[lysosomal]] compartment such as [[MHC II DM]], [[MHC II DQ]], and [[MHC II DP]].   || On [[antigen-presenting 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'' region  || Encodes for other immune components, such as [[Complement system|complement]] components (e.g., [[Complement component 2|C2]], [[Complement component 4|C4]], [[factor B]]) and some that encode [[cytokine]]s (e.g., [[TNF-α]]) and also [[Heat shock protein|hsp]]. || Variable (see below)
+ | '''[[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.
 |}
+<!--This text will not appear in the published version:-->
+==MHC proteins==
-Class III has a very different function than class I and II, but it has a locus between the other two (on [[chromosome 6]] in humans), so they are frequently discussed together.
+MHC proteins have [[immunoglobulin]]-like structure.
+ [[File:MHC Class 1.svg|right|200px|thumb|'''MHC class I protein molecule''']]
-===Responses===
-The MHC proteins act as "signposts" that display fragmented pieces of an [[antigen]] on the host cell's surface. They may be ''self'' or ''nonself''. If they are ''nonself'', there are two ways by which the foreign protein can be processed and recognized as being "nonself".
+=== Class I ===
-* If the host is a [[white blood cell|leukocyte]], such as a [[monocyte]] or [[neutrophil]], it may engulf the particle (be it bacterial, viral, or particulate matter), break it apart using lysozymes, and display the fragments on ''Class II MHC molecules''.
+{{Main|MHC class I}}
+MHC I occurs as an α chain composed of three domains—α1, α2, α3. The α1 rests upon a unit of the non-MHC molecule [[Beta-2 microglobulin|β2 microglobulin]] (encoded on human chromosome 15). The α3 subunit is transmembrane, anchoring the MHC class I molecule to the cell membrane. The peptide being presented is held by the floor of the [[peptide-binding groove]], in the central region of the α1/α2 [[heterodimer]] (a molecule composed of two nonidentical subunits). The genetically encoded and expressed sequence of amino acids, the sequence of ''residues'', of the peptide-binding groove's floor determines which particular peptide residues it binds.<ref name="pmid10935972">{{cite journal | author = Toh H, Savoie CJ, Kamikawaji N, Muta S, Sasazuki T, Kuhara S | title = Changes at the floor of the peptide-binding groove induce a strong preference for proline at position 3 of the bound peptide: molecular dynamics simulations of HLA-A*0217 | journal = Biopolymers | volume = 54 | issue = 5 | pages = 318–27 | year = 2000 | month = October | pmid = 10935972 | doi = 10.1002/1097-0282(20001015)54:5<318::AID-BIP30>3.0.CO;2-T }}</ref>
-* On the other hand, if a host cell is infected by a [[bacteria|bacterium]] or [[virus]], or is [[cancerous]], it may display the antigens on its surface with a ''Class I MHC molecule''. In particular, virus infected and cancerous cells have a tendency to display unusual, ''nonself'' antigens on their surface. These nonself antigens, regardless of which type of MHC molecule they are displayed on, will initiate the [[specific immunity]] of the host's body.
+ [[File:MHC Class 2.svg|right|150px|thumb|'''MHC class II protein molecule''']]
-It is important to note that cells constantly process endogenous proteins and present them within the context of MHC I.  Immune effector cells are trained not to react to self peptides within MHC, and as such are able to recognize when foreign peptides are being presented during an infection/cancer.
+'''Classical MHC molecules''' present epitopes to the [[T-cell receptor|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, 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.
-==HLA genes==
-{{main|Human leukocyte antigen}}
+=== Class II ===
-The best-known genes in the MHC region are the subset that encodes cell-surface antigen-presenting proteins.  In humans, these genes are referred to as ''[[human leukocyte antigen]]'' (HLA) genes, although people often use the abbreviation MHC to refer to HLA gene products.  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; however this convention is not consistently adhered to.
+{{Main|MHC class II}}
+MHC class two is formed of two chains, α and β, each having two domains—α1 and α2 and β1 and β2—each chain having a transmembrane domain, α2 and β2, respectively, anchoring the MHC class II molecule to the cell membrane.<ref name="ABBAS" /> The peptide-binding groove is formed of the heterodimer of α1 and β1.
-The most intensely-studied HLA genes are the nine so-called 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 is divided into three regions: Class 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 class II molecules in humans have five to six isotypes. '''Classic molecules''' present peptides to CD4+ lymphocytes. '''Nonclassic molecules''', accessories, with intracellular functions, are not exposed on cell membranes, but in internal membranes in [[lysosome]]s, normally loading the antigenic peptides onto classic MHC class II molecules.
-Besides being scrutinized by immunologists for its pivotal role in the immune system, the MHC has also attracted the attention of many [[evolution]]ary biologists, due to the high levels of [[allele|allelic]] diversity found within many of its genes.  Indeed, much theory has been devoted to explaining why this particular region of the genome harbors so much diversity, especially in light of its immunological importance.
+=== Class III ===
-==Molecular biology of MHC proteins==
+Class III molecules have physiologic roles unlike classes I and class II, but are encoded between them in 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), [[cytokine]]s (such as [[TNF-alpha|TNF-α]], LTA, LTB), and [[heat shock protein]]s (hsp).
+== Antigen processing and presentation ==
-The classical MHC molecules (also referred to as HLA molecules in humans) have a vital role in the complex immunological dialogue that must occur between [[T cell]]s and other cells of the body.  At maturity, MHC molecules are anchored in the cell membrane, where they display short [[polypeptide]]s to T cells, via the T cell receptors (TCRs).  The polypeptides may be "self," that is, originating from a protein created by the organism itself, or they may be foreign, originating from bacteria, viruses, pollen, etc.  The overarching design of the MHC-TCR interaction is that T cells should ignore self peptides while reacting appropriately to the foreign peptides.
+[[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 secratory 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:
-The immune system has ''another'' and equally important method for identifying an antigen: [[B cell]]s with their membrane-bound [[antibody|antibodies]], also known as B cell receptors (BCRs).  However, whereas the BCRs of B cells can bind to antigens without much outside help, the TCRs of T cells require "presentation" of the antigen: this is the job of MHC.  It is important to realize that, during the vast majority of the time, MHC are kept busy presenting '''self'''-peptides, which the T cells should appropriately ignore.  A full-force immune response usually requires the activation of B cells via BCRs ''and'' T cells via the MHC-TCR interaction.  This duplicity creates a system of "checks and balances" and underscores the immune system's potential for running amok and causing harm to the body (see [[autoimmune disorder]]s).
+* In '''MHC class II''' [[phagocytes]] such as [[macrophages]] and immature [[dendritic cells]] uptake 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 | author = Aderem A, Underhill DM | title = Mechanisms of phagocytosis in macrophages | journal = Annu. Rev. Immunol. | volume = 17 | issue = | pages = 593–623 | year = 1999 | pmid = 10358769 | doi = 10.1146/annurev.immunol.17.1.593 }}</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.
+{| class="wikitable" style="text-align:center"
-All MHC molecules receive polypeptides from inside the cells they are part of and display them on the cell's exterior surface for recognition by [[T cell]]s.  However, there are major differences between [[MHC class I]] and [[MHC class II]] in the method and outcome of peptide presentation.
+|+ '''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 β2 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 synthetized 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==
-==MHC evolution and allelic diversity==
+{{Main|MHC restriction}}
+In their development in the [[thymus]], T lymphocytes are selected to recognize MHC molecules of the host but not recognize other self antigens. Following selection each T lymphocyte shows dual specificity: The T cell receptor (TCR) recognizes ''self'' MHC but only ''non-self'' antigens.
-MHC gene families are found in essentially all [[vertebrate]]s, though the gene composition and genomic arrangement vary widely.  [[Chicken]]s, for instance, have  one of the smallest known MHC regions (19 genes), though most [[mammal]]s have an MHC structure and composition fairly similar to that of humans.
-[[Gene duplication]] is almost certainly responsible for much of the genetic diversity.  In humans, the MHC is littered with many [[pseudogene]]s.
+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).
-One of the most striking features of the MHC, particularly in humans, is the astounding [[gene pool|allelic diversity]] found therein, and especially among the nine classical genes.  In humans, the most conspicuously-diverse loci, HLA-A, HLA-B, and HLA-DRB1, have roughly 250, 500, and 300 known alleles respectively -- diversity truly exceptional in the human genome. The MHC gene is the most polymorphic in the genome.  And population surveys of the other classical loci routinely find tens to a hundred alleles -- still highly diverse.  And perhaps even more remarkable is that many of these alleles are quite ancient: It is often the case that an allele from a particular HLA gene is more closely related to an allele found in chimpanzees than it is to another human allele from the same gene!
+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]], on the other hand, ligate diverse epitopes—[[peptide]], [[lipid]], [[carbohydrate]], and [[nucleic acid]]—and recognize [[conformational epitope]]s, which have [[Three-dimensional space|3D]] structure.)
-Phylogenetically the marsupial MHC lies between eutherian mammals and the minimal essential MHC of birds, although it is closer in organization to non-mammals. Its Class I genes have amplified within the Class II region, resulting in a unique Class I/II region.<ref name="belov" />
+==MHC in sexual mate selection==
-The allelic diversity of MHC genes has created fertile grounds for evolutionary biologists.  The most important task for theoreticians is to explain the evolutionary forces that have created and maintained such diversity.  Most explanations invoke [[balancing selection]], a broad term that identifies any kind of [[natural selection]] in which no single allele is absolutely most fit.  [[Frequency-dependent selection]] and [[heterozygote advantage]] are two types of balancing selection that have been suggested to explain MHC allelic diversity.  However, recent models suggest that a high number of alleles is not plausibly achievable through heterozygote advantage alone.  Pathogenic co-evolution, a counter-hypothesis has recently emerged; it theorizes that the most common alleles will be placed under the greatest pathogenic pressure, thus there will always be a tendency for the least common alleles to be positively selected for.  This creates a "moving target" for pathogen evolution.  As the pathogenic pressure decreases on the previously common alleles, their concentrations in the population will stabilize, and they will usually not go extinct if the population is large enough, and a large number of alleles will remain in the population as a whole.  This explains the high degree of MHC polymorphism found in the population, although an individual can have a maximum of 18 MHC I or II alleles.
+{{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 preference by male mice for females of different MHC. Similar results have been obtained with [[fish]]<ref name="boehm">{{cite journal | title=MHC peptides and the sensory evaluation of genotype | author=Boehm T | coauthors=Zufall F | year=2006 | journal=Trends Neurosci | issue=2 | volume=29 | pages=100–107 | pmid=16337283 | doi=10.1016/j.tins.2005.11.006}}</ref> and [[bird]]s (e.g. the [[black-throated blue warbler]]s).<ref>{{cite journal|last=Smith|first=S.B.|coauthors=Webster, M.S.; Holmes, R.T.|title=The heterozygosity theory of extra-pair mate choice in birds: a test and a cautionary note|journal=Journal of Avian Biology|year=2005|volume=36|pages=146–154 |url=http://onlinelibrary.wiley.com/doi/10.1111/j.0908-8857.2005.03417.x/abstract}}{{paywall}}</ref> Some data find lower rates of [[early pregnancy loss]] in human couples of dissimilar MHC genes.<ref name="Haig">{{cite journal | author = Haig D | title = Maternal-fetal interactions and MHC polymorphism | journal = J. Reprod. Immunol. | volume = 35 | issue = 2 | pages = 101–9 | year = 1997 | month = November | pmid = 9421795 | doi = }}</ref>
-==MHC and sexual selection==
+It has been proposed that MHC is related to mate choice in some human populations, a theory that has found support by studies by Ober and colleagues in 1997,<ref name="ober">{{cite journal | author = Ober C, Weitkamp LR, Cox N, Dytch H, Kostyu D, Elias S | title = HLA and mate choice in humans. | journal = Am. J. Hum. Genet. | volume = 61 | issue = 3 | pages = 497–504 | year = 1997 | month = September | pmid = 9326314 | doi=10.1086/515511}}</ref> as well as by Chaix and colleagues in 2008.<ref name="chaix">{{cite journal | author = Chaix R, Chen C, Donnelly P | title = Is Mate Choice in Humans MHC-Dependent? | journal = PLoS Genetics | volume = 4 | issue = 9 | pages = e1000184 | year = 2008 | month = September | doi = 10.1371/journal.pgen.1000184 | pmid=18787687 | pmc=2519788}}</ref> However, the latter findings have been controversial.<ref name="Derti2010">{{cite journal | author = 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 | year = 2010 | month = April | doi = 10.1371/journal.pgen.1000925 | pmid=20442868 | pmc=2861700 }}</ref> If it exists, the phenomena 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 | author = 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 }}</ref>
-It has been suggested that MHC plays a role in the selection of potential mates, via [[olfaction]]. MHC genes make molecules that enable the immune system to recognise invaders; generally, the more diverse the MHC genes of the parents, the stronger the immune system of the offspring. It would obviously be beneficial, therefore, to have evolved systems of recognizing individuals with different MHC genes and preferentially selecting them to breed with.
+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), by far most women chose shirts worn by men of dissimilar MHCs, a preference reversed if the women were on oral contraceptives.<ref name="wedekind">{{cite journal | author = Wedekind C, Seebeck T, Bettens F, Paepke AJ | title = MHC-dependent mate preferences in humans | journal = Proc. Biol. Sci. | volume = 260 | issue = 1359 | pages = 245–9 | year = 1995 | month = June | pmid = 7630893 | doi = 10.1098/rspb.1995.0087 }}</ref> Results of a 2002 experiment likewise suggest HLA-associated odors influence odor preference and may mediate social cues.<ref name="jacob">{{cite journal | author = Jacob S, McClintock MK, Zelano B, Ober C | title = Paternally inherited HLA alleles are associated with women's choice of male odor | journal = Nat. Genet. | volume = 30 | issue = 2 | pages = 175–9 | year = 2002 | month = February | pmid = 11799397 | doi = 10.1038/ng830 | url = }}</ref> In 2005 in a group of 58 subjects, women were more indecisive when presented with MHCs alike their own,<ref name="santos">{{cite journal | title=New evidence that the MHC influences odor perception in humans: A study with 58 southern Brazilian students | last=Santos | first=P S | coauthors=Schinemann JA, Gabardo J, Bicalho MG | journal=Horm Behav. | year=2005 | month=April | volume=47 | issue=4 | pages=384–388 | pmid=15777804 | doi=10.1016/j.yhbeh.2004.11.005 }}</ref> although without oral contraceptives, the women showed no particular preference.<ref>[http://www.livescience.com/culture/080812-contraceptive-smell.html "The pill makes women pick bad mates"]</ref> There are no studies on the extent to which odor preference determines mate selection (or vice versa).
-Yamazaki et al. (1976) showed this to be the case for male mice, who show such a preference for females of different MHC. Similar results have been obtained with fish.<ref>Boehm T, Zufall F. "MHC peptides and the sensory evaluation of genotype." ''Trends Neurosci.'' 2006 Feb;29(2):100-7. PMID 16337283</ref>
+==MHC evolutionary diversity==
-In a 1995 experiment, a group of female college students smelled t-shirts that had been worn by male students for two nights, without deodorant, cologne or scented soaps. Overwhelmingly, the women preferred the odors of men with dissimilar MHCs to their own. However, their preference was reversed if they were taking oral contraceptives. <ref>{{cite journal | title=MHC-dependent mate preferences in humans | last=Wedekind | first=C. | coauthors=Seebeck, T., Bettens, F. and Paepke, A. J. | year=1995 | journal=Proc Biol Sci | volume=260 | issue=1359 | pages=245-249}}</ref> The hypothesis is that MHCs affect mate choice and that oral contraceptives can interfere with this. A study in 2005 showed similar results.<ref>Santos PS, Schinemann JA, Gabardo J, Bicalho Mda G. "New evidence that the MHC influences odor perception in humans: a study with 58 Southern Brazilian students." ''Horm Behav.'' 2005 Apr;47(4):384-8. PMID 15777804</ref>
+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. The most diverse loci, namely HLA-A, HLA-B, and HLA-DRB1, have roughly 1000, 1600, and 870 known alleles, respectively. Many HLA alleles are ancient, sometimes of greater [[Homology (biology)|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]] and [[heterozygote advantage]]. Recent models suggest that a high number of alleles is implausible via heterozygote advantage alone.{{citation needed|date=April 2013}}
-These results are still subject to much contention.
+Pathogenic co-evolution, a counter-hypothesis, 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. Despite great MHC polymorphism at the population level, an individual bears at most 18 MHC I or II alleles.
-==References==
-{{Reflist|2}}
+Relatively low MHC diversity has been observed in the [[cheetah]] (''Acinonyx jubatus''),<ref name="Castro-Prieto">{{cite journal | author = Castro-Prieto A, Wachter B, Sommer S | title = Cheetah paradigm revisited: MHC diversity in the world's largest free-ranging population | journal = Mol. Biol. Evol. | volume = 28 | issue = 4 | pages = 1455–68 | year = 2011 | month = April | pmid = 21183613 | doi = 10.1093/molbev/msq330 | url = }}</ref> [[Eurasian beaver]] (''Castor fiber''),<ref name="Babik">{{cite journal | author = Babik W, Durka W, Radwan J | title = Sequence diversity of the MHC DRB gene in the Eurasian beaver (Castor fiber) | journal = Mol. Ecol. | volume = 14 | issue = 14 | pages = 4249–57 | year = 2005 | month = December | pmid = 16313590 | doi = 10.1111/j.1365-294X.2005.02751.x | url = }}</ref> and [[giant panda]] (''Ailuropoda melanoleuca'').<ref name="pmid17555583">{{cite journal | author = 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 Genet. | volume = 8 | issue = | pages = 29 | year = 2007 | pmid = 17555583 | pmc = 1904234 | doi = 10.1186/1471-2156-8-29 }}</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 | author = 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 = Proc. Natl. Acad. Sci. U.S.A. | volume = 104 | issue = 41 | pages = 16221–6 | year = 2007 | month = October | pmid = 17911263 | pmc = 1999395 | doi = 10.1073/pnas.0704580104 | url = }}</ref> To offset [[inbreeding]], efforts to sustain genetic diversity in populations of endangered species and of captive animals have been suggested.
-==Additional images==
-<gallery>
- Image:TCR-MHC bindings.png|TCR-MHC bindings
-</gallery>
+== MHC in transplant rejection ==
-==See also==
+In a transplant procedure, as of an organ or [[stem cells]], MHC molecules act themselves as [[antigen]]s and can provoke immune response in the recipient—thus 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 | last =Abbas | authorlink = | coauthors = Lichtman A.H. | editor = | others = | title = Basic Immunology. Functions and disorders of the immune system | edition = 3rd | date = | year = 2009| month = | location = | isbn = 978-1-4160-4688-2 | pages = | chapter = Ch.10 Immune responses against tumors and transplant | chapterurl = | citation = | page = A.B. | editor3 = Saunders (Elsevier) }}</ref>
-*[[Cell-mediated immunity]]
-*[[Disassortative sexual selection]]
-*[[Humoral immunity]]
-*[[Transplant rejection]]
+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 2 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 not identical twins 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}}
-==External links==
-* {{MeshName|Major+Histocompatibility+Complex}}
+When maturing in the [[thymus]], [[T lymphocyte]]s are selected for their T cell receptors ([[T-cell receptor|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''. The T lymphocytes' recognition of the foreign MHC as self is ''[[allorecognition]]''.{{Clarify|date=August 2013}}
+Transplant rejection has two types known as mediated by MHC (HLA):
+* '''Hyperacute rejection''' occurs when, before the trasplantation, 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 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 either situation, 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.
+==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 intensely studied HLA genes are the nine so-called 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 is divided into three regions: classes I, II, and III. The A, B, C, E, F, and G genes belong to MHC class I, whereas the six D genes belong to class II.
+MHC genes are expressed in codominant fashion.<ref name="ABBAS">{{cite book | last =Abbas | authorlink = | coauthors = Lichtman A.H. | editor = | others = | title = Basic Immunology. Functions and disorders of the immune system | edition = 3rd | date = | year = 2009| month = | location = | isbn = 978-1-4160-4688-2 | pages = | chapter = Ch.3 Antigen capture and presentation to lymphocytes | chapterurl = | citation = | page = A.B. | editor3 = Saunders (Elsevier) }}</ref> This means that the [[allele]]s (variants) inherited from both progenitors are expressed in equivalent way:
+* As there are 3 Class-I genes, named in humans HLA-A, HLA-B and HLA-C, and as each person inherits a set of genes from each progenitor, that means that any cell in an individual can express 6 different types of MHC-I molecules (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 6 or 8 functioning Class-II alleles, three or more from each progenitor. The role of DQA2, 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 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 in each chromosome (one of paternal origin and the other of maternal origin).
+The MHC genes are highly polymorphic; this means that there are many different alleles in the different individuals inside a population. The polymorphism is so high that in a mixed population (non-[[endogamy|endogamic]]) there are not two individuals with exactly the same set of MHC genes and molecules, with the exception of [[twin|identical twins]].
+The polymorphic regions in each allele are located in the region for peptide contact, which is going to be displayed to the lymphocyte. For this reason, the contact region for each allele of MHC molecule is highly variable, as the polymorphic residues of the MHC will create specific clefts in which only certain types of residues of the peptide can enter. This imposes a very specific link between the MHC molecule and the peptide, and it implies that each MHC variant will be able to bind specifically only those peptides that are able to properly enter in the cleft of the MHC molecule, which is variable for each allele. In this way, the MHC molecules have a broad specificity, because they can bind many, but not all types of possible peptides. This is an essential characteristic of MHC molecules: In a given individual, it is enough to have a few different molecules to be able to display a high variety of peptides.
+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.{{Citation needed|date=March 2009}}
+== See also ==
+* [[Cell-mediated immunity]]
+* [[Disassortative sexual selection]]
+* [[Humoral immunity]]
+* [[MHC multimer]]
+* [[Transplant rejection]]
+== References ==
+{{Reflist|2}}
+== External links ==
+* {{MeshName|Major+Histocompatibility+Complex}}
+* [http://www.meine-molekuele.de/polymorphismus Molecular individuality (German online-book 2012)]
+* [http://www.divinecaroline.com/article/22081/42913 Sexual attraction is linked to MHC compatibility]
+* [http://www.cbs.dtu.dk/services/NetMHC/ NetMHC 3.0 server] — predicts binding of peptides to a number of different MHC (HLA) alleles
+* [http://www.tcells.org/pMHCI.html T-cell Group - Cardiff University]
+* [http://www.pdbe.org/quips?story=MHCstory The story of 2YF6: A Chicken MHC]
+* [http://www.pdb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb62_1.html RCSB Protein Data Bank: Molecule of the Month - Major Histocompatibility Complex]
+* [http://www.ncbi.nlm.nih.gov/gv/mhc/ dbMHC Home, NCBI's database of the Major Histocompatibility Complex]
 {{immune_system}}
 {{Surface antigens}}
 {{T cell receptor}}
-[[Category:Genes]]
+[[Category:Gene families]]
 [[Category:Immune system]]
 [[Category:Glycoproteins]]
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