Major Histocompatibility Complex

Major histocompatibility complex (MHC) is a cell surface molecule 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).

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, somewhat alike a hot dog (epitope) within a bun (MHC). 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 multiple ways: (1) the MHC's genetic encoding is polygenic, (2) MHC genes are highly polymorphic and have many variants, (3) several MHC genes are expressed from both inherited alleles.

MHC in animal immunity
Of the three MHC classes identified, human focus commonly goes to class I and class II. MHC class II mediates immunization—specific immunity—to an antigen. MHC class I thereafter mediates destruction of host cells displaying that antigen.

Some mature leukocytes of the lineage lymphocyte—residing in peripheral lymphoid tissues such as lymphoid follicles and lymph nodes—bear receptors that ligate MHC. T cells, which are lymphocytes of specific immunity, as well as natural killer cells (NK cells), which lymphocytes act innately, interact with MHC. When MHC class I expression is low altogether—suggesting abnormal cell function—NK cells prompt programmed cell death of the cell. (B cells—the other lymphocyte mediating specific immunity—secrete antibody molecules but do not ligate MHC.)

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 a antigen, performs antigen processing, and returns a molecular fraction—the epitope—to the APC's surface within an MHC class II molecule for antigen presentation. The CD4 receptors borne by naive helper T cells ligate MHC class II. The epitope within the MHC class II molecule thereby imprints the T cell receptor (TCR), between CD4 molecules, of the naive helper T cell, which so memorizes that epitope. The APC meanwhile secretes cytokines prompting differentiation of the helper T cell (Th) from naive phenotype (Th0) into a particular effector phenotype, either type 1 (Th1), type 2 (Th2), type 17 (Th17), or regulatory phenotype (Treg), as so far identified. Thus MHC class II mediates immunization to—or, if helping prime Treg, mediates immune tolerance of—an antigen.

MHC class I occurs on all nucleated cells—in essence all cells but red blood cells. MHC class I presents epitopes to cytotoxic T cells, also called killer T cells, which express the CD8 molecule. When its CD8 docks to MHC class I, if its TCR recognizes its matching epitope, the killer T cell transduces signals prompting the target cell's apoptosis. Thus MHC class I helps mediate cellular immunity. (B cells express MHC class II to present antigen to Th0, but when its B cell receptor is ligated by its own matching epitope—an interaction not mediated by MHC—the activated B cell, then called plasma cell, secretes soluble immunoglobulins: antibody molecules mediating humoral immunity.)

MHC genes
MHC gene families are found in all vertebrates, though they vary widely, chickens having among the smallest known MHC regions (19 genes). In humans the MHC region occurs on chromosome 6, between the flanking genetic markers MOG and COL11A2, and contains 140 genes spanning 3.6 mega base pairs (3.6 Mb or 3 600 000 bps). 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. 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.

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.

MHC proteins
MHC proteins have immunoglobulin-like structure.



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 II molecule to the cell membrane. The peptide being presented is held by the floor of the peptide-binding groove, in the central region of 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.



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 both CD8+ T cells, NKT cells, and NK cells.

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. 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 foles unlike classes I and class II, but are encoded between them in the short arm of human chromosome 6, and includes 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


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.


 * 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.

T lymphocyte recognition restrictions
In their development in the thymus, T lymphocytes are selected to recognize MHC molecules of the host but not recognize other self antigens. Each T lymphocyte shows dual specificity: The T cell receptor (TCR) recognizes self MHC but only nonself 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 present 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—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
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. Some data find lower rates of early pregnancy loss in human couples of dissimilar MHC genes.

In 2008 Peter Donnelly and colleagues proposed that MHC is related to mate choice in some human populations. 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.

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. Results of a 2002 experiment likewise suggest HLA-associated odors influence odor preference and may mediate social cues. In 2005 in a group of 58 subjects, women were more indecisive when presented with MHCs alike their own, although without oral contraceptives, the women showed no particular preference.

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 allele than to some other HLA alleles of the same gene.

MHC allelic diversity has challenged evolutionary biologists for explanation. Most posit balancing selection [see polymorphism (biology)], 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.

Pathogenic co-evolution, a counter-hypothesis, posits that common alleles are under greatest pathogenic pressure, positively selecting 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), Eurasian beaver (Castor fiber) , and giant panda (Ailuropoda melanoleuca). In 2007 low MHC diversity was attributed a role in disease susceptibility in the Tasmanian devil (Sarcophilus harrisii), native to the isolated island Madagascar, such that an antigen of a transmissible tumor, involved in devil facial tumour disease, appears to be recognized as a self antigen. 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).

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.

When maturing in the thymus gland, 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.

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 trasplantation;


 * 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


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. 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 couple of genes HLA-DP (DPA1 and DPA2, which encode α and β chains), a couple of genes HLA-DQ (DQA1 and DQA2, for α and β chains), one gene HLA-DRα (DRA1) and one or two genes HLA-DRβ (DRB1 and DRB3, -4 o -5). That means that one heterozygous individual can inherit 6 or 8 Class-II alleles, three or four from each progenitor.

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.