Major histocompatibility complex
Encyclopedia
Major histocompatibility
complex (MHC) is a cell surface molecule 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).
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.
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
.)
s, though they vary widely, chicken
s having among the smallest known MHC regions (19 genes). In human
s the MHC region occurs on chromosome 6, between the flanking genetic marker
s 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 bird
s—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.
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.
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.
(such as C2, C4, and B factor), cytokine
s (such as TNF-α, LTA, LTB), and heat shock protein
s (hsp).
Peptides are processed and presented by two classical pathways:
, 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.)
. 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.
s 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 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
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.
s 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):
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.
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 allele
s (variants) inherited from both progenitors are expressed in equivalent way:
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 evolution
ary biologists.
Histocompatibility
Histocompatibility is the property of having the same, or mostly the same, alleles of a set of genes called the major histocompatibility complex. These genes are expressed in most tissues as antigens, to which the immune system makes antibodies...
complex (MHC) is a cell surface molecule encoded by a large gene family
Gene family
A gene family is a set of several similar genes, formed by duplication of a single original gene, and generally with similar biochemical functions...
in all vertebrate
Vertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...
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
Organ transplant
Organ transplantation is the moving of an organ from one body to another or from a donor site on the patient's own body, for the purpose of replacing the recipient's damaged or absent organ. The emerging field of regenerative medicine is allowing scientists and engineers to create organs to be...
as well as one's susceptibility to an autoimmune disease
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
via crossreacting immunization. In humans, MHC is also called human leukocyte antigen
Human leukocyte antigen
The human leukocyte antigen system is the name of the major histocompatibility complex in humans. The super locus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and...
(HLA).
Protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
molecules—either of the host's own phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
or of other biologic entities—are continually synthesized and degraded in a cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
. Occurring on the cell surface, each MHC molecule displays a molecular fraction, called epitope
Epitope
An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that recognizes the epitope is called a paratope...
, 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
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
—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
Programmed cell death
Programmed cell-death is death of a cell in any form, mediated by an intracellular program. PCD is carried out in a regulated process which generally confers advantage during an organism's life-cycle...
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
Antigen processing
Antigen processing is a biological process that prepares antigens for presentation to special cells of the immune system called T lymphocytes. This process involves two distinct pathways for processing of antigens from an organism's own proteins or intracellular pathogens , or from phagocytosed...
, and returns a molecular fraction—the epitope—to the APC's surface within an MHC class II molecule for antigen presentation
Antigen presentation
Antigen presentation is a process in the body's immune system by which macrophages, dendritic cells and other cell types capture antigens and then enable their recognition by T-cells....
. The CD4
CD4
CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
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
T cell receptor
The T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is responsible for recognizing antigens bound to major histocompatibility complex molecules...
(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
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
(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
Immune tolerance
Immune tolerance or immunological tolerance is the process by which the immune system does not attack an antigen. It can be either 'natural' or 'self tolerance', in which the body does not mount an immune response to self antigens, or 'induced tolerance', in which tolerance to external antigens can...
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
CD8
CD8 is a transmembrane glycoprotein that serves as a co-receptor for the T cell receptor . Like the TCR, CD8 binds to a major histocompatibility complex molecule, but is specific for the class I MHC protein. There are two isoforms of the protein, alpha and beta, each encoded by a different gene...
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
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. 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
Plasma cell
Plasma cells, also called plasma B cells, plasmocytes, and effector B cells, are white blood cells which produce large volumes of antibodies. They are transported by the blood plasma and the lymphatic system...
, secretes soluble immunoglobulins: antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
molecules mediating humoral immunity
Humoral immunity
The Humoral Immune Response is the aspect of immunity that is mediated by secreted antibodies produced in the cells of the B lymphocyte lineage . B Cells transform into plasma cells which secrete antibodies...
.)
MHC genes
MHC gene families are found in all vertebrateVertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...
s, though they vary widely, chicken
Chicken
The chicken is a domesticated fowl, a subspecies of the Red Junglefowl. As one of the most common and widespread domestic animals, and with a population of more than 24 billion in 2003, there are more chickens in the world than any other species of bird...
s having among the smallest known MHC regions (19 genes). In human
Human
Humans are the only living species in the Homo genus...
s the MHC region occurs on chromosome 6, between the flanking genetic marker
Genetic marker
A genetic marker is a gene or DNA sequence with a known location on a chromosome that can be used to identify cells, individuals or species. It can be described as a variation that can be observed...
s 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
Marsupial
Marsupials are an infraclass of mammals, characterized by giving birth to relatively undeveloped young. Close to 70% of the 334 extant species occur in Australia, New Guinea, and nearby islands, with the remaining 100 found in the Americas, primarily in South America, but with thirteen in Central...
, span 3.95 Mb yielding 114 genes, 87 shared with humans. Marsupial MHC genotypic
Genotype
The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...
variation lies between eutherian mammals
Eutheria
Eutheria is a group of mammals consisting of placental mammals plus all extinct mammals that are more closely related to living placentals than to living marsupials . They are distinguished from noneutherians by various features of the feet, ankles, jaws and teeth...
and bird
Bird
Birds are feathered, winged, bipedal, endothermic , egg-laying, vertebrate animals. Around 10,000 living species and 188 families makes them the most speciose class of tetrapod vertebrates. They inhabit ecosystems across the globe, from the Arctic to the Antarctic. Extant birds range in size from...
s—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.
| Class | Encoding | Expression >- | I MHC class I MHC class I molecules are one of two primary classes of major histocompatibility complex molecules and are found on every nucleated cell of the body... |
(1) peptide-binding proteins, which select short sequences of amino acids for antigen presentation Antigen presentation Antigen presentation is a process in the body's immune system by which macrophages, dendritic cells and other cell types capture antigens and then enable their recognition by T-cells.... , as well as (2) molecules aiding antigen-processing Antigen processing Antigen processing is a biological process that prepares antigens for presentation to special cells of the immune system called T lymphocytes. This process involves two distinct pathways for processing of antigens from an organism's own proteins or intracellular pathogens , or from phagocytosed... (such as TAP Transporter associated with antigen processing Transporter associated with antigen processing is a member of the ATP-binding-cassette transporter family. It delivers cytosolic peptides into the endoplasmic reticulum , where they bind to nascent MHC class I molecules.... and Tapasin Tapasin TAP-associated glycoprotein also known as tapasin or TAPBP is a protein that in humans is encoded by the TAPBP gene.- Function :... ). |
CD8 CD8 CD8 is a transmembrane glycoprotein that serves as a co-receptor for the T cell receptor . Like the TCR, CD8 binds to a major histocompatibility complex molecule, but is specific for the class I MHC protein. There are two isoforms of the protein, alpha and beta, each encoded by a different gene... receptor—borne notably by cytotoxic T cells—and inhibitory receptors borne by NK cells. >- | II MHC class II MHC Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells and B cells, all of which are professional antigen-presenting cells .... |
(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). | CD4 CD4 CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984... receptors borne by helper T cells. >- | III |
Other immune proteins, outside antigen processing and presentation, such as components of the complement cascade Complement system The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime... (e.g., C2 Complement component 2 Complement C2 is a protein that in humans is encoded by the C2 gene. The protein encoded by this gene is part of the classical pathway of complement system.-Further reading:... , C4 Complement component 4 Complement component 4 is a protein involved in the complement system.It is cleaved into proteins 4a and 4b.* C4a is an anaphylatoxin.* C4b forms part of C3-convertase, in conjunction with 2a:* C4b can bind CR1.... , factor B), the cytokine Cytokine Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication... s of immune signaling (e.g., TNF-α), and heat shock proteins buffering cells from stresses. |
Varoius. |
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 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 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.TCR
TCR can mean:*Time Code Reading, a method of accounting for video or film footage and frames in media editing*T cell receptor*Tobacco Control Research*Toronto Civic Railways...
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 lysosome
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
s, 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 systemComplement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
(such as C2, C4, and B factor), cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s (such as TNF-α, LTA, LTB), and heat shock protein
Heat shock protein
Heat shock proteins are a class of functionally related proteins involved in the folding and unfolding of other proteins. Their expression is increased when cells are exposed to elevated temperatures or other stress. This increase in expression is transcriptionally regulated...
s (hsp).
Antigen processing and presentation
- 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 endocytosisEndocytosisEndocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
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.
| 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 cell Dendritic cell Dendritic cells are immune cells forming part of the mammalian immune system. Their main function is to process antigen material and present it on the surface to other cells of the immune system. That is, dendritic cells function as antigen-presenting cells... s, mononuclear phagocytes, B lymphocytes, some endothelial cells, epithelium of thymus Thymus The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system.... |
| T lymphocytes able to respond | Cytotoxic T lymphocytes (CD8+) | Helper T lymphocytes (CD4+) |
| Origin of antigenic proteins | cytosol Cytosol The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments.... ic proteins (mostly synthetized by the cell; may also enter from the extracellular medium via phagosome Phagosome In cell biology, a phagosome is a vacuole formed around a particle absorbed by phagocytosis. The vacuole is formed by the fusion of the cell membrane around the particle. A phagosome is a cellular compartment in which pathogenic microorganisms can be killed and digested... s) |
Proteins present in endosome Endosome In biology, an endosome is a membrane-bound compartment inside eukaryotic cells. It is a compartment of the endocytic membrane transport pathway from the plasma membrane to the lysosome. Molecules internalized from the plasma membrane can follow this pathway all the way to lysosomes for... s or lysosome Lysosome thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]... s (mostly internalized from extracellular medium) |
| Enzymes responsible for peptide generation | Cytosolic proteasome Proteasome Proteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks... |
Protease Protease A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein.... s from endosomes and lysosomes (for instance, cathepsin Cathepsin Cathepsins are proteases: proteins that break apart other proteins, found in many types of cells including those in all animals. There are approximately a dozen members of this family, which are distinguished by their structure, catalytic mechanism, and which proteins they cleave... ) |
| Location of loading the peptide on the MHC molecule | Endoplasmic reticulum Endoplasmic reticulum The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae... |
Specialized vesicular compartment |
| Molecules implicated in transporting the peptides and loading them on the MHC molecules | TAP TAP -Mechanical and electrical:* Tap , a device for controlling the release of a liquid or gas* Tap , part of an electrical device* A cutting tool, part of a tap and die set-Entertainment:* Tap dance... (transporter associated with antigen processing) |
DM, invariant chain |
T lymphocyte recognition restrictions
In their development in the thymusThymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
, 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
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. 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
Plasma cell
Plasma cells, also called plasma B cells, plasmocytes, and effector B cells, are white blood cells which produce large volumes of antibodies. They are transported by the blood plasma and the lymphatic system...
, on the other hand, ligate diverse epitopes—peptide, lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
, carbohydrate
Carbohydrate
A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...
, and nucleic acid
Nucleic acid
Nucleic acids are biological molecules essential for life, and include DNA and RNA . Together with proteins, nucleic acids make up the most important macromolecules; each is found in abundance in all living things, where they function in encoding, transmitting and expressing genetic information...
—and recognize conformational epitopes, which have 3D
3D
3D or 3-D may refer to:*Three-dimensional space, the physical universe*Stereoscopy, any technique capable of recording three-dimensional visual information or creating the illusion of depth in an image-Music:*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 presentationAntigen presentation
Antigen presentation is a process in the body's immune system by which macrophages, dendritic cells and other cell types capture antigens and then enable their recognition by T-cells....
. 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
Peter Donnelly
Peter Donnelly, FRS is an Australian mathematician and Professor of Statistical Science at the University of Oxford. He is a specialist in applied probability and has made contributions to coalescent theory...
and colleagues proposed that MHC is related to mate choice in some human populations. The phenomena might be mediated by olfaction
Olfaction
Olfaction is the sense of smell. This sense is mediated by specialized sensory cells of the nasal cavity of vertebrates, and, by analogy, sensory cells of the antennae of invertebrates...
, as MHC phenotype appears strongly involved in the strength and pleasantness of perceived odour of compounds from sweat
SWEAT
SWEAT is an OLN/TSN show hosted by Julie Zwillich that aired in 2003-2004.Each of the 13 half-hour episodes of SWEAT features a different outdoor sport: kayaking, mountain biking, ice hockey, beach volleyball, soccer, windsurfing, rowing, Ultimate, triathlon, wakeboarding, snowboarding, telemark...
. 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
Claus Wedekind
Claus Wedekind is a Swiss biological researcher notable for his 1995 study that determined a major histocompatibility complex dependent mate preference in humans....
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 mammalMammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
s have MHC variants similar to those of humans, who bear great allelic diversity
Gene pool
In population genetics, a gene pool is the complete set of unique alleles in a species or population.- Description :A large gene pool indicates extensive genetic diversity, which is associated with robust populations that can survive bouts of intense selection...
, especially among the nine classical genes—seemingly due largely to gene duplication
Gene duplication
Gene duplication is any duplication of a region of DNA that contains a gene; it may occur as an error in homologous recombination, a retrotransposition event, or duplication of an entire chromosome.The second copy of the gene is often free from selective pressure — that is, mutations of it have no...
—though human MHC regions have many pseudogene
Pseudogene
Pseudogenes are dysfunctional relatives of known genes that have lost their protein-coding ability or are otherwise no longer expressed in the cell...
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
Homology
Homology may refer to:* Homology , analogy between human beliefs, practices or artifacts owing to genetic or historical connections* Homology , any characteristic of biological organisms that is derived from a common ancestor....
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
Balancing selection
Balancing selection refers to a number of selective processes by which multiple alleles are actively maintained in the gene pool of a population at frequencies above that of gene mutation. This usually happens when the heterozygotes for the alleles under consideration have a higher adaptive value...
[see polymorphism (biology)
Polymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
], any natural selection
Natural selection
Natural selection is the nonrandom process by which biologic traits become either more or less common in a population as a function of differential reproduction of their bearers. It is a key mechanism of evolution....
process whereby no single allele is absolutely most fit, such as frequency-dependent selection and heterozygote advantage
Heterozygote advantage
A heterozygote advantage describes the case in which the heterozygote genotype has a higher relative fitness than either the homozygote dominant or homozygote recessive genotype. The specific case of heterozygote advantage is due to a single locus known as overdominance...
. 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
Cheetah
The cheetah is a large-sized feline inhabiting most of Africa and parts of the Middle East. The cheetah is the only extant member of the genus Acinonyx, most notable for modifications in the species' paws...
(Acinonyx jubatus), Eurasian beaver (Castor fiber), and giant panda
Giant Panda
The giant panda, or panda is a bear native to central-western and south western China. It is easily recognized by its large, distinctive black patches around the eyes, over the ears, and across its round body. Though it belongs to the order Carnivora, the panda's diet is 99% bamboo...
(Ailuropoda melanoleuca). In 2007 low MHC diversity was attributed a role in disease susceptibility in the Tasmanian devil
Tasmanian Devil
The Tasmanian devil is a carnivorous marsupial of the family Dasyuridae, now found in the wild only on the Australian island state of Tasmania. The size of a small dog, it became the largest carnivorous marsupial in the world following the extinction of the thylacine in 1936...
(Sarcophilus harrisii), native to the isolated island Madagascar
Madagascar
The Republic of Madagascar is an island country located in the Indian Ocean off the southeastern coast of Africa...
, such that an antigen of a transmissible tumor, involved in devil facial tumour disease
Devil facial tumour disease
Devil facial tumour disease is an aggressive non-viral transmissible parasitic cancer—which likely originated in Schwann cells—that affects Tasmanian devils. The first "official case" was described in 1996, in Australia...
, appears to be recognized as a self antigen. To offset inbreeding
Inbreeding
Inbreeding is the reproduction from the mating of two genetically related parents. Inbreeding results in increased homozygosity, which can increase the chances of offspring being affected by recessive or deleterious traits. This generally leads to a decreased fitness of a population, which is...
, 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 antigenAntigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
s and can provoke immune response in the recipient—thus transplant rejection. MHC molecules were identified and named after their role in transplant
Organ transplant
Organ transplantation is the moving of an organ from one body to another or from a donor site on the patient's own body, for the purpose of replacing the recipient's damaged or absent organ. The emerging field of regenerative medicine is allowing scientists and engineers to create organs to be...
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
Thymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
gland, T lymphocytes are selected for their T cell receptors (TCR
TCR
TCR can mean:*Time Code Reading, a method of accounting for video or film footage and frames in media editing*T cell receptor*Tobacco Control Research*Toronto Civic Railways...
) 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
Epitope
An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that recognizes the epitope is called a paratope...
for recognition by TCR, the matching paratope
Paratope
The paratope is the part of an antibody which recognises an antigen, the antigen-binding site of an antibody. It is a small region of the antibody's Fv region and contains parts of the antibody's heavy and light chains....
. 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
Human leukocyte antigen
The human leukocyte antigen system is the name of the major histocompatibility complex in humans. The super locus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and...
(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-A
HLA-A are a group of human leukocyte antigens that are encoded by the HLA-A locus on human chromosome 6p. The HLA genes constitute a large subset of the Major histocompatibility complex of humans. HLA-A is a component of certain MHC class I cell surface receptor isoforms that resides on the...
, HLA-B
HLA-B
HLA-B is a human gene that provides instructions for making a protein that plays a critical role in the immune system. HLA-B is part of a family of genes called the human leukocyte antigen complex...
, HLA-C
HLA-C
HLA-C belongs to the MHC class I heavy chain receptors. The C receptor is a heterodimer consisting of a HLA-C mature gene product and β2-microglobulin. The mature C chain is anchored in the membrane...
, HLA-DPA1, HLA-DPB1
HLA-DPB1
HLA class II histocompatibility antigen, DP beta chain is a protein that in humans is encoded by the HLA-DPB1 gene.-Further reading:...
, HLA-DQA1
HLA-DQA1
Major histocompatibility complex, class II, DQ alpha 1, also known as HLA-DQA1, is a human gene present on short arm of chromosome 6 and also denotes the genetic locus which contains this gene...
, HLA-DQB1
HLA-DQB1
Major histocompatibility complex, class II, DQ beta 1, also known as HLA-DQB1, is a human gene and also denotes the genetic locus that contains this gene...
, HLA-DRA
HLA-DRA
HLA class II histocompatibility antigen, DR alpha chain is a protein that in humans is encoded by the HLA-DRA gene. HLA-DRA encodes the alpha subunit of HLA-DR. Unlike the alpha chains of other Human MHC class II molecules, the alpha subunit is practically invariable...
, and HLA-DRB1
HLA-DRB1
HLA class II histocompatibility antigen, DRB1-9 beta chain is a protein that in humans is encoded by the HLA-DRB1 gene. DRB1 encodes the most prevalent beta subunit of HLA-DR.- Function :...
. 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 allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
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 locusLocusThe word locus is Latin for "place". It can mean:-Positions:*Locus of control, in industrial psychology, having an internal or external locus of control...
, 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
Haplotype
A haplotype in genetics is a combination of alleles at adjacent locations on the chromosome that are transmitted together...
. 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
Endogamy
Endogamy is the practice of marrying within a specific ethnic group, class, or social group, rejecting others on such basis as being unsuitable for marriage or other close personal relationships. A Greek Orthodox Christian endogamist, for example, would require that a marriage be only with another...
) there are not two individuals with exactly the same set of MHC genes and molecules, with the exception of identical twins
Twin
A twin is one of two offspring produced in the same pregnancy. Twins can either be monozygotic , meaning that they develop from one zygote that splits and forms two embryos, or dizygotic because they develop from two separate eggs that are fertilized by two separate sperm.In contrast, a fetus...
.
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
Recombination
Recombination may refer to:* Recombination , the process by which genetic material is broken and joined to other genetic material* Recombination , in semiconductors, the elimination of mobile charge carriers...
, as it is the case for the antigen receptors
Immune receptor
An immune receptor is a receptor, usually on a cell membrane, which binds to a substance and causes a response in the immune system.-Types:...
.
Because of the high levels of allelic
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
diversity found within its genes, MHC has also attracted the attention of many evolution
Evolution
Evolution is any change across successive generations in the heritable characteristics of biological populations. Evolutionary processes give rise to diversity at every level of biological organisation, including species, individual organisms and molecules such as DNA and proteins.Life on Earth...
ary biologists.
See also
- Cell-mediated immunityCell-mediated immunityCell-mediated immunity is an immune response that does not involve antibodies but rather involves the activation of macrophages, natural killer cells , antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen...
- Disassortative sexual selection
- Humoral immunityHumoral immunityThe Humoral Immune Response is the aspect of immunity that is mediated by secreted antibodies produced in the cells of the B lymphocyte lineage . B Cells transform into plasma cells which secrete antibodies...
- Transplant rejectionTransplant rejectionTransplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after...
- Monell Chemical Senses CenterMonell Chemical Senses CenterThe Monell Chemical Senses Center is a non-profit independent scientific institute located at the University City Science Center research campus in Philadelphia, Pennsylvania...
, a research facility that works in this field
External links
- Molecular individuality (German online-book 2009)
- 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
- RCSB Protein Data Bank: Molecule of the Month - Major Histocompatibility Complex