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is a large genomic region or gene family found in most vertebrates that encodes MHC molecules.

MHC molecules play an important role in the immune system and autoimmunity.

Protein images comparing the MHC I (1hsa) and MHC II (1dlh) molecules.

 Proteins are continually synthesized in the cell. These include normal proteins (self) and microbial invaders (nonself). A MHC molecule

inside the cell takes a fragment of those proteins and displays it on the cell surface. (The protein fragment is sometimes compared to a hot dog, and the MHC protein to the bun.[1]) When the MHCprotein complex is displayed on the surface of the cell, it can be presented to a nearby immune cell, usually a T cell or natural killer (NK) cell.

 . The MHC is the most gene-dense region of the

mammalian genome. MHC genes vary greatly from individual to individual MHC alleles have polymorphisms (diversity). This polymorphism is adaptive in evolution because it increases the likelihood that at least some individuals of a population will survive an epidemic

Class I MHC molecules are found on almost all cells and present proteins to cytotoxic T cells. and digest them into fragments. The Class II MHC molecules on the APCs present the fragments to helper T cells. which stimulate an immune reaction from other cells .MHC molecules: Class I and Class II  . destroy them. These APCs ingest microbes. chieflymacrophages and B cells. also known as antigen-presenting cells (APCs). Class II MHC molecules are found on certain immune cells themselves.

MHC class I Encodes non-identical pairs (heterodimers) of peptide-binding proteins. . They present antigen fragments to cytotoxic T-cells via theCD8 receptor on the cytotoxic T-cells and also bind inhibitory receptors on NK cells. and MHC II DP. and class III. C2. as well as antigenprocessing molecules such as TAP and Tapasin. class I. such as complement components (e.. MHC class IIIregion Variable (see below). Name Function Expression All nucleated cells. TNF-α) and also hsp. MHC II DQ. MHC II DR. MHC class II Encodes heterodimeric peptidebinding proteins and proteins that modulate antigen loading onto MHC class II proteins in the lysosomal compartment such as MHC II DM. Encodes for other immune components.g..g. MHC class II proteins contain α & β chains and they present antigen fragments to T-helper cells by binding to the CD4receptor on the T-helper cells. On most immune system cells. specifically on antigen-presenting cells. class II. C4. MHC class I proteins contain an α chain & β2micro-globulin(not part of the MHC encoded by chromosome 15). factor B) and some that encode cytokines (e.The MHC region is divided into three subgroups.

Responses  The MHC proteins act as "signposts" that serve to alert the immune system if foreign material is present inside a cell. . If they are nonself. These antigens may be self or nonself. there are two ways by which the foreign protein can be processed and recognized as being "nonself". They achieve this by displaying fragmented pieces of antigens on the host cell's surface.

neutrophils. Phagocytic cells such as macrophages. Degraded particles are then presented on MHC Class II molecules . and monocytes degrade foreign particles that are engulfed during a process known as phagocytosis.

if a host cell was infected by a bacterium or virus. nonself antigens on their surface. On the other hand. cancerous cells and cells infected by a virus have a tendency to display unusual. will initiate the specific immunity of the host's body . or was cancerous. it may have displayed the antigens on its surface with a Class I MHC molecule. These nonself antigens. regardless of which type of MHC molecule they are displayed on.

 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 .

HLA-DPA1. and HLA-DRB1. the MHC is divided into three regions: Class I. II. HLADQB1. F. E. HLA-DPB1. and G genes belong to MHC class I. HLA-DQA1. HLA-B. and III. whereas the six D genes belong to class II. B. . C. HLAC. The A. In humans. HLA-DRA.The best-known genes in the MHC region are the subset that encodes antigen-presenting proteins on the cell surface as human leukocyte antigen (HLA) genes The most intensely studied HLA genes are the nine socalled classical MHC genes: HLA-A.

This means that the alleles (variants) inherited from both progenitors are expressed in equivalent way  As there are 3 Class-I genes.MHC genes are expressed in codominant fashion[6]. that means that any cell in an individual can express 6 different types of MHC-I molecules . and as each person inherits a set of genes from each progenitor. HLA-B and HLA-C. named in humans HLA-A.

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

HLA-B5. . HLA-DR3. In humans. each HLA allele is named with a number. Each heterozygous individual will have two MHC haplotypes. For instance. one in each chromosome (one of paternal origin and the other of maternal origin). for a given individual. etc.The set of alleles which is present in each chromosome is called MHC haplotype  ... his haplotype might be HLA-A2.

 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 the identical twins .The MHC genes are highly polymorphic.

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

The variations in the MHC molecules (responsibles for the polymorphism) are the result of the inheritance of different MHC molecules. as it is the case for the antigen receptors . are not induced by recombination. because at least some individuals will be able to develop an adecuate immune response to win over the pathogen. the presence of many different alleles ensures that it 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 sucumb face to a new pathogen or a mutated one.inside a population .

MHC molecules are anchored in the cell membrane at the bottom of the illustration. The MHC Class II molecule (right) on immune cells binds to the TCR and CD4 receptor on other immune cells (top). they can then bind to immune cells at the top of the illustration. . The MHC Class I molecule (left) on most cells binds to the Tcell receptor (TCR) and CD8 receptor (top).

viruses. .The classical MHC molecules (also referred to as HLA molecules in humans) have a vital role  the complex immunological dialogue that must occur between T cells and other cells of the body. MHC molecules are anchored in the cell membrane. originating from a protein created by the organism itself. At maturity. The overarching design of the MHC-TCR interaction is that T cells should ignore self-peptides while reacting appropriately to the foreign peptides. The polypeptides may be "self. pollen." that is. originating from bacteria. or they may be foreign ("nonself"). where they display short polypeptides to T cells. via the T cell receptors (TCR). .

the TCRs require "presentation" of the antigen through the help of MHC. This duality creates a system of "checks and balances" and underscores the immune system's potential for running amok and causing harm to the body . which T cells should appropriately ignore.method for identifying an antigen: B cells with their membraneboundantibodies.  . however. MHC are kept busy presenting self-peptides. B cell receptors (BCR). whereas the BCRs of B cells can bind to antigens without much outside help. A full-force immune response usually requires the activation of B cells via BCRs and T cells via the MHC-TCR interaction.

However. MHC class I and MHC class II differ significantly in the method of peptide presentation. MHC molecules retrieve polypeptides from the interior of the cell they are part of and display them on the cell's surface for recognition by T cells.Structure of a molecule of MHC Class-I. .

which is coded by an independent region on chromosome 15. subdivided in three regions: α1. The α chain is always asociated to a molecule of β2 microglobulin. . α2 y α3. These molecules are present in the surface of all nucleated cells. HLA-B y HLAC. with immunoglobulin structure:  they present one heavy chain type α. The antigenic peptide is located in a cleft existing between the α1 and α2 regions in the heavy chain. whose function consist in antigen presentation to the T8 lymphocytes: inside this group we find HLA-A.  different isotypes (different genes) for the Class-I molecules.MHC Class-I genes (MHC-I) code glucoproteins.[6]  The most important function of the gene products for the Class-I genes is the presentation of intracellular antigenic peptides to the cytotoxic T lymphocytes (CD8+). are exposed to the extracellular space. and they are linked to the cellular membrane through a transmembrane region. which can be grouped as:  "classic molecules".

. HLA-F. "non classic molecules" (named also MHC class IB). with specialized functions: they do not present antigens to T lymphocytes. HLA-G. but they interact with inhibitory receptors in NK cells. inside this group we find HLA-E.

in this case the functional complex is formed by two chains.Structure of a molecule of MHC MHC Class-II genes code glucoproteins with immunoglobulin structure. Each chain is linked to the cellular membrane through a transmembrane region. The antigenic peptide is located in a cleft formed by α1 and β1 peptides . β1 and β2). one α and one β (each one with two domains: α1 and α2. in the extracellular espace. and both chains are confronted. with domains 1 and 2 consecutives. where they present processed extracellular antigenic peptides to the helper T lymphocytes (CD4+).[6] These molecules are present mostly in the membrane of the antigen presenting cells (dendritic and phagocytic cells).

MHC-II molecules in humans present 5-6 isotypes. and can be grouped in  "classic molecules". accesories. they load the antigenic peptides on the classic MHC-II molecules. HLA-DQ. such as TAP (transporter associated with antigen processing) or Tapasin . in this group are included HLA-DM and HLADO. HLA-DR.  "non classic molecules". with intracellular functions (they are not exposed in the cellular membrane.  On top of the MHC-II molecules. but in internal membrares inlysosomes). normally. presenting peptides to T4 lymphocytes. inside this group we find HLA-DP. in the Class-II region are located genes coding for antigen processing molecules.

.  Class-III molecules do not share the same function as class. and for this reason they are frequently described together. LTB) or heat shock proteins (hsp).MHC Class-III  This class include genes coding several secreted proteins with immune functions: components of the complement system (such as C2. but they are located between them in the short arm of human chromosome 6.I and II molecules. LTA. C4 and B factor) and molecules related with inflammation (cytokines such as TNF-α.

and are associated to two different systems of immune defense .Functions of MHC-I and II molecules  Both types of molecules present antigenic peptides to T lymphocytes. Class-I and II molecules correspond to two different pathways of antigen processing. However. which are responsible for the specific immune response to destroy the pathogen producing those antigens.

peptide bound to α chain Types of antigen presenting cells (APC) Dendritic cells. peptide binds to both Polymorphic chain α and β2 microglobulin.Functions of MHC-I and II molecules Table 2. mononuclear phagocytes. B lymphocytes. some endothelial cells. epithelium of thymus All nucleated cells T lymphocytes able to respond Helper T lymphocytes (CD4+) Cytotoxic T lymphocytes (CD8+) Origin of antigenic proteins Proteins present in endosomes or lysosomes (mostly internalized from extracellular medium) cytosolic proteins (mostly synthetized by the cell. may also enter from the extracellular medium via phagosomes) . Characteristics of the antigen processing pathways Characteristic MHC-II pathway MHC-I pathway Composition of the stable peptide-MHC complex Polymorphic chains α and β.

MHC II Enzymes responsible for peptide generation Proteases from endosomes and lysosomes (for instance. invariant chain TAP (transporter associated with antigen processing) .cathepsin) MHC I Cytosolic proteasome Location of loading the peptide on the MHC molecule Specialized vesicular compartment Endoplasmic reticulum Molecules implicated in transporting the peptides and loading them on the MHC molecules DM.

and during their development. during the complex process of maturation and selection having place in the thymus . This property is of great importance in organ transplantation. T lymphocytes belonging to one specific individual present a property called MHC restriction (see below): they only can detect an antigen if it is displayed by an MHC molecule from the same individual. This is due to the fact that each T lymphocyte has a dual specificity: the T cell receptor (TCR) recognizes at the same time some residues from the peptide and some residues from the displaying MHC molecule. T lymphocytes must "learn" to recognize the MHC molecules belonging to the individual (the "self" recognition).

nor sugars). Each MHC molecule can display only one peptideeach time. because the cleft in the molecule has space only to load one peptide. they only can react to antigens of proteic origin (coming from microbes) and not to other types of chemical compounds (neither lipids. However. because it can display many different peptides (although not all). MHC molecules can only display peptides. one given MHC molecule has a broad specificity. as T lymphocytes can only recognize an antigen if it is displayed by an MHC molecule. For this reason. nor nucleic acids. .

Peptide processing for peptides associated to MHC-I molecules: proteins present in the cytosol are degraded by the proteasome. which fuse with the cell membrane. In this way. where they become associated with MHC-I molecules freshly synthesized. The MHC-I/peptide complexes enter in the Golgi apparatus. and the resulting peptides are internalized by the TAP channel in theendoplasmic reticulum. the complexes become exposed to the outside of the cell. . allowing the contact with circulating T lymphocytes. and from there they enter in secreting vesicles. where they are glycosylated.

This is the reason why T lymphocytes. inside the cell. MHC molecules obtain the peptide that they display to the outside of the cell during their own biosynthesis. developing only an immune response against intracellular microbes. That means that those peptides come from microbes that are inside the cell. . which only can recognize a peptide if it is displayed by an MHC molecule. are only able to detect microbes associated to cells.

MHC molecules are stable on the cell membrane only if they display a loaded peptide: the peptide stabilizes the structure of the MHC molecules. whereas MHC-II molecules acquire peptides from proteins contained in intracellular vesicles. . display peptides coming from microbes ingested in vesicles (MHC-II molecules are present only in cells with phagocytic capacity). MHC-I molecules display "self" peptides. It is important to notice that MHC-I molecules acquire peptides coming from cytosolic proteins. whereas "empty" molecules are degraded inside the cell. viral peptides (synthesized by the own cell) or peptides coming from ingested microbes in phagosomes. For this reason. however. MHC-II molecules.

 In each individual. only a small fraction of the MHC molecules in one cell will display a foreign peptide: most of the displayed peptides will be self peptides.1%-1% of the MHC molecules to initiate an immune response . MHC molecules can display both foreign peptides (coming from pathogens) as well as peptides coming from the self proteins of this individual. For this reason. However. T lymphocytes are able to detect a peptide displayed by only 0. because these are much more abundant. in a given moment.

However. they will initiate an immune response . On the other hand. because the specific T lymphocytes for the self peptides are destroyed or inactivated in the thymus. the presence of self peptides displayed by MHC molecules is essential for the supervising function of the T lymphocytes: these cells are constantly patrolling the organism. verifying the presence of self peptides associated to MHC molecules. the self peptides cannot initiate an immune response (except in the case of autoimmune diseases). In the rare cases in which they detect a foreign peptide.

400 alleles for DR and 90 alleles for DQ. each human cell express 6 MHC class-I alleles (one HLA-A. 620 alleles for HLA-B. and some combinations of these). -B and -C allele from each progenitor) and 6-8 MHC class-2 alleles (one HLA-DP and -DQ. The MHC polymorphism is very high: it is estimated that in the population there are at least 350 alleles for HLA-A genes. and one or two HLA-DR from each progenitor.Role of MHC molecules in transplants rejection  As previously described. .

and most likely they are less important in rejection . All MHC molecules can be targets for transplant rejection. As these alleles can be inherited and expressed in many different combinations. but HLA-C and HLA-DP molecules show low polymorphism. except in the case of identical twins. each individual in the population will most likely express some molecules which will be different from the molecules in another individual.

. MHC molecules recognition in cells from another individual is one of the most intense immune responses currently known. MHC molecules work as antigens: they can initiate an immune response in the receptor. thus provoking the transplant rejection. In a tranplant (an organ transplantation or stem cells transplantation). The reason why an individual reacts against the MHC molecules from another individual is pretty well understood.

these cells are selected according to their TCR capacity to weakly recognize complexes "self peptide:self MHC". During T lymphocytes maturation in the thymus. what seems to happen is a kind of cross-reaction: T lymphocytes from the receptor individual can be mistaken. For this reason. which is what can be found in transplanted cells. . because the MHC molecule of the donor is similar to self MHC molecule in the binding region to the TCR (the MHC variable region is in the binding motif for the peptide they display). However. in principle T lymphocytes should not react against a complex "foreign peptide:foreign MHC".

to the generation of anti-HLA during pregnancy (against the HLA molecules from the father present in the fetus) and due to a previous trasplantation. generated before the trasplantation. hyperacute rejection: it happens when the receptor individual has preformed anti-HLA antibodies. expressing HLA molecules). . this can be due to previous blood transfusions (because this includes donor lymphocytes.

against the HLA molecules present in the endothelial cells of the transplanted tissue. .  In both cases. acute humoral rejection and chronic disfunction of the transplanted organ: due to the formation of anti-HLA antibodies in the receptor individual. and progressive in the second one. which can produce lesions in the organ. there is an immune reaction against the transplanted organ. eventually producing lost of function. immediately in the first case.

what is checked is the compatibility between HLA-A. -B and -DR molecules: the higher the number of incompatibilities. it is crucial to realize a cross-reaction test between donor cells and receptor serum. to detect the potential presence of preformed anti-HLA antibodies in the receptor against donor HLA molecules. Normally. the lower the 5 years survival of the transplant . For this reason. in order to avoid the hyperacute rejection .