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

MHC molecules: Class I and Class II

. Class I MHC molecules are found on almost all cells

and present proteins to cytotoxic T cells. Class II MHC molecules are found on certain immune cells themselves, chieflymacrophages and B cells, also known as antigen-presenting cells (APCs). These APCs ingest microbes, destroy them, 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

The MHC region is divided into three subgroups, class I, class II, and class III.

Name

Function

Expression All nucleated cells. MHC class I proteins contain an chain & 2micro-globulin(not part of the MHC encoded by chromosome 15). They present antigen fragments to cytotoxic T-cells via theCD8 receptor on the cytotoxic T-cells and also bind inhibitory receptors on NK cells. On most immune system cells, specifically on antigen-presenting cells. MHC class II proteins contain & chains and they present antigen fragments to T-helper cells by binding to the CD4receptor on the T-helper cells.

MHC class I

Encodes non-identical pairs (heterodimers) of peptide-binding proteins, as well as antigenprocessing molecules such as TAP and Tapasin.

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, MHC II DQ, MHC II DR, and MHC II DP. Encodes for other immune components, such as complement components (e.g., C2, C4, factor B) and some that encode cytokines (e.g., TNF-) and also hsp.

MHC class IIIregion

Variable (see below).

Responses
The MHC proteins act as "signposts" that serve to alert

the immune system if foreign material is present inside a cell. They achieve this by displaying fragmented pieces of antigens on the host cell's surface. These antigens may be self or nonself. If they are nonself, there are two ways by which the foreign protein can be processed and recognized as being "nonself".

 Phagocytic cells such as macrophages, neutrophils,

and monocytes degrade foreign particles that are engulfed during a process known as phagocytosis. Degraded particles are then presented on MHC Class II molecules

 On the other hand, if a host cell was infected by

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

 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

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, HLA-B, HLAC, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLADQB1, HLA-DRA, and HLA-DRB1. In humans, the MHC is divided into three regions: Class 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[6]. 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

the Class-II locus

person inherits a couple of genes HLA-DP (DPA1 and

DPA2, which encode and chains), a couple of genes HLA-DQ (DQA1 and DQA2, for and chains), one gene HLA-DR (DRA1) and one or two genes HLADR (DRB1 and DRB3, -4 o -5). one heterozygous individual can inherit 6 or 8 Class-II alleles, three or four from each progenitor

The set of alleles which 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 the 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
, 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 which are able to properly enter in the cleft of the MHC molecule, which is variable for each allele. this way, the MHC molecules have a broad specificity, because they can bind many, but not all types of possible peptides. 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.

inside a population
, 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, because at least some individuals will be able to develop an adecuate immune response to win over the pathogen. The variations in the MHC molecules (responsibles for the polymorphism) are the result of the inheritance of different MHC molecules, are not induced by recombination, as it is the case for the antigen receptors

MHC molecules are anchored in the cell membrane at the bottom of the illustration; 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). The MHC Class II molecule (right) on immune cells binds to the TCR and CD4 receptor on other immune cells (top).

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. At maturity, MHC molecules are anchored in the cell membrane, where they display short polypeptides to T cells, via the T cell receptors (TCR). The polypeptides may be "self," that is, originating from a protein created by the organism itself, or they may be foreign ("nonself"), originating from bacteria, viruses, pollen, . The overarching design of the MHC-TCR interaction is that T cells should ignore self-peptides while reacting appropriately to the foreign peptides.

method for identifying an antigen: B cells with their membraneboundantibodies, B cell receptors (BCR).
, whereas the BCRs of B cells can bind to antigens without

much outside help, the TCRs require "presentation" of the antigen through the help of MHC. however, MHC are kept busy presenting self-peptides, which T cells should appropriately ignore. A full-force immune response usually requires the activation of B cells via BCRs and T cells via the MHC-TCR interaction. This duality creates a system of "checks and balances" and underscores the immune system's potential for running amok and causing harm to the body

Structure of a molecule of MHC Class-I.

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. However, MHC class I and MHC class II differ significantly in the method of peptide presentation.

MHC Class-I genes (MHC-I) code glucoproteins, with immunoglobulin structure:

they present one heavy chain type , subdivided in three regions: 1,

2 y 3. are exposed to the extracellular space, and they are linked to the cellular membrane through a transmembrane region. The chain is always asociated to a molecule of 2 microglobulin, which is coded by an independent region on chromosome 15. These molecules are present in the surface of all nucleated cells.[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+). The antigenic peptide is located in a cleft existing between the 1 and 2 regions in the heavy chain. different isotypes (different genes) for the Class-I molecules, which can be grouped as: "classic molecules", whose function consist in antigen presentation to the T8 lymphocytes: inside this group we find HLA-A, HLA-B y HLAC.

 "non classic molecules" (named also MHC class IB),

with specialized functions: they do not present antigens to T lymphocytes, but they interact with inhibitory receptors in NK cells; inside this group we find HLA-E, HLA-F, HLA-G.

Structure of a molecule of MHC MHC Class-II

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

MHC-II molecules in humans present 5-6 isotypes, and can be grouped in

"classic molecules", presenting peptides to T4

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

MHC Class-III
This class include genes coding several secreted

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

Functions of MHC-I and II molecules

Both types of molecules present antigenic peptides to

T lymphocytes, which are responsible for the specific immune response to destroy the pathogen producing those antigens. However, Class-I and II molecules correspond to two different pathways of antigen processing, and are associated to two different systems of immune defense

Functions of MHC-I and II molecules

Table 2. Characteristics of the antigen processing pathways Characteristic MHC-II pathway MHC-I pathway

Composition of the stable peptide-MHC complex

Polymorphic chains and , peptide binds to both

Polymorphic chain and 2 microglobulin, peptide bound to chain

Types of antigen presenting cells (APC)

Dendritic cells, 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)

MHC II
Enzymes responsible for peptide generation Proteases from endosomes and lysosomes (for instance,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, invariant chain

TAP (transporter associated with antigen processing)

 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. This property is of great importance in organ transplantation, and during their development, T lymphocytes must "learn" to recognize the MHC molecules belonging to the individual (the "self" recognition), during the complex process of maturation and selection having place in the thymus

 MHC molecules can only display peptides. For this reason,

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

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

 MHC molecules obtain the peptide that they display to the

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

 It is important to notice that MHC-I molecules acquire

peptides coming from cytosolic proteins, whereas MHC-II molecules acquire peptides from proteins contained in intracellular vesicles. For this reason, MHC-I molecules display "self" peptides, viral peptides (synthesized by the own cell) or peptides coming from ingested microbes in phagosomes. MHC-II molecules, however, display peptides coming from microbes ingested in vesicles (MHC-II molecules are present only in cells with phagocytic capacity). 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 "empty" molecules are degraded inside the cell.

 In each individual, 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, in a given moment, 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, because these are much more abundant. However, T lymphocytes are able to detect a peptide displayed by only 0.1%-1% of the MHC molecules to initiate an immune response

 On the other hand, the self peptides cannot initiate an

immune response (except in the case of autoimmune diseases), because the specific T lymphocytes for the self peptides are destroyed or inactivated in the thymus. However, 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. In the rare cases in which they detect a foreign peptide, they will initiate an immune response

Role of MHC molecules in transplants rejection

As previously described, each human cell express 6 MHC

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

 As these alleles can be inherited and expressed in many

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

 In a tranplant (an organ transplantation or stem

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

 During T lymphocytes maturation in the thymus, these

cells are selected according to their TCR capacity to weakly recognize complexes "self peptide:self MHC". For this reason, in principle T lymphocytes should not react against a complex "foreign peptide:foreign MHC", which is what can be found in transplanted cells. However, what seems to happen is a kind of cross-reaction: T lymphocytes from the receptor individual can be mistaken, 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).

 hyperacute rejection: it happens when the receptor

individual has preformed anti-HLA antibodies, generated before the trasplantation; this can be due to previous blood transfusions (because this includes donor lymphocytes, expressing HLA molecules), 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;

 acute humoral rejection and chronic disfunction of

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

 For this reason, 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, in order to avoid the hyperacute rejection . Normally, what is checked is the compatibility between HLA-A, -B and -DR molecules: the higher the number of incompatibilities, the lower the 5 years survival of the transplant