Major compatibility complex (MHC) is a 7-megabase region with dense clustering of more than 300 genes coordinating immune function.
MHC has an average gene density of 1/16 kb and more than 420 associations to more than 35 common complex autoimmune, inflammatory, infectious diseases and malignancy have been described.
The main HLA loci are the best characterized MHC genes.
In response to differentiating elements released by inflammatory cells and an underlying pathologic process dendritic cells differentiate into antigen presenting cells and migrate to lymphoid tissue where T cells become activated when their antigen specific T cell receptor binds the antigen-MHC complex presented on the surface of the antigen presenting cell.
The major histocompatibility complex (MHC) is a set of cell surface proteins essential for the acquired immune system to recognize foreign molecules, which in turn determines histocompatibility.
MHC molecules main function is to bind to antigens derived from pathogens and display them on the cell surface for recognition by the appropriate T-cells.
MHC molecules mediate interactions of immune cells, with other leukocytes or with body cells.
MHC determines compatibility of donors for organ transplant, as well as one’s susceptibility to an autoimmune disease via crossreacting immunization.
The human MHC is also called the HLA (human leukocyte antigen) complex (often just the HLA).
HLA refers 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 commentary.
In a cell, protein molecules of the host’s own phenotype or of other biologic entities are continually synthesized and degraded.
Each MHC molecule on the cell surface displays a molecular fraction of a protein, called an epitope.
The presented antigen can be either self or non-self, thus preventing an organism’s immune system targeting its own cells.
The MHC gene family is divided into three subgroups: class I, class II, and class III.
Class I MHC molecules have β2 subunits which can only be recognised by CD8 co-receptors.
Class II MHC molecules have β1 and β2 subunits and can be recognised by CD4 co-receptors.
MHC molecules chaperone which type of lymphocytes may bind to the given antigen with high affinity, since different lymphocytes express different T-Cell Receptor (TCR) co-receptors.
Diversity of antigen presentation, mediated by MHC classes I and II.
Of the three MHC classes identified, attention commonly focuses on classes I and II.
MHC class II mediates establishment of specific immunity, also called acquired immunity or adaptive immunity by interacting with CD4 molecules on surfaces of helper T cells,
MHC class I mediates destruction of infected or malignant host cells by interacting with CD8 molecules on the surface of cytotoxic T cells.
MHC affects humoral immunity indirectly.
MHC is the tissue-antigen that allows the T cells of the immune system to bind to, recognize, and tolerate itself.
MHC is the chaperone for intracellular peptides that are complexed with MHCs and presented to T cell receptors (TCRs) as potential foreign antigens.
MHC interacts with T cell receptors and its co-receptors to optimize binding conditions for the TCR-antigen interaction, in terms of antigen binding affinity and specificity, and signal transduction effectiveness.
The MHC-peptide complex is a complex of autoantigen/alloantigen.
Upon binding, T cells should in principle tolerate the auto-antigen, but activate when exposed to the allo-antigen.
When T cells do not tolerate the auto-antigen, and activate when exposed to an alo-antigen disease states occur.
MHC molecules bind to both T cell receptor and CD4/CD8 co-receptors on T lymphocytes, and the antigen epitope held in the peptide-binding groove of the MHC molecule interacts with the variable Ig-Like domain of the TCR to trigger T-cell activation.
Some MHC molecules increases the risk of autoimmune diseases more than having others.
HLA-B27 tissue type increases the risk of ankylosing spondylitis and other associated inflammatory diseases.
MHC molecules in complex with peptide epitopes are essentially ligands for TCR.
T cells are activated by binding to the peptide-binding grooves of any MHC molecule that T cells were not trained to recognize during thymus positive selection.
Lymphocytes reside in lymphoid tissues, including lymphoid follicles and lymph nodes, and include B cells, T cells, and natural killer cells (NK cells).
B cells, secrete antibody molecules, but do not bind MHC.
T cells act specifically to interact with MHC.
NK cells act innately with MHC.
NK cells express Killer Ig-like receptors (KIRs) that bind to MHC I molecules.
NK cells signal through immunoreceptor tyrosine inhibition motif recruitment and activation of protein tyrosine phosphatases.
The CD8 TCR interaction activates Tc lymphocytes.
NK cells becomes deactivated when bound to MHC I.
When MHC class I expression is low, it is typically seen with abnormal cell function during viral infection or tumourigenesis,
When MHC class is low NK cells lose the inhibitory Killer Ig-like receptor signal and trigger programmed cell death of the abnormal cell.
NK cells also prevent progress of malignant cells by contributing to tumor surveillance.
MHC class II can be conditionally expressed by all cell types, but normally occurs only on antigen-presenting cells (APCs) which include: macrophages, B cells, and dendritic cells (DCs).
An APC takes up an antigenic protein, and processes the antigen, returning a molecular fraction of it.
This fraction is termed the epitope, and displays it on the APC’s surface coupled within an MHC class II molecule.
The epitope on the cell’s surface can be recognized by immunologic structures like T cell receptors (TCRs).
The paratope is the region which binds to the epitope.
On surfaces of helper T cells are CD4 receptors, as well as TCRs.
Helper T cell’s CD4 molecule docks to an APC’s MHC class II molecule.
Helper T cell’s TCR can meet and be imprinted by the epitope coupled within the MHC class II, priming the naive helper T cell.
Cytokines secreted by APCs in the microenvironment, allows the naive helper T cell (Th0) to polarize into either a memory Th cell or an effector Th cell of phenotype either type 1 (Th1), type 2 (Th2), type 17 (Th17), or regulatory/suppressor (Treg), the Th cell’s terminal differentiation.
MHC class II thus mediates immunization to immune tolerance of an antigen.
The primary exposure to an antigen is key in determining a number chronic diseases, such as inflammatory bowel diseases and asthma, as it skews the immune response that memory Th cells adopt when their memory recall is triggered upon secondary exposure to similar antigens.
MHC class I occurs on all nucleated cells and also in platelets.
MHC class I does not occur on red blood cells.
MHC class I cells presents epitopes to killer T cells, also called cytotoxic T lymphocytes.
A cytotoxic T lymphocyte expresses CD8 receptors, in addition to TCRs.
When a cytotoxic T lymphocyte’s CD8 receptor docks to a MHC class I molecule, if the CTL’s TCR fits the epitope within the MHC class I molecule, the CTL triggers the cell to undergo programmed cell death by apoptosis.
MHC class I helps mediate cellular immunity.
MHC class I addresses intracellular pathogens, such as viruses and some bacteria, including bacterial L forms, bacterial genus Mycoplasma, and bacterial genus Rickettsia.
MHC class I comprises HLA-A, HLA-B, and HLA-C molecules.
The MHC region occurs on chromosome 6, and contains 224 genes spanning 3.6 megabase pairs (3 600 000 bases).
Class III functions very differently from class I and class II, and its locus occurs between the other two classes, on chromosome 6 in humans, and are frequently discussed together.
MHC proteins have immunoglobulin-like structure.
MHC I occurs as an α chain composed of three domains―α1, α2, and α3.
MHC class II is formed of two chains, α and β, each having two domains―α1 and α2 and β1 and β2.
Each chain has a transmembrane domain, α2 and β2, anchoring the MHC class II molecule to the cell membrane.
MHC class II molecules have five to six isotypes.
Class III molecules are encoded between the short arm of human chromosome 6.
Class III molecules include several secreted proteins with immune functions: components of the complement system (such as C2, C4, and B factor), cytokines (such as TNF-α, LTA, and LTB), and heat shock proteins.
Proteins in the cytosol are degraded by the proteasome, liberating peptides internalized in the endoplasmic reticulum, there associating with MHC-I molecules.
T lymphocytes are selected in the thymus to recognize MHC molecules of the host, but not recognize other self antigens. lymphocyte shows dual specificity:
The TCR recognizes self MHC, but only non-self antigens.
MHC restriction occurs
During lymphocyte development in the thymus a process known as positive selection occurs so that T cells do not receive a positive survival signal to their TCR and undergo apoptosis.
Positive selection ensures that mature T cells can functionally recognize MHC molecules elsewhere in the body.
MHC molecules allow immune system surveillance of the population of protein molecules in a host cell, and greater MHC diversity permits greater diversity of antigen presentation.
There is lower rates of early pregnancy loss in human couples of dissimilar MHC genes.
MHC phenotype appears involved in the strength and pleasantness of perceived odor of compounds from sweat.
Fatty acid esters have strong connection to MHC.
HLA-associated odors influence odor preference and may mediate social cues.
HLA-A, HLA-B, and HLA-DRB1, have roughly 1000, 1600, and 870 known alleles, respectively.
An individual bears at most 18 MHC I or II alleles.
With transplantation MHC molecules act themselves as antigens and can provoke immune response in the recipient, thus causing transplant rejection.
Each human cell expresses six MHC class I alleles-one HLA-A, -B, and -C allele from each parent) and six to eight MHC class II alleles-one HLA-DP and -DQ, and one or two HLA-DR from each parent, and combinations of these
The MHC variation is high, with 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 who are not identical twins will express different MHC molecules.
HLA-C and HLA-DP, showing low polymorphism, and are least important for transplant matching.
In the thymus, T lymphocytes are selected for their TCR incapacity to recognize self antigens.
T lymphocytes can react against the donor MHC’s peptide-binding groove, holding the presented antigen’s epitope for recognition by TCR, the matching paratope.
Transplant rejection has various types known to be mediated by MHC (HLA):
Hyperacute rejection occurs when, before the transplantation, the recipient has preformed anti-HLA antibodies, perhaps by previous blood transfusions, by anti-HLA generated during pregnancy,, or by previous transplantation.
Acute cellular rejection occurs when the recipient’s T lymphocytes are activated by the donor tissue, causing damage by direct cytotoxicity from CD8 cells.
Acute humoral rejection occurs when the recipient’s anti-HLA antibodies form directed at HLA molecules present on endothelial cells of the transplanted tissue.
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.
The compatibility between HLA-A, -B, and -DR molecules is assessed.
The higher the number of incompatibilities, the lower the five-year survival rates or transplantation.
Human MHC class I and II are also called human leukocyte antigen (HLA).
The most studied HLA genes are the nine classical MHC genes: HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, and HLA-DRB1.
The MHC gene cluster is divided into three regions: classes I, II, and III.
The A, B and C genes belong to MHC class I, whereas the six D genes belong to class II.
MHC alleles are inherited from both parents are expressed equally.
Each person carries 2 alleles of each of the 3 class-I genes, (HLA-A, HLA-B and HLA-C), and so can express six different types of MHC-I.
In the class-II locus, each person inherits a pair of HLA-DP genes (DPA1 and DPB1, which encode α and β chains), a couple of genes HLA-DQ (DQA1 and DQB1, for α and β chains), one gene HLA-DRα (DRA1), and one or more genes HLA-DRβ (DRB1 and DRB3, -4 or -5).
An individual can inherit six or eight functioning class-II alleles, three or more from each parent.
The set of alleles that is present in each chromosome is called the MHC haplotype.
Each HLA allele is named with a number: Eg. HLA-A2, HLA-B5, HLA-DR3, etc…
Each heterozygous individual will have two MHC haplotypes, one each from the paternal and maternal chromosomes.
No two individuals have exactly the same set of MHC molecules, with the exception of identical twins.