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98-601: One of the earlier genetic studies on the C4 protein identified two different groups, found within a human serum, called the Chido/Rogers (Ch/Rg) blood groups. O’Neill et al. have demonstrated that two different C4 loci express the different Ch/Rg antigens on the membranes of erythrocytes. More specifically, the two proteins, Ch and Rg, function together as a medium for interaction between the Ab-Ag complex and other complement components. Moreover,

196-521: A reference genome and play a significant role in human phenotypic variation and disease development. The RCCX cluster consists of one or more modules each having a series of genes close to each other: serine/threonine kinase 19 ( STK19 ), complement 4 ( C4 ), steroid 21-hydroxylase ( CYP21 ), and tenascin-X ( TNX ). The RCCX abbreviation is composed of the names of the genes R P (a former name for STK19 serine/threonine kinase 19), C 4 , C YP21 and TN X ). The RCCX abbreviation

294-446: A self antigen . To offset inbreeding , efforts to sustain genetic diversity in populations of endangered species and of captive animals have been suggested. In ray-finned fish like rainbow trout, allelic polymorphism in MHC class II is reminiscent of that in mammals and predominantly maps to the peptide binding groove. However, in MHC class I of many teleost fishes, the allelic polymorphism

392-668: A species ). Sexual selection has been observed in male mice choosing to mate with females with different MHCs. Also, at least for MHC I presentation, there has been evidence of antigenic peptide splicing , which can combine peptides from different proteins, vastly increasing antigen diversity. The first descriptions of the MHC were made by British immunologist Peter Gorer in 1936. MHC genes were first identified in inbred mice strains. Clarence Little transplanted tumors across different strains and found rejection of transplanted tumors according to strains of host versus donor. George Snell selectively bred two mouse strains, attained

490-407: 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 small peptide (a molecular fraction of a protein) called an epitope . The presented self-antigens prevent an organism 's immune system from targeting its own cells. The presentation of pathogen-derived proteins results in

588-410: A chimpanzee MHC alleles than to some other human alleles of the same gene. MHC allelic diversity has challenged evolutionary biologists for explanation. Most posit balancing selection (see polymorphism (biology) ), which is any natural selection process whereby no single allele is absolutely most fit, such as frequency-dependent selection and heterozygote advantage . Pathogenic coevolution, as

686-622: A combination of homozygous or heterozygous L or S genes), LLL or LLS or LSS (trimodular RCCX with three L or S C4 genes), LLLL (quadrimodular structure with four L or S C4 genes). Not all the structural groups have the same percentage of appearance, possibly even further differences within separate ethnic groups. For example, the Caucasian population studied showed 69% bimodular configuration (C4A-C4B, C4A-C4A, or C4B-C4B) and 31% trimodular configuration (equally split between LLL as C4A-C4A-C4B or LSS as C4A-C4B-C4B). Regarding C4 protein sequence polymorphism,

784-411: A group of female college students who smelled T-shirts worn by male students for two nights (without deodorant, cologne, or scented soaps), the majority of women chose shirts worn by men of dissimilar MHCs, a preference reversed if the women were on oral contraceptives. In 2005 in a group of 58 subjects, women were more indecisive when presented with MHCs like their own, although with oral contraceptives,

882-535: A hypothesis developed by Sharon Meglathery, a US psychiatrist, an author of a few publications on psychiatry, and oncology, highlights the links between certain autoimmune and psychiatric disorders due to variations in the RCCX cluster. According to the hypothesis, these variations contribute to the development of autoimmune disorders, such as lupus and rheumatoid arthritis, as well as psychiatric conditions, such as anxiety and depression. The hypothesis provides insights into

980-504: A mechanism by which schizophrenia could arise from the genetic predisposition of the human complement C4. As shown in Figure 1, four common structural variations discovered in genome-wide association studies (GWAS) studies have pointed to the high turnout of schizophrenia. Possibly, the higher levels of expression of C4 protein due to pattern of variants of the C4 gene, allows for the unwanted increase in synaptic pruning (an effect produced by

1078-444: A mechanism to effect genetic diversity. As discussed before, the different phenotypes allowed for by the varying genetic variety of complement C4 include a wide range of plasma or serum C4 proteins among two isotypes—C4A and C4B—with multiple protein allotypes that can have unique physiological functions. CNVs are sources of inherent genetic diversity and are engaged in gene-environment interaction. CNVs (and associated polymorphisms) play

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1176-523: A new strain nearly identical to one of the progenitor strains, but differing crucially in histocompatibility —that is, tissue compatibility upon transplantation—and thereupon identified an MHC locus . Later Jean Dausset demonstrated the existence of MHC genes in humans and described the first human leucocyte antigen, the protein which we call now HLA-A2. Some years later  Baruj Benacerraf showed that polymorphic MHC genes not only determine an individual’s unique constitution of antigens but also regulate

1274-441: A role in filling in the gap towards understanding the genetic basis of quantitative traits and the different susceptibilities to autoimmune and neurobiological diseases. Substantial data from all over the world has been collected and analyzed to determine that schizophrenia, indeed, has a strong genetic relationship with a region in the MHC locus on chromosome arm 6. Data and information collected internationally can shed light onto

1372-415: A role in regulating the activity of neuroblastoma RAS viral oncogene homolog (NRAS), a protein involved in cellular signaling. STK19 phosphorylates NRAS, which means it adds a phosphate functional group to NRAS. This phosphorylation event facilitates interactions between NRAS and its downstream effectors , which are molecules that carry out specific cellular functions. By increasing the activation of

1470-563: A theory that found support by studies by Ober and colleagues in 1997, as well as by Chaix and colleagues in 2008. However, the latter findings have been controversial. If it exists, the phenomenon 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

1568-407: A total of 24 polymorphic residues were found. Among them, the β-chain expressed of five, as the α-chain and γ-chain produced 18 and one, respectively. These polymorphisms can be further categorized into groups: 1) four isotypic residues at specific positions, 2) Ch/Rg antigenic determinants at specific positions, 3) C5 binding sites, 4) private allelic residues. Additionally, the same study identified

1666-414: A type of balancing selection, posits that common alleles are under greatest pathogenic pressure, driving positive selection of 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. Genetic drift is also a major driving force in some species. It

1764-445: Is actually a structural difference between the two variants. Moreover, they implicated that a lack of C4 activity could be attributed to the structural differences between the α-chains. Nevertheless, Carroll and Porter demonstrated that there is a 1,500-bp region that acts as an intron in the genomic sequence, which they believed to be the known C4d region, a byproduct of C4 activity. Carroll et al. later published work that characterized

1862-799: Is also associated with an increased risk of autoimmune diseases . Genetic variations in the RCCX module have been linked to many other disorders, including autism spectrum disorder , and drug addiction . The CYP21 gene is associated with developing congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH), a genetic disorder that affects the adrenal glands and causes cortisol deficiencies and excessive androgen biosynthesis (that may lead to virilization of female infants) and in severe cases also aldosterone deficiencies (that may lead to salt wasting - large amounts of sodium in urine that causes such life-threatening consequences as hypotension , hyponatremia , and hyperkalemic metabolic acidosis ). The TNXB gene, also known as tenascin-X,

1960-590: Is associated with such disorders of connective tissue, such as Ehlers-Danlos syndrome (EDS), characterized by joint hypermobility , skin hyperextensibility, and tissue fragility. Another disorder, when recombination events occur between a pseudogene TNXA and the functional gene TNXB within the RCCX module, resulting in CYP21A2 deletion along with impaired TNXB function, is called CAH-X Syndrome and leads to both congenital adrenal hyperplasia (CAH) symptoms and features consistent with EDS. This impaired function of

2058-497: Is cleaved by the protease into two parts, a peptide C4a (small at ~9 kDa, and anaphylotoxic ), and the higher molecular weight protein C4b, at about 190 kDa. The cleavage of the C4 results in C4b bearing a thioester functional group [-S-C(O)-]: work in the 1980s on C3, and then on C4, indicated the presence, within the parent C3 and C4 structures, of a unique protein modification, a 15-atom (15-membered) thionolactone ring serving to connect

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2156-856: Is formed by the N-terminal domains of both subunits of the heterodimer, α1 and β1, unlike MHC-I molecules, where two domains of the same chain are involved. In addition, both subunits of MHC-II contain transmembrane helix and immunoglobulin domains α2 or β2 that can be recognized by CD4 co-receptors. In this way, MHC molecules guide the type of lymphocytes that may bind to the given antigen with high affinity, as different lymphocytes express different T-Cell Receptor (TCR) co-receptors. MHC class II molecules in humans have five to six isotypes . Classical molecules present peptides to CD4+ lymphocytes. Nonclassical molecules , also known as accessories, have intracellular functions. They are not exposed on cell membranes, but are found in internal membranes, where they assist with

2254-453: Is much more extreme than in mammals in the sense that the sequence identity levels between alleles can be very low and the variation extends far beyond the peptide binding groove. It has been speculated that this type of MHC class I allelic variation contributes to allograft rejection, which may be especially important in fish to avoid grafting of cancer cells through their mucosal skin. The MHC locus (6p21.3) has 3 other paralogous loci in

2352-569: Is non-covalently bound to MHC-I, it is held by the several pockets on the floor of the peptide-binding groove . Amino acid side-chains that are most polymorphic in human alleles fill the central and widest portion of the binding groove, while conserved side-chains are clustered at the narrower ends of the groove. 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

2450-443: Is part of the major histocompatibility complex (MHC) class III ( MHC class III ), which is the most gene-dense region of the human genome, containing many genes that yet have unknown function or structure. RCCX modules exhibit a high degree of linkage disequilibrium , meaning that genes are inherited together more frequently than would be expected by chance. It indicates that there is a non-random association or correlation between

2548-468: Is possible that the combined effects of some or all of these factors cause the genetic diversity. MHC diversity has also been suggested as a possible indicator for conservation, because large, stable populations tend to display greater MHC diversity than smaller, isolated populations. Small, fragmented populations that have experienced a population bottleneck typically have lower MHC diversity. For example, relatively low MHC diversity has been observed in

2646-541: 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, and H60); the antigen/ligand for many of these molecules remain unknown, but they can interact with each of CD8+ T cells, NKT cells, and NK cells. The oldest evolutionary nonclassical MHC class I lineage in humans was deduced to be the lineage that includes the CD1 and PROCR (also known as EPCR ) molecules. This lineage may have been established before

2744-567: Is the tissue-antigen that allows the immune system (more specifically T cells) to bind to, recognize, and tolerate itself (autorecognition). MHC is also the chaperone for intracellular peptides that are complexed with MHCs and presented to T cell receptors (TCRs) as potential foreign antigens. MHC interacts with TCR 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. Essentially,

2842-436: Is thought to play a role in regulating their organization and function. The RCCX module is related to personality traits such as novelty seeking and impulsivity as major histocompatibility complex (MHC), where the RCCX module is located, may affect these traits through its role in immune function and neurodevelopment , still, the exact mechanisms are not fully understood. Variations in complement component C4 genes within

2940-517: Is triggered upon secondary exposure to similar antigens. B cells express MHC class II to present antigens to Th 0 , but when their B cell receptors bind matching epitopes, interactions which are not mediated by MHC, these activated B cells secrete soluble immunoglobulins: antibody molecules mediating humoral immunity . Class II MHC molecules are also heterodimers, genes for both α and β subunits are polymorphic and located within MHC class II subregion. The peptide-binding groove of MHC-II molecules

3038-511: Is very rare. In a monomodular structure, all of the genes are functional i.e. protein-coding , but if a module count is two or more, there is only one copy of each functional gene rest being non-coding pseudogenes with the exception of the C4 gene which always has active copies. Each copy of the C4 gene, due to five adjacent nucleotide substitutions cause four amino acid changes and immunological subfunctionalization (different functions related to

Complement component 4 - Misplaced Pages Continue

3136-653: The TNXB gene refers to the decreased production or abnormal structure of the tenascin-X protein due to genetic changes within the TNXB gene. The exact molecular mechanisms through which alterations or deficiencies in the TNXB gene or its impaired function lead to these conditions (the EDS and the CAH-X syndrome) are not fully understood yet but are believed to be related to defects in extracellular matrix organization and cell adhesion processes mediated by tenascin-X protein. An "RCCX theory",

3234-459: 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 of Tasmania , such that an antigen of a transmissible tumor, involved in devil facial tumour disease , appears to be recognized as

3332-555: The enzyme 21-hydroxylase involved in synthesizing cortisol and aldosterone . The TNXB gene encodes the Tenascin X , an extracellular matrix glycoprotein. Tenascin X is involved in the formation and maintenance of the extracellular matrix, which provides structural support and regulates cell behavior. It is also involved in tissue repair and regeneration and musculoskeletal development. Tenascin X interacts with other extracellular matrix proteins such as fibrillin-1 and collagen and

3430-517: The epitope —and displays it on the APC's surface coupled within an MHC class II molecule ( antigen presentation ). On the cell's surface, the epitope can be recognized by immunologic structures like T-cell receptors (TCRs). The molecular region which binds to the epitope is the paratope . On surfaces of helper T cells are CD4 receptors, as well as TCRs. When a naive helper T cell's CD4 molecule docks to an APC's MHC class II molecule, its TCR can meet and bind

3528-460: The mitogen-activated protein kinase (MAPK) cascade, STK19 ultimately influences cellular processes such as cell growth, proliferation, and differentiation. The C4 gene encodes the complement component 4 , which is involved in the complement system and is an important part of the innate immune system . The gene has two forms: C4A and C4B , encoding form A and B of the complement component 4 protein, respectively. The CYP21A2 gene encodes

3626-536: The steroid hormones cortisol , aldosterone , and androgen precursors, in extracellular matrix glycoprotein synthesis, and in innate immune system . The RP gene (a former name for the STK19 gene) is involved in cell growth and differentiation , but its exact functions remain unclear. Current knowledge suggests that the STK19 gene encodes the protein called nuclear serine/threonine kinase 19. This protein probably plays

3724-608: The C4 complex, laying down the foundations that paved the way to discovering the gene and protein structures. C. Yu successfully determined the complete sequence of the human complement component C4A gene. In the findings, the whole genome was found to have of 41 exons, with a total of 1744 residues (despite avoiding the sequence of a large Intron 9). The C4 protein is synthesized into a single chain precursor, which then undergoes proteolytic cleavage into three chains (in order of how they are chained, β-α-γ). The β-chain consists of 656 residues, coded by exons 1-16. The most prominent aspect of

3822-483: The C4 gene is also being investigated for the role it may play in schizophrenia risk and development. In the Wu et al. study, they utilized the real-time polymerase chain reaction (rt-PCR) as an assay to determine the copy number variance (CNV) or genetic diversity of C4. Accordingly, with these results, future prognoses, flares, and remissions will become more feasible to determine. The results basically show copy number variants as

3920-506: The C4 promoter at the nuclear factor 1, two E box (-98 to -93 and -78 to -73), and Sp1 binding domains. These findings were later added to in another extensive study, that found a third E box site. In addition, the same findings postulated that two physical entities within the gene sequence could have a role in the expression levels of human C4A and C4B, which include the both presence of the endogenous retrovirus that can have positive or negative regulatory influences affecting C4 transcription and

4018-620: The C4B gene may be associated with an increased risk of rheumatoid arthritis . The HERV-K retrovirus within the C4 gene has also been associated with autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis , probably because retrovirus may activate the C4 gene, leading to increased production of C4 proteins, which can contribute to autoimmune responses, and can probably lead to neuroinflammation , and increased risk of developing diseases such as schizophrenia and bipolar disorder . The presence of multiple RCCX modules

Complement component 4 - Misplaced Pages Continue

4116-734: The C4b-C2a complex of the two proteins then exhibits a further system-associated protease activity toward protein C3 (cleaving it), with subsequent release of both proteins, C4b and C2a, from their complex (whereupon C4b can bind another protein C2, and conduct these steps again). Because C4b is regenerated, and a cycle is created, the C4b-C2a complex with protease activity has been termed the C3 convertase. Protein 4b can be further cleaved into 4c and 4d. Although other diseases (i.e. systemic lupus erythematosus ) have been implicated,

4214-617: The H-2, whereas it has been referred to as the RT1 complex in rats, and the B locus in chickens. The MHC gene family is divided into three subgroups: MHC class I , MHC class II , and MHC class III . Among all those genes present in MHC, there are two types of genes coding for the proteins MHC class I molecules and MHC class II molecules that are directly involved in the antigen presentation . These genes are highly polymorphic, 19031 alleles of class I HLA, and 7183 of class II HLA are deposited for human in

4312-507: The IMGT database. MHC class I molecules are expressed in some nucleated cells and also in platelets —in essence all cells but red blood cells . It presents epitopes to killer T cells , also called cytotoxic T lymphocytes (CTLs). A CTL expresses CD8 receptors, in addition to T-cell receptors (TCRs). When a CTL's CD8 receptor docks to a MHC class I molecule, if the CTL's TCR fits the epitope within

4410-491: The MHC class I molecule, the CTL triggers the cell to undergo programmed cell death by apoptosis . Thus, MHC class I helps mediate cellular immunity , a primary means to address intracellular pathogens , such as viruses and some bacteria , including bacterial L forms , bacterial genus Mycoplasma , and bacterial genus Rickettsia . In humans, MHC class I comprises HLA-A , HLA-B , and HLA-C molecules. The first crystal structure of Class I MHC molecule, human HLA-A2,

4508-452: 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. RCCX RCCX is a complex, multiallelic, and tandem copy number variation (CNV) human DNA locus on chromosome 6p21.3, a cluster located in the major histocompatibility complex (MHC) class III region. CNVs are segments of DNA that vary in copy number compared to

4606-745: The MHC molecule interacts with the variable Ig-Like domain of the TCR to trigger T-cell activation Autoimmune reaction : The presence of certain MHC molecules can increase the risk of autoimmune diseases more than others. HLA-B27 is an example. It is unclear how exactly having the HLA-B27 tissue type increases the risk of ankylosing spondylitis and other associated inflammatory diseases, but mechanisms involving aberrant antigen presentation or T cell activation have been hypothesized. Tissue allorecognition : MHC molecules in complex with peptide epitopes are essentially ligands for TCRs. T cells become activated by binding to

4704-475: The MHC-peptide complex is a complex of auto-antigen/allo-antigen. Upon binding, T cells should in principle tolerate the auto-antigen, but activate when exposed to the allo-antigen. Disease states occur when this principle is disrupted. Antigen presentation : 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

4802-456: The RCCX module have been associated with psychiatric disorders such as schizophrenia and neurodegenerative diseases such as Alzheimer's disease . The RCCX module may be involved in developing autoimmune diseases such as rheumatoid arthritis , systemic lupus erythematosus , and multiple sclerosis : the C4A gene may be associated with an increased risk of systemic lupus erythematosus , while

4900-480: The Th cell's terminal differentiation. MHC class II thus mediates immunization to—or, if APCs polarize Th 0 cells principally to T reg cells, immune tolerance of—an antigen . The polarization during primary exposure to an antigen is key in determining a number of chronic diseases , such as inflammatory bowel diseases and asthma , by skewing the immune response that memory Th cells coordinate when their memory recall

4998-607: The UK, USA and Japan in Nature . It was a "virtual MHC" since it was a mosaic from different individuals. A much shorter MHC locus from chickens was published in the same issue of Nature . Many other species have been sequenced and the evolution of the MHC was studied, e.g. in the gray short-tailed opossum ( Monodelphis domestica ), a marsupial , MHC spans 3.95 Mb, yielding 114 genes, 87 shared with humans. Marsupial MHC genotypic variation lies between eutherian mammals and birds , taken as

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5096-431: The Z lineage was well conserved in ray-finned fish but lost in tetrapods is not understood. 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 takes up an antigenic protein, performs antigen processing , and returns a molecular fraction of it—a fraction termed

5194-421: The above situations, 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

5292-400: The alleles of different genes within the RCCX modules. The high degree of linkage disequilibrium observed in the RCCX modules suggests that the genes within this module are inherited as a group, rather than independently. This makes the RCCX module well-suited for genetic association studies, especially in the context of autoimmune diseases . The RCCX module is involved in the synthesis of

5390-722: The basal Metazoan Trichoplax adhaerens . In a transplant procedure, as of an organ or stem cells , MHC molecules themselves act as antigens and can provoke immune response in the recipient, thus causing 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 II alleles (one HLA-DP and -DQ, and one or two HLA-DR from each parent, and combinations of these). The MHC variation in

5488-425: The cell surface and short cytoplasmic tail. Two domains, α1 and α2, form deep peptide-binding groove between two long α-helices and the floor of the groove formed by eight β-strands. Immunoglobulin-like domain α3 involved in the interaction with CD8 co-receptor. β 2 microglobulin provides stability of the complex and participates in the recognition of peptide-MHC class I complex by CD8 co-receptor. The peptide

5586-439: The complement pathways (classical, alternative, and lectin); the alternative pathway is "triggered spontaneously," while the classical and lectin pathways are elicited in response to the recognition of particular microbes. All three pathways converge at a step in which complement protein C3 is cleaved into proteins C3a and C3b, which results in a lytic pathway and formation of a macromolecular assembly of multiple proteins, termed

5684-399: The difference in the number of genes included in the MHC of different species, the overall organization of the locus is rather similar. Usual MHC contains about a hundred genes and pseudogenes, not all of which are involved in immunity. In humans , the MHC region occurs on chromosome 6 , between the flanking genetic markers MOG and COL11A2 (from 6p22.1 to 6p21.3 about 29Mb to 33Mb on

5782-534: The different reactivities of the C4 genes. More specifically, the C4B has shown to react much more efficiently and effectively despite the 7 kb difference between C4A and C4B. In whole serum, C4B alleles performed at a rate several fold greater during hemolytic activity, in direct comparison with C4A alleles. Biochemically, they also found that C4A reacted more steadily with an antibody’s amino acid side chains and antigens that are amino groups, while C4B reacted better with carbohydrate hydroxyl groups. Thus, upon analysis of

5880-458: The effector proteins of the complement system in which the C4 partakes). Major histocompatibility complex The major histocompatibility complex ( MHC ) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system . These cell surface proteins are called MHC molecules . The name of this locus comes from its discovery through

5978-445: The elimination of the infected cell by the immune system. Diversity of an individual's self-antigen presentation , mediated by MHC self-antigens, is attained in at least three ways: (1) an organism's MHC repertoire is polygenic (via multiple, interacting genes); (2) MHC expression is codominant (from both sets of inherited alleles ); (3) MHC gene variants are highly polymorphic (diversely varying from organism to organism within

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6076-459: The ends involved in binding carbon terminal ends along the peptide Unlike classes I and II, Class III molecules have physiological roles and are encoded between classes I and II on 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 . MHC

6174-426: The epitope coupled within the MHC class II. This event primes the naive T cell . According to the local milieu, that is, the balance of cytokines secreted by APCs in the microenvironment, the naive helper T cell (Th 0 ) polarizes into either a memory Th cell or an effector Th cell of phenotype either type 1 (Th 1 ), type 2 (Th 2 ), type 17 (Th 17 ), or regulatory/suppressor (T reg ), as so far identified,

6272-406: The expression of human complement C4 transcripts in multiple tissues. The results of a Northern blot analysis, using a C4d probe and RD probe as positive control, showed that the liver contains the majority of transcripts throughout the body. Even so, moderate quantities were expressed in adrenal cortices/medulla, thyroid, and kidney. As noted, C4 (mixture of C4A and C4B) participates in all three of

6370-576: The four structural genes were located between HLA-B and HLA-D. More specifically, they verified the proposed molecular map in which the gene order went from factor B , C4B, C4A, and C2 with C2 nearest to HLA-B. In another study, Law et al. then continued to delve deeper, this time comparing the properties of both the C4A and C4B, both of which are substantial players in the human immunity system. Through methods that include incubation, different pH levels, and treatment with methylamine, they had biochemically illustrated

6468-534: The genetic basis of these disorders. It highlights the importance of considering both immunological and psychological factors in their diagnosis and treatment, suggesting shared genetic underpinnings of these disorders and aiming to bridge the gap between immunology and psychiatry, ultimately paving the way for more comprehensive approaches to diagnosis and treatment strategies for patients suffering from these conditions. Meglathery encountered obstacles in initiating bench research for her hypothesis such as skepticism from

6566-579: The hg38 assembly), and contains 224 genes spanning 3.6 mega base pairs (3 600 000 bases). About half have known immune functions. The human MHC is also called the HLA ( human leukocyte antigen ) complex (often just the HLA). Similarly, there is SLA (Swine leukocyte antigens), BoLA (Bovine leukocyte antigens), DLA for dogs, etc. However, historically, the MHC in mice is called the Histocompatibility system 2 or just

6664-427: The human C4 gene showed that all six of their clones contained the same C4 gene. The C4 protein consists of 3 subunits (α, β, and γ) having molecular weights (MWs) of ~95,000, 78,000, and 31,000, respectively and they are all joined by interchain disulfide bridges. In a study by Roos et al., the α-chains between the C4A and C4B were found to be slightly different (MW of ~96,000 and 94,000, respectively), proving that there

6762-457: The human genome, namely 19pl3.1, 9q33–q34, and 1q21–q25. It is believed that the loci arouse from the two-round duplications in vertebrates of a single ProtoMHC locus, and the new domain organizations of the MHC genes were a result of later cis-duplication and exon shuffling in a process termed "the MHC Big Bang." Genes in this locus are apparently linked to intracellular intrinsic immunity in

6860-405: 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 who are not identical twins, triplets, or higher order multiple births, will 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

6958-410: The immune system), can be of one of two types: C4A and C4B . Each C4 gene contains 41 exons and has a dichotomous size variation (existence of two distinct sizes) between approximately 22 kb and 16 kb, with the longer variant being the result of the integration of the endogenous retrovirus HERV-K (C4) into intron 9. The RCCX module is the most complex gene cluster in the human genome. It

7056-460: The interaction among the various cells of the immunological system. These three scientists have been awarded the 1980 Nobel Prize in Physiology or Medicine for their discoveries concerning “genetically determined structures on the cell surface that regulate immunological reactions”. The first fully sequenced and annotated MHC was published for humans in 1999 by a consortium of sequencing centers from

7154-403: The loading of antigenic peptides onto classic MHC class II molecules. The important nonclassical MHC class II molecule DM is only found from the evolutionary level of lungfish, although also in more primitive fishes both classical and nonclassical MHC class II are found. β 2 chain (12 KDa in humans) β chain (26–29 KDa in humans) helices, blocked at both the ends helices, opened at both

7252-415: The long C4 gene uniquely contains a retrovirus HERV-K(C4) in its intron 9 that imposes transcription of an extra 6.36 kb, hence the “longer” string of gene. Thus, C4 genes have a complex pattern of variation in gene size, copy number, and polymorphisms. Examples of these mono-, bi-, tri-, and quadri-modular structures include: L or S (monomodular with one long or short C4 gene), LL or LS or SS (bimodular with

7350-471: The membrane-attack complex (MAC), which serves as a pore in the membrane of the targeted pathogen, leading to invading cell disruption and eventual lysis. In the classical pathway, the complement component—hereafter abbreviated by the "C" preceding the protein number— termed C1s, a serine protease , is activated by upstream steps of the pathway, resulting in its cleavage of the native, parent ~200 kilodalton (kDa) C4 protein—composed of three chains. The C4

7448-552: The microbial surface, some portion of the released C4b proteins, with this reactive thionolactone, react with nucleophilic amino acid side chains and other groups on the foreign microbe's cell surface, resulting in covalent attachment of the slightly modified C4b protein to the cell surface, via the original Glx residue of C4. C4b has further functions. It interacts with protein C2; the same protease invoked earlier, C1s, then cleaves C2 into two parts, termed C2a and C2b, with C2b being released, and C2a remaining in association with C4b;

7546-536: The minimal MHC encoding, but is closer in organization to that of non mammals . The IPD-MHC Database was created which provides a centralised repository for sequences of the Major Histocompatibility Complex (MHC) from a number of different species. As of the release on December 19, 2019, the database contains information on 77 species. The MHC locus is present in all jawed vertebrates ; it is assumed to have arisen about 450 million years ago. Despite

7644-417: The mysteries of schizophrenia . Sekar et al. analyzed single nucleotide polymorphisms (SNP) of 40 cohorts in 22 countries, in total adding up to nearly 29,000 cases. They found out two features: 1) A great number of SNPs reaching only 2Mb across the end, 2) peak of association centered at C4, predicting that C4A expression levels is most strongly correlated with schizophrenia. In addition, they have discovered

7742-475: The number of incompatibilities, the lower the five-year survival rate. Global databases of donor information enhance the search for compatible donors. The involvement in allogeneic transplant rejection appears to be an ancient feature of MHC molecules, because also in fish associations between transplant rejections and (mis-)matching of MHC class I and MHC class II were observed. Human MHC class I and II are also called human leukocyte antigen (HLA). To clarify

7840-401: The origin of tetrapod species. However, the only nonclassical MHC class I lineage for which evidence exists that it was established before the evolutionary separation of Actinopterygii (ray-finned fish) and Sarcopterygii (lobe-finned fish plus tetrapods) is lineage Z of which members are found, together in each species with classical MHC class I, in lungfish and throughout ray-finned fishes; why

7938-515: The peptide-binding grooves of any MHC molecule that they were not trained to recognize during positive selection in the thymus . Peptides are processed and presented by two classical pathways: In their development in the thymus , T lymphocytes are selected to recognize the host's own MHC molecules, but not other self antigens. Following selection, each T lymphocyte shows dual specificity: The TCR recognizes self MHC, but only non-self antigens. MHC restriction occurs during lymphocyte development in

8036-521: The performance of the C4 proteins with the immune complex. Finally, by overlapping cDNA cloned fragments, they were able to determine that the C4 loci, an estimated 16 kilobase (kb) long, are spaced by 10 kb and aligned 30 kb from the factor B locus. In the same year, studies relatedly identified a 98 kb region of the chromosome the four class III genes (that express C4A, C4B, C2, and factor B) are closely linked, which does not allow for cross-overs to occur. Using protein variants visualized by electrophoresis,

8134-659: The polymorphic sites cluster in this region. The γ-chain consists of 291 residues, encoding exons 33-41. Unfortunately, no specific function has been attributed to the γ-chain. The study completed by Vaishnaw et al. sought to identify the key region and factors related to the efforts of gene expression of the C4 gene. Their research concluded with the fact that the Sp1 binding site (positioned at -59 to -49) plays an important role in accurately starting basal transcription of C4. Utilization of electromobility shift assays and DNase I footprint analyses demonstrated specific DNA-protein correlations of

8232-457: The population of protein molecules in a host cell, and greater MHC diversity permits greater diversity of antigen presentation . In 1976, Yamazaki et al demonstrated a sexual selection mate choice by male mice for females of a 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. MHC may be related to mate choice in some human populations,

8330-502: The presence (S+) or absence (s0/ s0) of four slow moving bands. The homogeneity or heterogeneity of the two loci, with the addition of these null (f0, s0) genes, allow for duplication/non-duplication of the C4 loci. Therefore, having separate loci for C4, C4F and C4S (later identified as C4A or C4B, respectively), possibly account for producing multiple allelic forms, leading to the great size and copy number variation . Two important contributors, Carroll and Porter, in their study of cloning

8428-532: The structure and organization of the C4 genes, which are situated in the HLA class III region and linked with C2 and factor B on the chromosome. Through experiments involving restriction mapping, nucleotide sequence analysis, and hybridization with C4A and C4B, they found that the genes are actually fairly similar though they have their differences. For example, single nucleotide polymorphisms were detected, which allowed them to be class differences between C4A and C4B. Furthermore, class and allelic differences would affect

8526-614: The study of transplanted tissue compatibility. Later studies revealed that tissue rejection due to incompatibility is only a facet of the full function of MHC molecules, which is to bind an antigen derived from self-proteins, or from pathogens, and bring the antigen presentation to the cell surface for recognition by the appropriate T-cells . MHC molecules mediate the interactions of leukocytes , also called white blood cells (WBCs), with other leukocytes or with body cells. The MHC determines donor compatibility for organ transplant , as well as one's susceptibility to autoimmune diseases . In

8624-433: The thiol side chain of the amino acid cysteine (Cys) in a -Cys-Gly-Glu-Glx- sequence with a side chain acyl group of what began as a glutamine side chain (Glx, here) that resided three amino acid residues downstream (where the remaining atoms of the 15 were backbone and side chain atoms); upon cleavage, this unique thionolactone ring structure becomes exposed at the surface of the new C4b protein. Because of proximity to

8722-814: 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 presenting 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 (i.e. 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 , though, recognize diverse epitopes— peptide , lipid , carbohydrate , and nucleic acid —and recognize conformational epitopes , which have three-dimensional structure.) MHC molecules enable immune system surveillance of

8820-489: The thymus, T lymphocytes are selected for their 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. There are various types of transplant rejection that are known to be mediated by MHC (HLA): In all of

8918-425: The two loci are linked to the HLA, or the human analog of the major histocompatibility complex (MHC) on the short arm of chromosome 6, whereas previously they were believed to have been expressed by two codominant alleles at a single locus. In gel electrophoresis studies, O’Neill et al. have identified two genetic variants: F, signifying the presence (F+) or absence (f0/ f0) of four fast moving bands, and S, signifying

9016-403: 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 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 . In humans,

9114-433: The varying genetic environment (dependent on which genetic modular component is present) past position -1524. To provide more context, in the latter study, the previously noted bimodular structure (C4A-C4B) has been updated to a quadrimodular structure of one to four discrete segments, containing one or more RP-C4-CYP21-TNX ( RCCX ) modules. The size of either C4A or C4B gene can be 21 kb (long, L) or 14.6 kb (short, S). Also,

9212-402: The varying reactivities, they proposed that the exceptional polymorphism of C4 genes may bring about some biological advantages (i.e. complement activation with a more extensive range of Ab-Ag complexes formed upon infections). Though at this point in time, the genomic and derived amino acid sequence of either C4A or C4B had yet to be determined. The early studies vastly expanded the knowledge of

9310-557: The women showed no particular preference. No studies show the extent to which odor preference determines mate selection (or vice versa). Most mammals have MHC variants similar to those of humans, who bear great allelic diversity , especially among the nine classical genes—seemingly due largely to gene duplication —though human MHC regions have many pseudogenes . The most diverse loci, namely HLA-A, HLA-B, and HLA-C, have roughly 6000, 7200, and 5800 known alleles, respectively. Many HLA alleles are ancient, sometimes of closer homology to

9408-516: The β-chain is the presence of a large intron, ranging from six to seven kilobases in size. It is present in the first locus (coding for C4A) for all C4 genes and in the second locus (coding for C4B) only in a few C4 genes. The α-chain consists of residues 661-1428, encoding exons 16-33. Within this chain, two cleavage sites marked by exons 23 and 30 produces the C4d fragment (where the thioester, Ch/Rg antigens, and isotypic residues are located); moreover, most of

9506-517: Was first mentioned in a 1994 article published in Immunogenetics , an academic journal, for a study by Dangel et al. The number of RCCX segments varies between one and four in a chromosome , with the prevalence of approximately 15% for monomodular, 75% for bimodular (STK19-C4A-CYP21A1P-TNXA-STK19B-C4B-CYP21A2-TNXB), and 10% for trimodular in Europeans. The quadrimodular structure of the RCCX unit

9604-436: Was published in 1989. The structure revealed that MHC-I molecules are heterodimers . They have a polymorphic heavy α-subunit whose gene occurs inside the MHC locus and small invariant β 2 microglobulin subunit whose gene is usually located outside of it. Polymorphic heavy chain of MHC-I molecule contains N-terminal extra-cellular region composed by three domains, α1, α2, and α3, transmembrane helix to hold MHC-I molecule on

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