HLA-DR is an MHC class II cell surface receptor encoded by the human leukocyte antigen complex on chromosome 6 region 6p21.31. The complex of HLA-DR ( H uman L eukocyte A ntigen – DR isotype) and peptide, generally between 9 and 30 amino acids in length, constitutes a ligand for the T-cell receptor (TCR). HLA ( human leukocyte antigens ) were originally defined as cell surface antigens that mediate graft-versus-host disease . Identification of these antigens has led to greater success and longevity in organ transplant.
41-432: Antigens most responsible for graft loss are HLA-DR (first six months), HLA-B (first two years), and HLA-A (long-term survival). Good matching of these antigens between host and donor is most critical for achieving graft survival. HLA-DR is also involved in several autoimmune conditions, disease susceptibility and disease resistance. It is also closely linked to HLA-DQ and this linkage often makes it difficult to resolve
82-580: A gene family that occurs in many species. Genes in this complex are separated into three basic groups: class I , class II , and class III . In humans, the HLA-B gene and two related genes, HLA-A and HLA-C , are the major genes in MHC class I. MHC class I genes provide instructions for making proteins that are present on the surface of almost all cells. On the cell surface, these proteins are bound to protein fragments ( peptides ) that have been exported from within
123-434: A gene that serves as an initial binding site—resulting in slightly modified transcripts and protein isoforms. Generally, one protein isoform is labeled as the canonical sequence based on criteria such as its prevalence and similarity to orthologous —or functionally analogous—sequences in other species. Isoforms are assumed to have similar functional properties, as most have similar sequences, and share some to most exons with
164-530: A group of related inflammatory joint diseases. Some of these diseases are associated with a common skin condition called psoriasis or chronic inflammatory bowel disorders ( Crohn's disease and ulcerative colitis ). One of the spondyloarthropathies, reactive arthritis , is typically triggered by bacterial infections of the gastrointestinal or genital tract. Following an infection, affected individuals may develop arthritis, back pain, and eye inflammation. Like ankylosing spondylitis, many factors probably contribute to
205-413: A severe skin disorder called Stevens–Johnson syndrome in response to carbamazepine (a drug used to treat seizures). Another version, HLA-B*5801, is associated with an increased risk of severe skin reactions in people treated with allopurinol (a drug used to treat gout , which is a form of arthritis caused by uric acid in the joints). Among people with human immunodeficiency virus (HIV) infection,
246-548: A single individual, and no more than two on a single chromosome. Sometimes an individual may only possess 2 copies of the same locus, DRB1*. The HLA-DRB1 locus is ubiquitous and encodes a very large number of functionally variable gene products ( HLA-DR1 to HLA-DR17 ). The HLA-DRB3 locus encodes the HLA-DR52 specificity, is moderately variable and is variably associated with certain HLA-DRB1 types. The HLA-DRB4 locus encodes
287-474: A version of HLA-B designated HLA-B*5701 is associated with an extreme sensitivity to abacavir . This drug is a treatment for HIV-1 that slows the spread of the virus in the body. People with abacavir hypersensitivity often develop a fever, chills, rash, upset stomach, and other symptoms when treated with this drug. Several other variations of the HLA-B gene appear to play a role in the progression of HIV infection to acquired immunodeficiency syndrome ( AIDS ). AIDS
328-432: Is a human gene that provides instructions for making a protein that plays a critical role in the immune system . HLA-B is part of a family of genes called the human leukocyte antigen (HLA) complex. The HLA complex helps the immune system distinguish the body's own proteins from proteins made by foreign invaders such as viruses and bacteria . HLA is the human version of the major histocompatibility complex (MHC),
369-435: Is a disease that damages the immune system, preventing it from effectively defending the body against infections. The signs and symptoms of AIDS may not appear until 10 years or more after infection with HIV. Studies suggest that people with HIV infection who have HLA-B27 or HLA-B57 tend to progress more slowly than usual to AIDS. On the other hand, researchers believe that HIV-positive individuals who have HLA-B35 tend to develop
410-526: Is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have unique functions. A set of protein isoforms may be formed from alternative splicings , variable promoter usage, or other post-transcriptional modifications of a single gene; post-translational modifications are generally not considered. (For that, see Proteoforms .) Through RNA splicing mechanisms, mRNA has
451-399: Is given a particular number (such as HLA-B27 ). Closely related alleles are categorized together; for example, at least 28 very similar alleles are subtypes of HLA-B27. These subtypes are designated as HLA-B*2701 to HLA-B*2728. The HLA-B gene is located on the short (p) arm of chromosome 6 at cytoband 21.3, from base pair 31,353,871 to 31,357,211 Ankylosing spondylitis : A version of
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#1732790486187492-532: Is no conclusive evidence that it acts primarily by producing novel protein isoforms. Alternative splicing generally describes a tightly regulated process in which alternative transcripts are intentionally generated by the splicing machinery. However, such transcripts are also produced by splicing errors in a process called "noisy splicing," and are also potentially translated into protein isoforms. Although ~95% of multi-exonic genes are thought to be alternatively spliced, one study on noisy splicing observed that most of
533-415: Is often in response to stimulation, and, therefore, DR is also a marker for immune stimulation. HLA-DR is an αβ heterodimer , cell surface receptor , each subunit of which contains two extracellular domains, a membrane-spanning domain and a cytoplasmic tail. Both α and β chains are anchored in the membrane. The N-terminal domain of the mature protein forms an alpha-helix that constitutes the exposed part of
574-543: Is often used as a proxy for the abundance of protein isoforms, though proteomics experiments using gel electrophoresis and mass spectrometry have demonstrated that the correlation between transcript and protein counts is often low, and that one protein isoform is usually dominant. One 2015 study states that the cause of this discrepancy likely occurs after translation, though the mechanism is essentially unknown. Consequently, although alternative splicing has been implicated as an important link between variation and disease, there
615-558: Is possible to assert that more than a dozen major variants survived the population bottleneck. This observation is supported by the concept of a heterozygous selection coefficient operating on the HLA-DR, and at the HLA-DRB1 locus to a greater degree relative to HLA-DQB1 and HLA-DPB1 . Most of the HLA alleles currently present in the human population can be explained by gene conversion between these ancient ancestral types, some that persist into
656-450: Is rapidly evolving, much more rapidly than almost all other protein encoding loci. Much of the variation at HLA DRB1 occurs at peptide contact positions in the binding groove, as a result many of the alleles alter the way the DR binds peptide ligands and changes the repertoire each receptor can bind. This means that most of the changes are functional in nature, and therefore are under selection. In
697-692: Is the main post-transcriptional modification process that produces mRNA transcript isoforms, and is a major molecular mechanism that may contribute to protein diversity. The spliceosome , a large ribonucleoprotein , is the molecular machine inside the nucleus responsible for RNA cleavage and ligation , removing non-protein coding segments ( introns ). Because splicing is a process that occurs between transcription and translation , its primary effects have mainly been studied through genomics techniques—for example, microarray analyses and RNA sequencing have been used to identify alternatively spliced transcripts and measure their abundances. Transcript abundance
738-415: Is to present peptide antigens, potentially foreign in origin, to the immune system for the purpose of eliciting or suppressing T-(helper)-cell responses that eventually lead to the production of antibodies against the same peptide antigen. Antigen-presenting cells (macrophages, B-cells and dendritic cells ) are the cells in which DR are typically found. Increased abundance of DR 'antigen' on the cell surface
779-507: The 5' AMP-activated protein kinase (AMPK), an enzyme, which performs different roles in human cells, has 3 subunits: In human skeletal muscle, the preferred form is α2β2γ1. But in the human liver, the most abundant form is α1β2γ1. The primary mechanisms that produce protein isoforms are alternative splicing and variable promoter usage, though modifications due to genetic changes, such as mutations and polymorphisms are sometimes also considered distinct isoforms. Alternative splicing
820-599: The HLA-DR53 specificity, has some variation, and is associated with certain HLA-DRB1 types. The HLA-DRB5 locus encodes the HLA-DR51 specificity, which is typically invariable, and is linked to the HLA-DR2 types. There is a high level of allelic diversity at HLA DRB1, it is second only to HLA-B locus in number of allelic variants. These two loci are highest sequence variation rate within human genome. This means HLA-DRB1
861-520: The HLA-DRA locus . Unlike the other DR loci, functional variation in mature DRA gene products is absent. (Note: see table Number of Variant Alleles HLA-DR Loci - reduces the potential functional combinations from ~1400 to ~400 ([table is not exact because new alleles are continually being added; not all new alleles are functional variants of the mature subunits]). The DR β-chain is encoded by 4 loci, however no more than 3 functional loci are present in
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#1732790486187902-562: The HLA region, genes are under heterozygous or balancing selection, although certain alleles appear to be under positive or negative selection, either in the past or present HLA generally evolve through a process of gene conversion , which is a form of short distance or 'abortive' genetic recombination . Functional motifs in genes are exchanged to form new alleles, and frequently new, functionally different DR isoforms . HLA-DR represents an extreme example of this. A survey of X-linked loci reveals that most human loci have undergone fixation within
943-487: The HLA-B gene called HLA-B27 increases the risk of developing ankylosing spondylitis. It is uncertain how HLA-B27 causes this increased risk. Researchers speculate that HLA-B27 may abnormally display to the immune system peptides that trigger arthritis. Other research suggests that joint inflammation characteristic of this disorder may result from improper folding of the HLA-B27 protein or the presence of abnormal forms of
984-456: The ability to select different protein-coding segments ( exons ) of a gene, or even different parts of exons from RNA to form different mRNA sequences. Each unique sequence produces a specific form of a protein. The discovery of isoforms could explain the discrepancy between the small number of protein coding regions of genes revealed by the human genome project and the large diversity of proteins seen in an organism: different proteins encoded by
1025-470: The binding groove, the C-terminal cytoplasmic region interact with the other chain forming a beta-sheet under the binding groove spanning to the cell membrane. The majority of the peptide contact positions are in the first 80 residues of each chain. The genetics of HLA-DR is complex. HLA-DR is encoded by several loci and several 'genes' of different function at each locus. The DR α-chain is encoded by
1066-491: The canonical sequence. However, some isoforms show much greater divergence (for example, through trans-splicing ), and can share few to no exons with the canonical sequence. In addition, they can have different biological effects—for example, in an extreme case, the function of one isoform can promote cell survival, while another promotes cell death—or can have similar basic functions but differ in their sub-cellular localization. A 2016 study, however, functionally characterized all
1107-418: The cell. MHC class I proteins display these peptides to the immune system. If the immune system recognizes the peptides as foreign (such as viral or bacterial peptides), it responds by destroying the infected cell. The HLA-B gene has many different normal variations, allowing each person's immune system to react to a wide range of foreign invaders. Hundreds of versions (alleles) of HLA-B are known, each of which
1148-525: The development of reactive arthritis and other spondyloarthropathies. A large number of studies have shown an association between HLA-B51 And Behçet's disease . Other disorders: Several variations of the HLA-B gene are associated with adverse reactions to certain drugs. For example, two specific versions of this gene are related to increased drug sensitivity among the Han Chinese population. Individuals who have HLA-B*1502 are more likely to experience
1189-486: The different low-abundance transcripts are noise, and predicts that most alternative transcript and protein isoforms present in a cell are not functionally relevant. Other transcriptional and post-transcriptional regulatory steps can also produce different protein isoforms. Variable promoter usage occurs when the transcriptional machinery of a cell ( RNA polymerase , transcription factors , and other enzymes ) begin transcription at different promoters—the region of DNA near
1230-1626: The extant population. The table below provides links to subpages with information about distribution, genetic linkage and disease association for the HLA-DR serogroups. DRB1 is linked with other DRB loci in four ways. HLA-B 3VCL , 4U1H , 4U1K , 5EO1 , 5EO0 ,%%s 1AGB , 1AGC , 1AGD , 1AGE , 1AGF , 1M05 , 1MI5 , 3FFC , 3SJV , 3SKM , 3SKO , 3SPV , 3X13 , 3X14 , 4QRP , 4QRQ , 4QRS , 4QRT , 4QRU ,%%s 4O2C , 4O2E , 4O2F ,%%s 3LN4 , 3LN5 ,%%s 4U1J , 4U1M , 4U1N ,%%s 4U1I , 4U1L , 4U1S ,%%s 1HSA , 1JGD , 1JGE , 1K5N , 1OF2 , 1OGT , 1UXS , 1UXW , 1W0V , 1W0W , 2A83 , 2BSR , 2BSS , 2BST , 3B3I , 3B6S , 3BP4 , 3BP7 , 3CZF , 3D18 , 3DTX , 3HCV , 3LV3 , 4G8G , 4G8I , 4G9D , 4G9F , 5DEF , 5DEG ,%%s 1A1N , 1A9B , 1A9E , 1CG9 , 1XH3 , 1ZHK , 1ZHL , 1ZSD , 2AK4 , 2AXF , 2AXG , 2H6P , 2NW3 , 2NX5 , 3BW9 , 3BWA , 3KWW , 3KXF , 3LKN , 3LKO , 3LKP , 3LKQ , 3LKR , 3LKS , 3MV7 , 3MV8 , 3MV9 , 3VFS , 3VFT , 3VFU , 3VFV , 3VFW , 4LNR , 4PR5 , 4PRN , 4QRR ,%%s 1A1M , 1A1O ,%%s 2BVO , 2BVP , 2BVQ , 2HJL , 2RFX , 2YPK , 2YPL , 3UPR , 3VH8 , 3VRI , 3VRJ , 3WUW , 3X11 , 3X12 , 5B39 , 5B38 ,%%s 4JQV , 4XXC ,%%s 1XR8 , 1XR9 , 3C9N ,%%s 4LCY ,%%s 1M6O , 1N2R , 1SYV , 3DX6 , 3DX7 , 3DX8 , 3DXA , 3KPL , 3KPM , 3KPN , 3KPO , 3KPP , 3KPQ , 3KPR , 3KPS , 3L3D , 3L3G , 3L3I , 3L3J , 4JQX ,%%s 1E27 , 1E28 , 4MJI ,%%s 3W39 3106 n/a ENSG00000232126 n/a P01889 n/a NM_005514 n/a NP_005505 n/a HLA-B ( major histocompatibility complex, class I, B )
1271-464: The function of each isoform must generally be determined separately, most identified and predicted isoforms still have unknown functions. A glycoform is an isoform of a protein that differs only with respect to the number or type of attached glycan . Glycoproteins often consist of a number of different glycoforms, with alterations in the attached saccharide or oligosaccharide . These modifications may result from differences in biosynthesis during
HLA-DR - Misplaced Pages Continue
1312-413: The isoforms of 1,492 genes and determined that most isoforms behave as "functional alloforms." The authors came to the conclusion that isoforms behave like distinct proteins after observing that the functional of most isoforms did not overlap. Because the study was conducted on cells in vitro , it is not known if the isoforms in the expressed human proteome share these characteristics. Additionally, because
1353-421: The last 600,000 years, and diploid loci have undergone significant proportion of fixation in that period of time. The level of deep branching at X-linked loci indicates loci were close to fixation or fixed at the end of the human population bottleneck 100,000 to 150,000 years ago. The HLA-DR locus represents a major exception to this observation. Based on distribution of major groupings in the human population it
1394-432: The more causative factor in disease. HLA-DR molecules are upregulated in response to signalling. In the instance of an infection, the peptide (such as the staphylococcal enterotoxin I peptide) is bound into a DR molecule and presented to a few of a great many T-cell receptors found on T-helper cells. These cells then bind to antigens on the surface of B-cells stimulating B-cell proliferation. The primary function of HLA-DR
1435-477: The parasite that causes malaria. HLA-B is one of three major HLAs that should be matched between donors and recipients. They are HLA-A, HLA-B, (both Class I MHCs) and HLA-DR (a Class II MHC). If the two tissues have the same genes coding for these three HLAs, the likelihood and severity of rejection is minimized. This article incorporates public domain text from The U.S. National Library of Medicine Isoform A protein isoform , or " protein variant ",
1476-404: The process of glycosylation , or due to the action of glycosidases or glycosyltransferases . Glycoforms may be detected through detailed chemical analysis of separated glycoforms, but more conveniently detected through differential reaction with lectins , as in lectin affinity chromatography and lectin affinity electrophoresis . Typical examples of glycoproteins consisting of glycoforms are
1517-422: The protein on the cell surface. Although most patients with ankylosing spondylitis have the HLA-B27 variation, many people with this particular variation never develop the disorder. Other genetic and environmental factors are likely to affect the chances of developing ankylosing spondylitis and influence its progression. In addition to Ankylosing spondylitis, HLA-B27 is associated with other spondyloarthropathies ,
1558-472: The same gene could increase the diversity of the proteome . Isoforms at the RNA level are readily characterized by cDNA transcript studies. Many human genes possess confirmed alternative splicing isoforms. It has been estimated that ~100,000 expressed sequence tags ( ESTs ) can be identified in humans. Isoforms at the protein level can manifest in the deletion of whole domains or shorter loops, usually located on
1599-500: The signs and symptoms of AIDS more quickly than usual. Other factors also influence the progression of HIV to AIDS. Another version of the HLA-B gene, HLA-B53, has been shown to help protect against severe malaria. HLA-B53 is most common in West African populations, where malaria is a frequent cause of death in children. Researchers suggest that this version of the HLA-B gene may help the immune system respond more effectively to
1640-438: The structure of most isoforms in the human proteome has been predicted by AlphaFold and publicly released at isoform.io . The specificity of translated isoforms is derived by the protein's structure/function, as well as the cell type and developmental stage during which they are produced. Determining specificity becomes more complicated when a protein has multiple subunits and each subunit has multiple isoforms. For example,
1681-565: The surface of the protein. One single gene has the ability to produce multiple proteins that differ both in structure and composition; this process is regulated by the alternative splicing of mRNA, though it is not clear to what extent such a process affects the diversity of the human proteome, as the abundance of mRNA transcript isoforms does not necessarily correlate with the abundance of protein isoforms. Three-dimensional protein structure comparisons can be used to help determine which, if any, isoforms represent functional protein products, and