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Encyclopedia > Human leukocyte antigen
HLA region of Chromosome 6

The human leukocyte antigen system (HLA) is the name of the human major histocompatibility complex (MHC). This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins. The chance of two non-identical individuals having identical HLA molecules on all loci is very low, except for siblings, which have a 25% chance of being HLA-identical. Image File history File links No higher resolution available. ... MHC I (1hsa) vs MHC II (1dlh) (more details. ... Chromosome 6 is one of the 23 pairs of chromosomes in humans. ... An antigen is a molecule that stimulates an immune response. ... Short and long arms Chromosome. ...

Contents

Classification of HLAs/alleles

There are two parallel systems of nomenclature that are applied to HLA. The, first, and oldest system is based on serological (antibody based) recognition. In this system antigens were eventually assign letters and numbers (e.g. HLA-B27 or, shortened, B27). A parallel system was developed that allowed more refined definition of alleles, in this system a "HLA" is used in conjunction with a letter * and four or more digit number (e.g. HLA-B*0801, A*68011, A*240201N N=Null) to designate a specific allele at a given HLA locus. HLA loci can be further classified into MHC class I and MHC class II (or rarely, D locus). Every two years a nomenclature is put forth to aid researchers in interpreting serotypes to alleles.[1] Human Leukocyte Antigen B*27 (subtypes B*2701-2724) is a class I surface antigen encoded by the B locus in the major histocompatibility complex (MHC) on chromosome 6. ... For the hard rock band, see Allele (band). ... Short and long arms Chromosome. ... MHC class I molecules are cell surface proteins found on most cells of the body. ... The major histocompatibility complex (MHC) is a large genomic region or gene family found in most vertebrates. ...


There are 3 major Class I HLA genes: HLA-A, HLA-B and HLA-C (minor genes are HLA-E, HLA-F and HLA-G). HLA Class I gene products combine with β2-Microglobulin protein to form a functional receptor on most nucleated cells of the body.


The genes of the Class II combine to form heterodimeric (αβ) protein receptors that are typically expressed on the surface of antigen presenting cells. The alpha subunit is encoded by the "A" (or "A1") locus and the beta subunit are encoded by the "B" ("B1" of DP and DQ; "B1","B3","B4",or "B5" of DR). The HLA-DP protein is encoded at the HLA-DPA1 and HLA-DPB1 loci and the HLA-DQ protein is encoded at the HLA-DQA1 and HLA-DQB1 loci. The HLA-DR antigens have a more complex encoding, the alpha chain is encoded by a single gene, HLA-DRA (with few minor variants), but the beta subunit is encoded by HLA-DRB1 locus and other minor loci (HLA-DRB3, -DRB4, -DRB5) appear variably from inidividual to individual. The most intensely studied HLA genes are the nine so-called classical MHC genes: are Class I genes , HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, and HLA-DRB1. ... HLA-DP is a protein/peptide-antigen receptor and graft-versus-host disease antigen that is composed of 2 subunits, DPα and DPβ. DPα and DPβ are encoded by two loci, HLA-DPA1 and HLA-DPB1, that are found in the MHC Class II (or HLA-D) region in the... HLA DQ is a protein/peptide-antigen receptor and graft-versus-host disease antigen that is composed of 2 subunits DQα and DQβ. DQα and DQβ are encoded by two loci, HLA-DQA1 and HLA-DQB1 which are found in the MHC Class II (or HLA-D) region in the... HLA-DR antigens are a group of antigens in the Class II/HLA-D family which can be used as indicators of several different diseases (per MeSH): HLA-DR1 Antigen - unknown HLA-DR2 Antigen - Goodpasture syndrome, multiple sclerosis, and narcolepsy HLA-DR3 Antigen - celiac disease, Graves disease, dermatitis herpetiformis... HLA-DR antigens are a group of antigens in the Class II/HLA-D family which can be used as indicators of several different diseases (per MeSH): HLA-DR1 Antigen - unknown HLA-DR2 Antigen - Goodpasture syndrome, multiple sclerosis, and narcolepsy HLA-DR3 Antigen - celiac disease, Graves disease, dermatitis herpetiformis...


Besides functional HLA antigens, there are two additional HLA antigens in humans, HLA-DM and HLA-DO, which are important in loading the antigenic peptides generated from pathogens onto the HLA molecules of antigen-presenting cell. An antigen-presenting cell (APC) is a cell that displays foreign antigen complexed with MHC on its surface. ...


HLA are extremely variable loci

MHC loci are some of the most genetically variable coding loci in mammals, and the human HLA loci are no exception. Despite the fact that the human population went through a constriction >150kya that was capable of fixing many loci, the HLA loci appear to have survived such a constriction with a great deal of variation. Of the 9 loci mentioned above, most retained a dozen or more allele-groups for each locus, far more preserved variation than the vast majority of human loci. This is consistent with a heterozygous or balancing selection coefficient for these loci. In addition, some HLA Loci are among the fastest evolving coding regions in the human genome. One mechanism of diversification has been noted in the study of Amazonian tribes of South America that appear to have undergone intense gene conversion between variable alleles and loci within each HLA gene class.[2] Less frequently, longer range productive recombinations through HLA genes have been noted producing chimeric genes. Gene conversion is a phenomenon which occurs during meiotic division. ...


Five loci have over 100 alleles that have been detected in the human population, of these the most variable are HLA B and HLA DRB1. As of 2004 the number of alleles have been determined are listed in the table to the right. To interpret this table simply remember that an allele is a variant of the nucleotide (DNA) sequence at a locus, such that each allele differs from all other alleles in a least one (single nucleotide polymorphism, SNP) position. Most of these changes result in a change in the amino acid sequences that result in slight to major functional differences in the protein.


There are issues that limit this variation. Certain alleles like DQA1*0501 and DQA1*0505 encode proteins with identically processed products. Other proteins like DQB1*0201 and DQB1*0202 produce proteins that are functionally similar. For class II (DR, DP and DQ), amino acid variants within the receptor's peptide binding cleft tend to produce molecules with different binding capability.


Tables of variant alleles

Number of Variant Alleles at Class I Loci:

MHC Class I
Locus #[1]
Major Antigens
HLA A 349
HLA B 627
HLA C 182
Minor Antigens
HLA E 5
HLA F 2
HLA G 15

Number of Variant Alleles at Class II Loci (DP and DQ):

MHC Class II
HLA -A1 -B1 -B3 to -B51 Potential
Locus #[1] #[1] #[1] Combinations
DM- 4 7 28
DO- 8 9 72
DP- 22 116 2552
DQ- 28 61 1708
DR- 3 394 72 1398
1DRB3, DRB4, DRB5 have variable presense in humans

Serotypes versus Genotypes

Long before PCR based gene sequencing and gene identification were available, these antigens were recognized as factors interfering with or, occasionally, permitting successful transplantion. Donor organs transplanted into recipients elicit antibodies against the donor's tissues and turning the donor's HLA receptors into antigens of the recipients immune system, hence the name 'human leucotrophic antigens'. The types of receptors could be classified based on the antibodies they produced. These antibodies, particularly to donor's who were homozygotes of a particular Class II haplotype could be used to identify different receptor types and isoforms. In order to create a typing reagent, blood from animals or humans would be taken, the blood cells allowed to separate from the sera, and the sera diluted to its optimal sensitivity and used to type cells from other individuals or animals. Thus serotyping became a way of crudely identifying HLA receptors and receptor isoforms. Over the years serotyping antibodies became more refined as techniques for increasing sensitivity improved and new serotyping antibodies continue to appear. One of the goals of serotype analysis is to fill gaps in the analysis. It is possible to predict based on 'square root','maximum-likelihood' method, or analysis of familial haplotypes to account for adequately typed alleles. These studies using serotyping techniques frequently revealed, particularly for non-european or north east Asian populations a large number of null or blank serotypes. This was particularly problematic for the Cw locus until recently, and almost half of the Cw serotypes went untyped in the 1991 survey of the human population. Wikipedia does not yet have an article with this exact name. ... Gene sequencing refers to the process of recording the exact sequence of nucleotides in the section of an organisms DNA corresponding to a specific gene. ... An antigen is any molecule that is recognized by antibodies. ... Receptor may refer to: In telecommunication, a receiver. ... A haplotype is the genetic constitution of an individual chromosome. ...


There are several types of serotypes. A broad antigen serotype is a crude measure of identity of cells. For example HLA A9 serotype recognizes cells of A23 and A24 bearing individuals, it may also recognize cells that A23 and A24 miss because of small variations. A23 and A24 are split antigens, but antibodies specific to either are typically used more often than antibodies to broad antigens. Minor reactions to subregions that show similarity to other types can be observed to the gene products of alleles of a serotype group. The sequence of the antigens determines the antibody reactivities and so having a good sequencing capability (or sequence based typing) obviates then need for serological reactions. Broad antigen types are still useful, such as typing very diverse populations with many unidentified HLA alleles (Africa, Arabia,[3] Southeastern Iran[4] and Pakistan, India[5]). Southern Iran and Arabia shows the difficulty in typing more ancient areas, allelic diversity makes it necessary to use broad antigen typing followed by sequencing because there is an increased risk of misidentifying by serotyping techiniques.


In the end, a workshop, based on sequence, decides which new allele goes into which serogroup either by sequence or reactivity. Once the sequence is verified it is assigned a number. For example, a new allele of B44 May get a serotype B*4465 as it is the 65th B44 allele discovered. Marsh et al. (2005)[1] can be considered a code book for HLA serotypes and genotypes and a new book biannually with monthly updates in Tissue Antigens. Because genetyping is based on PCR it is possible that new variants, particularly in the Class I and DRB1 locus may be missed.


Importance of HLA allelic variation

Studies of humans and other animals infer a heterozygous selection mechanism operating on these loci as an explanation for this exceptional variability.[6] One credible mechanism is sexual selection in which females are able to detect males with different HLA relative to their own type.[7] While the DQ and DP encoding loci have fewer alleles combinations of A1:B1 can produce a theoretical potential of 1586 DQ and 2552 DP αβ heterodimers, respectively. While certainly nowhere near this number of isoforms exist in the human population, each individual can carry 4 variable DQ and DP isoforms increasing the potential number of antigens that these receptors can present to the immune system in individual immune system. Studies of the variable positions of DP, DR, and DQ reveal that peptide antigen contact residues on Class II molecules are most frequently the site of variation in the protein primary structure. Therefore, through a combination of intense allelic variation and/or subunit pairing the Class II 'peptide' receptors are capable of binding an almost endless variation of peptides of 9 amino acids or longer in length, protecting interbreeding subpopulations from nascent or epidemic diseases. Individuals in a population have frequently different haplotypes and as a result many combinations, even in small groups, affords the survival of the groups and thwarts evolution of epitopes in pathogens to hide from the immune system.


HLA functions

The proteins encoded by HLAs are the proteins on the outer part of body cells that are (effectively) unique to that person. The immune system uses the HLAs to differentiate self cells and non-self cells. Any cell displaying that person's HLA type belongs to that person (and therefore is not an invader). A representation of the 3D structure of myoglobin, showing coloured alpha helices. ... A scanning electron microscope image of a single neutrophil (yellow), engulfing anthrax bacteria (orange). ...


In infectious disease. When a foreign pathogen enters the body, specific cells called antigen-presenting cells (APCs) engulf the pathogen through a process called phagocytosis. Proteins from the pathogen are digested into small pieces (peptides) and loaded onto HLA antigens (specifically MHC class II). They are then displayed by the antigen presenting cells for certain cells of the immune system called T cells, which then produce a variety of effects to eliminate the pathogen. A pathogen or infectious agent is a biological agent that causes disease or illness to its host. ... Drawing of the structure of cork as it appeared under the microscope to Robert Hook from Micrographia which is the origin of the word cell. POOP Cells in culture, stained for keratin (red) and DNA (green). ... An antigen-presenting cell (APC) is a cell that displays foreign antigen complexed with MHC on its surface. ... Phagocytosis is a form of endocytosis wherein large particles are enveloped by the cell membrane of a (usually larger) cell and internalized to form a phagosome, or food vacuole. ... Peptides (from the Greek πεπτος, digestible), are the family of short molecules formed from the linking, in a defined order, of various α-amino acids. ... The major histocompatibility complex (MHC) is a large genomic region or gene family found in most vertebrates. ... An antigen presenting cell (APC) is a cell that displays foreign antigen complexed with MHC on its surface. ... T cells are a subset of lymphocytes that play a large role in the immune response. ...


Through a similar process, proteins (both native and foreign, such as the proteins of viruses) produced inside most cells are displayed on HLA antigens (specifically MHC class I) on the cell surface. Infected cells can be recognized and destroyed by components of the immune system (specifically CD8+ T cells). A representation of the 3D structure of myoglobin, showing coloured alpha helices. ... Groups I: dsDNA viruses II: ssDNA viruses III: dsRNA viruses IV: (+)ssRNA viruses V: (-)ssRNA viruses VI: ssRNA-RT viruses VII: dsDNA-RT viruses A virus (from the Latin noun virus, meaning toxin or poison) is a microscopic particle (ranging in size from 20 - 300 nm) that can infect the... MHC class I molecules are cell surface proteins found on most cells of the body. ... T cells are a subset of lymphocytes that play a large role in the immune response. ...


In graft rejection. Any cell displaying some other HLA type is "non-self" and is an invader, resulting in the rejection of the tissue bearing those cells. Because of the importance of HLA in transplantation, the HLA loci are amoung of the most frequently typed by serology or PCR relative to any other autosomal alleles.


In autoimmunity. HLA types are inherited, and some of them are connected with autoimmune disorders and other diseases. People with certain HLA antigens are more likely to develop certain autoimmune diseases, such as Ankylosing spondylitis, Celiac Disease, SLE (Lupus erythematosus), Myasthenia Gravis, inclusion body myositis and Sjögren's Syndrome. HLA typing has lead to some improvement and acceleration in the diagnosis of Celiac Disease and Type 1 diabetes; however for DQ2 typing to be useful it requires either high resolution B1*typing (resolving *0201 from *0202), DQA1*typing, or DR serotyping. Current serotyping can resolve, in one step, DQ8. HLA typing in autoimmunity is being increasingly used as a tool in diagnosis. In GSE is the only effective means of determing 1st degree relative who are at risk from those who are not at risk, prior to the appearance of sometimes irreversible symptoms such a allergies and secondary autoimmune disease. Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. ... Coeliac disease (also termed non-tropical sprue, celiac disease and gluten intolerance) is an autoimmune disease characterised by chronic inflammation of the proximal portion of the small intestine caused by exposure to certain dietary gluten proteins. ... Myasthenia gravis (sometimes abbreviated MG; from the Greek myastheneia, lit. ... Inclusion body myositis (IBM) is an inflammatory muscle disease, characterized by slowly progressive wasting and weakness of the arms and legs. ... Sjögrens syndrome is an autoimmune disorder in which immune cells attack and destroy the glands that produce tears and saliva. ... Coeliac disease or celiac disease is an autoimmune disorder of the small bowel that occurs in genetically predisposed individuals in all age groups after early infancy. ...


In cancer. Some HLA mediated diseases are directly involved in the promotion of cancer. Gluten sensitive enteropathy is associated with increased prevelance of enteritus associated T-cell Lymphoma, and DR3-DQ2 homozygotes are within the highest risk group with close to 80% of gluten sensitive EATL cases. More often; however, HLA molecules play a protective role, recognizing the increase in antigens that were not tolerated because of low levels in the normal state. Abnormal cells may be targeted for aptosis mediating many cancers before clinical diagnosis. Prevention of cancer may be a portion of heterozygous selection acting on HLA.


HLA antibodies

HLA antibodies are typically not naturally occurring, with few exceptions are formed as a result of an immunologic challenge of a foreign material containing non-self HLAs via blood transfusion, pregnancy (paternally-inherited antigens), or organ or tissue transplant.


Antibodies against disease associated HLA haplotypes have been proposed as a treatment for severe autoimmune diseases.[8]


Donor-specific HLA antibodies have been found to be associated with graft failure in kidney, heart, lung and liver transplantation.


External links

The Anthony Nolan Trust is a UK charity that focuses on leukaemia and bone marrow transplantation. ... The European Bioinformatics Institute (EBI) part of EMBL is a centre for research and services in bioinformatics. ... Medical Subject Headings (MeSH) is a huge controlled vocabulary (or metadata system) for the purpose of indexing journal articles and books in the life sciences. ...

References

  1. ^ a b c d e f Marsh SG, Albert ED, Bodmer WF, Bontrop RE, Dupont B, Erlich HA, Geraghty DE, Hansen JA, Hurley CK, Mach B, Mayr WR, Parham P, Petersdorf EW, Sasazuki T, Schreuder GM, Strominger JL, Svejgaard A, Terasaki PI, and Trowsdale J. (2005). "Nomenclature for factors of the HLA System, 2004.". Tissue antigens 65: 301-369. PMID 15787720. 
  2. ^ P. Parham and T. Ohta (1996). "Population Biology of Antigen Presentation by MHC Class I Molecules.". Science 272. PMID 8600539. .
  3. ^ Valluri V, Mustafa M, Santhosh A, Middleton D, Alvares M, El Haj E, Gumama O, and Abdel-Wareth L (2005). "Frequencies of HLA-A, HLA-B, HLA-DR, and HLA-DQ phenotypes in the United Arab Emirates population". Tissue Antigens 66 (2): 107-113. PMID 16029430. 
  4. ^ Farjadian S, Naruse T, Kawata H, Ghaderi A, Bahram S, and Inoko H (2004). "Molecular analysis of HLA allele frequencies and haplotypes in Baloch of Iran compared with related populations of Pakistan". Tissue Antigens 64 (5): 581-587. PMID 15496201. 
  5. ^ Shankarkumar U, Prasanavar D, Ghosh K, and Mohanty D (2003). "HLA A*02 allele frequencies and B haplotype associations in Western Indians". Hum Immunol. 64 (5): 562-566. PMID 12691707. 
  6. ^ V. Apanius, D. Penn, P.R. Slev, L.R. Ruff, and W.K. Potts (1997). "The nature of selection on the major histocompatibility complex.". Critical Reviews in Immunology 17: 179-224. PMID 9094452. .
  7. ^ Wedekind C, Seebeck T, Bettens F, and Paepke AJ (1995). "MHC-dependent mate preferences in humans". Proc Biol Sci. 260 (1359): 245-249. PMID 7630893. 
  8. ^ Oshima M, Deitiker P, Ashizawa T, Atassi M (2002). "Vaccination with a MHC class II peptide attenuates cellular and humoral responses against tAChR and suppresses clinical EAMG.". Autoimmunity 35 (3): 183-90. PMID 12389643. 

  Results from FactBites:
 
Human leukocyte antigen - Wikipedia, the free encyclopedia (495 words)
The human leukocyte antigen system (sometimes human lymphocyte antigen) (HLA) is the general name of a group of genes in the human major histocompatibility complex (MHC) region on human chromosome 6 (mouse chromosome 17) that encodes the cell-surface antigen-presenting proteins.
HLA types were important in matching tissues and organs for donation and organ transplantation under outdated immunosuppression protocols.
HLA antibodies are typically not naturally occurring, with few exceptions are formed as a result of an immunologic challenge of a foreign material containing non-self HLAs via blood transfusion, pregnancy (paternally-inherited antigens), or organ or tissue transplant.
  More results at FactBites »

 
 

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