Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: HLA-A
Cytogenetic location: 6p22.1 Genomic coordinates (GRCh38): 6:29,942,532-29,945,870 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p22.1 | {Hypersensitivity syndrome, carbamazepine-induced, susceptibility to} | 608579 | 3 |
The human major histocompatibility complex (MHC) has been divided into 3 regions on chromosome 6p21.3: class II (centromeric), class III, and class I (telomeric), with extended class I and class II regions on either side. The MHC encodes highly polymorphic proteins, many of which are associated with the immune system. The products of classical polymorphic class I genes, human leukocyte antigen-A (HLA-A), HLA-B (142830), and HLA-C (142840), interact with T-cell receptor (TCR; see 186880) molecules, as well as killer immunoglobulin-like receptors (KIRs; see 604936) expressed on natural killer cells and some T cells (review by Trowsdale, 2001).
Evidence from amino acid sequences suggests an evolutionary relatedness of transplantation antigens, immunoglobulins and beta-2-microglobins (Tragardh et al., 1979). Both the class I MHC antigens (A, B, and C) and the class II antigens DR and DC1 are polymorphic 2-chain cell surface glycoproteins; they are recognized by different subsets of T cells and have different functions, tissue distributions, and structures. The light chain of class I antigens is beta-2-microglobulin (B2M; 109700), which is coded by chromosome 15. The heavy chain, coded by chromosome 6, has a molecular mass of 44,000 and is made up of 3 N-terminal extracellular domains of 90 amino acids each, a small hydrophobic membrane-spanning segment and a small hydrophilic intracellular C-terminal domain. The 2 N-terminal domains are polymorphic, bear the carbohydrate and have no sequence homology with immunoglobulin. The third domain, closest to the membrane, and the 11.6-kD B2M light chain are highly conserved and have strong sequence homology with immunoglobulin.
The sequence of a human class I gene was determined by Malissen et al. (1982). As in mouse, the domain organization of the HLA protein is reflected precisely in the exon-intron structure of the gene: separate exons encode the signal peptide, each of the 3 external domains and the transmembrane region, and 3 exons encode the small cytoplasmic domain. (See Hood et al., 1982.)
Studying a family with a pericentric inversion, Lamm et al. (1974) confirmed assignment of the HLA complex to chromosome 6. In a familial 6-21 translocation (Borgaonkar et al., 1973), Borgaonkar and Bias (1974) could show that HLA is proximal to 6p22. Francke and Pellegrino (1977) concluded that HLA is distal to 6p21. Thus, rather precise localization is possible. Kompf et al. (1978) and Schunter et al. (1978) presented evidence suggesting that PGM3 (172100) is on the HLA-A side of MHC rather than on the HLA-B side, as had previously been thought. From study of a 3-generation family segregating for variation of the centromeric heterochromatic region of chromosome 6p11 (6ph), Bakker et al. (1979) concluded that the HLA cluster and 6ph are about 6 cM apart (with peak lod score of 3.466 at a recombination fraction of 0.0588; 95% confidence limits 0-0.18), that GLO is on the centromeric side of HLA, that PGM-3 is not on the short arm, and that HLA-B is closer to the centromere than HLA-A.
In a child partially trisomic for chromosome 6, Berger et al. (1979) discovered 3 haplotypes for HLA-A, -B and -C from the mother. The patient had only 2 HLA-DR specificities. The region was assigned to 6p2105.
By in situ hybridization, Morton et al. (1984) showed that class I HLA determinants (HLA-A, -B, -C) are located in 6p21.3 and class II determinants in 6p21.1. The findings suggested that one can resolve loci separated by as little as 1 cM by this technique. Using C-band heteromorphisms in linkage studies, Polacek et al. (1983) estimated the centromere-HLA distance as 14 cM with 95% confidence limits of 0.012 and 0.263. Reference to the chiasma map of Morton et al. (1977) suggested that a map distance of 14 cM corresponds to 6p21-6p22, the region where HLA is mapped physically. Mulley et al. (1983) estimated that the genetic distance of HLA from fragile site 6p23 is 20 cM, with a lower 95% probability limit of 8.5 cM, placing HLA proximal to the midpoint of 6p22. This agreed closely with the other regionalization of HLA at 6p21.3. The work suggests that the fragile site does not distort recombination and that the genetic determinant predisposing to expression of the fragile site is situated at the fragile site.
By FISH, Hirai et al. (1991) placed the MHC loci on 5p21.3 in the chimpanzee, which corresponds precisely to their location on human chromosome 6p21.3. The chimpanzee has 48 chromosomes with 2 pairs of group D-like chromosomes which, in the human, are represented by the 2 arms of chromosome 2. The MHC loci were shown by Hirai et al. (1991) to be located on the long arm of the rhesus monkey chromosome 5; by study of somatic cell hybrids, the MHC loci had been thought to be on chromosome 2 of the rhesus.
The T-locus in the mouse is on the same chromosome as the H-2 locus and is likewise highly complex in its genetics (Gluecksohn-Waelsch and Erickson, 1970). The linkage of the T and H-2 loci may have significance since the T-locus is concerned with development, and surface antigens of the sort coded by H-2 (and HLA) are also important in development. The MHC antigens are differentiation antigens. Because of the close homologies, information on MHC of the mouse is of great relevance (Klein, 1979).
Lawrance et al. (1987) demonstrated the feasibility of megabase-scale mapping of the HLA gene complex by pulsed-field gel electrophoresis. With previous methods, there existed a 'resolution gap' between molecular cloning experiments and meiotic linkage analyses. The enzymes used in the study were initially selected as those which recognize 8-basepair cleavage sites and/or contain CpG in their recognition sequences. Because of the rarity of CpG in mammalian genomes, these enzymes are expected to generate fragments that are much larger than would be predicted statistically in random sequence DNA. Enzyme restriction endonucleases used were NotI, SalI, and NruI. The data indicated that the HLA complex spans over 3 million bases (Ragoussis et al., 1986; Lawrance et al., 1987).
To avoid problems of interpretation resulting from heterozygosity, Ragoussis et al. (1989) used a monosomy 6 mutant cell line to establish a molecular map of the MHC region. Field-inversion gel electrophoresis and Southern blotting techniques were used. The HLA complex has a length of 4,200 kb. Five HTF islands were positioned on the map: between DX (HLA-DQA1; 613503) and DOB, close to DOB; between DRA and C4; between C2 and TNFA, close to C2; within 50 kb telomeric to HLA-C; and within 200 kb telomeric to HLA-A. The total length of the MHC region represents about 2.5% of the total length of chromosome 6. The class I region has a size of about 2,000 kb. The class II region has a size of 1,000 kb and is separated from the class I region by about 1,200 kb.
Ziegler et al. (1989) presented a physical map of the human MHC locus derived from pulsed field gel electrophoresis data.
Trowsdale et al. (1991) and Campbell and Trowsdale (1993) provided maps compiling the physical mapping and cloning data related to the entire MHC region of the human.
Abderrahim et al. (1994) isolated 53 YACs with an average size of 490 kb and organized them into a single large contig covering more than 4,000 kb spanning the entire MHC region.
Class I HLA Pseudogenes
HLA-H is a class I HLA pseudogene. (The designation HLAH, rather than HFE (613609), has been used by some for the gene mutant in hereditary hemochromatosis (235200). HLAHP may an appropriate symbol for this presumed pseudogene, thus avoiding confusion.) By a combination of cosmid cloning, chromosomal jumping, and pulsed field gel electrophoresis (PFGE), Shukla et al. (1991) performed fine mapping of the HLA-A subregion of the major histocompatibility complex. They demonstrated that the Qa-like HLA-G class I gene (142871) is within 100 kb of HLA-H. Furthermore, these 2 genes are linked to HLA-A, with HLA-H lying no more than 200 kb from HLA-A. The data were interpreted as supporting the existence of a Qa-like subregion composed of nonclassic HLA class I genes within the human MHC and situated telomeric to the HLA-A locus. HLA-H is probably a pseudogene due to an in-frame termination codon in its fourth exon; however, at the RNA level, the gene is expressed. The human Qa-like subregion appears to be less densely populated with genes than is its mouse equivalent.
HLA-J is another class I HLA pseudogene. Nucleotide sequence comparisons show that the HLA-A, H, J, and G genes form a well-defined group of 'HLA-A-related' loci (Messer et al., 1992). Evolutionary relationships suggested that the 4 modern loci were formed by successive duplications from a common ancestral gene. It is thought that one intermediate locus gives rise to A and H, the other to G and J.
Bodmer (1986) suggested that the gene products of the major histocompatibility complex be referred to as histoglobulins, a term parallel to immunoglobulins, with which they share an evolutionary origin. The chimpanzee has 2 main allelic series of leukocyte antigens (Balner et al., 1974) and the Rhesus monkey has histocompatibility-linked immune-response genes (Dorf et al., 1974). The existence of one or more Ir (immune response) loci in man is suggested by the comparative studies of the MHC of mice and lower primates; furthermore, 2 separate loci in the MHC code for B-lymphocyte alloantigens (see 146880).
Klein and Figueroa (1986) reviewed the evolution of the major histocompatibility complex, using the designation Mhc for the mouse system. They reproduced the figure of the banding pattern of mouse chromosomes as revealed by Giemsa staining following treatment with trypsin and chymotrypsin. They concluded that the Mhc region represents a 'frozen linkage group;' that the complement and P-450 genes were transferred to the Mhc region from another chromosome at the time the beta-2-microglobulin gene separated from the Mhc cluster and that they are therefore foreign elements in the Mhc region and not functional parts of Mhc proper; and that class Ib loci (Qa and Tla) constitute the junkyard of the Mhc region, these being either pseudogenes or on the way to becoming pseudogenes. Figueroa et al. (1988) described MHC polymorphism that must have arisen before the separation of mice and rats from a common ancestor more than 10 million years ago. Similarly, Lawlor et al. (1988) found close similarity in the HLA-A and HLA-B (142830) alleles of human and chimpanzee. Indeed, individual alleles were found to be more closely related to individual chimpanzee alleles than to other HLA-A or -B alleles. Thus, again, a considerable proportion of contemporary HLA-A and -B polymorphism existed before divergence of the chimpanzee and human lines.
MHC class I molecules play an essential role in the immune defense against intracellular infections. The hallmark of the MHC is its extensive degree of polymorphism at the population level. However, de Groot et al. (2002), comparing MHC class I gene intron variation, found that chimpanzees have experienced a severe repertoire reduction at the orthologs of the HLA-A, -B, and -C loci. The loss of variability predated the (sub)speciation of chimpanzees and did not affect other known gene systems. Therefore, the selective sweep in the MHC class I gene may have resulted from a widespread viral infection. Based on their results and the fact that chimpanzees have a natural resistance to the development of AIDS, de Groot et al. (2002) hypothesized that the selective sweep was caused by the chimpanzee-derived simian immunodeficiency virus, the closest relative of HIV-1, or a closely related retrovirus. Hence, contemporary chimpanzee populations represent the offspring of AIDS-resistant animals, the survivors of an HIV-like pandemic that took place in the distant past.
Danchin et al. (2003) claimed to have confirmed for the first time with robust evidence the existence of a region of conserved synteny between the human genome and the Drosophila genome. Evolutionarily conserved synteny involved the human MHC and paralogous regions. The authors identified 19 conserved genes between these 2 species in a Drosophila genomic region of less than 2 Mb. The statistical analysis of the distribution of these 19 genes between the 2 genomes showed that it could not be explained by chance. Danchin et al. (2003) suggested that their study constituted a first step toward the reconstruction of the genome of Urbilateria (the ancestor of all bilaterians) and allowed for a better understanding of the evolutionary history of the human genome as well as other metazoan genomes.
The usefulness of HLA typing for selection of kidney donors was demonstrated by Patel et al. (1968).
Salter et al. (1989) demonstrated that the binding of CD8 (186910) glycoprotein on the surface of cytotoxic T-lymphocytes is mediated through the alpha-3 domain of class I MHC molecules. They demonstrated that 2 HLA-A alleles, which do not bind CD8, have a valine for alanine substitution at position 245. Further studies using site-directed mutagenesis demonstrated that this substitution in the alpha-3 domain mediates the CD8 binding.
Although the major histocompatibility complex (MHC) is named for its association with graft rejection, clearly the prevention of tissue engraftment between individuals is not the raison d'etre for MHC-encoded molecules. Through the progress of knowledge concerning MHC and the evolution of concepts over a period of more than 50 years (see outline by Colombani, 1992), it is now recognized that the products of the MHC genes are antigen-presenting molecules (APM) designed for the presentation of antigen fragments (peptides) to the T-cell receptor, thus participating in the immune response (Hedrick, 1992). Indeed, Colombani (1992) suggested that instead of MHC the complex should be called MPHC, for major presentation and histocompatibility complex.
MHC class I molecules present peptides that are derived from endogenous proteins. These antigens can also be transferred to professional antigen-presenting cells in a process called crosspresentation, which precedes initiation of a proper T-cell response. Neijssen et al. (2005) tested whether peptides can be transferred directly from the cytoplasm of one cell into the cytoplasm of its neighbor through gap junctions. They demonstrated that peptides with a molecular mass of up to approximately 1,800 diffuse intercellularly through gap junctions unless a 3-dimensional structure is imposed. This intercellular peptide transfer causes cytotoxic T-cell recognition of adjacent, innocent bystander cells as well as activated monocytes. Gap junction-mediated peptide transfer is restricted to a few coupling cells owing to the high cytosolic peptidase activity. Neijssen et al. (2005) presented a mechanism of antigen acquisition for crosspresentation that couples the antigen presentation system of 2 adjacent cells and is lost in most tumors: gap junction-mediated intercellular peptide coupling for presentation by bystander MHC class I molecules and transfer to professional antigen-presenting cells for crosspriming.
Transfusion-associated graft-versus-host disease (GVHD; see 614395) is fatal in most cases. Since gamma irradiation of cellular blood components before transfusion can prevent the development of transfusion-associated GVHD, identification of susceptible hosts is critical. Shivdasani et al. (1993) reported a case of transfusion-associated GVHD in the US that occurred after platelets from an HLA-homozygous donor, born of nonconsanguineous parents, were transfused into an immunocompetent patient who was heterozygous for the donor's haplotype. Because the likelihood that donors who are homozygous for a given HLA haplotype will provide blood for unrelated recipients who share that haplotype has been judged to be remote in the US, the general use of gamma irradiation of cellular blood components has not been recommended. Shivdasani et al. (1993) suggested the existence of an HLA-related predisposition to transfusion-associated GVHD in immunocompetent patients and recommended that the guidelines for the irradiation of blood components be reassessed.
Modulators of immune regulation 1 and 2 (MIR1 and MIR2) are E3 ubiquitin ligases encoded by Kaposi sarcoma-associated herpesvirus that mediate the ubiquitination of MHC I molecules and subsequent internalization. Cadwell and Coscoy (2005) found that MIR1 but not MIR2 promoted downregulation of MHC I molecules lacking lysine residues in their intracytoplasmic domain. In the presence of MIR1, these MHC I molecules were ubiquitinated, and their association with ubiquitin was sensitive to beta-2-mercaptoethanol, unlike lysine-ubiquitin bonds. This form of ubiquitination required a cysteine residue in the intracytoplasmic tail of MHC I molecules. An MHC I molecule containing a single cysteine residue in an artificial glycine and alanine intracytoplasmic domain was endocytosed and degraded in the presence of MIR1. Thus, Cadwell and Coscoy (2005) concluded that ubiquitination can occur on proteins lacking accessible lysines or an accessible N terminus.
Ramsuran et al. (2018) analyzed 9,763 HIV-infected individuals from 21 cohorts and found that higher HLA-A levels confer poorer control of HIV. Elevated HLA-A expression provides enhanced levels of an HLA-A-derived signal peptide that specifically binds and determines expression levels of HLA-E (143010), the ligand for the inhibitory NKG2A (see 161555) natural killer cell receptor. HLA-B (142830) haplotypes that favor NKG2A-mediated NK cell licensing (i.e., education) exacerbate the deleterious effect of high HLA-A on HIV control, consistent with NKG2A-mediated inhibition impairing NK cell clearance of HIV-infected targets.
Lawlor et al. (1991) used PCR to amplify brain DNA from the Windover pond of central Florida, which contains human remains about 7,500 years old. From 1 individual they characterized segments from 6 nuclear genes: that for beta-2-microglobulin and 5 members of the class I HLA heavy chain gene family. Distinctive patterns of nucleotide substitution in the cloned heavy chain gene segments permitted tentative assignment of the HLA-A,B type of the ancient individual. One of the HLA-A alleles that was found is observed at high frequency in the modern Amerindian population.
Carrington et al. (1999) reported that the extended survival of 28 to 40% of HIV-1-infected Caucasian patients who avoided AIDS for 10 or more years (see 609423) could be attributed to their being fully heterozygous at HLA class I loci, to lacking the AIDS-associated alleles B*35 and Cw*04, or to both.
MacDonald et al. (2000) examined the influence of HLA types on susceptibility to HIV-1 infection in a population of chronically and highly exposed commercial sex workers enrolled in a prospective study in Nairobi, Kenya. MHC class I serologically defined alleles HLA-A2, HLA-A28, and HLA-B18 were associated with decreased risk of HIV-1 infection in this population, while HLA-A23 was associated with increased risk. Molecular subtyping identified a supertype, which consisted of the HLA-A2 subtypes HLA-A*0202, -A*0205, and -A*0214 and an HLA-A28 subtype, HLA-A*6802, that was associated with a significantly decreased rate of HIV-1 seroconversion. Molecular typing for MHC class II alleles revealed a significantly decreased risk of HIV-1 seroconversion associated with the HLA-DRB1*0102 allele of the HLA-DRB1*01 determinant. MacDonald et al. (2000) noted that in this cohort resistance to HIV-1 infection was associated with immunologic responses to the virus but not with chemokine receptor polymorphisms (see CCR2; 601267). They proposed that the A2/6802 supertype and the DRB1*01 determinant may mediate protection against HIV-1 through the presentation and restriction of conserved epitopes; however, these alleles are neither completely necessary nor sufficient for resistance.
Szpak et al. (2001) noted that the human MHC class I specificity HLA-A29 has been observed in nearly all patients (95.8%) with birdshot chorioretinopathy (BSCR; 605808) compared with 7% in healthy controls. BSCR is characterized by multiple small, cream-colored lesions, symmetrically scattered mainly around the optic disc and radiating toward the equator. These depigmented spots, the most distinctive sign of the syndrome, appear at the level of the retinal pigment epithelium but, on occasion, suggest an even deeper infiltration. In an attempt to develop an animal model of HLA-A29-associated disease, Szpak et al. (2001) produced transgenic mice expressing HLA-A29 molecules. They found that an eye disorder spontaneously arising in these transgenic mice included many of the features of HLA-A29-associated BSCR in humans. In humans the retinal vasculopathy and inflammatory signs associated with the funduscopic findings lead regularly to visual loss.
Cardoso et al. (2002) found linkage disequilibrium between all HLA-A29-containing haplotypes and the hemochromatosis-producing H63D mutation (613609.0002), favoring the hypothesis of a coselection of H63D and HLA-A29. They considered that support and insight were provided by the finding of significantly higher CD8+ T-lymphocyte counts in subjects simultaneously carrying the H63D mutation and the HLA-A29 allele.
Zareparsi et al. (2002) noted that several studies had found an increased frequency of the HLA-A2 allele in patients with early-onset Alzheimer disease (AD; 104300) and that others had found an association between the A2 allele and earlier age of onset of AD. Among 458 unrelated patients with AD, Zareparsi et al. (2002) found that HLA-A2 homozygotes had an average 5-year earlier age of onset than either A2 heterozygotes or those without A2. The risk associated with the A2 homozygous genotype was 2.6 times greater in patients with early-onset AD (less than age 60) than in those with late-onset AD, reflecting a dosage effect. These effects were present regardless of gender, familial or sporadic nature of the disease, or presence or absence of the APOE (107741) E4 allele. The authors suggested that the A2 allele may have a role in regulating an immune response in the pathogenesis of AD or that there may be a responsible gene in close linkage to A2.
In a study of 40 Japanese patients with SJS/toxic epidermal necrolysis (TEN; 608579) with ocular complications and 113 healthy Japanese individuals, Ueta et al. (2007) found a significant association with HLA-A*0206 (Pc less than .0005, OR = 5.1), but not with HLA-B, HLA-C, or other HLA-A alleles tested.
Infectious mononucleosis (IM) is an immunopathologic disease caused by Epstein-Barr virus (EBV) that occurs in young adults and is a risk factor for Hodgkin lymphoma (236000). McAulay et al. (2007) analyzed 2 microsatellite markers, D6S510 and D6S265, and 2 SNPs, rs253088 and rs6457110, from the HLA class I region in patients with acute IM and in asymptomatic EBV-seropositive and -seronegative individuals. Alleles of both microsatellite markers were significantly associated with development of IM, and allele A of rs253088 and allele T of rs6457110 were significantly more frequent in patients with IM than in EBV-seronegative individuals. IM patients with the associated microsatellite alleles had fewer lymphocytes, more neutrophils, and higher EBV titers than IM patients lacking the alleles. McAulay et al. (2007) proposed that HLA class I polymorphisms predispose patients to development of IM upon primary EBV infection, possibly due to genetic variation in T-cell responses and the level of viral persistence.
Nejentsev et al. (2007) used several large type I diabetes (222100) data sets to analyze a combined total of 1,729 polymorphisms, and applied statistical methods--recursive partitioning and regression--to pinpoint disease susceptibility to the MHC class I genes HLA-B (142830) and HLA-A (risk ratios greater than 1.5; P(combined) = 2.01 x 10(-19) and 2.35 x 10(-13), respectively) in addition to the established associations of the MHC class II genes HLA-DQB1 (604305) and HLA-DRB1 (142857). Nejentsev et al. (2007) suggested that other loci with smaller and/or rarer effects might also be involved, but to find these future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, Nejentsev et al. (2007) concluded that MHC class I-mediated events, principally involving HLA-B*39, contribute to the etiology of type I diabetes.
In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, the International Multiple Sclerosis Genetics Consortium and Wellcome Trust Case Control Consortium 2 (2011) replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci for multiple sclerosis (126200). Within the MHC the International Multiple Sclerosis Genetics Consortium and Wellcome Trust Case Control Consortium 2 (2011) refined the identity of the HLA-DRB1 risk alleles as DRB1*1501 (142857.0002) and DRB1*1303, and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes were significantly overrepresented among those mapping close to identified loci and particularly implicated T helper cell differentiation in the pathogenesis of multiple sclerosis. The International Multiple Sclerosis Genetics Consortium and Wellcome Trust Case Control Consortium 2 (2011) confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. HLA allele HLA*0201 has a combined odds ratio (OR) of 0.73 across independent populations of European descent.
Lutz (2014) reviewed HLA Bw4 and Bw6. As a result of transplantation, blood transfusion, or pregnancy, people are immunized and produce antibodies to 'private' epitopes, which are shared by few other HLA allele products, or 'public' epitopes, which are encoded by many HLA alleles. The most prominent public epitopes are Bw4 and Bw6. Either the Bw4 or the Bw6 epitope is expressed by virtually all HLA-B molecules, and Bw4 is also found on a few HLA-A proteins. Parham et al. (2012) reported that Bw4, along with HLA-A3, HLA-A11, HLA-C1, and HLA-C2, is a KIR (e.g., KIR3DL1; 604946) ligand. Habegger de Sorrentino et al. (2013) listed 14 HLA-B alleles and 4 HLA-A alleles expressing Bw4 epitopes.
Reviews
Gruen et al. (1996) applied cDNA hybridization selection to 9 YACs spanning 3 Mb of genomic DNA from a region centromeric to HLA-A to the histone cluster that lies telomeric to the major histocompatibility complex. In addition to class I genes and pseudogenes, they described over 63 genes and 23 additional expressed sequence tags distributed throughout the region. Many of the full-length genes belong to gene families. Prominent among these was a group of genes encoding proteins showing homology to the C-terminal sequences of butyrophilin and an additional group of zinc finger genes. Gruen et al. (1996) also detected several previously undefined genes that are specifically expressed in cells of the immune system, indicating a more complex role of the MHC in the immune response than had been appreciated.
Shiina et al. (2009) provided an extensive review of what they termed the 'HLA super-locus,' a genomic region on 6p21 that contains the 6 classical transplantation HLA genes and at least 132 protein coding genes that have important roles in the regulation of the immune system as well as some other fundamental molecular and cellular processes. The review included a tabulation of MHC monogenic and polygenic disease associations.
Major Histocompatibility Complex Database
Newell et al. (1994) described a database of the human major histocompatibility complex, MHCDB, which allows access, retrieval, and display of physical and genetic data relating to the human MHC. The contents of the database included: (1) location of over 100 genes and other markers; (2) location of over 250 YAC and cosmid clones; (3) 150 kb of genomic DNA sequence including full annotation (exon/intron boundaries, repeats, promoters, etc.); (4) cDNA sequences of currently known class I and class II alleles; and (5) accompanying descriptive data--references, comments, laboratory addresses, and so on.
Teshima et al. (2002) transferred bone marrow into irradiated wildtype and MHC class II-deficient recipient mice. Donors and recipients differed at only a single class II allele. The class II-knockout recipient chimeras, therefore, expressed class II only on hemopoietic cells or antigen-presenting cells (APCs). CD4+ T lymphocytes expressing CD25 (147730) and CD49 expanded in the wildtype but not the class II-null mice. Wildtype mice also had increased serum Ifng (147570). All wildtype but no knockout mice succumbed to acute graft-versus-host disease (GvHD) by day 7 after transplant. Other experiments showed that host APC, but not epithelial cell, class II alloantigens are sufficient to induce CD4+ T cell expansion, cytokine secretion, and lethal GvHD. Furthermore, blockade of inflammatory cytokines TNF (191160) and IL1B (147720) can block the effector phase of acute GvHD without blocking CD4 T cell expansion. Similarly, in mice lacking class I expression, host APC alloantigen expression is required for the development of CD8+ T lymphocyte-mediated GvHD. Fatal disease onset, but not target organ damage in surviving mice, is reduced in mice lacking epithelial cell class I expression. Teshima et al. (2002) concluded that host APCs are sufficient in both activation and effector phases of acute GvHD and that alloantigen expression on target cells is not always required, particularly for CD4-mediated disease. They proposed that blockade of inflammatory cytokines could be beneficial in clinical bone marrow transplantation by preventing the toxicity of GvHD while allowing beneficial graft-versus-leukemia effects.
Leinders-Zufall et al. (2004) showed that small peptides that serve as ligands for MHC class I molecules function also as sensory stimuli for a subset of vomeronasal sensory neurons located in the basal G-alpha-o- (139311) and V2R receptor (see 605234)-expressing zone of the vomeronasal epithelium. In behaving mice, the same peptides function as individuality signals underlying mate recognition in the context of pregnancy block. MHC peptides constitute a previously unknown family of chemosensory stimuli by which MHC genotypic diversity can influence social behavior.
Strachan (1987) reviewed the molecular genetics of class I HLA antigens. The genes for the classical HLA-A, -B, and -C heavy chains are members of a large multigene family of highly related sequences.
Bach and Amos (1967) concluded that a single locus with 15 or more alleles controls reactivity in mixed leukocyte culture tests, and that genes at this locus also control most of the specificities measured by cytotoxic antiserums to leukocytes. This may be the major histocompatibility locus in man. Bernard (1967) called discovery of the Hu-1 (now called HLA) system as important an event in biology as discovery of the ABO and Rh systems, perhaps more important.
By gel filtration, Mann et al. (1969) separated soluble preparations of HLA alloantigens into components having either 'LA' specificity or 'FOUR' specificity. This may indicate that the HLA 'locus' is a region with several different cistrons. Furthermore, family data indicate the existence of 2 'segregant series.' Antigens 1, 2, 3, 9, 10 and 11 are mutually exclusive members of one allelic series whereas a different array of antigens constitutes a second series (Bach and Bach, 1970). The relation of the isoantigenic variants identified in human fibroblast cultures to the HLA system is not known. Both the HLA system in man and the H-2 system in mice seem to have haploid expression in sperm.
Recombination has been observed within the HLA system (Bodmer et al., 1970). The LA and 'FOUR' loci are very closely linked (Kissmeyer-Nielsen and Thorsby, 1970). The ratio of female to male recombination fractions is 1.6 (Lamm et al., 1971). The HLA loci are linked to the PGM3 locus, the distance being about 0.15 morgans in females (Lamm et al., 1971). Lamm et al. (1972) reviewed the evidence that the 'FOUR' and LA loci are about 1 centimorgan apart and presented evidence that the PGM-3 locus is on the 'FOUR' side of the HLA region. Kissmeyer-Nielsen et al. (1972) reviewed the genetics of HLA, including the close linkage of 'LA' and 'FOUR' and the linkage of HLA to other loci. An immune response locus (146880) is thought to be closely linked to the HLA locus or part of the HLA region. Studies of HLA antigens solubilized from cell membranes indicate that the products of the 2 loci reside on different molecules, and no firm association or bond between the 2 molecular products exists in the cell membrane. Solheim et al. (1973) presented evidence for a third segregant HLA series, the 'AJ' series. AJ appears to be between LA and 'FOUR' but closer to 'FOUR.' Weitkamp et al. (1973) showed that recombination between the LA and 'FOUR' loci was 50% greater in females than in males but age had no effect.
From the study of the primary structure of cross-reactive human histocompatibility antigens, Lopez de Castro et al. (1982) concluded that gene conversion may have played a role in the generation of HLA polymorphism.
Extended haplotypes in the MHC are evidenced by allelic association, better known as linkage disequilibrium, which is usually attributed to recent mutation of closely linked genes, founder effects, inbreeding, and so on. Due to crossover events, such effects are rapidly dissipated at chromosome map distances of 2 to 7 cM. The operation of crossover suppression was suggested by the findings of extended haplotypes that take in A1, at one end, and the GLO2 allele at the GLO1 locus, at the other end, and occur at frequencies significantly higher than expected (Awdeh et al., 1983). One of the haplotypes was found to be transmitted from males to 83% of their offspring. A possible mechanism for the maintenance of extended haplotypes is represented by possible human analogs of murine T mutants which are characterized by crossover suppression and male transmission bias. (According to Van Rood and Amos (1988), Ruggero Ceppellini introduced the term haplotype.) Dausset (1983) stated that he had probes that correlate with specific HLA haplotypes, e.g., the following Weissmann probes: EcoRV 8.6 kb with HLA-B8; EcoRV 4.6 kb with HLA-B35. He suggested the term genotope for a DNA fragment and the derivative terms allogenotope for a DNA fragment with polymorphism and isogenotope for one without polymorphism. Of course, polymorphism is probably usually present, even though not demonstrated with the restriction enzymes employed.
McCormack et al. (2011) performed a genomewide association study of samples obtained from 22 subjects with carbamazepine (CBZ)-induced hypersensitivity syndrome (HSS; see 608579), 43 subjects with CBZ-induced maculopapular exanthema (MPE), and 3,987 control subjects, all of European descent. They replicated the associations in samples from 145 subjects with CBZ-induced hypersensitivity reactions. The HLA-A*3101 allele, which has a prevalence of 2 to 5% in northern European populations, was significantly associated with HSS (p = 3.5 x 10(-8)). An independent genomewide association study of samples from subjects with MPE also showed an association with the HLA-A*3101 allele (p = 1.1 x 10(-6)). Follow-up genotyping confirmed the variant as a risk factor for HSS (OR, 12.41; 95 CI, 1.27-121.03), MPE (OR, 8.33; 95% CI, 3.59-19.36), and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS-TEN) (OR, 25.93; 95% CI, 4.93-116.18). The presence of the HLA-A*3101 allele was associated with CBZ-induced hypersensitivity reactions among subjects of northern European ancestry. The presence of the allele increased the risk from 5.0% to 26.0%, whereas its absence reduced the risk from 5.0% to 3.8%.
Among 18 Chinese patients, Hung et al. (2006) found a significant association between nonbullous adverse skin reactions induced by the drug carbamazepine and the HLA-A*3101 allele (p = 2.2 x 10(-3), OR of 17.5). The association was specific for maculopapular eruptions and not SJS (see 608579).
Among 42 Canadian children of diverse ancestries who experienced carbamazepine (CBZ)-induced hypersensitivity reactions and 91 CBZ-tolerant control children, Amstutz et al. (2013) found that HLA-A*3101 was significantly associated with CBZ-HSS (OR, 26.4; p = 0.0025) and MPE (OR, 8.6; p = 0.0037) but not with CBZ-SJS.
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