Alternative titles; symbols
HGNC Approved Gene Symbol: HLA-DRA
Cytogenetic location: 6p21.32 Genomic coordinates (GRCh38): 6:32,439,887-32,445,046 (from NCBI)
Class II major histocompatibility complex (MHC) molecules present antigens to CD4 (186940)-positive cells. Human class II MHC molecules are of 3 major isotypes, HLA-DR, HLA-DP (see 142880), and HLA-DQ (see 146880), each of which consists of an alpha and a beta chain. Both the alpha and beta chains of HLA-DP and HLA-DQ are polymorphic, whereas HLA-DR alpha (HLA-DRA) is invariant and HLA-DR beta (HLA-DRB; see 142857) is polymorphic. Thus, differences in the HLA-DR beta chain account for different peptide-binding motifs of HLA-DR molecules (Dai et al., 2008).
Shackelford et al. (1981) stated that 10 HLA-DR alleles had been well defined. The HLA-DR antigens were reviewed by Shackelford et al. (1982); they are homologous to the I-E alloantigens of the mouse.
Lee et al. (1982) described 2 cDNA clones containing sequences corresponding to HLA-DR antigens, specifically the 34,000 MW glycoprotein chain. The authors stated that the heavy chain is largely invariant and that the light chain (MW about 28,000) carries the major polymorphic determinants. Other HLA-D/DR-associated antigens with different heavy and light chains (also called alpha and beta, respectively) have been identified on B cells (Accolla et al., 1981; Shackelford et al., 1981).
Korman et al. (1982) provided information on the primary structure of the heavy and light chains of DR. The HLA-DR antigen heterodimer consists of 4 extracellular domains, 2 of which are Ig-like (1 in the heavy chain, alpha-2, and 1 in the light chain, beta-2). The third is the amino-terminal polymorphic domain of the light chain (beta-1), and the fourth is an invariant domain in the heavy chain (alpha-1). Both the light and the heavy chains have a large glycosylated amino-terminal extracellular region, a small hydrophobic membranous region, and a small hydrophilic carboxy-terminal region; in this they resemble class I MHC antigens. Kaufman and Strominger (1982) applied limited proteolysis to demonstrate further that the extracellular region of the light chain consists of 2 domains, each with a disulfide loop. The amino-terminal domain bears the carbohydrate and is polymorphic, while the carboxy-terminal domain is relatively conserved and has significant amino acid homology with immunoglobulins. In DR, it is the light chain that is polymorphic; in class I antigens, beta-2-microglobulin is invariant or highly conserved. Larhammar et al. (1982) likewise commented on similarities to both the immunoglobulins and the class I MHC antigens. They referred to the 2 chains of the class II molecules as alpha and beta. They provided the complete nucleotide sequence of a beta-chain gene and deduced the corresponding amino acid sequence. Kratzin et al. (1981) published the sequence of another beta chain which shows about 70% homology with the one reported by Larhammar et al. (1982). This is consistent with the conclusion that the HLA-D region contains at least 2 (Accolla et al., 1981) and probably more (Shackelford et al., 1981) genes for class II antigens.
The DR, DP (146880), and DQ (142880) gene products resemble each other fairly closely and also resemble Ia of the mouse. They are heterodimers of 1 alpha, or heavy, chain (MW 33,000) and 1 beta, or light, chain (MW 28,000). The serologic specificity resides mainly in the beta chain (Erlich et al., 1983).
Walker et al. (1983) determined the N-terminal amino acid sequences of the alpha and beta chains of HLA-DR1 and HLA-DR2 antigens. No differences were found in the alpha chains. However, in the first 35 N-terminal residues of the beta chains, 2 regions of variability were apparent, each comprising about 6 amino acids. The authors suggested that these variable regions may be responsible for the serologically defined polymorphism of HLA-DR antigens.
Location of at least one HLA-DR heavy chain gene on chromosome 6 was confirmed by analysis of DNA from man-mouse somatic cell hybrids by Southern transfer of restriction endonuclease transfers. The sequences coding for HLA-DR heavy chain appear to be present in only one or a few copies in the genome and to be relatively simple in structure (Lee et al., 1982).
By studies of a cell line with a small visible deletion of 6p, Erlich et al. (1983) mapped the alpha chain of HLA-DR to 6p2105-6p23. The genes for all the class I antigens map in the same region. Under conditions of high stringency and considering the most intensely hybridizing bands, 1 gene locus each was recognized by HLA-DR alpha and HLA-DR beta probes and 2 by the HLA-DC beta probe (Levine et al., 1984). By study of variants with various breakpoints, they defined 3 subregions in the following order from centromere distally: subregion I, HLA-DC beta-1; subregion II, HLA-DC beta-2 and HLA-DR alpha; subregion III, HLA-DR beta. Both the alpha and the beta chains map to the HLA region. (In the case of the class I antigens, only the alpha chain maps to the HLA region; the beta chain, beta-2-microglobulin, maps to chromosome 15.) There are about 25 copies of HLA class I genes and 15, in all, of alpha and beta class II genes. The class III genes, C2, BF, C4A, C4B, are present in single copy. The beta chain is responsible for DR polymorphism. Class II molecules, located predominantly on B cells and macrophages, play a key role in immune response, functioning in the presentation of antigen to regulatory T lymphocytes.
Strominger (1986) indicated that the findings with DNA probes 'suggest that the multiple HLA-DR light chains and the multiple HLA-DR heavy chains are encoded in a 5 centimorgan region of human 6p'--specifically, 6p21.1.
Hardy et al. (1986) reported mapping studies of the class II region by means of pulsed field gel electrophoresis (PFGE). Their findings, together with linkage studies and data on linkage disequilibrium, indicate that the order of the class II genes is centromere--DP--DZ-alpha--DO-beta--DX (HLA-DQA2; 613503)--DQ--DR-beta--DR-alpha. The map order indicates that DQ molecules are analogous to the I-A molecules in the mouse and that DR molecules are analogous to the products of the murine I-E locus. No recombination between DQ and DR genes had been reported and alleles of these genes are in very strong linkage disequilibrium. In contrast, a high recombination frequency of about 1 to 3% is found between DP genes and DQ-DR genes. Furthermore, there is very little linkage disequilibrium between DP and DR alleles. These observations suggest that either the DP subregion is located some distance centromeric to the DQ-DR subregions or that a recombination 'hotspot' exists between DP and DQ-DR. The results of Hardy et al. (1986) excluded the first possibility as the distance between DP and DQ is similar to the distance separating DQ and DR. See also HLA-DQB1 (604305).
Reviews
Strominger (1986) and Auffray and Strominger (1986) gave superb discussions of the molecular structure of the HLA system, particularly the class II region and also presented a useful map of the region and a hypothesis for the generation of autoimmunity that depends on somatic mutation in the immune system.
Trowsdale (1987) provided a useful review of the molecular genetics of the class II antigens, including his latest version of the working map of the human HLA-D region.
Mayer et al. (1993) showed that a retrovirus related to the mouse mammary tumor viruses was inserted into intron 1 of DRB6 more than 23 million years ago. The insertion was either accompanied or followed by the deletion of exon 1 in the promoter region of DRB6. In the 3-prime long terminal repeat (LTR) of the retrovirus, however, an open reading frame for a new exon arose, which codes for a sequence that could function as a leader for the truncated DRB6 gene. The new exon has a functional donor splice site at its 3-prime end which enables it to be spliced in register with DRB6 exon 2. Upstream from the new exon is a promoter enabling transcription of the DRB6 gene. Besides providing an example of a de novo generation of an exon, the study suggested a potential mechanism for generating new genes through the replacement of old exons with newly generated ones.
By pulsed field gel electrophoresis, Dunham et al. (1989) found differences in the amount of DNA present in the DQ and DR subregions of the class II region dependent on the DR type. Specifically, cell lines that carry DR2 had about 30 kb more DNA within the DR subregion than those that carry DR3, DR5, or DR6. The DR4 haplotype had an additional 110 kb of DNA within the DQ or DR subregion compared to DR3, DR5, and DR6. These haplotype-specific differences may be of significance for the maintenance of linkage disequilibrium within the DR and DQ subregions and the low frequency of recombination between DQ and DR.
Moen et al. (1980) concluded that HLA-DR matching of cadaveric kidneys improves survival of the transplanted organ.
Tiercy et al. (1988) demonstrated micropolymorphism undetectable by serologic typing procedures which should permit more accurate HLA matching for transplantation and for more precise correlations between HLA and disease susceptibility. Micropolymorphism was detected by hybridization with allele-specific oligonucleotides, a method they referred to as HLA oligotyping.
Chelladurai et al. (1991) demonstrated that HLA-DR has procoagulant activity and suggested that it is responsible for thromboembolic complications in cancer patients and in recipients of mismatched organ transplants.
Olerup et al. (1991) investigated DRB-DQA-DQB gene polymorphism by TaqI restriction fragment length polymorphism analysis in West Africans and found polymorphism to be almost twice as extensive in this population as in North European Caucasians. They interpreted this finding as indicating that Africans comprise the oldest and genetically most diverse human population and supporting the hypothesis of a population bottleneck in the emergence of the white race. They could find little evidence for parasite-driven overdominant selection and proposed instead that one of the forces maintaining a low frequency of HLA homozygotes might be a decreased likelihood of potentially autoreactive T-cell clones escaping thymic selection in HLA heterozygotes. This would be consistent with the central role of HLA molecules as self/nonself discriminators.
Terasaki et al. (1976) described a high frequency of a B-lymphocyte antigen (group 4) in multiple sclerosis (MS; see 126200). Association with HLA-A3, HLA-B7, and HLA-Dw2 has been demonstrated also.
In a multistage genomewide association study involving a total of 1,540 multiple sclerosis family trios, 2,322 case subjects, and 5,418 control subjects, the International Multiple Sclerosis Genetics Consortium (2007) used the HLA-DRA A/G SNP rs3135388 as a proxy for the DRB1*1501 allele (complete concordance between the rs3135388 A allele and DRB1*1501 was found in 2730 of 2757 subjects in whom data were available) and confirmed unequivocally that the HLA-DRA locus was associated with MS (p = 8.94 X 10(-81); OR, 1.99).
Ferber et al. (1999) evaluated the association of HLA class II alleles DR and DQ with gestational diabetes mellitus (GDM) and the postpartum development of IDDM (222100). DR3 allele frequency was significantly increased in 43 women with islet autoantibodies, in particular in those with glutamic acid decarboxylase autoantibodies (GADA), or in the 24 women who developed IDDM postpartum. In women with GADA, DR4 and DQB1*0302 were significantly elevated. Twenty-five (59.5%) islet antibody-positive women and 17 (74%) women who developed IDDM postpartum had a DR3- or DR4-containing genotype. The cumulative risk to develop IDDM within 2 years postpartum in GDM women with either DR3 or DR4 was 22%, compared to 7% in women without those alleles and rose to 50% in the DR3- or DR4-positive women who had required insulin during pregnancy. Combining the determination of the susceptible HLA alleles DR3 and DR4 with islet autoantibody measurement increased the sensitivity of identifying GDM women developing postpartum IDDM to 92%, but did not improve risk assessment above that achieved using GADA measurement alone, which was the strongest predictor of IDDM.
Kent et al. (2005) examined T cells from pancreatic draining lymph nodes, the site of islet cell-specific self-antigen presentation. They cloned single T cells in a nonbiased manner from pancreatic draining lymph nodes of patients with type I diabetes and from nondiabetic controls. A high degree of T-cell clonal expansion was observed in pancreatic lymph nodes from long-term diabetic patients but not from controls. The oligoclonally expanded T cells from diabetic patients with DR4, a susceptibility allele for type I diabetes, recognized the insulin A 1-15 epitope restricted by DR4. Kent et al. (2005) concluded that their results identified insulin-reactive, clonally expanded T cells from the site of autoinflammatory drainage in long-term type I diabetics, indicating that insulin may indeed be the target antigen causing autoimmune diabetes.
Expression of HLA-DR antigen and ICAM1 in human conjunctival epithelium is upregulated in patients with dry eyes associated with Sjogren syndrome (270150). Tsubota et al. (1999) reported that this upregulation in Sjogren syndrome patients may be controlled by interferon-gamma (147570) through the activation of transcription factor NFKB (nuclear factor kappa-B; see 164011).
Pisella et al. (2000) reported that a significant increase of HLA-DR and ICAM1 expression by epithelial cells was consistently found in patients with keratoconjunctivitis sicca (Sjogren syndrome) compared with expression in normal eyes. These 2 markers were well correlated with each other and correlated inversely with tear break-up time and tear production as measured by the Schirmer test. The percentage of conjunctival goblet cells was significantly decreased in dry eye patients with a significant negative correlation with both HLA-DR and ICAM1 markers.
By adulthood, 90% of the population in West Africa have been infected with hepatitis B virus (HBV). Thursz et al. (1997) noted that in most people this is manifest as an asymptomatic self-limiting infection during childhood, but approximately 15% of patients develop a persistent infection, and this often results in chronic liver disease and hepatocellular carcinoma. Because HBV-induced hepatocellular carcinoma is commonly a disease of working-age males in West Africa, resistance to HBV persistence probably confers some reproductive advantage. Almarri and Batchelor (1994) found that particular HLA class II region haplotypes affect the probability that an HBV infection will become persistent. Thursz et al. (1997) presented evidence supporting models of overdominant selection in which MHC homozygotes are less likely to clear an HBV infection and thus more likely to become persistently infected. In tests of 632 Gambian subjects of whom 223 had evidence of persistent infection and 409 had successfully cleared the virus, they found no differences in the class I loci; however, significantly fewer subjects with persistent infection were heterozygous for haplotypes of the HLA class II region genes, HLA-DR and HLA-DQ.
For a discussion of a possible association between variation in the HLA-DRA gene and susceptibility to the development of Parkinson disease, see 168600.
Bodmer et al. (1990) presented a consensus on nomenclature for factors in the HLA system. The HLA-DR molecule has a single species of alpha chain encoded by the HLA-DRA gene. In the case of the beta chain, there are DRB1, DRB3 (612735), DRB4, and DRB5 genes. (DRB2 is a pseudogene with DR-beta-like sequences.) HLA-DRB6 is a truncated gene in both humans and chimpanzees, lacking exon 1, which normally codes for the leader and the first 4 amino acid residues of the mature protein. However, a human DRB6 exon 2 sequence has been obtained by PCR amplification of cDNA reversely transcribed from RNA of a B-cell line, implying that the DRB6 gene is, in fact, transcribed.
Dupont et al. (1974) suggested that the genetic control of stimulation in the mixed lymphocyte culture (MLC) reaction in man is determined by a separate gene, which they called MLR-S (HLA-D), closely linked to the FOUR locus of the HLA-A (142800) chromosomal region. They reported 3 children with recombination between the FOUR and MLR-S locus in 2 families and confirmed that the MLR-S locus is located outside the HLA-A chromosomal region.
In addition to HLA-D, genes controlling secondary mixed lymphocyte response were assigned to the HLA-A region (Eijsvoogel et al., 1972) and to SB (142880), a region at least 2 cM proximal to HLA-D. Mempel et al. (1973) came to the same conclusion.
The focus of the 7th International Workshop on Histocompatibility Testing held in Oxford in August 1977 was the definition of determinants present only in B lymphocytes. By analogy to the H-2 nomenclature in the mouse, these antigens have been called Ia (immune-associated). The Oxford workshop identified 7 specificities as defined by homozygous typing cells (HTC) in mixed lymphocyte culture (MLC) tests. These were designated DRw, for D-related and workshop, i.e., tentative. It was not certain whether the Dw and DRw specificities were determined by the same gene or by genes at 2 separate but closely linked loci. It was concluded that the 7 DRw specificities are determined by codominant alleles. In the mouse, and presumably in man, there are lymphocyte alloantigens, designated Ia (immune response-associated) antigens, found mainly on B lymphocytes. The existence of immune response-associated antigens in man is highly probable because of the close homology of the H-2 and HLA regions in mouse and man. See McDevitt and Bodmer (1974) for discussion and references.
Mann et al. (1975, 1976) demonstrated 2 separate genetic loci for B-lymphocyte alloantigens in the HLA region. These were demonstrated using sera derived from multiparous Amish women and testing large Amish families. HLA-A (142800), HLA-B (142830), and HLA-C (142840) are serologically defined antigens found on both T and B lymphocytes. Antigens tested for by mixed lymphocyte reactions appear to be expressed only in B lymphocytes. The relation of the serologically demonstrated B-lymphocyte alloantigens to those demonstrated by MLC was not established. Mann et al. (1975) suggested identity to the Ia antigens of the mouse. There may be more than 2 loci for B alloantigens in the HLA area. The Histocompatibility Workshop 1977 was unable to distinguish with certainty between Ia and HLA-D, i.e., that separate loci are represented was not established.
Markert and Cresswell (1980) concluded that HLA-DR specificity is carried on the alpha subunit. A second type of specificity, called MB, is thought to be determined by a locus closely linked to HLA-DR and, from studies of Markert and Cresswell (1980), may reside on the beta subunit. They found that a third closely linked gene locus, MT, determines Ia antigen-like molecules distinct from those carrying MB and HLA-DR determinants. HLA-DR in man and Ia in the mouse are termed class II histocompatibility antigens. One hypothesis to account for the relationship between MT and DR is that the DR locus is a complex one that has 3 (or more) 'tightly linked loci, similar to the Rh locus. As in the Gm system, the product of this complex gene could be located on separate domains of the gene products. Thus, MT1, DR1, and MT5 could be on 3 different sites of the Ia molecule, while being determined by a single complex locus' (Park et al., 1980).
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