Alternative titles; symbols
HGNC Approved Gene Symbol: HLA-DPA1
Cytogenetic location: 6p21.32 Genomic coordinates (GRCh38): 6:33,064,569-33,080,748 (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 (see 142860), HLA-DP, 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 (Dai et al., 2008).
Application of the primed lymphocyte test (PLT) led to the identification of the SB (DP) system (Shaw et al., 1980) and the PL3A system (Termijtelen et al., 1980; Termijtelen and van Rood, 1981) as separate loci in the HLA-D region coding for determinants that confer weak or moderate stimulation in primary mixed lymphocyte culture (MLC) but strong stimulation in primed lymphocyte culture. Termijtelen et al. (1983) demonstrated the identity of PL3A and SB1.
Kavathas et al. (1981) selected HLA-mutant lymphoblastoid cell lines that had lost expression of specific genetic markers; thereby, new B-cell antigens were defined. They are called SB (secondary B-cell locus) because they evoke strong secondary allogeneic proliferative and cytotoxic responses in B cells. Separateness from HLA-DR, which the SB antigens resemble functionally, was demonstrated by the finding that the cis-linked SB antigen continued to be expressed after loss of HLA-A (142800), HLA-B (142830), and HLA-DR antigen expression in a mutagenized cell line which had a visible deletion of the region of the short arm of chromosome 6 coding for HLA. Population studies indicated that the 5 SB antigens are a single mendelian segregant series in Hardy-Weinberg equilibrium. Both family studies (Shaw et al., 1981) and analysis of mutant cell lines (Kavathas et al., 1981) indicated the distinctness of the HLA-SB locus. Shaw et al. (1981) showed that the determinant previously described by Mawas et al. (1978, 1980) is identical to SB1.
Hartzman et al. (1983) described another HLA-D/SB recombinant person.
Gustafsson et al. (1987) made deductions about the evolution of the DP region from the nucleotide sequences of the 4 genes: 2 alpha genes and 2 beta genes. Alpha-1 and beta-1 (142858) encode the expressed DP histocompatibility antigen molecule.
Using 2 DP-beta probes and a DP-alpha probe with a series of restriction enzymes, Bodmer et al. (1987) identified RFLP patterns characteristic of various DP serotypes.
Eckels et al. (1983) showed that SB-restricted antigen recognition may form an integral part of normal human immune responses.
Since SB maps between HLA-B and glyoxalase (138750; Shaw et al., 1980), HLA-SB must be located centromeric to HLA-DR on chromosome 6.
By analysis of cosmid clones, Spielman et al. (1984) identified 6 genes in the HLA-D region coding for alpha chains: DR alpha, DC alpha, DX alpha (HLA-DQA2; 613503), which is closely related to DC alpha, SB alpha-1, SB alpha-2 (2 closely linked genes in the same cosmid clones), and DZ alpha.
Erlich et al. (1986) performed Southern blot analysis of human lymphoblastoid cell lines homozygous for deletions. They localized the deletion breakpoint within the DP genes and, on the basis of their findings, suggested a general map order for the HLA class II region.
Kamatani et al. (2009) performed a 2-stage genomewide association study using 786 Japanese chronic hepatitis B (see 610424) cases and 2,201 controls, and identified a significant association of chronic hepatitis B with 11 SNPs in a region including HLA-DPA1 and HLA-DPB1 (142858). Kamatani et al. (2009) validated these associations by genotyping 2 SNPs from the region in 3 additional Japanese and Thai cohorts consisting of 1,300 cases and 2,100 controls (combined P = 6.34 x 10(-39) and 2.31 x 10(-38), odds ratio = 0.57 and 0.56, respectively). Subsequent analyses revealed risk haplotypes (HLA-DPA1*0202-DPB1*0501 and HLA-DPA1*0202-DPB1*0301, odds ratio = 1.45 and 2.31, respectively) and protective haplotypes (HLA-DPA1*0103-DPB1*0402 and HLA-DPA1*0103-DPB1*0401, odds ratio = 0.52 and 0.57, respectively). Kamatani et al. (2009) concluded that genetic variants in the HLA-DP locus are strongly associated with risk of persistent infection with hepatitis B virus in Asians.
The coding regions of many of the major histocompatibility complex (MHC) molecules are believed to be subject to balancing selection. To determine whether the regulatory regions of such coding sequences are also subject to the same type of selection, Liu et al. (2006) studied the polymorphism of the regulatory regions of the HLA-DPA1 and HLA-DPB1 (142858) genes among ethnic minorities in southwestern China. Phylogenetic analysis revealed 2 deep clades more than 10 million years old. There was almost complete linkage disequilibrium between the regulatory and coding regions of HLA-DPA1, which hints at coadaptive balancing selection on the entire region. Thus, the molecular mechanism of balancing selection in MHC may involve expression modulation in addition to coding region polymorphisms. Although the frequency of clade II is more than 30% in some ethnic minorities, it decreases to less than 5% among southern Han Chinese and vanishes among Europeans. As suspected, some ancient balanced polymorphisms, lost in major populations, still exist in isolated ethnicities. These isolated polymorphisms may thus contribute disproportionately to the total diversity of modern humans.
Austin, P., Trowsdale, J., Rudd, C., Bodmer, W., Feldmann, M., Lamb, J. Functional expression of HLA-DP genes transfected into mouse fibroblasts. Nature 313: 61-64, 1985. [PubMed: 2578218] [Full Text: https://doi.org/10.1038/313061a0]
Bodmer, J., Bodmer, W., Heyes, J., So, A., Tonks, S., Trowsdale, J., Young, J. Identification of HLA-DP polymorphism with DP-alpha and DP-beta probes and monoclonal antibodies: correlation with primed lymphocyte typing. Proc. Nat. Acad. Sci. 84: 4596-4600, 1987. [PubMed: 2885841] [Full Text: https://doi.org/10.1073/pnas.84.13.4596]
Dai, S., Crawford, F., Marrack, P., Kappler, J. W. The structure of HLA-DR52c: comparison to other HLA-DRB3 alleles. Proc. Nat. Acad. Sci. 105: 11893-11897, 2008. [PubMed: 18697946] [Full Text: https://doi.org/10.1073/pnas.0805810105]
Eckels, D. D., Lake, P., Lamb, J. R., Johnson, A. H., Shaw, S., Woody, J. N., Hartzman, R. J. SB-restricted presentation of influenza and herpes simplex virus antigens to human T-lymphocyte clones. Nature 301: 716-718, 1983. [PubMed: 6186920] [Full Text: https://doi.org/10.1038/301716a0]
Erlich, H., Lee, J. S., Petersen, J. W., Bugawan, T., DeMars, R. Molecular analysis of HLA class I and class II antigen loss mutants reveals a homozygous deletion of the DR, DQ, and part of the DP region: implications for class II gene order. Hum. Immun. 16: 205-219, 1986. [PubMed: 3459724] [Full Text: https://doi.org/10.1016/0198-8859(86)90049-2]
Gustafsson, K., Emmoth, E., Widmark, E., Bohme, J., Peterson, P. A., Rask, L. Isolation of a cDNA clone coding for an SB beta-chain. Nature 309: 76-78, 1984. [PubMed: 6325928] [Full Text: https://doi.org/10.1038/309076a0]
Gustafsson, K., Widmark, E., Jonsson, A.-K., Servenius, B., Sachs, D. H., Larhammar, D., Rask, L., Peterson, P. A. Class II genes of the human major histocompatibility complex: evolution of the DP region as deduced from nucleotide sequences of the four genes. J. Biol. Chem. 262: 8778-8786, 1987. [PubMed: 3036829]
Hartzman, R. J., Robbins, F., Johnson, A., Ward, F. E., Amos, D. B. Genetic mapping of SB: recombinant family studies. Transplant. Proc. 15: 79-83, 1983.
Kamatani, Y., Wattanapokayakit, S., Ochi, H., Kawaguchi, T., Takahashi, A., Hosono, N., Kubo, M., Tsunoda, T., Kamatani, N., Kumada, H., Puseenam, A., Sura, T., Daigo, Y., Chayama, K., Chantratita, W., Nakamura, Y., Matsuda, K. A genome-wide association study identifies variants in the HLA-DP locus associated with chronic hepatitis B in Asians. Nature Genet. 41: 591-595, 2009. [PubMed: 19349983] [Full Text: https://doi.org/10.1038/ng.348]
Kavathas, P., Bach, F. H., DeMars, R. Gamma ray-induced loss of expression of HLA and glyoxalase I alleles in lymphoblastoid cells. Proc. Nat. Acad. Sci. 77: 4251-4255, 1980. [PubMed: 6933474] [Full Text: https://doi.org/10.1073/pnas.77.7.4251]
Kavathas, P., DeMars, R., Bach, F. H., Shaw, S. SB: a new HLA-linked human histocompatibility gene defined using HLA-mutant cell lines. Nature 293: 747-749, 1981. [PubMed: 6974827] [Full Text: https://doi.org/10.1038/293747a0]
Kelly, A., Trowsdale, J. Complete nucleotide sequence of a functional HLA-DP-beta gene and the region between the DP-beta-1 and DP-alpha-1 genes: comparison of the 5-prime ends of HLA class II genes. Nucleic Acids Res. 13: 1607-1621, 1985. [PubMed: 2987832] [Full Text: https://doi.org/10.1093/nar/13.5.1607]
Lawrance, S. K., Das, H. K., Pan, J., Weissman, S. M. The genomic organisation and nucleotide sequence of the HLA-SB(DP) alpha gene. Nucleic Acids Res. 13: 7515-7528, 1985. [PubMed: 2997750] [Full Text: https://doi.org/10.1093/nar/13.20.7515]
Liu, X., Fu, Y., Liu, Z., Lin, B., Xie, Y., Liu, Y., Xu, Y., Lin, J., Fan, X., Dong, M., Zeng, K., Wu, C., Xu, A. An ancient balanced polymorphism in a regulatory region of human major histocompatibility complex is retained in Chinese minorities but lost worldwide. Am. J. Hum. Genet. 78: 393-400, 2006. [PubMed: 16465617] [Full Text: https://doi.org/10.1086/500593]
Mawas, C., Charmot, D., Mercier, P. Split of HLA-D into two regions alpha and beta by a recombination between HLA-D and GLO. I. Study in a family and primed lymphocyte typing for determinants coded by the beta region. Tissue Antigens 15: 458-466, 1980. [PubMed: 6160646] [Full Text: https://doi.org/10.1111/j.1399-0039.1980.tb00209.x]
Mawas, C., Charmot, D., Sivy, M., Mercier, P., North, M. L., Hauptmann, G. A weak human MLR locus mapping at the right of a crossing-over between HLA-D, Bf and GLO. J. Immunogenet. 5: 383-395, 1978. [PubMed: 153369] [Full Text: https://doi.org/10.1111/j.1744-313x.1978.tb00667.x]
Okada, K., Prentice, H. L., Boss, J. M., Levy, D. J., Kappes, D., Spies, T., Raghupathy, R., Mengler, R. A., Auffray, C., Strominger, J. L. SB subregion of the human major histocompatibility complex: gene organization, allelic polymorphism and expression in transformed cells. EMBO J. 4: 739-748, 1985. [PubMed: 2988934] [Full Text: https://doi.org/10.1002/j.1460-2075.1985.tb03691.x]
Segall, M., Reinsmoen, N. L., Noreen, H. J., Bach, F. H. Complexity of the HLA-D region studied by primed-lymphocyte test. J. Exp. Med. 152: 156s-163s, 1980. [PubMed: 6157765]
Shaw, S., Johnson, A. H., Shearer, G. M. Evidence for a new segregant series of B cell antigens that are encoded in the HLA-D region and that stimulate secondary allogeneic proliferative and cytotoxic responses. J. Exp. Med. 152: 565-580, 1980. [PubMed: 6967946] [Full Text: https://doi.org/10.1084/jem.152.3.565]
Shaw, S., Kavathas, P., Pollack, M. S., Charmot, D., Mawas, C. Family studies define a new histocompatibility locus, SB, between HLA-DR and GLO. Nature 293: 745-747, 1981. [PubMed: 6974826] [Full Text: https://doi.org/10.1038/293745a0]
Spielman, R. S., Lee, J., Bodmer, W. F., Bodmer, J. G., Trowsdale, J. Six HLA-D region alpha-chain genes on human chromosome 6: polymorphisms and associations of DC alpha-related sequences with DR types. Proc. Nat. Acad. Sci. 81: 3461-3465, 1984. [PubMed: 6328517] [Full Text: https://doi.org/10.1073/pnas.81.11.3461]
Termijtelen, A., Bradley, B. A., van Rood, J. J. A new determinant defined by PLT, coded for in the HLA region and apparently independent of the HLA-D and DR loci. Tissue Antigens 15: 267-274, 1980. [PubMed: 6162224] [Full Text: https://doi.org/10.1111/j.1399-0039.1980.tb00917.x]
Termijtelen, A., Shaw, S., van Rood, J. J. Identity of PL3A and SB1. Tissue Antigens 21: 400-401, 1983. [PubMed: 6223410] [Full Text: https://doi.org/10.1111/j.1399-0039.1983.tb00191.x]
Termijtelen, A., van Rood, J. J. The role in primary MLC of the non HLA-D/DR determinant PL3A. Tissue Antigens 17: 57-63, 1981. [PubMed: 6166084] [Full Text: https://doi.org/10.1111/j.1399-0039.1981.tb00666.x]