Alternative titles; symbols
HGNC Approved Gene Symbol: HLA-DPB1
Cytogenetic location: 6p21.32 Genomic coordinates (GRCh38): 6:33,075,990-33,089,696 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.32 | {Beryllium disease, chronic, susceptibility to} | 3 |
The DP (formerly SB) subregion of the HLA class II D region contains genes encoding the alpha (142880) and beta chains of a heterodimeric, cell-surface glycoprotein that presents antigens to CD4+ (helper) T lymphocytes. Because the HLA class II molecules are highly polymorphic, they can embrace a wide variety of antigens in their antigen-binding groove and present them to diverse T-lymphocyte antigen receptors, triggering antigen recognition. Amino acids located at key positions along the alpha-helical portions of these HLA heterodimers dictate which peptide antigens can bind. Even single amino acid substitutions in these regions may alter the shape of HLA-peptide binding pocket sufficiently to change its specificity.
Chronic beryllium disease (CBD) is a hypersensitivity lung disorder caused by exposure to beryllium that is not strictly dependent on beryllium concentration. CBD is a disorder that occurs in diverse industries, including high-technology ceramics, electronics, dental alloy preparation, nuclear weapons, metal extraction, and aerospace. Only a subset of exposed workers develop the disease. Its immunopathologic features predict that CBD is maintained by an accumulation of large numbers of beryllium-specific CD4+ T cells in the lungs of patients. Granulomas form around beryllium particles in the walls of the alveoli. Blood lymphocytes from a person sensitive to beryllium proliferate in vitro when cultured in the presence of beryllium salts. This reaction is the basis of the beryllium lymphocyte proliferation test that is used in the specific diagnosis of CBD and for detection of early CBD in industrial screening programs. Richeldi et al. (1993) demonstrated that a glutamic acid residue at position 69 of the HLA-DPB1 polypeptide confers susceptibility to CBD. In an evaluation of MHC class II genes in 33 CBD cases and 44 beryllium-exposed unaffected controls, they found that 97% of the CBD cases expressed the form with glutamic acid at residue 69, whereas only 30% of an unaffected population showed that residue rather than the positively charged lysine. The situation has a parallel to ankylosis spondylitis in which about 90% of persons with the disorder are positive for HLA-B27 but only 2% of HLA-B27-positive persons in the general population develop the disorder. The genetic connection raises ethical and societal issues concerning genetic screening in the workplace.
Taylor et al. (1995) obtained preliminary evidence in a small series of patients suggesting that susceptibility to childhood common acute lymphoblastic leukemia (ALL) was associated with an allele at the HLA-DPB1 locus, DPB1*0201. Taylor et al. (2002) tested this hypothesis by comparing the frequency of children with leukemia (n = 982) who typed for specific DPB1 alleles and 2 groups of non-leukemic children (1 with solid tumors, excluding lymphomas, and a group of normal infants). The authors found that significantly more children with common ALL and T-cell ALL (but not progenitor B-cell ALL or acute non-lymphocytic ALL) typed for DPB1*0201, as compared with children with solid tumors (odds ratio, 95% CI for common ALL: 1.76, 1.20-2.56; T-cell ALL: 1.93, 1.01-3.80) and normal infants (odds ratio, 95% CI for common ALL: 1.83, 1.34-2.48; T-cell ALL: 2.00, 1.10-3.82). In childhood common ALL, significantly more children than those with solid tumors or normal infants typed for DPB1 alleles coding specific polymorphic amino acids lining the antigen-binding site of the DPB1*0201 allotypic protein. The authors suggested that susceptibility to childhood common ALL may be influenced by DPB ABS amino acid polymorphisms shared by DPB1*0201 and other DPB1 allotypes, which activate T-helper cells responsible for proliferation of preleukemic cells.
In a study of patients with sarcoidosis (181000) and case-matched controls, Rossman et al. (2003) found that the HLA-DPB1 locus contributed to susceptibility for sarcoidosis but, in contrast to chronic beryllium disease, a non-glu69-containing allele, HLA-DPB1*0101, conveyed most of the risk.
For a discussion of a possible association between variation in the DPB1 gene and chronic thromboembolic pulmonary hypertension (CTEPH) without deep vein thrombosis, see 612862.
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 (142880) and HLA-DPB1. 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 (142880) and HLA-DPB1 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.
Temme et al. (2014) investigated the assembly and carbohydrate maturation of isotype-mixed HLA class II alpha and beta heterodimers and found that they were dependent on the groove-binding section of the invariant chain (Ii, or CD74; 142790). Mutation analysis showed that lys69 and the GGPM motif (residues 84 to 87) of DPB1 were engaged in Ii-dependent assembly of HLA-DPB with HLA-DRA (142860). These motifs are found in the Neanderthal genome and are related to the modern human allele HLA-DPB1*0401. Because HLA-DPB1*0401 is rare in sub-Saharan populations but frequent in European populations, Temme et al. (2014) proposed that the allele may have arisen in modern humans by admixture with Neanderthals in Europe.
Roux-Dosseto et al. (1983) isolated a class II antigen beta-chain cDNA clone from a human B-cell cDNA library by using the mouse I-A(beta) gene as a probe. It was shown to be distinct from DC-beta- and DR-beta-related loci by DNA sequence analysis, and corresponded to SB beta in all characteristics.
Richeldi et al. (1993) demonstrated that the HLA-DPB1 polypeptide had glutamic acid at residue 69 in 97% of cases of chronic beryllium disease but only 30% of an unaffected population.
Fontenot et al. (2000) isolated beryllium-specific T-cell lines from the lungs of patients with chronic beryllium disease. These CD4+ T-cell lines specifically responded to beryllium in culture in the presence of antigen-presenting cells that expressed class II MHC molecules HLA-DR, -DQ, and -DP. The response to beryllium was nearly completely and selectively blocked by monoclonal antibody to HLA-DP. Additional studies showed that only certain HLA-DP alleles allowed presentation of beryllium. Overall, the DP alleles that presented beryllium to disease-specific T-cell lines matched those implicated in disease susceptibility, providing a mechanism for this association.
Fontenot, A. P., Torres, M., Marshall, W. H., Newman, L. S., Kotzin, B. L. Beryllium presentation to CD4(+) T cells underlies disease-susceptibility HLA-DP alleles in chronic beryllium disease. Proc. Nat. Acad. Sci. 97: 12717-12722, 2000. [PubMed: 11050177] [Full Text: https://doi.org/10.1073/pnas.220430797]
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]
Kominami, S., Tanabe, N., Ota, M., Naruse, T. K., Katsuyama, Y., Nakanishi, N., Tomoike, H., Sakuma, M., Shirato, K., Takahashi, M., Shibata, H., Yasunami, M., Chen, Z., Kasahara, Y., Tatsumi, K., Kuriyama, T., Kimura, A. HLA-DPB1 and NFKBIL1 may confer the susceptibility to chronic thromboembolic pulmonary hypertension in the absence of deep vein thrombosis. J. Hum. Genet. 54: 108-114, 2009. [PubMed: 19165231] [Full Text: https://doi.org/10.1038/jhg.2008.15]
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]
Richeldi, L., Sorrentino, R., Saltini, C. HLA-DPB1 glutamate 69: a genetic marker of beryllium disease. Science 262: 242-244, 1993. [PubMed: 8105536] [Full Text: https://doi.org/10.1126/science.8105536]
Rossman, M. D., Thompson, B., Frederick, M., Maliarik, M., Iannuzzi, M. C., Rybicki, B. A., Pandey, J. P., Newman, L. S., Magira, E., Beznik-Cizman, B., Monos, D., ACCESS Group. HLA-DRB1*1101: a significant risk factor for sarcoidosis in blacks and whites. Am. J. Hum. Genet. 73: 720-735, 2003. [PubMed: 14508706] [Full Text: https://doi.org/10.1086/378097]
Roux-Dosseto, M., Auffray, C., Lillie, J. W., Boss, J. M., Cohen, D., DeMars, R., Mawas, C., Seidman, J. G., Strominger, J. L. Genetic mapping of a human class II antigen beta-chain cDNA clone to the SB region of the HLA complex. Proc. Nat. Acad. Sci. 80: 6036-6040, 1983. [PubMed: 6310612] [Full Text: https://doi.org/10.1073/pnas.80.19.6036]
Taylor, G. M., Dearden, S., Ravetto, P., Ayres, M., Watson, P., Hussain, A., Greaves, M., Alexander, F., Eden, O. B., UKCCS Investigators. Genetic susceptibility to childhood common acute lymphoblastic leukaemia is associated with polymorphic peptide-binding pocket profiles in HLA-DPB1*0201. Hum. Molec. Genet. 11: 1585-1597, 2002. [PubMed: 12075003] [Full Text: https://doi.org/10.1093/hmg/11.14.1585]
Taylor, G. M., Robinson, M. D., Binchy, A., Birch, J. M., Stevens, R. F., Jones, P. M., Carr, T., Dearden, S., Gokhale, D. A. Preliminary evidence of an association between HLA-DPB1*0201 and childhood common acute lymphoblastic leukaemia supports an infectious aetiology. Leukemia 9: 440-443, 1995. [PubMed: 7885043]
Temme, S., Zacharias, M., Neumann, J., Wohlfromm, S., Konig, A., Temme, N., Springer, S., Trowsdale, J., Koch, N. A novel family of human leukocyte antigen class II receptors may have its origin in archaic human species. J. Biol. Chem. 289: 639-653, 2014. [PubMed: 24214983] [Full Text: https://doi.org/10.1074/jbc.M113.515767]