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Gene Review

HLA-DRB4  -  major histocompatibility complex, class II...

Homo sapiens

Synonyms: DR-4, DR4, DRB4, HLA class II histocompatibility antigen, DR beta 4 chain, HLA-DR4B, ...
 
 
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Disease relevance of HLA-DRB4

  • The cross-reactivity between HLA-DR53 and H-2Ek, extensive mimicry of the immunodominant epitope of HLA-DR53 by several carcinogenic viruses, and the extra amount of DNA in the vicinity of the HLA-DRB4 gene argue for the case that HLA-DRB4*01 may be one of the genetic risk factors for childhood ALL [1].
  • We selected 38 consecutive celiac disease (CD) patients (from a group of 316 consecutive CD patients) and 91 healthy blood donors, all of whom were HLA-DQ2 (DQA1*0501/DQB1*0201) negative, and investigated the presence of the classically associated alleles HLA-DQ8 and HLA-DRB4 [2].
  • Interactions of HLA-DRB4 and CTLA-4 genes influence thyroid function in Hashimoto's thyroiditis in Japanese population [3].
  • The protective alleles for Graves' disease were DRB1 *0901 (0.9% vs. 20.2%; RR = 0.04; Pc < 0.001), DRB1*1001 (0.0% vs. 11%; RR = 0.0%; Pc < 0.01) and DRB4 *0101 (0.0% vs. 12.5%; RR = 0.0; Pc < 0.05) [4].
  • The observed decreased virus load in HLA-DRB-1 heterozygotes may be due to a better control of M. tb. infection in the context of HIV-1 disease [5].
 

Psychiatry related information on HLA-DRB4

  • The distribution of HLA-DRB1 and -DQB1 alleles and presence or absence of DRB3/4/5 alleles were examined in 60 narcoleptic patients with clear-cut cataplexy, and the results were compared with two groups of healthy controls: 200 randomly selected controls and 144 DRB1*1501-DQB1*0602 positive controls [6].
 

High impact information on HLA-DRB4

  • Conditioning on either HLA-DRB1 or the most significant HLA class II haplotype block found no additional block or SNP association independent of the HLA class II genomic region [7].
  • Genetic susceptibility to multiple sclerosis is associated with genes of the major histocompatibility complex (MHC), particularly HLA-DRB1 and HLA-DQB1 (ref. 1). Both locus and allelic heterogeneity have been reported in this genomic region [7].
  • To clarify whether HLA-DRB1 itself, nearby genes in the region encoding the MHC or combinations of these loci underlie susceptibility to multiple sclerosis, we genotyped 1,185 Canadian and Finnish families with multiple sclerosis (n = 4,203 individuals) with a high-density SNP panel spanning the genes encoding the MHC and flanking genomic regions [7].
  • Immunization of HLA-DRB1* 0301 (DR3) transgenic mice with mouse or human Tg resulted in severe thyroiditis [8].
  • HLA-DRB1 polymorphism determines susceptibility to autoimmune thyroiditis in transgenic mice: definitive association with HLA-DRB1*0301 (DR3) gene [8].
 

Chemical compound and disease context of HLA-DRB4

  • METHODS: Our research focused on the relationship between nonresponse to Hepatitis B vaccine and HLA-DRB1, DRB3, DRB4, DRB5 and DQB1 genotype/haplotype in Chinese population, collected from a community in Guangxi Zhuang Autonomous Region [9].
  • RESULTS: Comparison of marker frequencies in HHV-8 infected AIDS patients with or without KS showed a positive association between KS and HLA-DRB1 alleles containing phenylalanine at position 13 [odds ratio (OR), 2.24; P = 0.016] [10].
  • We observed a strong negative association between HLA-DRB1 alleles that encode lysine at position 71 in their beta-chain and susceptibility to ulcerative colitis [11].
 

Biological context of HLA-DRB4

  • Measurements of genetic distances indicate DRB6 to be closely related to the DRB2 pseudogene and to the HLA-DRB4 functional gene [12].
  • Approximately 50 million years (my) ago, DRB1*04 and an ancestor of the DRB1*03 cluster (DRB1*03, DRB1*15, and DRB3) diverged from each other and DRB5, DRB7, DRB8, and an ancestor of the DRB2 cluster (DRB2, DRB4, and DRB6) arose by gene duplication [13].
  • HLA class II haplotypes often contain a second expressed DRB locus which can be either DRB3, DRB4 or DRB5 [14].
  • With respect to the DRB4 gene (DR53), the gene frequency of DRB4*0101 was 35.0% [15].
  • Although the alteration in the DRB1 gene might involve sequences important in regulating the expression of the DRB4 gene, it is more likely that the association results from strong positive linkage disequilibrium between these DR beta chain genes [16].
 

Anatomical context of HLA-DRB4

  • Depending on the T cell donor, the presentation of a given antigen or peptide could be restricted by HLA-DRB1, HLA-DRB3, and/or HLA-DRB4 products [17].
  • Differential surface expression of HLA-DRB1 and HLA-DRB4 among peripheral blood cells of DR4 positive individuals [18].
  • Differential regulation of DR4 and DRB4 was shown for peripheral blood monocytes [18].
  • Thus the differential expression of the DR7 beta 1 and DR beta 4 proteins in the DR7,Dw7 cell lines arises at the level of mRNA production; the lack of detectable DR beta 4 protein in the DR7,Dw11 cell line, however, appears to be due to a different mechanism in which transcribed DRB4 sequences fail to be processed into mature mRNA molecules [19].
  • Two new HLA-DRB1 alleles (DRB1*0704 and DRB1*1507) were detected during routine polymerase chain reaction (PCR)-based typing of two Caucasoid bone marrow panel donors due to apparent DRB1* "blanks" being associated with unexpected DRB4, DRB5 and DQB1 alleles [20].
 

Associations of HLA-DRB4 with chemical compounds

  • Antigen presentation of the immunodominant T-cell epitope of the major mugwort pollen allergen, Art v 1, is associated with the expression of HLA-DRB1 *01 [21].
  • MATERIALS AND METHODS: We investigated the relationships of the patients( *) HLA-DRB1 allele with both the presence of a small population of CD55(-)CD59(-) (PNH-type) blood cells and the response to antithymocyte globulin (ATG) plus cyclosporin (CsA) therapy in 140 Japanese AA patients [22].
  • HLA-DRB1 genes and disease severity in rheumatoid arthritis. The MIRA Trial Group. Minocycline in Rheumatoid Arthritis [23].
  • METHODS: One hundred nine patients of a trial comparing intramuscular (im) gold sodium thiomalate (GSTM) and im methotrexate (MTX) in early erosive RA were followed for 6 years with regular assessments of clinical and laboratory data and yearly radiographs of hands and feet, and they were typed for HLA-DRB1 genes [24].
 

Regulatory relationships of HLA-DRB4

  • To probe into the genetic background and immunopathogenesis of dilated cardiomyopathy (DCM), HLA-DRB1 gene polymorphism in 68 patients with DCM and 175 normal control subjects were analyzed by using the polymerase chain reaction/sequence specific primer (PCR/SSP) techniques [25].
 

Other interactions of HLA-DRB4

  • RESULTS: No statistically significant differences were observed in the frequency of the HLA-DR antigen or HLA-DRB3, DRB4, or DRB5 genes between the patients and a healthy control group [26].
  • The same DRB1 allele does not necessarily share an identical DRB4 allele [27].
  • The HLA-DRB4 gene is present in half of the Spanish HLA-DQ2-negative celiac patients [28].
  • Phototyping: comprehensive DNA typing for HLA-A, B, C, DRB1, DRB3, DRB4, DRB5 & DQB1 by PCR with 144 primer mixes utilizing sequence-specific primers (PCR-SSP) [29].
  • The association of this altered HindIII fragment with defective beta 4 chain expression suggested the possibility that the polymorphic fragment was derived from the DRB4 gene and might, therefore, be related to the defect in expression [16].
 

Analytical, diagnostic and therapeutic context of HLA-DRB4

  • With the aim of confirming this polymorphism, RNA isolated from G081 was subjected to RT-PCR using primers designed to recognize specifically the 5' and 3' UT regions of HLA-DRB4 and the product was cloned and sequenced [30].
  • We have developed a single DNA typing method which uses 144 sequence-specific primer (SSP) reactions to simultaneously detect all known HLA-A, B, C, DRB1, DRB3, DRB4, DRB5 and DQB1 specificities in an allele specific or group specific manner using the same method, reagents, PCR parameters and protocols for all loci [29].
  • However, detailed Southern blot analysis has now mapped the polymorphic fragment to the 3' end of the DRB1 gene, approximately 100 kb away from the defective DRB4 gene [16].
  • RESULTS: The frequencies of HLA-DRB1*0405, DRB4 and DQB1*0401 alleles were significantly higher in AIH patients [31].
  • High incidences of graft failure and graft-versus-host disease in the recipients of bone marrow transplantations (BMT) from unrelated donors (URD) may reflect the existence of allelic disparities between the patient and the URD despite apparent HLA identity at HLA-A, HLA-B, and HLA-DRB1 loci [32].

References

  1. Unravelling an HLA-DR association in childhood acute lymphoblastic leukemia. Dorak, M.T., Lawson, T., Machulla, H.K., Darke, C., Mills, K.I., Burnett, A.K. Blood (1999) [Pubmed]
  2. MICA-A5.1 allele is associated with atypical forms of celiac disease in HLA-DQ2-negative patients. Lopez-Vazquez, A., Rodrigo, L., Fuentes, D., Riestra, S., Bousoño, C., Garcia-Fernandez, S., Martinez-Borra, J., Gonzalez, S., Lopez-Larrea, C. Immunogenetics (2002) [Pubmed]
  3. Interactions of HLA-DRB4 and CTLA-4 genes influence thyroid function in Hashimoto's thyroiditis in Japanese population. Terauchi, M., Yanagawa, T., Ishikawa, N., Ito, K., Fukazawa, T., Maruyama, H., Saruta, T. J. Endocrinol. Invest. (2003) [Pubmed]
  4. HLA-DRB3*0101 is associated with Graves' disease in Jamaicans. Smikie, M.F., Pascoe, R.W., Barton, E., Morgan, O., Christian, N., Dowe, G., Roye-Green, K., Bailey, V., James, O. Clin. Endocrinol. (Oxf) (2001) [Pubmed]
  5. Association of high HIV-1 RNA levels and homozygosity at HLA class II DRB1 in adults coinfected with Mycobacterium tuberculosis in Harare, Zimbabwe. Zijenah, L.S., Hartogensis, W.E., Katzenstein, D.A., Tobaiwa, O., Mutswangwa, J., Mason, P.R., Louie, L.G. Hum. Immunol. (2002) [Pubmed]
  6. Association of HLA-DR and -DQ Genes with Narcolepsy in Koreans Comparison with Two Control Groups, Randomly Selected Subjects and DRB1*1501-DQB1*0602-Positive Subjects. Roh, E.Y., Park, M.H., Park, H., Park, D.H., Choi, J.B., Kim, S.J., Jeong, D.U. Hum. Immunol. (2006) [Pubmed]
  7. A predominant role for the HLA class II region in the association of the MHC region with multiple sclerosis. Lincoln, M.R., Montpetit, A., Cader, M.Z., Saarela, J., Dyment, D.A., Tiislar, M., Ferretti, V., Tienari, P.J., Sadovnick, A.D., Peltonen, L., Ebers, G.C., Hudson, T.J. Nat. Genet. (2005) [Pubmed]
  8. HLA-DRB1 polymorphism determines susceptibility to autoimmune thyroiditis in transgenic mice: definitive association with HLA-DRB1*0301 (DR3) gene. Kong, Y.C., Lomo, L.C., Motte, R.W., Giraldo, A.A., Baisch, J., Strauss, G., Hämmerling, G.J., David, C.S. J. Exp. Med. (1996) [Pubmed]
  9. The relationship between nonresponse to hepatitis B vaccine and HLA genotype/haplotype. Li, M., Li, R., Huang, S., Gong, J., Zeng, X., Li, Y., Lu, M., Li, H. Zhonghua Yu Fang Yi Xue Za Zhi (2002) [Pubmed]
  10. Amino acid residue at position 13 in HLA-DR beta chain plays a critical role in the development of Kaposi's sarcoma in AIDS patients. Gayà, A., Esteve, A., Casabona, J., McCarthy, J.J., Martorell, J., Schulz, T.F., Whitby, D. AIDS (2004) [Pubmed]
  11. Amino acid polymorphism at residue 71 in HLA-DR beta chain plays a critical role in susceptibility to ulcerative colitis. de la Concha, E.G., Fernandez-Arquero, M., Martinez, A., Vigil, P., Vidal, F., Lopez-Nava, G., Diaz-Rubio, M., Garcia-Paredes, J. Dig. Dis. Sci. (1999) [Pubmed]
  12. Primate DRB6 pseudogenes: clue to the evolutionary origin of the HLA-DR2 haplotype. Figueroa, F., O'hUigin, C., Inoki, H., Klein, J. Immunogenetics (1991) [Pubmed]
  13. Evolutionary relationship of HLA-DRB genes inferred from intron sequences. Satta, Y., Mayer, W.E., Klein, J. J. Mol. Evol. (1996) [Pubmed]
  14. Increased heterozygosity for MHC class II lineages in newborn males. Dorak, M.T., Lawson, T., Machulla, H.K., Mills, K.I., Burnett, A.K. Genes Immun. (2002) [Pubmed]
  15. Determination of HLA class II alleles by genotyping in a Manchu population in the northern part of China and its relationship with Han and Japanese populations. Geng, L., Imanishi, T., Tokunaga, K., Zhu, D., Mizuki, N., Xu, S., Geng, Z., Gojobori, T., Tsuji, K., Inoko, H. Tissue Antigens (1995) [Pubmed]
  16. Mapping of a restriction fragment length polymorphism associated with defective DR beta 4 chain expression to the HLA-DRB1 gene. Sutton, V.R., Knowles, R.W. Hum. Immunol. (1988) [Pubmed]
  17. HLA-restricted immune response to mycobacterial antigens: relevance to vaccine design. Mustafa, A.S. Hum. Immunol. (2000) [Pubmed]
  18. Differential surface expression of HLA-DRB1 and HLA-DRB4 among peripheral blood cells of DR4 positive individuals. Czerwony, G., Alten, R., Gromnica-Ihle, E., Hagemann, D., Reuter, U., Sörensen, H., Müller, B. Hum. Immunol. (1999) [Pubmed]
  19. HLA-DRB1 and -DRB4 genes are differentially regulated at the transcriptional level. Stunz, L.L., Karr, R.W., Anderson, R.A. J. Immunol. (1989) [Pubmed]
  20. Molecular, serological and genetic studies on two new HLA-DRB1 alleles--HLA-DRB1*0704 and HLA-DRB1*1507. Darke, C., Guttridge, M.G., Street, J., Thompson, J., Thomas, M. Tissue Antigens (2000) [Pubmed]
  21. Antigen presentation of the immunodominant T-cell epitope of the major mugwort pollen allergen, Art v 1, is associated with the expression of HLA-DRB1 *01. Jahn-Schmid, B., Fischer, G.F., Bohle, B., Faé, I., Gadermaier, G., Dedic, A., Ferreira, F., Ebner, C. J. Allergy Clin. Immunol. (2005) [Pubmed]
  22. Roles of DRB1( *)1501 and DRB1( *)1502 in the pathogenesis of aplastic anemia. Sugimori, C., Yamazaki, H., Feng, X., Mochizuki, K., Kondo, Y., Takami, A., Chuhjo, T., Kimura, A., Teramura, M., Mizoguchi, H., Omine, M., Nakao, S. Exp. Hematol. (2007) [Pubmed]
  23. HLA-DRB1 genes and disease severity in rheumatoid arthritis. The MIRA Trial Group. Minocycline in Rheumatoid Arthritis. Reveille, J.D., Alarcón, G.S., Fowler, S.E., Pillemer, S.R., Neuner, R., Clegg, D.O., Mikhail, I.S., Trentham, D.E., Leisen, J.C., Bluhm, G., Cooper, S.M., Duncan, H., Tuttleman, M., Heyse, S.P., Sharp, J.T., Tilley, B. Arthritis Rheum. (1996) [Pubmed]
  24. The effect of HLA-DRB1 genes, rheumatoid factor, and treatment on radiographic disease progression in rheumatoid arthritis over 6 years. Rau, R., Herborn, G., Zueger, S., Fenner, H. J. Rheumatol. (2000) [Pubmed]
  25. HLA-DRB1 gene polymorphism in patients with dilated cardiomyopathy. Wang, Q., Liao, Y., Gong, F., Mao, H., Zhang, J. J. Tongji Med. Univ. (2000) [Pubmed]
  26. HLA-DRB genotypes in Japanese patients with renal cell carcinoma. Kojima, Y., Takahara, S., Nonomura, N., Sada, M., Tsuji, T., Hatori, M., Fujioka, H., Kuroda, H., Miki, T., Okuyama, A. Oncology (2000) [Pubmed]
  27. HLA-DRB4 genotyping by PCR-RFLP: diversity in the associations between HLA-DRB4 and DRB1 alleles. Naruse, T.K., Ando, R., Nose, Y., Kagiya, M., Ando, H., Kawata, H., Nabeya, N., Isshiki, G., Inoko, H. Tissue Antigens (1997) [Pubmed]
  28. The HLA-DRB4 gene is present in half of the Spanish HLA-DQ2-negative celiac patients. Garrote, J.A., Arranz, E., Blanco-Quirós, A. Immunogenetics (2000) [Pubmed]
  29. Phototyping: comprehensive DNA typing for HLA-A, B, C, DRB1, DRB3, DRB4, DRB5 & DQB1 by PCR with 144 primer mixes utilizing sequence-specific primers (PCR-SSP). Bunce, M., O'Neill, C.M., Barnardo, M.C., Krausa, P., Browning, M.J., Morris, P.J., Welsh, K.I. Tissue Antigens (1995) [Pubmed]
  30. Specific amplification of the HLA-DRB4 gene from c-DNA. Complete coding sequence of the HLA alleles DRB4*0103101 and DRB4*01033. De Pablo, R., Solís, R., Balas, A., Vilches, C. Tissue Antigens (2002) [Pubmed]
  31. Genetic analysis of the HLA region of Japanese patients with type 1 autoimmune hepatitis. Yoshizawa, K., Ota, M., Katsuyama, Y., Ichijo, T., Matsumoto, A., Tanaka, E., Kiyosawa, K. J. Hepatol. (2005) [Pubmed]
  32. DNA typing for HLA-A and HLA-B identifies disparities between patients and unrelated donors matched by HLA-A and HLA-B serology and HLA-DRB1. Prasad, V.K., Kernan, N.A., Heller, G., O'Reilly, R.J., Yang, S.Y. Blood (1999) [Pubmed]
 
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