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. 1992 Apr;89(4):1208–1213. doi: 10.1172/JCI115704

Association of polar amino acids at position 26 of the HLA-DQB1 first domain with the anticentromere autoantibody response in systemic sclerosis (scleroderma).

J D Reveille 1, D Owerbach 1, R Goldstein 1, R Moreda 1, R A Isern 1, F C Arnett 1
PMCID: PMC442980  PMID: 1556182

Abstract

HLA class II alleles (detected by DNA typing) were determined in 116 Caucasians with systemic sclerosis positive and negative for anticentromere autoantibodies (ACA). Significantly increased frequencies of HLA-DR5(DRw11) (P = 0.009) and the Dw13(DRB1*0403, *0407) subtypes of DR4 (probability corrected, Pc = 0.005) were seen in ACA positive patients, and HLA-DR1 and DRw8 were also increased. These findings appeared to reflect linkage disequilibrium of DR5(DRw11) and many DR4(Dw13) haplotypes with HLA-DQw7 and DR1 with DQw5. In fact, the presence of a DQB1 allele having a polar glycine or tyrosine at position 26 of the DQB1 first domain versus a hydrophobic leucine accounted for 100% of ACA positive Caucasian systemic sclerosis patients compared to 69% of the ACA negative SS patients (P = 0.0008) and 71% of Caucasian controls (P = 0.0003) as well as all 7 ACA patients of non-Caucasian background. Furthermore, the genotype frequency of DQB1 alleles lacking leucine at position 26 was 73% in ACA positive SS patients, compared to 42% of ACA negative patients (P = 1.2 x 10(-5)) and 38% of controls (P = 5.8 x 10(-7)). These data, then, suggest that the second hypervariable region of the HLA-DQB1 chain may form the candidate epitope associated with the ACA response.

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Selected References

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  1. Alarcón G. S., Phillips R. M., Wasner C. K., Acton R. T., Barger B. O. DR antigens in systemic sclerosis: lack of clinical correlations. Tissue Antigens. 1985 Aug;26(2):156–158. doi: 10.1111/j.1399-0039.1985.tb00950.x. [DOI] [PubMed] [Google Scholar]
  2. Arnett F. C., Bias W. B., McLean R. H., Engel M., Duvic M., Goldstein R., Freni-Titulaer L., McKinley T. W., Hochberg M. C. Connective tissue disease in southeast Georgia. A community based study of immunogenetic markers and autoantibodies. J Rheumatol. 1990 Aug;17(8):1029–1035. [PubMed] [Google Scholar]
  3. Bell J. I., Denney D., Jr, MacMurray A., Foster L., Watling D., McDevitt H. O. Molecular mapping of class II polymorphisms in the human major histocompatibility complex. I. DR beta. J Immunol. 1987 Jul 15;139(2):562–573. [PubMed] [Google Scholar]
  4. Bidwell J. L., Bidwell E. A., Savage D. A., Middleton D., Klouda P. T., Bradley B. A. A DNA-RFLP typing system that positively identifies serologically well-defined and ill-defined HLA-DR and DQ alleles, including DRw10. Transplantation. 1988 Mar;45(3):640–646. doi: 10.1097/00007890-198803000-00027. [DOI] [PubMed] [Google Scholar]
  5. Birnbaum N. S., Rodnan G. P., Rabin B. S., Bassion S. Histocompatibility antigens in progressive systemic sclerosis (scleroderma). J Rheumatol. 1977 Winter;4(4):425–428. [PubMed] [Google Scholar]
  6. Black C. M., Welsh K. I., Maddison P. J., Jayson M. I., Bernstein R. M. HLA antigens, autoantibodies and clinical subsets in scleroderma. Br J Rheumatol. 1984 Nov;23(4):267–271. doi: 10.1093/rheumatology/23.4.267. [DOI] [PubMed] [Google Scholar]
  7. Blin N., Stafford D. W. A general method for isolation of high molecular weight DNA from eukaryotes. Nucleic Acids Res. 1976 Sep;3(9):2303–2308. doi: 10.1093/nar/3.9.2303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bodmer J. G., Marsh S. G., Parham P., Erlich H. A., Albert E., Bodmer W. F., Dupont B., Mach B., Mayr W. R., Sasazuki T. Nomenclature for factors of the HLA system, 1989. Hum Immunol. 1990 Jul;28(3):326–342. doi: 10.1016/0198-8859(90)90060-3. [DOI] [PubMed] [Google Scholar]
  9. Briggs D. C., Welsh K., Pereira R. S., Black C. M. A strong association between null alleles at the C4A locus in the major histocompatibility complex and systemic sclerosis. Arthritis Rheum. 1986 Oct;29(10):1274–1277. doi: 10.1002/art.1780291014. [DOI] [PubMed] [Google Scholar]
  10. Carlsson B., Wallin J., Böhme J., Möller E. HLA-DR-DQ haplotypes defined by restriction fragment analysis. Correlation to serology. Hum Immunol. 1987 Oct;20(2):95–113. doi: 10.1016/0198-8859(87)90025-5. [DOI] [PubMed] [Google Scholar]
  11. Catoggio L. J., Skinner R. P., Maddison P. J. Frequency and clinical significance of anticentromere and anti Scl-70 antibodies in an English connective tissue disease population. Rheumatol Int. 1983;3(1):19–21. doi: 10.1007/BF00541227. [DOI] [PubMed] [Google Scholar]
  12. Clements P. J., Opelz G., Terasaki P. I., Mickey M. R., Furst D. Association of HLA antigen a9 with progressive systemic sclerosis (scleroderma). Tissue Antigens. 1978 Apr;11(4):357–361. doi: 10.1111/j.1399-0039.1978.tb01268.x. [DOI] [PubMed] [Google Scholar]
  13. Crouzet J., Marbach M. C., Camus J. P., Godeau P., Herreman G., Richier D., Hors J., Dausset J. Recherche d'une association entre antigènes HL-A et sclérodermie systémique. Nouv Presse Med. 1975 Oct 18;4(35):2489–2492. [PubMed] [Google Scholar]
  14. DiBartolomeo A. G., Rabin B. S., Rodnan G. P. HLA-D antigens in progressive systemic sclerosis (scleroderma). Immunol Commun. 1981;10(8):733–740. doi: 10.3109/08820138109051959. [DOI] [PubMed] [Google Scholar]
  15. Dunckley H., Jazwinska E. C., Gatenby P. A., Serjeantson S. W. DNA-DR typing shows HLA-DRw11 RFLPs are increased in frequency in both progressive systemic sclerosis and CREST variants of scleroderma. Tissue Antigens. 1989 Mar;33(3):418–420. doi: 10.1111/j.1399-0039.1989.tb01686.x. [DOI] [PubMed] [Google Scholar]
  16. Ercilla M. G., Arriaga F., Gratacós M. R., Coll J., Lecha V., Vives J., Castillo R. HLA antigens and scleroderma. Arch Dermatol Res. 1981;271(4):381–385. doi: 10.1007/BF00406682. [DOI] [PubMed] [Google Scholar]
  17. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  18. Fritzler M. J., Kinsella T. D. The CREST syndrome: a distinct serologic entity with anticentromere antibodies. Am J Med. 1980 Oct;69(4):520–526. doi: 10.1016/0002-9343(80)90462-3. [DOI] [PubMed] [Google Scholar]
  19. Gao X. J., Fernandez-Vina M., Shumway W., Stastny P. DNA typing for class II HLA antigens with allele-specific or group-specific amplification. I. Typing for subsets of HLA-DR4. Hum Immunol. 1990 Jan;27(1):40–50. doi: 10.1016/0198-8859(90)90094-6. [DOI] [PubMed] [Google Scholar]
  20. Genth E., Mierau R., Genetzky P., von Mühlen C. A., Kaufmann S., von Wilmowsky H., Meurer M., Krieg T., Pollmann H. J., Hartl P. W. Immunogenetic associations of scleroderma-related antinuclear antibodies. Arthritis Rheum. 1990 May;33(5):657–665. doi: 10.1002/art.1780330508. [DOI] [PubMed] [Google Scholar]
  21. Germain B. F., Espinoza L. R., Bergen L. L., Vagesh M., Vasey F. B. Increased prevalence of DRw3 in the CREST syndrome. Arthritis Rheum. 1981 Jun;24(6):857–859. doi: 10.1002/art.1780240615. [DOI] [PubMed] [Google Scholar]
  22. Gladman D. D., Keystone E. C., Baron M., Lee P., Cane D., Mervert H. Increased frequency of HLA-DR5 in scleroderma. Arthritis Rheum. 1981 Jun;24(6):854–856. doi: 10.1002/art.1780240614. [DOI] [PubMed] [Google Scholar]
  23. Hughes P., Gelsthorpe K., Doughty R. W., Rowell N. R., Rosenthal F. D., Sneddon I. B. The association of HLA-B8 with visceral disease in systemic sclerosis. Clin Exp Immunol. 1978 Mar;31(3):351–356. [PMC free article] [PubMed] [Google Scholar]
  24. Kallenberg C. G., Pastoor G. W., Wouda A. A., The T. H. Antinuclear antibodies in patients with Raynaud's phenomenon: clinical significance of anticentromere antibodies. Ann Rheum Dis. 1982 Aug;41(4):382–387. doi: 10.1136/ard.41.4.382. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kallenberg C. G., Van der Voort-Beelen J. M., D'Amaro J., The T. H. Increased frequency of B8/DR3 in scleroderma and association of the haplotype with impaired cellular immune response. Clin Exp Immunol. 1981 Mar;43(3):478–485. [PMC free article] [PubMed] [Google Scholar]
  26. Kohonen-Corish M. R., Serjeantson S. W. HLA-DR beta gene DNA polymorphisms revealed by Taq I correlate with HLA-DR specificities. Hum Immunol. 1986 Mar;15(3):263–271. doi: 10.1016/0198-8859(86)90002-9. [DOI] [PubMed] [Google Scholar]
  27. Larhammar D., Hyldig-Nielsen J. J., Servenius B., Andersson G., Rask L., Peterson P. A. Exon-intron organization and complete nucleotide sequence of a human major histocompatibility antigen DC beta gene. Proc Natl Acad Sci U S A. 1983 Dec;80(23):7313–7317. doi: 10.1073/pnas.80.23.7313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Livingston J. Z., Scott T. E., Wigley F. M., Anhalt G. J., Bias W. B., McLean R. H., Hochberg M. C. Systemic sclerosis (scleroderma): clinical, genetic, and serologic subsets. J Rheumatol. 1987 Jun;14(3):512–518. [PubMed] [Google Scholar]
  29. Long E. O., Wake C. T., Gorski J., Mach B. Complete sequence of an HLA-dR beta chain deduced from a cDNA clone and identification of multiple non-allelic DR beta chain genes. EMBO J. 1983;2(3):389–394. doi: 10.1002/j.1460-2075.1983.tb01435.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Lynch C. J., Singh G., Whiteside T. L., Rodnan G. P., Medsger T. A., Jr, Rabin B. S. Histocompatibility antigens in progressive systemic sclerosis (PSS; scleroderma). J Clin Immunol. 1982 Oct;2(4):314–318. doi: 10.1007/BF00915073. [DOI] [PubMed] [Google Scholar]
  31. MacMurray A. J., Bell J. I., Denney D., Jr, Watling D., Foster L. S., McDevitt H. O. Molecular mapping class II polymorphisms in the human major histocompatibility complex. II. DQ beta. J Immunol. 1987 Jul 15;139(2):574–586. [PubMed] [Google Scholar]
  32. Marsh S. G., Bodmer J. G. HLA-DRB nucleotide sequences, 1990. Immunogenetics. 1990;31(3):141–144. doi: 10.1007/BF00211548. [DOI] [PubMed] [Google Scholar]
  33. McDaniel D. O., Acton R. T., Barger B. O., Koopman W. J., Reveille J. D. Association of a 9.2-kilobase Pvu II class I major histocompatibility complex restriction fragment length polymorphism with ankylosing spondylitis. Arthritis Rheum. 1987 Aug;30(8):894–900. doi: 10.1002/art.1780300808. [DOI] [PubMed] [Google Scholar]
  34. Mollenhauer E., Schmidt R., Heinrichs M., Rittner C. Scleroderma: possible significance of silent alleles at the C4B locus. Arthritis Rheum. 1984 Jun;27(6):711–712. doi: 10.1002/art.1780270619. [DOI] [PubMed] [Google Scholar]
  35. Moraes M. E., Fernandez-Viña M., Stastny P. DNA typing for class II HLA antigens with allele-specific or group-specific amplification. IV. Typing for alleles of the HLA-DR2 group. Hum Immunol. 1991 Jun;31(2):139–144. doi: 10.1016/0198-8859(91)90017-4. [DOI] [PubMed] [Google Scholar]
  36. Niks M., Rovenský J., Nyulassy S., Buc M., Stefanovic J., Zitnan D. Lack of association of HLA-DR antigens with progressive systemic sclerosis (scleroderma). Tissue Antigens. 1982 Mar;19(3):238–239. doi: 10.1111/j.1399-0039.1982.tb01446.x. [DOI] [PubMed] [Google Scholar]
  37. Nishikai M., Okano Y., Yamashita H., Watanabe M. Characterisation of centromere (kinetochore) antigen reactive with sera of patients with a scleroderma variant (CREST syndrome). Ann Rheum Dis. 1984 Dec;43(6):819–824. doi: 10.1136/ard.43.6.819. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Owerbach D., Gunn S., Gabbay K. H. Primary association of HLA-DQw8 with type I diabetes in DR4 patients. Diabetes. 1989 Jul;38(7):942–945. doi: 10.2337/diab.38.7.942. [DOI] [PubMed] [Google Scholar]
  39. Pereira S., Black C., Welsh K., Ansell B., Jayson M., Maddison P., Rowell N. Autoantibodies and immunogenetics in 30 patients with systemic sclerosis and their families. J Rheumatol. 1987 Aug;14(4):760–765. [PubMed] [Google Scholar]
  40. Rabin B. S., Rodnan G. P., Bassion S., Gill T. J., 3rd Letter: HL-A antigens in progressive systemic sclerosis (scleroderma). Arthritis Rheum. 1975 Jul-Aug;18(4):381–382. doi: 10.1002/art.1780180418. [DOI] [PubMed] [Google Scholar]
  41. Reimer G., Steen V. D., Penning C. A., Medsger T. A., Jr, Tan E. M. Correlates between autoantibodies to nucleolar antigens and clinical features in patients with systemic sclerosis (scleroderma). Arthritis Rheum. 1988 Apr;31(4):525–532. doi: 10.1002/art.1780310409. [DOI] [PubMed] [Google Scholar]
  42. Reveille J. D., Anderson K. L., Schrohenloher R. E., Acton R. T., Barger B. O. Restriction fragment length polymorphism analysis of HLA-DR, DQ, DP and C4 alleles in Caucasians with systemic lupus erythematosus. J Rheumatol. 1991 Jan;18(1):14–18. [PubMed] [Google Scholar]
  43. Reveille J. D., Macleod M. J., Whittington K., Arnett F. C. Specific amino acid residues in the second hypervariable region of HLA-DQA1 and DQB1 chain genes promote the Ro (SS-A)/La (SS-B) autoantibody responses. J Immunol. 1991 Jun 1;146(11):3871–3876. [PubMed] [Google Scholar]
  44. Reveille J. D., Schrohenloher R. E., Acton R. T., Barger B. O. DNA analysis of HLA-DR and DQ genes in American blacks with systemic lupus erythematosus. Arthritis Rheum. 1989 Oct;32(10):1243–1251. doi: 10.1002/anr.1780321009. [DOI] [PubMed] [Google Scholar]
  45. Shero J. H., Bordwell B., Rothfield N. F., Earnshaw W. C. High titers of autoantibodies to topoisomerase I (Scl-70) in sera from scleroderma patients. Science. 1986 Feb 14;231(4739):737–740. doi: 10.1126/science.3003910. [DOI] [PubMed] [Google Scholar]
  46. 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 Natl Acad Sci U S A. 1984 Jun;81(11):3461–3465. doi: 10.1073/pnas.81.11.3461. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Steen V. D., Powell D. L., Medsger T. A., Jr Clinical correlations and prognosis based on serum autoantibodies in patients with systemic sclerosis. Arthritis Rheum. 1988 Feb;31(2):196–203. doi: 10.1002/art.1780310207. [DOI] [PubMed] [Google Scholar]
  48. Steen V. D., Ziegler G. L., Rodnan G. P., Medsger T. A., Jr Clinical and laboratory associations of anticentromere antibody in patients with progressive systemic sclerosis. Arthritis Rheum. 1984 Feb;27(2):125–131. doi: 10.1002/art.1780270202. [DOI] [PubMed] [Google Scholar]
  49. Tan E. M., Rodnan G. P., Garcia I., Moroi Y., Fritzler M. J., Peebles C. Diversity of antinuclear antibodies in progressive systemic sclerosis. Anti-centromere antibody and its relationship to CREST syndrome. Arthritis Rheum. 1980 Jun;23(6):617–625. doi: 10.1002/art.1780230602. [DOI] [PubMed] [Google Scholar]
  50. Weiner E. S., Earnshaw W. C., Senécal J. L., Bordwell B., Johnson P., Rothfield N. F. Clinical associations of anticentromere antibodies and antibodies to topoisomerase I. A study of 355 patients. Arthritis Rheum. 1988 Mar;31(3):378–385. doi: 10.1002/art.1780310309. [DOI] [PubMed] [Google Scholar]

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