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J Clin Invest. 1992 Sep; 90(3): 973–980.
PMCID: PMC329953

Association of amino acid sequences in the HLA-DQB1 first domain with antitopoisomerase I autoantibody response in scleroderma (progressive systemic sclerosis).


Previous studies in Caucasians with progressive systemic sclerosis (PSS) have suggested associations of antitopoisomerase I (antitopo I) autoantibodies with either serologically defined HLA-DR2 or DR5. To better define class II HLA associations with the antitopo I response, 161 PSS patients (132 Caucasians and 29 American blacks) were studied for antitopo I autoantibodies by immunodiffusion and immunoblotting, and their HLA-DRB1, DRB3, DQA1, and DQB1 alleles were determined by restriction fragment length polymorphic analysis and DNA oligotyping. Among Caucasians with antitopo I, HLA-DR5(DRB1*1101-*1104), DRB3*0202 and DQw3 (DQw7,8,9) were significantly increased in frequency. In American blacks, however, only HLA-DQB1*0301(DQw7) was significantly increased. The presence of HLA-DQB1*0301(DQw7) and other HLA-DQB1 alleles bearing the uncharged polar amino acid residue tyrosine at position 30 of the outermost domain was found in all antitopo I-positive Caucasian PSS patients compared with 66% of antitopo I-negative PSS patients (pc = 0.007) and 70% of normal controls (pc = 0.008), as well as all antitopo I-positive black patients. The association with HLA-DQB1 was independent of HLA-DR5(DRB1*1101-*1104) or any other HLA-DRB1, DRB3, or DQA1 alleles. Alternative or additional candidate epitopes for this autoimmune response include alanine at position 38 and threonine at position 77 of these same DQB1 alleles. These data suggest that genetic predisposition to the antitopo I response in PSS is associated most closely with the HLA-DQB1 locus.

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  • Lilis R, Anderson H, Nicholson WJ, Daum S, Fischbein AS, Selikoff IJ. Prevalence of disease among vinyl chloride and polyvinyl chloride workers. Ann N Y Acad Sci. 1975 Jan 31;246:22–41. [PubMed]
  • Finch WR, Rodnan GP, Buckingham RB, Prince RK, Winkelstein A. Bleomycin-induced scleroderma. J Rheumatol. 1980 Sep-Oct;7(5):651–659. [PubMed]
  • Mateo IM, Izquierdo M, Fernandez-Dapica MP, Navas J, Cabello A, Gomez-Reino JJ. Toxic epidemic syndrome: musculoskeletal manifestations. J Rheumatol. 1984 Jun;11(3):333–338. [PubMed]
  • Palestine RF, Millns JL, Spigel GT, Schroeter AL. Skin manifestations of pentazocine abuse. J Am Acad Dermatol. 1980 Jan;2(1):47–55. [PubMed]
  • Medsger TA, Jr, Masi AT. Epidemiology of systemic sclerosis (scleroderma). Ann Intern Med. 1971 May;74(5):714–721. [PubMed]
  • Buckman KJ, Moore SK, Ebbin AJ, Cox MB, Dubois EL. Familial systemic lupus erythematosus. Arch Intern Med. 1978 Nov;138(11):1674–1676. [PubMed]
  • Flores RH, Stevens MB, Arnett FC. Familial occurrence of progressive systemic sclerosis and systemic lupus erythematosus. J Rheumatol. 1984 Jun;11(3):321–323. [PubMed]
  • Clements PJ, Opelz G, Terasaki PI, Mickey MR, Furst D. Association of HLA antigen a9 with progressive systemic sclerosis (scleroderma). Tissue Antigens. 1978 Apr;11(4):357–361. [PubMed]
  • Ercilla MG, Arriaga F, Gratacós MR, Coll J, Lecha V, Vives J, Castillo R. HLA antigens and scleroderma. Arch Dermatol Res. 1981;271(4):381–385. [PubMed]
  • Hughes P, Gelsthorpe K, Doughty RW, Rowell NR, Rosenthal FD, Sneddon IB. The association of HLA-B8 with visceral disease in systemic sclerosis. Clin Exp Immunol. 1978 Mar;31(3):351–356. [PMC free article] [PubMed]
  • Kallenberg CG, Van der Voort-Beelen JM, D'Amaro J, The TH. 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]
  • 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. [PubMed]
  • Lynch CJ, Singh G, Whiteside TL, Rodnan GP, Medsger TA, Jr, Rabin BS. Histocompatibility antigens in progressive systemic sclerosis (PSS; scleroderma). J Clin Immunol. 1982 Oct;2(4):314–318. [PubMed]
  • DiBartolomeo AG, Rabin BS, Rodnan GP. HLA-D antigens in progressive systemic sclerosis (scleroderma). Immunol Commun. 1981;10(8):733–740. [PubMed]
  • Black CM, Welsh KI, Maddison PJ, Jayson MI, Bernstein RM. HLA antigens, autoantibodies and clinical subsets in scleroderma. Br J Rheumatol. 1984 Nov;23(4):267–271. [PubMed]
  • Alarcón GS, Phillips RM, Wasner CK, Acton RT, Barger BO. DR antigens in systemic sclerosis: lack of clinical correlations. Tissue Antigens. 1985 Aug;26(2):156–158. [PubMed]
  • Germain BF, Espinoza LR, Bergen LL, Vagesh M, Vasey FB. Increased prevalence of DRw3 in the CREST syndrome. Arthritis Rheum. 1981 Jun;24(6):857–859. [PubMed]
  • Gladman DD, Keystone EC, Baron M, Lee P, Cane D, Mervert H. Increased frequency of HLA-DR5 in scleroderma. Arthritis Rheum. 1981 Jun;24(6):854–856. [PubMed]
  • Briggs DC, Welsh K, Pereira RS, Black CM. 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. [PubMed]
  • Dunckley H, Jazwinska EC, Gatenby PA, Serjeantson SW. 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. [PubMed]
  • Rabin BS, Rodnan GP, Bassion S, Gill TJ., 3rd Letter: HL-A antigens in progressive systemic sclerosis (scleroderma). Arthritis Rheum. 1975 Jul-Aug;18(4):381–382. [PubMed]
  • Crouzet J, Marbach MC, Camus JP, 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]
  • Birnbaum NS, Rodnan GP, Rabin BS, Bassion S. Histocompatibility antigens in progressive systemic sclerosis (scleroderma). J Rheumatol. 1977 Winter;4(4):425–428. [PubMed]
  • 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. [PubMed]
  • Livingston JZ, Scott TE, Wigley FM, Anhalt GJ, Bias WB, McLean RH, Hochberg MC. Systemic sclerosis (scleroderma): clinical, genetic, and serologic subsets. J Rheumatol. 1987 Jun;14(3):512–518. [PubMed]
  • Weiner ES, Earnshaw WC, Senécal JL, Bordwell B, Johnson P, Rothfield NF. Clinical associations of anticentromere antibodies and antibodies to topoisomerase I. A study of 355 patients. Arthritis Rheum. 1988 Mar;31(3):378–385. [PubMed]
  • Steen VD, Powell DL, Medsger TA., Jr Clinical correlations and prognosis based on serum autoantibodies in patients with systemic sclerosis. Arthritis Rheum. 1988 Feb;31(2):196–203. [PubMed]
  • Fritzler MJ, Kinsella TD. The CREST syndrome: a distinct serologic entity with anticentromere antibodies. Am J Med. 1980 Oct;69(4):520–526. [PubMed]
  • Tan EM, Rodnan GP, Garcia I, Moroi Y, Fritzler MJ, 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. [PubMed]
  • Kallenberg CG, Pastoor GW, Wouda AA, The TH. Antinuclear antibodies in patients with Raynaud's phenomenon: clinical significance of anticentromere antibodies. Ann Rheum Dis. 1982 Aug;41(4):382–387. [PMC free article] [PubMed]
  • Catoggio LJ, Skinner RP, Maddison PJ. 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. [PubMed]
  • Steen VD, Ziegler GL, Rodnan GP, Medsger TA., Jr Clinical and laboratory associations of anticentromere antibody in patients with progressive systemic sclerosis. Arthritis Rheum. 1984 Feb;27(2):125–131. [PubMed]
  • 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. [PMC free article] [PubMed]
  • Reimer G, Steen VD, Penning CA, Medsger TA, Jr, Tan EM. Correlates between autoantibodies to nucleolar antigens and clinical features in patients with systemic sclerosis (scleroderma). Arthritis Rheum. 1988 Apr;31(4):525–532. [PubMed]
  • Shero JH, Bordwell B, Rothfield NF, Earnshaw WC. High titers of autoantibodies to topoisomerase I (Scl-70) in sera from scleroderma patients. Science. 1986 Feb 14;231(4739):737–740. [PubMed]
  • Genth E, Mierau R, Genetzky P, von Mühlen CA, Kaufmann S, von Wilmowsky H, Meurer M, Krieg T, Pollmann HJ, Hartl PW. Immunogenetic associations of scleroderma-related antinuclear antibodies. Arthritis Rheum. 1990 May;33(5):657–665. [PubMed]
  • Reveille JD, Owerbach D, Goldstein R, Moreda R, Isern RA, Arnett FC. Association of polar amino acids at position 26 of the HLA-DQB1 first domain with the anticentromere autoantibody response in systemic sclerosis (scleroderma). J Clin Invest. 1992 Apr;89(4):1208–1213. [PMC free article] [PubMed]
  • Arnett FC, Bias WB, McLean RH, Engel M, Duvic M, Goldstein R, Freni-Titulaer L, McKinley TW, Hochberg MC. Connective tissue disease in southeast Georgia. A community based study of immunogenetic markers and autoantibodies. J Rheumatol. 1990 Aug;17(8):1029–1035. [PubMed]
  • Blin N, Stafford DW. A general method for isolation of high molecular weight DNA from eukaryotes. Nucleic Acids Res. 1976 Sep;3(9):2303–2308. [PMC free article] [PubMed]
  • McDaniel DO, Acton RT, Barger BO, Koopman WJ, Reveille JD. 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. [PubMed]
  • Moraes ME, 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. [PubMed]
  • Reveille JD, Schrohenloher RE, Acton RT, Barger BO. DNA analysis of HLA-DR and DQ genes in American blacks with systemic lupus erythematosus. Arthritis Rheum. 1989 Oct;32(10):1243–1251. [PubMed]
  • Reveille JD, Anderson KL, Schrohenloher RE, Acton RT, Barger BO. 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]
  • 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. [PubMed]
  • MacMurray AJ, Bell JI, Denney D, Jr, Watling D, Foster LS, McDevitt HO. Molecular mapping class II polymorphisms in the human major histocompatibility complex. II. DQ beta. J Immunol. 1987 Jul 15;139(2):574–586. [PubMed]
  • Bell JI, Denney D, Jr, MacMurray A, Foster L, Watling D, McDevitt HO. 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]
  • Bidwell JL, Bidwell EA, Savage DA, Middleton D, Klouda PT, Bradley BA. 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. [PubMed]
  • Bodmer JG, Marsh SG, Parham P, Erlich HA, Albert E, Bodmer WF, Dupont B, Mach B, Mayr WR, Sasazuki T, et al. Nomenclature for factors of the HLA system, 1989. Hum Immunol. 1990 Jul;28(3):326–342. [PubMed]
  • Gao XJ, 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. [PubMed]
  • Fernandez-Vina M, Shumway W, Stastny P. DNA typing for class II HLA antigens with allele-specific or group-specific amplification. II. Typing for alleles of the DRw52-associated group. Hum Immunol. 1990 May;28(1):51–64. [PubMed]
  • Reveille JD, Durban E, Goldstein R, Moreda R, Arnett FC. Racial differences in the frequencies of scleroderma-related autoantibodies. Arthritis Rheum. 1992 Feb;35(2):216–218. [PubMed]
  • Marsh SG, Bodmer JG. HLA-DRB nucleotide sequences, 1990. Immunogenetics. 1990;31(3):141–144. [PubMed]

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