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. 1994 May;96(2):267–274. doi: 10.1111/j.1365-2249.1994.tb06552.x

Anti-centromere antibodies (ACA) in systemic sclerosis patients and their relatives: a serological and HLA study.

N J McHugh 1, J Whyte 1, C Artlett 1, D C Briggs 1, C O Stephens 1, N J Olsen 1, N G Gusseva 1, P J Maddison 1, C M Black 1, K Welsh 1
PMCID: PMC1534886  PMID: 8187334

Abstract

Autoantibody reactivity to centromere proteins CENP-A, CENP-B and CENP-C was examined in 58 patients with systemic sclerosis (SSc), 218 first degree relatives and 22 spouses. HLA class II typing for HLA-DRB1 and HLA-DQA1 was performed by restriction fragment length polymorphism (RFLP) analysis in 50 families, and HLA-DRB1, HLA-DQA1 and HLA-DQB1 typing was performed by olignucleotide typing in 44 families. Eleven probands and two relatives had ACA. The two relatives with ACA also had SSc. One relative was an identical twin sister of a proband with ACA and the other relative was a sister of a proband with ACA. All ACA-positive probands and relatives were female, and all recognized CENP-A, CENP-B and CENP-C. The presence of at least one HLA-DQB1 allele not coding for leucine at position 26 of the first domain appeared necessary, although not sufficient for the generation of ACA. Therefore within SSc families ACA is strongly associated with female gender and disease phenotype, and is at least in part genetically determined.

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Selected References

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  1. Abraham D., Lupoli S., McWhirter A., Plater-Zyberk C., Piela T. H., Korn J. H., Olsen I., Black C. Expression and function of surface antigens on scleroderma fibroblasts. Arthritis Rheum. 1991 Sep;34(9):1164–1172. doi: 10.1002/art.1780340913. [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. Bernstein R. M., Callender M. E., Neuberger J. M., Hughes G. R., Williams R. Anticentromere antibody in primary biliary cirrhosis. Ann Rheum Dis. 1982 Dec;41(6):612–614. doi: 10.1136/ard.41.6.612. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bidwell J. DNA-RFLP analysis and genotyping of HLA-DR and DQ antigens. Immunol Today. 1988 Jan;9(1):18–23. doi: 10.1016/0167-5699(88)91351-5. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. Block S. R., Winfield J. B., Lockshin M. D., D'Angelo W. A., Christian C. L. Studies of twins with systemic lupus erythematosus. A review of the literature and presentation of 12 additional sets. Am J Med. 1975 Oct;59(4):533–552. doi: 10.1016/0002-9343(75)90261-2. [DOI] [PubMed] [Google Scholar]
  7. Briggs D., Stephens C., Vaughan R., Welsh K., Black C. A molecular and serologic analysis of the major histocompatibility complex and complement component C4 in systemic sclerosis. Arthritis Rheum. 1993 Jul;36(7):943–954. doi: 10.1002/art.1780360711. [DOI] [PubMed] [Google Scholar]
  8. Catoggio L. J., Bernstein R. M., Black C. M., Hughes G. R., Maddison P. J. Serological markers in progressive systemic sclerosis: clinical correlations. Ann Rheum Dis. 1983 Feb;42(1):23–27. doi: 10.1136/ard.42.1.23. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Claman H. N., Giorno R. C., Seibold J. R. Endothelial and fibroblastic activation in scleroderma. The myth of the "uninvolved skin". Arthritis Rheum. 1991 Dec;34(12):1495–1501. doi: 10.1002/art.1780341204. [DOI] [PubMed] [Google Scholar]
  10. Deapen D., Escalante A., Weinrib L., Horwitz D., Bachman B., Roy-Burman P., Walker A., Mack T. M. A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum. 1992 Mar;35(3):311–318. doi: 10.1002/art.1780350310. [DOI] [PubMed] [Google Scholar]
  11. Dubois E. L., Chandor S., Friou G. J., Bischel M. Progressive systemic sclerosis (PSS) and localized scleroderma (morphea) with positive LE cell test and unusual systemic manifesstations compatible with systemic lupus erythematous (SLE): presentation of 14 cases including one set of identical twins, one with scleroderma dn the other with SLE. Review of the literature. Medicine (Baltimore) 1971 May;50(3):199–222. doi: 10.1097/00005792-197105000-00003. [DOI] [PubMed] [Google Scholar]
  12. Earnshaw W. C., Rothfield N. Identification of a family of human centromere proteins using autoimmune sera from patients with scleroderma. Chromosoma. 1985;91(3-4):313–321. doi: 10.1007/BF00328227. [DOI] [PubMed] [Google Scholar]
  13. Earnshaw W. C., Sullivan K. F., Machlin P. S., Cooke C. A., Kaiser D. A., Pollard T. D., Rothfield N. F., Cleveland D. W. Molecular cloning of cDNA for CENP-B, the major human centromere autoantigen. J Cell Biol. 1987 Apr;104(4):817–829. doi: 10.1083/jcb.104.4.817. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Earnshaw W., Bordwell B., Marino C., Rothfield N. Three human chromosomal autoantigens are recognized by sera from patients with anti-centromere antibodies. J Clin Invest. 1986 Feb;77(2):426–430. doi: 10.1172/JCI112320. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Erlich H., Bugawan T., Begovich A. B., Scharf S., Griffith R., Saiki R., Higuchi R., Walsh P. S. HLA-DR, DQ and DP typing using PCR amplification and immobilized probes. Eur J Immunogenet. 1991 Feb-Apr;18(1-2):33–55. doi: 10.1111/j.1744-313x.1991.tb00005.x. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. Garcia-de la Torre I., Miranda-Mendez L. Studies of antinuclear antibodies in rheumatoid arthritis. J Rheumatol. 1982 Jul-Aug;9(4):603–606. [PubMed] [Google Scholar]
  18. 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]
  19. Goldman J. A. Anticentromere antibody in patients without CREST and scleroderma: association with active digital vasculitis, rheumatic and connective tissue disease. Ann Rheum Dis. 1989 Sep;48(9):771–775. doi: 10.1136/ard.48.9.771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hildebrandt S., Weiner E., Senécal J. L., Noell S., Daniels L., Earnshaw W. C., Rothfield N. F. The IgG, IgM, and IgA isotypes of anti-topoisomerase I and anticentromere autoantibodies. Arthritis Rheum. 1990 May;33(5):724–727. doi: 10.1002/art.1780330515. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. Kallenberg C. G., Wouda A. A., Hoet M. H., van Venrooij W. J. Development of connective tissue disease in patients presenting with Raynaud's phenomenon: a six year follow up with emphasis on the predictive value of antinuclear antibodies as detected by immunoblotting. Ann Rheum Dis. 1988 Aug;47(8):634–641. doi: 10.1136/ard.47.8.634. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kuwana M., Kaburaki J., Okano Y., Inoko H., Tsuji K. The HLA-DR and DQ genes control the autoimmune response to DNA topoisomerase I in systemic sclerosis (scleroderma). J Clin Invest. 1993 Sep;92(3):1296–1301. doi: 10.1172/JCI116703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. Maddison P. J., Stephens C., Briggs D., Welsh K. I., Harvey G., Whyte J., McHugh N., Black C. M. Connective tissue disease and autoantibodies in the kindreds of 63 patients with systemic sclerosis. The United Kingdom Systemic Sclerosis Study Group. Medicine (Baltimore) 1993 Mar;72(2):103–112. doi: 10.1097/00005792-199303000-00004. [DOI] [PubMed] [Google Scholar]
  27. McHugh N. J., James I. E., Fairburn K., Maddison P. J. Autoantibodies to mitochondrial and centromere antigens in primary biliary cirrhosis and systemic sclerosis. Clin Exp Immunol. 1990 Aug;81(2):244–249. doi: 10.1111/j.1365-2249.1990.tb03325.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. McHugh N. J., James I. E., Maddison P. J. Differential isotype recognition of two centromere associated polypeptides by immunoblotting in connective tissue disease. Clin Exp Immunol. 1988 Jun;72(3):457–464. [PMC free article] [PubMed] [Google Scholar]
  29. McNeilage L. J., Whittingham S., McHugh N., Barnett A. J. A highly conserved 72,000 dalton centromeric antigen reactive with autoantibodies from patients with progressive systemic sclerosis. J Immunol. 1986 Oct 15;137(8):2541–2547. [PubMed] [Google Scholar]
  30. Miller S. A., Dykes D. D., Polesky H. F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988 Feb 11;16(3):1215–1215. doi: 10.1093/nar/16.3.1215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Molta C. T., Khan M. A., Aponte C. J., Reynolds T. L., Macintyre S. S. Familial occurrence of systemic sclerosis, rheumatoid arthritis and other immunological disorders: report of two kindreds with study of HLA antigens and review of the literature. Clin Exp Rheumatol. 1989 May-Jun;7(3):229–236. [PubMed] [Google Scholar]
  32. Nomenclature for factors of the HLA system, 1990. The WHO Nomenclature Committee for factors of the HLA system. Immunogenetics. 1991;33(5-6):301–309. doi: 10.1007/BF00216689. [DOI] [PubMed] [Google Scholar]
  33. Reveille J. D., Durban E., MacLeod-St Clair M. J., Goldstein R., Moreda R., Altman R. D., Arnett F. C. Association of amino acid sequences in the HLA-DQB1 first domain with antitopoisomerase I autoantibody response in scleroderma (progressive systemic sclerosis). J Clin Invest. 1992 Sep;90(3):973–980. doi: 10.1172/JCI115974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Reveille J. D., Owerbach D., Goldstein R., Moreda R., Isern R. A., Arnett F. C. 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. doi: 10.1172/JCI115704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Rhodes G., Rumpold H., Kurki P., Patrick K. M., Carson D. A., Vaughan J. H. Autoantibodies in infectious mononucleosis have specificity for the glycine-alanine repeating region of the Epstein-Barr virus nuclear antigen. J Exp Med. 1987 Apr 1;165(4):1026–1040. doi: 10.1084/jem.165.4.1026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Roumm A. D., Whiteside T. L., Medsger T. A., Jr, Rodnan G. P. Lymphocytes in the skin of patients with progressive systemic sclerosis. Quantification, subtyping, and clinical correlations. Arthritis Rheum. 1984 Jun;27(6):645–653. doi: 10.1002/art.1780270607. [DOI] [PubMed] [Google Scholar]
  37. Saitoh H., Tomkiel J., Cooke C. A., Ratrie H., 3rd, Maurer M., Rothfield N. F., Earnshaw W. C. CENP-C, an autoantigen in scleroderma, is a component of the human inner kinetochore plate. Cell. 1992 Jul 10;70(1):115–125. doi: 10.1016/0092-8674(92)90538-n. [DOI] [PubMed] [Google Scholar]
  38. 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]
  39. Straniero N. R., Furst D. E. Environmentally-induced systemic sclerosis-like illness. Baillieres Clin Rheumatol. 1989 Apr;3(1):63–79. doi: 10.1016/s0950-3579(89)80036-6. [DOI] [PubMed] [Google Scholar]
  40. 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]
  41. Towbin H., Staehelin T., Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350–4354. doi: 10.1073/pnas.76.9.4350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Tramposch H. D., Smith C. D., Senecal J. L., Rothfield N. A long-term longitudinal study of anticentromere antibodies. Arthritis Rheum. 1984 Feb;27(2):121–124. doi: 10.1002/art.1780270201. [DOI] [PubMed] [Google Scholar]
  43. Watanabe Y., Tokunaga K., Matsuki K., Takeuchi F., Matsuta K., Maeda H., Omoto K., Juji T. Putative amino acid sequence of HLA-DRB chain contributing to rheumatoid arthritis susceptibility. J Exp Med. 1989 Jun 1;169(6):2263–2268. doi: 10.1084/jem.169.6.2263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Zorina V. Ia, Zorin S. P. Sklerodermiia u 5-letnykh devochek-bliznetsov. Pediatriia. 1982 Jul;(7):69–70. [PubMed] [Google Scholar]

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