Skip to main content
NCBI home page
Clinical and Experimental Immunology logoLink to Clinical and Experimental Immunology
. 1989 May;76(2):184–189.

Autoantibodies to DNA topoisomerase II in cryptogenic fibrosing alveolitis and connective tissue disease.

R Meliconi 1, M Bestagno 1, C Sturani 1, C Negri 1, V Galavotti 1, C Sala 1, A Facchini 1, G Ciarrocchi 1, G Gasbarrini 1, G C Astaldi Ricotti 1
PMCID: PMC1541827  PMID: 2547538

Abstract

Sera from patients with autoimmune lung and connective tissue diseases were investigated for antibodies to topoisomerase II. Anti-topoisomerase II antibodies were detected by ELISA in 37% of sera from patients with cryptogenic fibrosing alveolitis (CFA), in one (8%) case of sarcoidosis and in 31% of sera from systemic lupus erythematosus (SLE) patients. Sera from rheumatoid arthritis, juvenile rheumatoid arthritis, progressive systemic sclerosis, Sjögren's syndrome and undifferentiated connective tissue disease were negative. CFA and sarcoidosis sera strongly reacted in immunoblotting with a 170 kD protein, also recognized by rabbit antiserum to recombinant topoisomerase II, while SLE sera presented a weak reaction. Pre-adsorption with dsDNA dramatically decreased the topoisomerase II binding in ELISA by the most positive SLE serum, but did not affect the binding by the most positive CFA serum, thus indicating that anti-topoisomerase II reactivity of SLE sera is probably due either to cross-reacting antibodies or, in part, to minor DNA contamination of our enzyme preparation. The determination of DNA topoisomerase II relaxation activity, performed after incubation with antibody-positive sera, showed that only CFA sera precipitate enzymatic activity. The finding that CFA presents antibodies to an enzyme essential to cell survival stresses the role of autoimmunity in the pathogenesis of idiopathic pulmonary fibrosis. This may offer further insight into the cause of autoimmune disease and prove a valuable tool in the study of enzyme molecular biology.

Full text

PDF
184

Images in this article

187Fig. 3
on p.187

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Astaldi Ricotti G. C., Pazzaglia M., Martelli A. M., Cerino A., Bestagno M., Caprelli A., Riva S., Pedrini M. A., Facchini A. Autoantibodies to purified nuclear proteins related to DNA metabolism during ageing and in SLE patients. Immunology. 1987 Jul;61(3):375–381. [PMC free article] [PubMed] [Google Scholar]
  2. Bernstein R. M., Bunn C. C., Hughes G. R. Identification of antibodies to acidic antigens by counterimmunoelectrophoresis. Ann Rheum Dis. 1982 Oct;41(5):554–555. doi: 10.1136/ard.41.5.554. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bestagno M., Cerino A., Riva S., Astaldi Ricotti G. C. Improvements of Western blotting to detect monoclonal antibodies. Biochem Biophys Res Commun. 1987 Aug 14;146(3):1509–1514. doi: 10.1016/0006-291x(87)90820-5. [DOI] [PubMed] [Google Scholar]
  4. Brewer E. J., Jr, Bass J., Baum J., Cassidy J. T., Fink C., Jacobs J., Hanson V., Levinson J. E., Schaller J., Stillman J. S. Current proposed revision of JRA Criteria. JRA Criteria Subcommittee of the Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Section of The Arthritis Foundation. Arthritis Rheum. 1977 Mar;20(2 Suppl):195–199. [PubMed] [Google Scholar]
  5. Chapman J. R., Charles P. J., Venables P. J., Thompson P. J., Haslam P. L., Maini R. N., Turner Warwick M. E. Definition and clinical relevance of antibodies to nuclear ribonucleoprotein and other nuclear antigens in patients with cryptogenic fibrosing alveolitis. Am Rev Respir Dis. 1984 Sep;130(3):439–443. doi: 10.1164/arrd.1984.130.3.439. [DOI] [PubMed] [Google Scholar]
  6. Crystal R. G., Fulmer J. D., Roberts W. C., Moss M. L., Line B. R., Reynolds H. Y. Idiopathic pulmonary fibrosis. Clinical, histologic, radiographic, physiologic, scintigraphic, cytologic, and biochemical aspects. Ann Intern Med. 1976 Dec;85(6):769–788. doi: 10.7326/0003-4819-85-6-769. [DOI] [PubMed] [Google Scholar]
  7. Dreisin R. B., Schwarz M. I., Theofilopoulos A. N., Stanford R. E. Circulating immune complexes in the idiopathic interstitial pneumonias. N Engl J Med. 1978 Feb 16;298(7):353–357. doi: 10.1056/NEJM197802162980701. [DOI] [PubMed] [Google Scholar]
  8. Earnshaw W. C., Halligan B., Cooke C. A., Heck M. M., Liu L. F. Topoisomerase II is a structural component of mitotic chromosome scaffolds. J Cell Biol. 1985 May;100(5):1706–1715. doi: 10.1083/jcb.100.5.1706. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Epstein R. J. Topoisomerases in human disease. Lancet. 1988 Mar 5;1(8584):521–524. doi: 10.1016/s0140-6736(88)91308-6. [DOI] [PubMed] [Google Scholar]
  10. Fan K., D'Orsogna D. E. Diffuse pulmonary interstitial fibrosis. Evidence of humoral antibody mediated pathogenesis. Chest. 1984 Feb;85(2):150–155. doi: 10.1378/chest.85.2.150. [DOI] [PubMed] [Google Scholar]
  11. Fox R. I., Howell F. V., Bone R. C., Michelson P. Primary Sjogren syndrome: clinical and immunopathologic features. Semin Arthritis Rheum. 1984 Nov;14(2):77–105. doi: 10.1016/0049-0172(84)90001-5. [DOI] [PubMed] [Google Scholar]
  12. Harland R. M., Weintraub H., McKnight S. L. Transcription of DNA injected into Xenopus oocytes is influenced by template topology. Nature. 1983 Mar 3;302(5903):38–43. doi: 10.1038/302038a0. [DOI] [PubMed] [Google Scholar]
  13. Holgate S. T., Haslam P., Turner-Warwick M. The significance of antinuclear and DNA antibodies in cryptogenic fibrosing alveolitis. Thorax. 1983 Jan;38(1):67–70. doi: 10.1136/thx.38.1.67. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kallenberg C. G., Jansen H. M., Elema J. D., The T. H. Steroid-responsive interstitial pulmonary disease in systemic sclerosis. Monitoring by bronchoalveolar lavage. Chest. 1984 Sep;86(3):489–492. doi: 10.1378/chest.86.3.489. [DOI] [PubMed] [Google Scholar]
  15. Kallenberg C. G., Schilizzi B. M., Beaumont F., Poppema S., De Leij L., The T. H. Expression of class II MHC antigens on alveolar epithelium in fibrosing alveolitis. Clin Exp Immunol. 1987 Jan;67(1):182–190. [PMC free article] [PubMed] [Google Scholar]
  16. Kradin R. L., Divertie M. B., Colvin R. B., Ramirez J., Ryu J., Carpenter H. A., Bhan A. K. Usual interstitial pneumonitis is a T-cell alveolitis. Clin Immunol Immunopathol. 1986 Aug;40(2):224–235. doi: 10.1016/0090-1229(86)90025-5. [DOI] [PubMed] [Google Scholar]
  17. Krasnow M. A., Cozzarelli N. R. Site-specific relaxation and recombination by the Tn3 resolvase: recognition of the DNA path between oriented res sites. Cell. 1983 Apr;32(4):1313–1324. doi: 10.1016/0092-8674(83)90312-4. [DOI] [PubMed] [Google Scholar]
  18. LeRoy E. C., Maricq H. R., Kahaleh M. B. Undifferentiated connective tissue syndromes. Arthritis Rheum. 1980 Mar;23(3):341–343. doi: 10.1002/art.1780230312. [DOI] [PubMed] [Google Scholar]
  19. Ligthart G. J., Corberand J. X., Fournier C., Galanaud P., Hijmans W., Kennes B., Müller-Hermelink H. K., Steinmann G. G. Admission criteria for immunogerontological studies in man: the SENIEUR protocol. Mech Ageing Dev. 1984 Nov;28(1):47–55. doi: 10.1016/0047-6374(84)90152-0. [DOI] [PubMed] [Google Scholar]
  20. Mathews M. B., Bernstein R. M. Myositis autoantibody inhibits histidyl-tRNA synthetase: a model for autoimmunity. Nature. 1983 Jul 14;304(5922):177–179. doi: 10.1038/304177a0. [DOI] [PubMed] [Google Scholar]
  21. Mathews M. B., Reichlin M., Hughes G. R., Bernstein R. M. Anti-threonyl-tRNA synthetase, a second myositis-related autoantibody. J Exp Med. 1984 Aug 1;160(2):420–434. doi: 10.1084/jem.160.2.420. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Maul G. G., French B. T., van Venrooij W. J., Jimenez S. A. Topoisomerase I identified by scleroderma 70 antisera: enrichment of topoisomerase I at the centromere in mouse mitotic cells before anaphase. Proc Natl Acad Sci U S A. 1986 Jul;83(14):5145–5149. doi: 10.1073/pnas.83.14.5145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Miller K. G., Liu L. F., Englund P. T. A homogeneous type II DNA topoisomerase from HeLa cell nuclei. J Biol Chem. 1981 Sep 10;256(17):9334–9339. [PubMed] [Google Scholar]
  24. Mitchell D. N., Scadding J. G., Heard B. E., Hinson K. F. Sarcoidosis: histopathological definition and clinical diagnosis. J Clin Pathol. 1977 May;30(5):395–408. doi: 10.1136/jcp.30.5.395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Nelson W. G., Liu L. F., Coffey D. S. Newly replicated DNA is associated with DNA topoisomerase II in cultured rat prostatic adenocarcinoma cells. Nature. 1986 Jul 10;322(6075):187–189. doi: 10.1038/322187a0. [DOI] [PubMed] [Google Scholar]
  26. Oldstone M. B. Molecular mimicry and autoimmune disease. Cell. 1987 Sep 11;50(6):819–820. doi: 10.1016/0092-8674(87)90507-1. [DOI] [PubMed] [Google Scholar]
  27. Plotz P. H. Autoantibodies are anti-idiotype antibodies to antiviral antibodies. Lancet. 1983 Oct 8;2(8354):824–826. doi: 10.1016/s0140-6736(83)90740-7. [DOI] [PubMed] [Google Scholar]
  28. Query C. C., Keene J. D. A human autoimmune protein associated with U1 RNA contains a region of homology that is cross-reactive with retroviral p30gag antigen. Cell. 1987 Oct 23;51(2):211–220. doi: 10.1016/0092-8674(87)90148-6. [DOI] [PubMed] [Google Scholar]
  29. ROPES M. W., BENNETT G. A., COBB S., JACOX R., JESSAR R. A. 1958 Revision of diagnostic criteria for rheumatoid arthritis. Bull Rheum Dis. 1958 Dec;9(4):175–176. [PubMed] [Google Scholar]
  30. 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]
  31. Spadari S., Pedrali-Noy G., Focher F., Montecucco A., Bordoni T., Geroni C., Giuliani F. C., Ventrella G., Arcamone F., Ciarrocchi G. DNA polymerases and DNA topoisomerases as targets for the development of anticancer drugs. Anticancer Res. 1986 Sep-Oct;6(5):935–940. [PubMed] [Google Scholar]
  32. Tan E. M., Cohen A. S., Fries J. F., Masi A. T., McShane D. J., Rothfield N. F., Schaller J. G., Talal N., Winchester R. J. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982 Nov;25(11):1271–1277. doi: 10.1002/art.1780251101. [DOI] [PubMed] [Google Scholar]
  33. Walker E. J., Jeffrey P. D. Polymyositis and molecular mimicry, a mechanism of autoimmunity. Lancet. 1986 Sep 13;2(8507):605–607. doi: 10.1016/s0140-6736(86)92429-3. [DOI] [PubMed] [Google Scholar]

Articles from Clinical and Experimental Immunology are provided here courtesy of British Society for Immunology

RESOURCES