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Ann Rheum Dis 2009;68:1022-1029 doi:10.1136/ard.2008.093724
  • Basic and translational research

Exposure to nuclear antigens contributes to the induction of humoral autoimmunity during tumour necrosis factor alpha blockade

  1. T Cantaert1,
  2. L De Rycke1,
  3. C P Mavragani2,
  4. C A Wijbrandts1,
  5. T B Niewold2,3,
  6. T Niers4,
  7. B Vandooren1,5,
  8. E M Veys5,
  9. D Richel4,
  10. P P Tak1,
  11. M K Crow2,
  12. D Baeten1,5
  1. 1
    Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands
  2. 2
    Mary Kirkland Center for Lupus Research, Hospital for Special Surgery, New York, New York, USA
  3. 3
    Section of Rheumatology, University of Chicago, Chicago, Illinois, USA
  4. 4
    Division of Oncology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands
  5. 5
    Internal Medicine, Ghent University, Ghent, Belgium
  1. Dr D Baeten, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, F4-218, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; D.L.Baeten{at}amc.uva.nl
  • Accepted 11 June 2008
  • Published Online First 14 July 2008

Abstract

Objective: Type I interferons and apoptotic particles contribute to antinuclear autoimmunity in experimental models. This study assessed whether similar mechanisms contribute to break peripheral B-cell tolerance in humans by studying the induction of antinuclear antibodies by tumour necrosis factor blockade in spondyloarthritis.

Methods: 40 spondyloarthritis patients treated with infliximab or etanercept and 20 renal cell carcinoma patients treated with sorafenib were studied. Serum antinucleosome IgM and nucleosomes were measured by ELISA. Type I interferon serum activity was measured using a functional reporter cell assay. Synovial apoptosis was assessed by terminal transferase nick end-labelling (TUNEL) assay and anti-active caspase-3 immunostaining. Complement was measured by nephelometry.

Results: Despite a similar clinical improvement and reduction of synovial inflammation, antinucleosome IgM were induced by infliximab but not etanercept. This induction did not correlate with type I interferon activity, which was transiently downmodulated by infliximab but persistently upregulated by etanercept. In contrast, antinucleosome IgM levels did correlate with serum nucleosome levels, which were significantly upregulated by infliximab but not by etanercept treatment. This increase in serum nucleosome levels was not directly related to massive cell death, but rather to a decrease of complement 3 and 4 serum levels during infliximab treatment.

Conclusion: Infliximab and etanercept have a differential effect on both type I interferon activity and nucleosome levels. Only elevated serum nucleosomes relate to the induction of antinucleosome antibodies after infliximab treatment.

Footnotes

  • Competing interests: None.

  • Funding: This research was supported by the European Community’s FP6 funding. This publication reflects only the authors’ views. The European Community is not liable for any use that may be made of the information herein. This research was supported by a human immunology grant of the Dana Foundation. LDR is supported by a Veni grant of the Netherlands Organization for Scientific Research (NWO). BV is a research assistant of the Fund for Scientific Research–Flanders (FWO–Vlaanderen). DB is supported by a Vidi grant of the Netherlands Organization for Scientific Research.

  • Ethics approval: This study was approved by the local Medical Ethics Committee.

  • Patient consent: Obtained.

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