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Exposure to nuclear antigens contributes to the induction of humoral autoimmunity during TNF alpha blockade
  1. Tineke Cantaert (t.cantaert{at}amc.uva.nl)
  1. Academic Medical Center/ University of Amsterdam, Netherlands
    1. Leen De Rijcke (l.e.derycke{at}amc.uva.nl)
    1. Academic Medical Center/University of Amsterdam, Netherlands
      1. Clio P Mavragani
      1. Mary Kirkland Center for Lupus Research, Hospital for Special Surgery, New York, United States
        1. Carla A. Wijbrandts
        1. Academic Medical Center/University of Amsterdam, Netherlands
          1. Timothy B. Niewold
          1. Mary Kirkland Center for Lupus Research, Hospital for Special Surgery, New York/University Chicago, United States
            1. Tatjana Niers
            1. Academic Medical Center?University of Amsterdam, Netherlands
              1. Bernard Vandooren
              1. Academic Medical Center/University of Amsterdam, Netherlands
                1. Eric M Veys
                1. Internal Medicine, Ghent University, Belgium
                  1. Dick Richel
                  1. Academic Medical Center/ University of Amsterdam, Netherlands
                    1. Paul P. Tak
                    1. Academic Medical Center/ University of Amsterdam, Netherlands
                      1. Mary K Crow
                      1. Mary Kirkland Center for Lupus Research, Hospital for Special Surgery, New York, Netherlands
                        1. Dominique Baeten (d.l.baeten{at}amc.uva.nl)
                        1. Academic Medical Center/University of Amsterdam, Netherlands

                          Abstract

                          Objective: type I interferons and apoptotic particles contribute to anti-nuclear autoimmunity in experimental models. We assessed if similar mechanisms contribute to break peripheral B cell tolerance in humans by studying the induction of anti-nuclear antibodies by TNF blockade in spondyloarthritis (SpA).

                          Methods: We studied 40 SpA patients treated with infliximab or etanercept and 20 renal cell carcinoma patients treated with sorafenib. Serum anti-nucleosome IgM and nucleosomes were measured by ELISA. Type I IFN serum activity was measured using a functional reporter cell assay. Synovial apoptosis was assessed by TUNEL assay and anti-active caspase-3 immunostaining. Complement was measured by nephelometry.

                          Results: Despite similar clinical improvement and reduction of synovial inflammation, anti-nucleosome IgM were induced by infliximab but not etanercept. This induction did not correlate with type I IFN activity, which was transiently downmodulated by infliximab but persistently upregulated by etanercept. In contrast, anti-nucleosome 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 IFN activity and nucleosome levels. However, only elevated serum nucleosomes relate to the induction of anti-nucleosome antibodies after infliximab treatment.

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