JCI Insight (Mar 2022)

Context-dependent induction of autoimmunity by TNF signaling deficiency

  • Tam D. Quach,
  • Weiqing Huang,
  • Ranjit Sahu,
  • Catherine M.M. Diadhiou,
  • Chirag Raparia,
  • Roshawn Johnson,
  • Tung Ming Leung,
  • Susan Malkiel,
  • Peta Gay Ricketts,
  • Stefania Gallucci,
  • Çagla Tükel,
  • Chaim O. Jacob,
  • Martin L. Lesser,
  • Yong-Rui Zou,
  • Anne Davidson

Journal volume & issue
Vol. 7, no. 5

Abstract

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TNF inhibitors are widely used to treat inflammatory diseases; however, 30%–50% of treated patients develop new autoantibodies, and 0.5%–1% develop secondary autoimmune diseases, including lupus. TNF is required for formation of germinal centers (GCs), the site where high-affinity autoantibodies are often made. We found that TNF deficiency in Sle1 mice induced TH17 T cells and enhanced the production of germline encoded, T-dependent IgG anti-cardiolipin antibodies but did not induce GC formation or precipitate clinical disease. We then asked whether a second hit could restore GC formation or induce pathogenic autoimmunity in TNF-deficient mice. By using a range of immune stimuli, we found that somatically mutated autoantibodies and clinical disease can arise in the setting of TNF deficiency via extrafollicular pathways or via atypical GC-like pathways. This breach of tolerance may be due to defects in regulatory signals that modulate the negative selection of pathogenic autoreactive B cells.

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