Abstract
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.
Authors
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
Figure 3
Altered autoantibody specificity in Sle1 TNF–/– and Sle1 TNFR1–/– mice.
