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Context-dependent induction of autoimmunity by TNF signaling deficiency
Quach, Tam D. Huang, Weiqing Sahu, Ranjit Diadhiou, Catherine M.M. Raparia, Chirag Johnson, Roshawn Leung, Tung Ming Malkiel, Susan Ricketts, Peta Gay Gallucci, Stefani
Quach, Tam D.
Huang, Weiqing
Sahu, Ranjit
Diadhiou, Catherine M.M.
Raparia, Chirag
Johnson, Roshawn
Leung, Tung Ming
Malkiel, Susan
Ricketts, Peta Gay
Gallucci, Stefani
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Journal article
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2022-03-08
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Microbiology, Immunology and Inflammation
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http://dx.doi.org/10.1172/jci.insight.149094
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.
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Context-dependent induction of autoimmunity by TNF signaling deficiency Tam D. Quach, … , Yong-Rui Zou, Anne Davidson Published February 1, 2022 Citation Information: JCI Insight. 2022;7(5):e149094. https://doi.org/10.1172/jci.insight.149094.
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American Society for Clinical Investigation
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JCI Insight, Vol. 8, Iss. 5
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