| First Author | Quach TD | Year | 2022 |
| Journal | JCI Insight | Volume | 7 |
| Issue | 5 | PubMed ID | 35104241 |
| Mgi Jnum | J:329061 | Mgi Id | MGI:7260848 |
| Doi | 10.1172/jci.insight.149094 | Citation | Quach TD, et al. (2022) Context-dependent induction of autoimmunity by TNF signaling deficiency. JCI Insight 7(5):e149094 |
| abstractText | 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. |
