TNF deficiency induces breach of B cell tolerance via altering B cell regulatory signals

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PROJECT SUMMARY The induction of autoantibody and autoimmunity in patients treated with TNF inhibitors (TNFi) is well-known; however, the mechanism by which TNFi induce breach of B cell tolerance is yet to be determined. In humans, TNFi affect B and T cell homeostasis via disruption of germinal center (GC) formation which is pivotal for high affinity antigen-specific antibody production and negative selection of autoreactive B cells. Similarly, in mice, TNF signaling deficiency prevents GC formation, induces TFH and CD4+IL-17 producing cell expansion, and alters autoantibody profiles. This small focused study proposes that TNF deficiency, together with a second inducing stimulus, compromises B cell selection via reduction of negative B cell signaling and enhancement of T effector cell activities. To test this hypothesis, the first aim utilizes: 1) TNF deficient mice of 2 different backgrounds, autoreactive Sle1.TNF-/- mice induced with a TLR9 agonist and NZM2328.TNFR1/2 double deficient mice, and 2) Sle1.TNF-/-.Yaa, in which male mice over express TLR7, to determine the mechanism for the signaling defect of activated B cells that alters B cell selection via either GC and/or extrafollicular pathway. The second aim will address similar questions in TNFi treated patients by identifying changes in CD22 binding dynamics which thereby affect BCR signaling in autoreactive B cells. This aim is made possible due to the development of the novel ANA reagent that identify enriched autoreactive B cells in both humans and mice. The results from this study will elucidate the effects of TNFi on regulating B cell tolerance and improve our understanding of how the immune system regulates B cell tolerance in GC and extrafollicular pathways.