The Role of TNF in Breaking B Cell Tolerance

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Dr. Quach's central goal is to acquire new skills that will establish her as a systems immunologist. The proposed research combines murine and human studies to identify mechanisms by which TNF deficiency breaks tolerance. The gained knowledge will guide future efforts in designing personalized medicine for autoimmune patients. Candidate: Dr. Quach is an instructor at the Feinstein Institute for Medical Research (FIMR). Through her Ph.D and post-doctoral work, she focused on the development and regulation of B cells in humans. The proposed career development plan will build upon her previous experience with four training goals to enhance her trajectory toward becoming an independent investigator: 1) gain expertise in utilizing mouse models; 2) become proficient in computational biology; 3) gain insights into conducting clinically oriented research projects, and 4) build a foundation of data and methodologies to generate predictive models. Mentors/Environment: Dr. Quach and her mentor, Dr. Anne Davidson, have assembled a strong team of advisors and collaborators to guide her through the proposed training and research activities. The proposed project utilizes the intellectual, research and clinical facilities available at the FIMR and the resources available through her external advisors and collaborators, Dr. Steven Kleinstein and Dr. Inaki Sanz. FIMR is committed to support junior faculty members through internal grants and opportunities for networking and education. Dr. Quach will attend national seminars/workshops when optimal training is not available locally. Research: 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 study proposes that TNF deficiency, together with a second inducing stimulus, compromises GC B cell selection via reduction of negative GC B cell signaling and enhancement of T effector cell activities. To test this hypothesis, the first aim utilizes TNF deficient mice of 2 different backgrounds, autoreactive Sle1.TNF-/- mice induced with a TLR9 agonist and NZM2328.TNFR1/2 double deficient mice, to determine the mechanism for the signaling defect in GC B cells that alters B cell selection, and how T cells help to enhance this process. The second aim will address similar questions in TNFi treated patients using a novel fluorescent reagent to detect and isolate ANA reactive B cells combined with next generation sequencing technology. A combination of phenotyping and functional studies is used to determine T cells' influences. 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 when GC formation is abnormal.