Mechanisms of T Cell IFNy and IL-17 Production in Juvenile Idiopathic Arthritis

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PROJECT SUMMARY/ABSTRACT Juvenile idiopathic arthritis (JIA) is an autoimmune arthritis in children characterized by chronic joint inflammation. T helper type 1 (Th1), Th17, and pathologic Th17.1 cells and the inflammatory cytokines produced by these cells, interferon gamma (IFNγ) and interleukin-17 (IL-17), are implicated in JIA pathogenesis. A major knowledge gap is to understand how these inflammatory Th cells and cytokines develop. This proposal outlines a research and training plan focused on studying how IL-17 and dual IFNγ-IL- 17 producing cells inappropriately develop during JIA Th1 differentiation. A goal for these studies is to identify biologic factors that can be used to improve diagnostic and therapeutic decisions. The investigator conducted studies that described: 1) polyarticular JIA circulating cells that underwent Th1 differentiation produced high levels of IL-17 and IFNγ and dual IFNγ-IL-17 producing cells, 2) a JIA patient with a rare loss-of-function GATA3 mutation exhibited an exaggerated form of this phenotype, and 3) additional JIA patients carry rare protein-coding mutations in genes important for Th1 differentiation. The proposal’s central hypothesis is that JIA Th1 differentiation inappropriately produces IL-17 and Th1.17 cells and rare genetic mutations contribute to this phenotype. The proposed Specific Aims test this hypothesis. Aim 1 identifies the role of novel genetic mutations from JIA patients in production of IL-17, IFNγ, and Th1.17 cells during Th1 differentiation. Aim 2 identifies the cytokine and STAT signaling pathways that lead to the production of IL-17 and Th1.17 cells during polyarticular JIA Th1 differentiation. This proposal involves translational studies in human cells using advanced cytometry, molecular biology, and next generation sequencing. A major focus of this proposal is to support Dr. Patrick’s development as a physician-scientist. Her career goal is to study the pathogenesis of JIA in a basic research program and identify biologic factors that generate novel therapeutic targets and improve diagnostic and therapeutic decisions. She will accomplish this goal through career aims to become an immunology expert, gain advanced expertise in immunologic techniques, establish proficiency in the use and analysis of next-generation sequencing, and acquire skillsets to become an independent principal investigator. The research environment for the proposal is outstanding. Dr. Patrick has full departmental and institutional support for the development of her research program. Her mentors are immunologists with expertise in the planned advanced techniques. Vanderbilt has excellent facilities and shared resources for training in these techniques. Her mentoring team includes experts in immunology, gene regulation, and rheumatologic disease to guide development of her independent research program. This K08 will support the generation of data and lead to publications providing insight into the pathogenesis and genetics of JIA and in support of a successful R01 application.