Pathogenic Role of Islet Cell Autoantibodies in Type I Diabetes

Columbia University Health Sciences, New York NY

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Abstract

Abstract B cell targeted therapeutics have demonstrated a surprisingly broad potency in autoimmunity, with efficacy demonstrated even in diseases in which T cells are the ultimate mediators of tissue injury. Most of these studies have used B cell depleting antibodies, but alternative approaches targeting signaling pathways in B cells and other antigen presenting cells (APCs) with biologics and small molecule protein tyrosine kinase inhibitors have also met with early clinical success. Mechanistic evidence support two anti‐inflammatory pathways each contributing to the efficacy of targeting the B cell compartment in T cell mediated diseases;1) inhibition of BCR and Fc Receptor (FcR) mediated presentation of self antigen and;2) systemic induction of regulatory B cells. Over the past five years of funding, our NIH/NIDDK supported studies have provided key insights into both of these mechanisms. In animal models of Type I diabetes (T1D) our studies provided proof‐of‐principal for the pathogenic relevance of FcR‐mediated antigen presentation by dendritic cells (DCs). We further demonstrated that targeting the FcR‐associated protein tyrosine kinase SYK in DCs by genetic or pharmacologic means effectively uncouples autoantibodies and enhanced T cell priming in vivo. Use of a clinically relevant SYK inhibitor in the NOD T1D model halted disease progression in NOD mice and protection was associated with both reduced autoreactive T cell priming and the induction of regulatory B cells. Given the importance of SYK in immunoreceptor signaling in myeloid cells and B cells and the early success of SYK inhibitors in the clinic, in this proposal, we will;1) pursue the consequences of interrupting SYK signaling in DCs in T1D models;2) identify the roles of specific activatory FcRs in this process, including the human dendritic cell Fc receptor FcRIIA receptor, and;3) address the mechanism that SYK inhibition induces regulatory B cells in vivo, focusing on the induction of splenic regulatory B cells in the human and mouse.