نبذة مختصرة : Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing pancreatic β cells by immune cells, leading to insulin deficiency. T1D is driven by intricate interactions between the innate and adaptive immune mechanism, and autoreactive T-cells perpetuate destruction of islets cells following priming by proinflammatory cytokines and chemokines. Although the primary risk factor for T1D is genetic, environmental factors have been implicated as possible triggers or accelerators in the pathogenesis of T1D. Viral infections, especially enteroviruses have been implicated in the pathogenesis of T1D. Mechanisms proposed for such association include virus-induced innate immune responses including type I interferon (IFN) that unmask β-cells for recognition by autoreactive T-cells. Type I IFN has been implicated in the early stages of T1D autoimmunity and previous studies in our rat model highlight the essential role of virus-induced, type I IFN responses as rats lacking type I IFN signaling (Ifnar1-/- LEW.1WR1 rats) have delayed onset and up to 50% reduction in the incidence of autoimmune diabetes. The goal of my thesis research is to delineate type I IFN dependent and independent mechanisms that drive autoimmune diabetes using LEW.1WR1 rats, models in which autoimmune diabetes can be induced with combined poly I:C and virus infection. I hypothesize that in Ifnar1-/- LEW.1WR1 rats, type II IFN and non-interferon innate immune responses compensate for type I IFN responses and drive the adaptive immune cells to mediate autoimmune diabetes. Transcriptome profiles of wild type (WT) and Ifnar1-/- LEW.1WR1 rat islets over a time course were analyzed to define temporal transcriptional events that lead to autoimmune diabetes in prediabetic LEW.1WR1 rats following poly I:C and KRV treatment. Pancreatic sections of treated rats were also analyzed using RNA-in situ hybridization (RNA-ISH) to spatially map islet cells inflammation and to correlate with local islet T cell recruitment. In WT ...
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