The goal of this project is to better understand mechanistically, how viral infections could be involved in the pathogenesis of type 1 diabetes (T1 D) using the NOD and RIP-LCMV mouse models. Our approach is based on the hypothesis (which also unifies this PPG) that viruses, even if they are incapable of causing autoimmune disease per se, will modulate an ongoing autoimmune process or, conversely, provide 'fertile field' for autoaggressive lymphocytes. Our preliminary data indicate that Coxsackie Virus B3 (CVB) as well as LCMV cross-reactive viruses can accelerate the diabetogenic process and result in clinical disease, when the infection occurs during a susceptible period in prediabetic mice. Based on these findings we wish to deepen our mechanistic insight and will address the following 3 aims:1. How does CVB accelerate T1 D? Evaluation of bystander effects (cytokines, in analogy to Dr.Fujinami's approach) that affect the aggressive response and antigen presenting cells(immunoproteasome activation in collaboration with Dr. Whitton).2. Do subdominant viral responses accelerate disease if they encounter a 'fertile field' in thepancreas/islets, and which qualities needs the viral infection provide to achieve this?3. Which type of viral infections will provide a diabetogenic environment for autoreactive CD8+clones and which factors are essential (collaboration with Dr. Whitton and Fujinami)?Mechanistic insight will help us to search for causative agents in human patients at risk to develop T1D.
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