How do Viral Infections induce and/or enhance autoimmunity

该项目的目标是使用NOD和RIP-LCMV小鼠模型更好地从机制上理解病毒感染如何参与1型糖尿病（T1 D）的发病机制。我们的方法是基于这样的假设（这也统一了PPG），即病毒，即使它们本身不能引起自身免疫性疾病，也会调节正在进行的自身免疫过程，或者相反，为自身攻击性淋巴细胞提供“肥沃的土地”。我们的初步数据表明，科萨基病毒B3（CVB）以及LCMV交叉反应病毒可以加速糖尿病的过程，并导致临床疾病，当感染发生在易感期的糖尿病前期小鼠。基于这些发现，我们希望加深我们的机械洞察力，并将解决以下3个目标： 1. CVB如何加速T1 D？评价旁观者效应（细胞因子，类似于Dr. Fujinami的方法），影响攻击性反应和抗原呈递细胞 （与惠顿博士合作的免疫蛋白酶体活化）。 2.亚显性病毒反应是否会加速疾病，如果他们遇到一个“肥沃的土地”， 胰腺/胰岛，以及病毒感染需要提供哪些品质来实现这一点？ 3.哪种类型的病毒感染将为自身反应性CD 8+提供致糖尿病的环境 克隆和哪些因素是必不可少的（与惠顿博士和藤波合作）？ 机制的洞察力将有助于我们在有发展T1 D风险的人类患者中寻找致病因子。

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 the pancreas/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.