How do Viral Infections induce and/or enhance autoimmunity

该项目的目标是利用NOD和RIP-LCMV小鼠模型从机制上更好地了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，为自身侵袭性淋巴细胞提供“肥沃的田地”。我们的初步数据表明，当感染发生在糖尿病前期小鼠的敏感期时，柯萨奇病毒B3(CVB)以及LCMV交叉反应病毒可以加速糖尿病的发生过程并导致临床疾病。基于这些发现，我们希望加深我们的机械洞察力，并将解决以下三个目标： 1.CVB如何加速T1 D？旁观者效应的评估(细胞因子，类似于Dr。 Fujinami‘s方法)影响攻击性反应和抗原提呈细胞 (免疫蛋白酶体激活，与惠顿博士合作)。 2.如果亚显性病毒反应遇到一块肥沃的田地，是否会加速疾病 胰腺/胰岛，病毒感染需要提供哪些品质才能做到这一点？ 3.哪种类型的病毒感染将为自身反应性CD8+提供致糖尿病环境 克隆和哪些因素是必不可少的(与惠顿博士和藤奈美合作)？ 机械论的洞察力将帮助我们在有患T1D风险的人类患者中寻找病因。

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.