Type 1 Diabetes in Acute Pancreatitis Consortium, Pacific Northwest Clinical Center: Immune Pathogenesis of Post-Pancreatitis T1D

项目总结/摘要 该申请汇集了弗吉尼亚州的临床优势和大型急性胰腺炎患者人群 梅森医疗中心消化疾病研究所和贝纳罗亚研究所的专业知识 自身免疫和1型糖尿病，以了解发病率，临床过程，和潜在的机制， 急性胰腺炎后自身免疫性糖尿病本申请的基本主题是， 从研究胰腺炎后自身免疫性糖尿病中获得的知识将提供关键的见解， 1型糖尿病的发病机制 回顾和荟萃分析数据表明，几乎40%的人最终会患上糖尿病或糖尿病前期。 急性胰腺炎后糖尿病然而，在所包括的人口、 终点和评估急性胰腺炎和糖尿病的研究的随访持续时间。所以，真正的 胰腺炎后糖尿病发病率和自然史尚不清楚。虽然一般认为 是坏死导致β细胞损伤或破坏的结果，急性 胰腺炎坏死和糖尿病的发病率最近受到质疑， 来自动物或人类研究的数据。因此，糖尿病并发急性胰腺炎的发病机制尚不清楚 明白 相比之下，典型的1型糖尿病的自然史被很好地描述;自身抗体被认为是遗传性的， 高危个体，其中一些人随着时间的推移发展β细胞死亡，导致无症状，其次是 最终需要外源性胰岛素治疗的症状性精神障碍。证据表明， 适应性免疫系统在这一过程中包括与II类HLA类型的强遗传关联， 尸体标本中细胞浸润的存在，以及适应性免疫治疗改变疾病的能力 当然了在典型的1型糖尿病中，尚不清楚的是什么是适应性免疫最初触发的基础。 系统随着时间的推移，疾病的发病率不断增加，这表明基因-环境相互作用导致β 细胞损伤，但它仍然具有挑战性，以确定具体的触发器。由于胰腺损伤和先天激活 是急性胰腺炎的已知成分，在这种情况下糖尿病的发展可以允许 关于急性组织损伤如何导致自身免疫的研究，从而作为模型系统， 了解导致典型1型糖尿病的机制。在本提案中，我们将确定 并描述了急性胰腺炎后糖尿病和自身免疫的自然史（目的1），测试 假设急性胰腺炎在一个个体亚群中解决为改变的免疫状态， 使其易于发生胰岛自身免疫（目的2），并确定是否与急性胰腺炎相关 自身免疫导致与典型1型糖尿病中所见相似的免疫表型（目的3）。

Project Summary / Abstract This application brings together the clinical strengths and large acute pancreatitis patient population of Virginia Mason Medical Center's Digestive Disease Institute and Benaroya Research Institute's expertise in autoimmunity and type 1 diabetes to understand the incidence, clinical course, and potential mechanisms of autoimmune mediated diabetes after acute pancreatitis. The underlying theme of this application is that knowledge gained from studying autoimmune diabetes after pancreatitis will provide key insights as to mechanisms of disease in typical type 1 diabetes. Review and meta-analysis data suggest that almost 40% of individuals will eventually develop diabetes or pre- diabetes post-acute pancreatitis. There is, however, inconsistency as to populations included, definitions of endpoints, and duration of follow-up across studies evaluating acute pancreatitis and diabetes. Thus, the true incidence and natural history of diabetes post-pancreatitis is not clear. Moreover, while generally considered to be a consequence of necrosis resulting in beta cell injury or destruction, the relationship between acute pancreatitis necrosis and incidence of diabetes has recently been questioned and there is limited mechanistic data from either animal or human studies. Thus, the etiopathology of diabetes post-acute pancreatitis is not well understood. In contrast, the natural history of typical type 1 diabetes is well described; autoantibodies are seen in genetically at-risk individuals, some of whom over time develop beta cell death leading to asymptomatic, followed by symptomatic dysglycemia eventually requiring exogenous insulin therapy. Evidence for the clear role of the adaptive immune system in this process include the strong genetic association with class II HLA type, the presence of cellular infiltrates in cadaver specimens, and the ability of adaptive immune therapy to alter disease course. What is not clear in typical type 1 diabetes is what underlies the initial triggering of the adaptive immune system. The increasing incidence of disease over time suggests gene-environment interactions leading to beta cell injury, yet it remains challenging to identify specific triggers. Since pancreatic damage and innate activation are known components of acute pancreatitis, the development of diabetes in this setting can allow for investigation as to how acute tissue injury results in autoimmunity and thus serves as a model system to understand mechanisms resulting in typical type 1 diabetes. In this proposal, we will determine the incidence and describe the natural history of diabetes and autoimmunity in individuals after acute pancreatitis (Aim 1), test the hypothesis that acute pancreatitis resolves to an altered immune state in a subset of individuals that predisposes them to develop islet autoimmunity (Aim 2), and determine if acute pancreatitis associated autoimmunity results in immune phenotypes similar to that seen in typical type 1 diabetes (Aim 3).