Environment, innate immunity and type 1 diabetes

描述(申请人提供)：1型糖尿病(T1D)是遗传和环境因素相互作用的结果。最近的全基因组扫描提供了许多关于易患疾病的基因的信息，但对导致易感个体患T1D的环境相互作用知之甚少。我们最近在非肥胖糖尿病小鼠(NOD)中产生的证据表明，通过先天免疫适配器MyD88介导的先天免疫反应可能在影响疾病的发展中发挥关键作用。我们发现，MyD88基因缺陷的小鼠在无特定病原体(SPF)的环境中饲养时不会患上糖尿病。有证据表明，这些MyD88-/-小鼠的胰腺淋巴结中T调节细胞活性增加。然而，当小鼠被重新衍生到无菌设施时，它们在相同条件下患糖尿病的几率与野生型小鼠一样高。重新引入一组受限的肠道共生细菌(改变了舍德勒菌群)，再次降低了糖尿病的发病率。这表明，内部共生环境正在影响疾病的发展。了解共生体如何与内部粘膜相互作用来塑造我们的免疫系统，包括先天免疫和获得性免疫，对于解释包括自身免疫性疾病在内的慢性炎症性疾病是如何发展至关重要的。在这个项目中，我们将1)研究肠道菌群暴露影响疾病发展和相关免疫发育变化的关键时间窗口；2)测试MyD88在肠道树突状细胞中作为最强大的抗原提呈细胞的重要性，以及天然和获得性免疫反应之间的关键联系；3)研究MyD88在肠道上皮细胞中表达在响应和感知共生菌群中的重要性。我们的研究将加强我们对内部环境如何塑造免疫反应并导致遗传易感自身免疫性糖尿病模型的自身免疫的理解。反过来，这可能有助于指导对糖尿病遗传易感性人群的研究，并有助于开发预防和治疗1型糖尿病的新策略。

DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) occurs as a result of interplay of genetic and environmental factors. Recent genome-wide scans have given much information about the genes that predispose to disease but much less is known of the environmental interaction that causes susceptible individuals to develop T1D. We have recently generated evidence in the Non Obese Diabetic mouse (NOD) that the innate immune response, mediated through the innate immune adaptor MyD88, may plays a critical role influencing development of disease. We showed that mice deficient in MyD88 did not develop diabetes when bred in a Specific Pathogen free (SPF) environment. There was evidence of increased T regulatory cell activity in the pancreatic lymph nodes of these MyD88-/- mice. However, when the mice were rederived into a germ free facility, they developed the same high incidence of diabetes as wild type mice in the same conditions. Re-introduction of a restricted set of gut commensal bacteria (Altered Schaedler's flora) again reduced diabetes. This indicated that the internal commensal environment was influencing the development of disease. Understanding how commensals interact with the internal mucosa to shape our immune system, both innate and adaptive immunity, is critical to explain how chronic inflammatory diseases, including autoimmune diseases, develop. In this project we will 1) investigate the critical time windows for the exposure to intestinal flora in influencing whether disease develops and the associated immune developmental changes; 2) test the importance of expression of MyD88 in intestinal dendritic cells as the most potent antigen presenting cells and the critical link between innate and adaptive immune responses; 3) investigate the importance of expression of MyD88 in intestinal epithelial cells in responding to and sensing the commensal flora. Our studies will enhance our understanding of how the internal environment may shape the immune response and lead to autoimmunity in a genetically susceptible autoimmune diabetes model. In turn, this may help to direct investigation in people genetically susceptible to diabetes and aid development of new strategies for prevention and treatment of type 1 diabetes.