Role of the gut epithelium in pancreatic autoimmunity

1型糖尿病（T1 D）是一种自身免疫性疾病，其特征在于T细胞介导的胰腺炎性细胞破坏。 p细胞了解T细胞对p细胞的反应是如何被激发的是我们工作的长期目标。 该提议基于这样的假设：肠道上皮细胞的破坏会影响胃肠道的启动。 T1 D，通过将树突状细胞（DC）暴露于肠因子，增强其呈递p细胞抗原的能力， 潜在的致糖尿病T细胞。有几个发现导致了这一假设。第一，肠道渗透性， 在胰岛炎发作前的糖尿病易感大鼠和T1 D患者中，炎症被夸大。第二、 在早产儿中已经观察到肠异常，例如肠绒毛肥大或增生， 胰岛炎的糖尿病易感大鼠。第三，在T1 D患者中，谷蛋白诱导的 肠道炎症或乳糜泻，并且NOD小鼠表现出乳糜泻的致病标志。 第四，麸质在遗传易感受试者中表现出致糖尿病的潜力。最后，我们最近的研究 表明肠上皮扰动改变了T1 D的病程。尽管有大量的临床 和流行病学研究表明T1 D患者肠屏障功能障碍， 这种联系仍然难以捉摸。这项建议的目的是阐明细胞和分子 肠屏障功能调节胰腺自身免疫反应的机制。 具体目标是：1）确定肠上皮的改变是否影响两种MHC类别 I类和II类限制性T细胞对p细胞Ag的应答。这些实验将确定 肠屏障功能改变对p细胞增殖、活化、存活和效应功能的影响， 特异性，CD 4+和CD 8 + T细胞; 2）定义肠屏障功能的变化如何影响DC功能， pancLN。在这里，我们将确定对肠上皮细胞的轻度损伤对分化的影响， 成熟和pancLN的特异性DC亚群的Ag呈递能力。我们亦会评估 肠损伤改变DC功能的分子机制，通过检测NFicB激活在 这些过程; 3）评估膳食小麦面筋在激发抗-P-细胞免疫应答中的作用。 这些实验将监测谷蛋白对p-细胞反应性T细胞启动的影响。 pancLN中的细胞和DC的成熟。这些实验的目的是确定 麸质引起胰腺自身免疫的机制。 这项研究将有助于深入了解环境刺激和自身免疫性疾病之间的联系。 发病机制

Type-1 diabetes (T1D) is an autoimmune disorder characterized by T cell-mediated destruction of pancreatic p-cells. To understand how T cell responses against p cells are provoked is the long-term goal of our work. This proposal is based on the hypothesis that disruptions in the gut epithelium impinge on the initiation of T1D, by exposing dendritic cells (DCs) to enteric factors that boost their capacity to present p cell antigens to potentially diabetogenic T cells. Several findings lead to this hypothesis. First, intestinal permeability and inflammation are exaggerated in diabetes-prone rats before insulitis onset and in patients with T1D. Second, intestinal abnormalities such as hypertrophy or hyperplasia of intestinal villi have been observed in pre- insulitic, diabetes-prone rats. Third, there is a very high prevalence among T1D patients of gluten-induced intestinal inflammation, or celiac disease, and NOD mice exhibit pathogenic hallmarks of celiac disease. Fourth, gluten exhibits diabetogenic potential in genetically susceptible subjects. Finally, our recent studies indicate that perturbations of the gut epithelium modify the course of T1D. Despite an abundance of clinical and epidemiological studies implicating intestinal barrier dysfunction in T1D, the mechanistic underpinnings of this association remain elusive. The objective of this proposal is to elucidate the cellular and molecular mechanisms by which intestinal barrier function regulates the pancreatic autoimmune response. The specific aims are to: 1} Determine whether alterations to the intestinal epithelium affect both MHC class I- and class ll-restricted T cell responses to p cell Ags. These experiments will ascertain the impact of altered intestinal barrier function on the proliferation, activation, survival and effector functions of p cell- specific, CD4+ and CD8+ T cells; 2) Define how changes in intestinal barrier function impact DC function in pancLNs. Here we will determine the impact of mild injury to the intestinal epithelium on the differentiation, maturation, and Ag presentation capacity of specific DC subsets of pancLNs. We will also assess the molecular mechanism by which intestinal injury alters DC function by testing the role of NFicB activation in these processes; 3) Evaluate the role of dietary wheat gluten in provoking the anti-p-cell immune response. These experiments will monitor the impact of alimentary gluten proteins on the priming of p-cell-reactive T cells in pancLNs and the maturation of DCs. The aim of these experiments is to pinpoint the specific mechanism by which gluten provokes pancreatic autoimmunity. The proposed studies will yield insights into the link between environmental provocation and autoimmune pathogenesis.