Role of the gut epithelium in pancreatic autoimmunity

描述(申请人提供)：1型糖尿病(T1D)是一种以T细胞介导的胰腺B细胞破坏为特征的自身免疫性疾病。了解T细胞对p细胞的反应是如何激发的，这是我们工作的长期目标。这一建议基于这样的假设，即肠道上皮细胞的破坏通过将树突状细胞(DC)暴露于肠道因子，增强其将p细胞抗原呈递给潜在的致糖尿病T细胞的能力，从而影响T1D的启动。有几个发现导致了这一假设。首先，在糖尿病易患大鼠和T1D患者发病前，肠道通透性和炎症被夸大。其次，在胰岛素抵抗前、易患糖尿病的大鼠中观察到肠道异常，如肠道绒毛肥大或增生。第三，在T1D患者中，面筋诱导的肠炎或乳糜泻的患病率非常高，NOD小鼠表现出乳糜泻的致病特征。第四，面筋在遗传易感人群中显示出致糖尿病的潜力。最后，我们最近的研究表明，肠道上皮细胞的扰动改变了T1D的病程。尽管大量的临床和流行病学研究表明T1D患者存在肠道屏障功能障碍，但这种联系的机制基础仍然难以捉摸。本研究的目的是阐明肠道屏障功能调节胰腺自身免疫反应的细胞和分子机制。其具体目的是：1)确定肠上皮细胞的改变是否影响MHC I类和11类限制的T细胞对B细胞AGS的反应。这些实验将确定肠屏障功能改变对p细胞特异性、CD4+和CD8+T细胞的增殖、激活、存活和效应功能的影响；2)确定肠屏障功能的变化如何影响pancLN中的DC功能。在这里，我们将确定轻微的肠上皮损伤对pancLN的特定DC亚群的分化、成熟和抗原提呈能力的影响。我们还将通过测试NFicB激活在这些过程中的作用来评估肠道损伤改变DC功能的分子机制；3)评估饮食中小麦面筋蛋白在激发抗p细胞免疫反应中的作用。这些实验将监测消化性面筋蛋白对pancLN中p细胞反应性T细胞的启动和DC成熟的影响。这些实验的目的是明确面筋引发胰腺自身免疫的具体机制。拟议的研究将深入了解环境刺激和自身免疫发病机制之间的联系。

DESCRIPTION (provided by applicant): Type-1 diabetes (T1D) is an autoimmune disorder characterized by T cell-mediated destruction of pancreatic B-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 B 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.