Enhancement of autoimmunity in type 1 diabetes by gluten

麸质增强 1 型糖尿病的自身免疫能力

• 批准号: 10680525
• 负责人: ALEXANDER V CHERVONSKY
• 金额: $ 56.39万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680525
• 关键词: Address; Affect; Agonist; Animal Feed; Animal Model; Animals; Antigen Presentation; Attention; Autoimmune; Autoimmune Process; Autoimmunity; Beginning of Life; Beta Cell; Caseins; Cells; Cellular Stress; Cohort Studies; Communities; Development; Diet; Dietary Intervention; Digestion; Disease Progression; Environment; Environmental Risk Factor; Enzymes; Flow Cytometry; Food; Generations; Genes; Genetic Predisposition to Disease; Gluten; Gnotobiotic; Goals; Human; Immune; Immune System Diseases; Immune system; Immunity; In Vitro; Ingestion; Innate Immune Response; Innate Immune System; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Knowledge; Laboratories; Mediating; Microbe; Mus; Nature; Pancreas; Patients; Peptides; Persons; Play; Pre-Clinical Model; Probability; Property; Proteolysis; Reducing diet; Regulatory T-Lymphocyte; Research; Risk; Role; Supplementation; T-Lymphocyte; Technology; Testing; Translating; Uncertainty; Work; adaptive immune response; antigen test; cell type; commensal microbes; cross reactivity; dietary; dietary manipulation; disorder prevention; experimental study; genetic manipulation; gut microbiota; host-microbe interactions; human disease; in vivo; innate immune mechanisms; interest; islet; lymph nodes; microbial; microbial composition; microbiome; microbiota; protein biomarkers; response; single cell sequencing

Ingested food affects the composition of intestinal microbes, whereas microbes can affect the development of autoimmunity, including Type 1 diabetes (T1D). Many experiments conducted in animals and observations made in humans were suggestive of the importance of diet. Those dietary interventions that changed the development of T1D attracted our attention because they can be applied to large and diverse groups of people. We are interested in understanding how strongly dietary interventions depend on the microbiota and how they influence the immune system and disease development. The results of our preliminary experiments revealed that Hydrolyzed Casein (HC)-based diet was a microbiota-independent protector, whereas addition of gluten to HC diet caused a microbiota-dependent loss of protection. We hypothesized that protection works be relieving beta cells from stress minimizing activation of autoimmunity. Gluten’s mode of action is facilitation of both adaptive and innate immune mechanisms. To further uncover the mechanisms behind exacerbating properties of gluten, we will pursue the following aims: Specific Aim 1. Investigate the immune mechanisms involved in dietary protection from T1D and its reversal by gluten. · Analyze gene and protein marker expression at the single cell level in islets and pancreatic lymph nodes (PLN) of mice on different diets using single cell sequencing and multiparameter flowcytometry. · Perform functional testing of antigen presentation in animals fed different diets. · Perform functional comparisons of effector and regulatory T cell in these animals. · Perform analysis of other cell types in the islets and PLN. Specific Aim 2. Understand the autoimmune consequences of gluten and microbiota interactions. · Analyze the role of bacterial proteolysis in generation of the TCR agonists - peptides recognized by mouse T cells in the context of H-2g7. · To test the hypothesis that bacterial digest of gluten produces cross-reactive agonists that can cross- stimulate anti-islet responses. · Address the role of biologically active proteolytic products of gluten in innate immune system activation in vitro and, more importantly, in vivo.

摄入的食物会影响肠道微生物的组成，而微生物会影响 自身免疫，包括1型糖尿病（T1 D）。在动物身上进行的许多实验和观察 暗示了饮食的重要性。这些饮食干预改变了 T1 D的发展吸引了我们的注意力，因为它们可以应用于大量不同的人群。 我们感兴趣的是了解饮食干预对微生物群的依赖程度，以及它们如何影响微生物群。 影响免疫系统和疾病的发展。我们初步实验的结果显示， 水解酪蛋白（HC）为基础的饮食是一个微生物群独立的保护，而添加面筋 HC饮食导致了微生物群依赖性保护的丧失。我们假设保护工作是 减轻β细胞的压力，使自身免疫的激活最小化。麸质的作用模式是促进 适应性和先天免疫机制。为了进一步揭示恶化的机制， 我们将追求以下目标： 具体目标1。研究饮食保护T1 D的免疫机制及其 谷蛋白的逆转 ·在胰岛和胰腺淋巴中的单细胞水平上分析基因和蛋白质标记物表达 使用单细胞测序和多参数流式细胞术对不同饮食的小鼠的淋巴结（PLN）进行分析。 ·在喂食不同饮食的动物中进行抗原呈递的功能测试。 ·在这些动物中进行效应T细胞和调节T细胞的功能比较。 ·分析胰岛和PLN中的其他细胞类型。 具体目标2。了解麸质和微生物群相互作用的自身免疫后果。 ·分析细菌蛋白水解在产生TCR激动剂中的作用-TCR激动剂识别的肽， 小鼠T细胞在H-2g 7的背景下。 ·为了检验细菌消化麸质产生交叉反应性激动剂的假设， 刺激抗胰岛反应。 ·解决生物活性面筋蛋白水解产物在先天免疫系统激活中的作用 在体外，更重要的是，在体内。