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，而微生物会影响疾病的发育。 自身免疫，包括1型糖尿病(T1D)。在动物身上进行的许多实验和观察 人类制造的食物暗示了饮食的重要性。这些饮食干预改变了 T1D的发展吸引了我们的注意，因为它们可以应用于大量和不同的人群。 我们感兴趣的是了解饮食干预对微生物区系的依赖程度以及它们是如何 影响免疫系统和疾病的发展。我们的初步实验结果显示 这种以酪蛋白(HC)为基础的水解物是一种微生物区系独立保护剂，而添加面筋 对HC饮食造成了微生物区系依赖的保护作用丧失。我们假设保护工作是 缓解β细胞的压力，最大限度地减少自身免疫的激活。面筋蛋白的作用方式是促进 包括适应性免疫机制和先天免疫机制。以进一步揭示恶化背后的机制 对于面筋的特性，我们将追求以下目标： 具体目的1.探讨T1D及其受体参与饮食保护的免疫机制 由面筋逆转。 ·分析胰岛和胰腺淋巴中单细胞水平的基因和蛋白质标记物的表达 用单细胞测序和多参数流式细胞术检测不同饲料小鼠的结节数(PLN)。 ·对喂食不同食物的动物进行抗原提呈的功能测试。 ·对这些动物的效应器T细胞和调节性T细胞进行功能比较。 ·对小岛和PLN中的其他细胞类型进行分析。 明确目标2。了解面筋和微生物区系相互作用的自身免疫后果。 ·分析细菌蛋白分解在TCR激动剂产生中的作用-识别的多肽 H-2G7背景下的小鼠T细胞。 ·验证细菌消化面筋产生交叉反应激动剂的假设，该激动剂可以交叉- 刺激反胰岛反应。 ·解决具有生物活性的面筋蛋白水解物在天然免疫系统激活中的作用 在体外，更重要的是，在体内。