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: 10490911
• 负责人: ALEXANDER V CHERVONSKY
• 金额: $ 58.03万
• 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/10490911
• 关键词: Address; Affect; Agonist; 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; Food; Gene Proteins; Generations; Genetic Predisposition to Disease; Gluten; Gnotobiotic; Goals; Human; Immune; Immune System Diseases; 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; Property; Proteolysis; Reducing diet; Regulatory T-Lymphocyte; Research; Risk; Role; Suggestion; Supplementation; T-Lymphocyte; Technology; Testing; Translating; Uncertainty; Work; antigen test; base; 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 自身免疫性，包括1型糖尿病（T1D）。动物和观测中进行的许多实验 人类制造的是饮食的重要性。那些改变了改变的饮食干预措施 T1D的发展引起了我们的注意，因为它们可以应用于大型和潜水员的人群。 我们有兴趣了解饮食干预措施如何依赖微生物群以及它们如何 影响免疫系统和疾病发展。我们的初步实验的结果揭示了 水解酪蛋白（HC）的饮食是无菌依赖的保护剂，而添加面筋 HC饮食导致依赖微生物群的保护丧失。我们假设保护工作是 减轻β细胞的压力最小化自身免疫的激活。面筋的行动方式是 适应性和先天免疫力学。进一步发现加重的机制 面筋的属性，我们将追求以下目的： 特定目的1。调查T1D饮食保护涉及的免疫力学 面筋逆转。 分析胰岛和胰淋巴的单细胞水平上的基因和蛋白质标记物表达 使用单细胞测序和多参数流术仪，在不同饮食上的小鼠节点（PLN）。 ·对喂养不同饮食的动物中抗原表现的功能测试。 ·在这些动物中对效应子和调节性T细胞进行功能比较。 ·对胰岛和PLN中其他细胞类型进行分析。 特定目的2。了解面筋和微生物群相互作用的自身免疫性后果。 ·分析细菌蛋白水解在产生TCR激动剂的作用 - 由 小鼠T细胞在H-2G7的背景下。 ·为了检验以下假设，即麸质的细菌消化物会产生交叉反应激动剂，可以交叉 刺激反诉反应。 解决面筋的生物活性蛋白水解产物在先天免疫系统激活中的作用 体外，更重要的是体内。