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

基本信息

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
项目类别：
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

项目摘要

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，而微生物可以影响肠道菌群的发育。自身免疫，包括 1 型糖尿病 (T1D) 许多在动物身上进行的实验和观察。人类制造的这些饮食干预措施表明了饮食的重要性。 T1D 的发展引起了我们的关注，因为它们可以应用于大量且多样化的人群。我们有兴趣了解饮食干预对微生物群的依赖程度以及它们如何我们的初步实验结果显示，它会影响免疫系统和疾病的发展。基于水解酪蛋白 (HC) 的饮食是一种独立于微生物群的保护剂，而添加麸质 HC 饮食导致了依赖于微生物群的保护作用的丧失，我们进化出这种保护作用。麸质的作用方式是缓解β细胞的应激激活，从而减少自身免疫。适应性和先天性免疫机制，进一步揭示恶化背后的机制。鉴于麸质的特性，我们将追求以下目标：具体目标 1. 研究饮食保护 T1D 及其相关疾病的免疫机制麸质逆转。 · 在胰岛和胰腺淋巴液的单细胞水平上分析基因和蛋白质标记物的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。 · 对饲喂不同饮食的动物进行抗原呈递功能测试。 · 对这些动物中的效应 T 细胞和调节 T 细胞进行功能比较。 · 对胰岛和 PLN 中的其他细胞类型进行分析。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 TCR 激动剂（TCR 激动剂识别的肽）生成中的作用 H-2g7 背景下的小鼠 T 细胞。 · 检验麸质的细菌消化产生交叉反应激动剂的假设，这些激动剂可以交叉刺激抗胰岛反应。 · 解决麸质生物活性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。