Modulation of Th17 plasticity by intestinal paleobiomic fauna

肠道古生物群对 Th17 可塑性的调节

• 批准号: 10012257
• 负责人: DAVID E ELLIOTT
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10012257
• 关键词: Acute; Affect; Airway Disease; American; Anti-Inflammatory Agents; Apoptotic; Archaeology; Area; Arthritis; Asthma; Attenuated; Autoimmune Process; Back; Celiac Disease; Cell Compartmentation; Cell Differentiation process; Cell physiology; Cells; Chronic; Civilization; Clinical; Colitis; Country; Crohn' s disease; Data; Developed Countries; Developing Countries; Development; Diabetes Mellitus; Disease; Disease model; Encephalitis; Environment; Epithelial Cells; Europe; Exposure to; FOXP3 gene; Genome; Health; Helminths; Helper-Inducer T-Lymphocyte; Heterogeneity; Human; Human Microbiome; IL17 gene; Immune; Immune response; Immunity; Immunologics; In Vitro; Incidence; Individual; Infectious Agent; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injury; Insulin-Dependent Diabetes Mellitus; Interferon Type II; Interferons; Interleukin-10; Intestines; Lamina Propria; Link; Mediating; Modernization; Mucous Membrane; Multiple Sclerosis; Mus; Nematoda; North America; Organism; Pathogenicity; Pathologic; Pathway interactions; Phenotype; Plant Roots; Population; Prisoner; Production; Rare Diseases; Regulatory T-Lymphocyte; Research; Resistance; Resolution; Rheumatoid Arthritis; Risk; Risk Factors; Role; Shapes; Signal Transduction; Site; Specimen; Susceptibility Gene; T-Lymphocyte; Testing; Ulcerative Colitis; Veterans; Vietnam; War; atopy; cell injury; chronic inflammatory disease; experimental study; gut microbiome; helminth infection; immune health; immune system function; immunoregulation; in vivo; insight; intestinal epithelium; member; mesenteric lymph node; microbiome; microorganism; neglect; novel; novel therapeutics; pressure; prevent; response; socioeconomics; targeted treatment

Our microbiome influences how our immune system functions. Our microbiome has changed as a result of living in highly hygienic industrialized countries. A major change in our microbiome is loss of exposure to helminths (parasitic worms). Prior to the 1940's, helminth colonization was nearly universal and there is strong evidence that this exposure helped to shape our genome. Loss of these previously ubiquitous members of our paleobiome, can have far ranging immunologic effect. Inflammatory bowel disease (IBD) currently afflicts more than one million Americans and many thousands of veterans. The incidence of IBD and other immune-mediated diseases increased dramatically after the 1940's in North America and Europe. These diseases are rare in less developed tropical countries. Veterans that served in Vietnam or were prisoners of war are at lower risk of developing IBD than are other veterans. Moreover, as countries develop economically the incidence of IBD and other immune-mediated diseases increase. Now, IBD is a globally emerging disorder. Although specific genes predispose to IBD, there is strong evidence that a change in environment concurrent with socioeconomic improvement confers risk for developing the disorder. We propose that a change from our historic paleobiome, i.e. the lack of helminth exposure, in developed countries is an important risk factor for developing IBD and other immune-mediated diseases. We and others have shown that colonization with helminths protects mice from immune-mediated colitis, encephalitis, diabetes, and airway disease. These are models of diseases that have emerged within highly industrialized countries. Understanding how helminth exposure decreases immune mediated diseases will guide development of targeted therapy to prevent or treat those diseases. Th17 cells control pro-inflammatory pathological responses, like that of IBD. Recently it has become clear that Th17 cells are heterogeneous. In addition to making IL17, highly pro-inflammatory Th17 cells make IFNγ. Other Th17 cells with a regulatory phenotype express FoxP3 or make IL10. Immune mediated disease likely results from dysregulated Th17 plasticity. We discovered that mucosal IL17 production is inhibited by exposure to helminths and that this exposure decreases Th17IFN+ and increases Th17IL10+ percentages in lamina propria and mesenteric lymph node cell populations. Moreover, we find that helminth exposure alters Treg plasticity and in the absence of T cell Stat6-signaling massively induces a novel Foxp3+IFN+ population. Our hypothesis is that helminth exposure protects against colitis by altering Th17 and Treg heterogeneity/plasticity. This project will test this hypothesis with 3 specific aims. Our first aim will explore the mechanisms enabled by helminth exposure that alter Th17 plasticity. Our second aim will explore the mechanisms enabled by helminth exposure that augment Treg plasticity and the role of newly discovered musculin and TIGIT circuity in helminth-associated Treg function. Our third aim will explore how helminth-induced changes in Th circuitry increases intestinal epithelial cell resistance to targeted injury. Our research is unique in that we are exploring possible root causes for the emergence of autoimmune and immune-mediated inflammatory disease in modern civilizations. In addition, these studies will provide insight into how helminth-exposed individuals that live or served in less developed countries may respond to immunologic challenges. Furthermore, we are examining in vivo how intestinal organisms alter immune pathways to influence chronic inflammatory diseases like those that afflict veterans.

我们的微生物组影响我们的免疫系统的功能。我们的微生物组已经发生了变化 这是生活在高度卫生的工业化国家的结果。我们微生物群的一个主要变化是暴露的减少 蠕虫（寄生虫）。 20 世纪 40 年代之前，蠕虫定植几乎是普遍存在的 强有力的证据表明这种暴露有助于塑造我们的基因组。失去这些以前无处不在的成员 我们的古生物组，可以产生广泛的免疫效应。目前炎症性肠病（IBD） 困扰着超过一百万美国人和成千上万的退伍军人。 IBD 和其他疾病的发病率 20 世纪 40 年代后，北美和欧洲的免疫介导疾病急剧增加。这些 疾病在欠发达的热带国家很少见。在越南服役或被俘的退伍军人 战争中的退伍军人患 IBD 的风险低于其他退伍军人。而且，随着各国经济的发展 IBD 和其他免疫介导疾病的发病率增加。现在，IBD是一种全球新兴的疾病 紊乱。尽管特定基因易患 IBD，但有强有力的证据表明环境的变化 伴随着社会经济的改善，也带来了患上这种疾病的风险。我们建议 发达国家历史上古生物群系的变化，即缺乏蠕虫暴露，是一个 发生 IBD 和其他免疫介导疾病的重要危险因素。我们和其他人有 研究表明，蠕虫定植可以保护小鼠免受免疫介导的结肠炎、脑炎、糖尿病和 气道疾病。这些是高度工业化国家中出现的疾病模型。 了解蠕虫暴露如何减少免疫介导的疾病将指导免疫介导疾病的发展 针对性治疗来预防或治疗这些疾病。 Th17 细胞控制促炎病理 反应，如 IBD 的反应。最近，Th17 细胞具有异质性已经变得很清楚。此外 产生 IL17，高度促炎的 Th17 细胞产生 IFNγ。其他具有调节表型的 Th17 细胞 表达 FoxP3 或制造 IL10。免疫介导的疾病可能是由 Th17 可塑性失调引起的。我们 发现接触蠕虫会抑制粘膜 IL17 的产生，并且这种接触 降低固有层和肠系膜淋巴结中 Th17IFN+ 的百分比并增加 Th17IL10+ 的百分比 细胞群。此外，我们发现蠕虫暴露会改变 Treg 可塑性，并且在 T 细胞缺失的情况下 Stat6 信号传导大量诱导新的 Foxp3+IFN+ 群体。我们的假设是蠕虫 暴露可通过改变 Th17 和 Treg 异质性/可塑性来预防结肠炎。本项目将测试 这个假设有 3 个具体目标。我们的首要目标是探索蠕虫暴露所带来的机制 改变 Th17 可塑性。我们的第二个目标是探索蠕虫暴露所带来的机制， 增强 Treg 可塑性以及新发现的 musculin 和 TIGIT 回路在蠕虫相关疾病中的作用 Treg 功能。我们的第三个目标是探索蠕虫引起的 Th 回路变化如何增加肠道 上皮细胞对靶向损伤的抵抗力。我们的研究的独特之处在于我们正在探索可能的根源 现代文明中出现自身免疫性和免疫介导的炎症性疾病的原因。 此外，这些研究将深入了解在较少的环境中生活或服务的蠕虫暴露个体的情况。 发达国家可以应对免疫挑战。此外，我们正在研究体内如何 肠道微生物改变免疫途径来影响慢性炎症性疾病，例如那些困扰我们的疾病 退伍军人。