Modulation of Th17 plasticity by intestinal paleobiomic fauna

我们的微生物群会影响我们的免疫系统的功能。我们的微生物群已经改变为 生活在高度卫生的工业化国家的结果。我们的微生物群的一个主要变化是暴露时间的减少 到蠕虫(寄生蠕虫)。在1940年代S之前，蠕虫的殖民几乎是普遍的，有 强有力的证据表明，这种接触帮助塑造了我们的基因组。失去这些以前无处不在的成员 在我们的古生物群中，可以有广泛的免疫效果。炎症性肠病 折磨着100多万美国人和成千上万的退伍军人。IBD和其他疾病的发病率 1940年代S之后，免疫介导性疾病在北美和欧洲急剧增加。这些 疾病在欠发达的热带国家很少见。在越南服役的退伍军人或曾在 与其他退伍军人相比，战争中患IBD的风险较低。此外，随着各国经济的发展， IBD和其他免疫介导性疾病的发病率增加。现在，IBD是一种全球新兴的 无序。尽管特定基因易患IBD，但有强有力的证据表明，环境的变化 在社会经济改善的同时，也增加了患上这种疾病的风险。我们建议一项 与我们的历史古生物群的变化，即在发达国家缺乏蠕虫暴露是一种 IBD和其他免疫介导性疾病的重要危险因素。我们和其他人有 研究表明，寄生蠕虫可以保护小鼠免受免疫介导的结肠炎、脑炎、糖尿病和 呼吸道疾病。这些都是高度工业化国家出现的疾病模型。 了解蠕虫暴露如何减少免疫介导性疾病将指导 预防或治疗这些疾病的有针对性的治疗。Th17细胞控制促炎病理 反应，就像IBD。最近，Th17细胞的异质性变得很明显。除了……之外 产生IL-17，高度促炎的Th17细胞产生干扰素γ。其他具有调节性表型的Th17细胞 表达FoxP3或制作IL10。免疫介导性疾病可能是由于Th17可塑性失调所致。我们 发现接触蠕虫会抑制粘膜IL17的产生，而且这种接触 降低固有层和肠系膜淋巴结中Th17干扰素和Th17IL10百分比 细胞群。此外，我们发现蠕虫暴露改变了Treg的可塑性，并且在没有T细胞的情况下 STAT6信号大量诱导了一个新的Foxp3干扰素群体。我们的假设是蠕虫 暴露通过改变Th17和Treg的异质性/可塑性来预防结肠炎。该项目将测试 这一假设有三个具体目的。我们的第一个目标是探索蠕虫暴露的机制。 这会改变Th17的可塑性。我们的第二个目标将探索蠕虫暴露所致的机制 增强Treg可塑性及新发现的肌球蛋白和TIGIT环路在蠕虫相关疾病中的作用 Treg函数。我们的第三个目标将探索蠕虫引起的Th回路的变化如何增加肠道 上皮细胞对靶向损伤的抵抗力。我们的研究是独特的，因为我们正在探索可能的根源 现代文明中出现自身免疫和免疫介导性炎症性疾病的原因。 此外，这些研究将深入了解那些生活或服务较少的蠕虫接触者是如何 发达国家可能会对免疫学挑战做出反应。此外，我们正在体内研究如何 肠道微生物改变免疫途径以影响慢性炎症性疾病 退伍军人。

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.