Modulation of Th17 plasticity by intestinal paleobiomic fauna

我们的微生物群影响我们的免疫系统如何发挥作用。我们的微生物组已经改变， 这是生活在高度卫生的工业化国家的结果。我们的微生物组的一个主要变化是暴露的损失 蠕虫（寄生虫）。在20世纪40年代之前，蠕虫殖民几乎是普遍的， 强有力的证据表明，这种接触有助于塑造我们的基因组。失去这些以前无处不在的成员 可以产生广泛的免疫效应。炎症性肠病（IBD）目前 超过一百万美国人和成千上万的退伍军人受到折磨。IBD和其他疾病的发病率 免疫介导的疾病在20世纪40年代后在北美和欧洲急剧增加。这些 疾病在较不发达的热带国家很少见。在越南服役的老兵或战俘 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和其他免疫介导疾病的发病率增加。现在，IBD是一种全球新兴的 disorder.虽然特定的基因易患IBD，但有强有力的证据表明，环境的变化 与社会经济状况改善同时发生的风险赋予了发展障碍的风险。我们建议 从我们的历史古生物群的变化，即缺乏蠕虫暴露，在发达国家是一个 是发展IBD和其他免疫介导疾病的重要危险因素。我们和其他人已经 显示寄生虫定植保护小鼠免受免疫介导的结肠炎、脑炎、糖尿病和 呼吸道疾病这些是高度工业化国家出现的疾病模型。 了解寄生虫暴露如何减少免疫介导的疾病将指导 靶向治疗来预防或治疗这些疾病。Th 17细胞控制促炎病理学 反应，如IBD。最近已经清楚Th 17细胞是异质性的。除了 产生IL 17，高度促炎的Th 17细胞产生IFNγ。其他具有调节表型的Th 17细胞 表达FoxP 3或产生IL 10。免疫介导的疾病可能是由Th 17可塑性失调引起的。我们 发现粘膜IL 17的产生受到蠕虫的抑制， 固有层和肠系膜淋巴结中Th 17 IFN γ +百分比降低，Th 17 IL 10+百分比升高 细胞群此外，我们发现蠕虫暴露改变了Treg的可塑性，在T细胞缺乏的情况下， Stat 6信号转导大量诱导新的Foxp 3 +IFN γ +群体。我们假设寄生虫 暴露通过改变Th 17和Treg异质性/可塑性来保护免受结肠炎。该项目将测试 这个假设有三个具体目标。我们的第一个目标是探索蠕虫暴露的机制 改变Th 17的可塑性。我们的第二个目标是探索蠕虫暴露的机制， 增强Treg可塑性以及新发现的肌蛋白和TIGIT环在蠕虫相关免疫反应中的作用 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免疫功能。 上皮细胞对靶向损伤的抵抗力。我们的研究是独一无二的，因为我们正在探索可能的根源， 现代文明中自身免疫和免疫介导的炎症性疾病的出现的原因。 此外，这些研究将提供深入了解如何蠕虫暴露的个人，生活或服务， 发达国家可能会对免疫挑战作出反应。此外，我们正在研究如何在体内 肠道微生物改变免疫途径，影响慢性炎症性疾病， 老兵

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.