Gut Intrinsic Inflammatory Responses

胃肠道(GI)是一个巨大的表面，由暴露在外面的单层上皮构成 数以万亿计的微生物和饮食中的无害物质。最大的免疫收藏品 体内的细胞位于这一单层上皮之下，并监测管腔内容物以 在稳定状态下保持对饮食和共生抗原的耐受，同时保持 在感染期间快速诱导对病原体免疫的能力。虽然已经取得了很大的进展 阐明特定免疫细胞亚群、细胞因子和其他因素的作用(S) 促进耐受或免疫，这是肠道固有的过程，使免疫系统 从稳定状态中压倒性的耐受性语气切换到炎症反应 在感染期间仍然是我们认识上的一个空白。最近，我们发现了抑制作用 小肠(SI)中的杯状细胞相关抗原通道(GAP)迅速转移 免疫调节远离耐受性并促进快速诱导炎性Th17 在没有感染或受伤的情况下做出反应。我们假设对间隙的抑制是一种 肠道感染的生理反应本身促进了Th17的产生 细胞和炎性细胞因子，改变免疫系统的基调，使其远离耐受性 走向豁免权。通过在没有肠道感染或损伤的情况下研究这一过程，我们可以 辨析病原与损伤在炎症反应中的内在作用 肠道生态系统的特性促进了从耐受性状态到促炎性状态的转换。 了解肠道的固有属性，从而快速产生保护性 应对措施可以为治疗肠道感染提供新的方法，并提供对 肠道慢性炎症性疾病的发病机制。我们假设当SI缺口出现时 被抑制，其他途径取代了Th17细胞的发育和/或扩增 特定于饮食、微生物和/或自身抗原，从而将免疫系统的基调改变为 在肠道感染和/或损伤期间提供增强的保护。为了探索这一假设，我们 提出以下具体目标：在目标1中，我们将确定导致Th17的早期事件 在SI间隙抑制之后的扩展，在目标2中，我们将定义 当SI间隙被抑制时Th17细胞的扩张在目标3中我们将确定是否抑制 SI间隙在肠道感染模型中是否具有保护作用以及是否不适当地抑制SI GAP会加重肠炎性疾病。

The gastrointestinal (GI) tract is a large surface lined by a single layer epithelium which is exposed to trillions of microbes and innocuous substances from the diet. The largest collection of immune cells in the body underlies this single layer epithelium and monitors the luminal contents to maintain tolerance to dietary and commensal antigens in the steady-state while retaining the ability to rapidly induce immunity to pathogens during infection. While great progress has been made in elucidating the role(s) of specific immune cell subsets, cytokines, and other factors promoting tolerance or immunity, the processes intrinsic to the gut that enable the immune system to switch from an overwhelmingly tolerogenic tone in the steady-state to inflammatory responses during infection remains a gap in our understanding. Recently, we have uncovered that inhibiting goblet cell associated antigen passages (GAPs) in the small intestine (SI) rapidly shifts the immunologic tone away from tolerance and promotes the rapid induction of inflammatory Th17 responses in the absence of infection or injury. We hypothesize that the inhibition of GAPs is a physiologic response to enteric infection, which in and of itself, promotes the generation of Th17 cells and inflammatory cytokines and shifts the tone of the immune system away from tolerance toward immunity. By studying this process in the absence of enteric infection or injury we can disentangle contributions of the pathogen and injury to the inflammatory response from intrinsic properties of the gut ecosystem promoting the switch from a tolerogenic to pro-inflammatory state. Understanding intrinsic properties of the gut that allows the rapid generation of protective responses could provide new approaches to treat enteric infections and provide insight into the pathogenesis of chronic inflammatory diseases of the gut. We hypothesize that when SI GAPs are inhibited, other pathways take over driving the development and/or expansion of Th17 cells specific for dietary, microbial, and/or self antigens, which shifts the tone of the immune system to provide enhanced protection during enteric infection and/or injury. To explore this hypothesis we propose the following specific aims: In aim 1 we will identify the early events resulting in Th17 expansion following SI GAP inhibition, in aim 2 we will define the origins and specificities of the Th17 cells that expand when SI GAPs are inhibited in aim 3 we will determine if the inhibition of SI GAPs is protective in models of enteric infection and whether inappropriate inhibition of SI GAPs potentiates intestinal inflammatory disease.