Goblet Cells in Intestinal Homeostasis

肠道稳态中的杯状细胞

• 批准号: 10445291
• 负责人: Rodney D Newberry
• 金额: $ 46.87万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-17 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10445291
• 关键词: Acetylcholine; Affect; Antigen-Presenting Cells; Antigens; Award; B-Lymphocytes; Bacteria; Cells; Cellular Immunity; Collection; Data; Diet; Epidermal Growth Factor Receptor; Epithelial; Event; Exposure to; Gastrointestinal tract structure; Genetic; Goblet Cells; Grant; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Infection; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intestines; Lamina Propria; Ligands; Lymphoid Follicle; Lymphoid Tissue; Microbe; Modeling; Monitor; Mucous Membrane; Mus; Nature; Outcome; Pathogenesis; Pathway interactions; Pharmacology; Phenotype; Physiological; Plasma Cells; Property; Reporter; Role; Small Intestinal Goblet Cell; Small Intestines; Specificity; Stimulus; T cell response; Time; Tissue Expansion; base; commensal bacteria; cytokine; dietary; enteric infection; fighting; gut microbiota; imprint; improved outcome; intestinal homeostasis; macrophage; microbiota; microorganism antigen; novel; pathogen; programs; receptor; response

The body's largest collection of immune cells underlies the single layer epithelium lining the gastrointestinal (GI) tract and monitors the luminal contents, which includes trillions of microbes, their products, and substances from the diet. The basal tone of the healthy gut immune system is tolerogenic, despite being exposed to trillions of microbes and their products. While this strong tolerogenic capacity is beneficial to the host to avoid inflammatory responses to innocuous dietary and commensal antigens in the healthy state, the inability to dampen this tolerogenic capacity could be detrimental in the setting of enteric infection and inappropriately dampening this tolerogenic capacity could underlie the pathogenesis of intestinal inflammatory diseases. We propose that the gut has a capacity to turn off tolerogenic responses and generate inflammatory responses. While great progress has been made in elucidating the role of specific immune cell subsets, cytokines, and other factors promoting tolerance or immunity, how the gut immune system switches from tolerogenic responses in the steady-state to protective immunity when needed remains a significant gap in our understanding. Completion of the studies outlined in this proposal will fill this void in our understanding by identifying how inhibiting a major pathway delivering luminal substances activates cellular and humoral immune responses at the mucosa. In prior cycles of this award we have identified how goblet cell associated antigen passages (GAPs) are formed, the stimulus inducing GAPs in the steady-state, acetylcholine (ACh), the stimuli and receptors regulating GAP formation, including the luminal microbiota, cytokines, and epidermal growth factor receptor (EGFR) ligands, and the properties of GAPs in various regions of the GI tract. Further we have identified roles for GAPs, when physiologically present, in supporting tolerance to luminal substances including dietary and commensal microbial antigens. Moreover, we have now assembled genetic and pharmacologic models for the manipulation of GAPs and are poised to dissect the role of GAP inhibition in promoting protective/inflammatory immunity in the absence of enteric infection or overt changes in the gut microbiota. Based upon our prior studies and preliminary observations we hypothesize that when GAPs form in the steady state, they act to imprint the immune system to promote tolerance and when small intestine (SI) GAPs are inhibited they participate in a cascade of events promoting protective immunity. To explore this hypothesis we propose to (Aim 1) define the LP-APCs phenotypes, the origins of Th17 and TFH cells that expand, and the durability of the response that occurs when SI GAPs are inhibited, (Aim 2) define the drivers and specificities of the B cell responses arising when SI GAPs are inhibited and (Aim 3) determine if SI GAP inhibition improves outcomes and is required for appropriate responses during enteric infection.

人体最大的免疫细胞收集是胃肠道（GI）的单层上皮的基础 区域和监视腔内容物，其中包括数万亿微生物，它们的产品和物质 饮食。健康的肠道免疫系统的基础音调具有耐受性，尽管暴露于数万亿美元 微生物及其产品。尽管这种强大的耐受能力对宿主有益，以避免炎症 在健康状态下对无害饮食和共生抗原的反应，无法抑制这一点 在肠道感染的情况下，耐受能力可能有害，并且不适当地抑制了这一点 耐受性能力可能是肠道炎症性疾病的发病机理的基础。我们建议 肠道有能力关闭耐受性反应并产生炎症反应。虽然进步很大 已经在阐明特定免疫细胞亚群，细胞因子和其他促进因素的作用方面做出了 耐受性或免疫力，肠道免疫系统如何从稳态中的耐受性反应转变为 在需要时，保护性免疫仍然是我们理解的显着差距。完成研究 在本提案中概述将通过确定如何抑制主要途径来填补这一空白 传递腔内物质会激活粘膜处的细胞和体液免疫反应。 在此奖项的先前周期中，我们已经确定了杯状细胞相关的抗原段（GAPS）是如何的 形成，刺激在稳态，乙酰胆碱（ACH），刺激和受体调节的刺激中 间隙形成，包括腔菌群，细胞因子和表皮生长因子受体（EGFR） 配体，以及胃道各个区域中间隙的特性。此外，我们确定了空白的角色， 当生理上存在时，在支持对腔内物质（包括饮食和共生）的耐受性时 微生物抗原。此外，我们现在已经组装了用于操纵的遗传和药理模型 差距，并有望剖析差异抑制在促进保护/炎症免疫中的作用 肠道菌群中没有肠道感染或明显变化。根据我们先前的研究和 初步观察我们假设，当稳定状态形成差距时，它们的作用是为 免疫系统促进耐受性，当抑制小肠道（SI）差距时，它们会参与 促进保护性免疫的事件级联。为了探索这一假设，我们建议（目标1）定义（目标1） LP-APC表型，Th17和TFH细胞的起源以及响应的耐用性 当抑制Si间隙时发生，（AIM 2）定义出现的B细胞响应的驱动因素和特异性 当抑制SI间隙并（AIM 3）确定SI间隙抑制是否改善预后，并且需要 肠道感染期间的适当反应。