Mucosal Mechanisms Linking Pulmonary and Gastrointestinal Inflammation/Immunity

描述（由申请人提供）：粘液表面持续暴露于抗原、感染因子和固有微生物群。越来越多的人认识到，连续感染是对无关抗原/感染的免疫应答结果的决定因素。此外，通过抗生素使用、饮食变化、急性感染和炎症引起的胃肠道（GI）微生物群的扰动可改变粘膜中的免疫调节。生命早期的这些事件可能会减少以后生活中对特应性的易感性，相反，急性感染的减少和/或“更卫生”的生活方式中微生物群的改变可能会促进疾病（“卫生假说”）。虽然先前暴露于感染因子对炎症发展的影响已经在隔离的粘膜部位进行了研究，但解剖学上遥远的粘膜部位之间的免疫相互作用的程度和机制仍有待确定。证据开始积累肠肺免疫调节轴，但机制是未知的。我们的假设是胃肠道炎症（急性或慢性）产生免疫调节变化，影响气道免疫应答的发展和/或表现，包括调节性T细胞应答和骨髓生成的变化。在这个建议中，我们将研究两种潜在的机制，即炎症反应如何对肠道限制性病原体（啮齿类柠檬酸杆菌，肠致病性大肠杆菌的小鼠模型，其诱导结肠限制性、Th 1偏向性免疫应答）调节Th 2介导的对肺中不相关变应原（OVA）的免疫应答：1）对肺中变应原特异性调节和效应T细胞极化的影响，鼻内变应原激发后的肺相关淋巴结和肠系膜淋巴结，以及2）对树突状细胞和嗜酸性粒细胞前体从骨髓通过血液进入过敏原激发的肺的动员和迁移的影响。 公共卫生相关性越来越多的人认识到，连续性感染是对无关过敏原/感染的免疫应答结果的决定因素。此外，通过抗生素使用、饮食变化、急性感染和炎症引起的胃肠道微生物群的扰动可改变粘膜中的免疫调节。生命早期的这些事件可能会减少以后生活中过敏的倾向，相反，急性感染的减少和/或“更卫生”生活方式中微生物群的改变可能会促进疾病（“卫生假说”）。解剖学上远离的粘膜部位之间的免疫相互作用的程度和机制仍有待确定，本提案的数据将开始弥合我们对GI粘膜炎症变化可促进或预防气道过敏性疾病的机制的理解中的差距。这一信息将是非常有用的治疗或预防过敏性疾病的未来设计。

DESCRIPTION (provided by applicant): Mucosal surfaces are constantly exposed to antigens, infectious agents and the indigenous microbiota. Sequential infections are being increasingly recognized to be a determining factor in the outcome of an immune response to unrelated antigens/infections. In addition, perturbations in the gastrointestinal (GI) microbiota through antibiotic use, dietary changes, acute infection and inflammation can alter immunoregulation in the mucosa. Such events early in life may reduce the predisposition toward atopy later in life and, conversely, a reduction in acute infections and/or alterations of the microbiota in "more hygienic" lifestyles may promote disease (the "hygiene hypothesis"). While the influence of prior exposure to an infectious agent on the development of inflammation has been studied in isolated mucosal sites, the extent and mechanisms of the immune interaction between anatomically distant mucosal sites remains to be determined. Evidence is beginning to accumulate for a gut-lung immunoregulatory axis but the mechanisms are unknown. Our hypothesis is that gastrointestinal inflammation (acute or chronic) produces immunoregulatory changes that affect the development and/or manifestation of immune responses in the airways, including changes in regulatory T cell responses and myelopoiesis. In this proposal, we will investigate two potential mechanisms of how the inflammatory response to a gut-restricted pathogen (Citrobacter rodentium, the mouse model of enteropathogenic Escherichia coli, which induces a colon-restricted, Th1-biased immune response) modulates the Th2-mediated immune response to an unrelated allergen (OVA) in the lungs: 1) effects on allergen-specific regulatory and effector T cell polarization in the lungs, lung associated lymph nodes and mesenteric lymph nodes following intranasal allergen challenge and 2) effects on the mobilization and migration of dendritic cell and eosinophil precursors from the bone marrow through the blood and into allergen-challenged lungs. PUBLIC HEALTH RELEVANCE Sequential infections are being increasingly recognized to be a determining factor in the outcome of an immune response to unrelated allergens/infections. In addition, perturbations in the gastrointestinal microbiota through antibiotic use, dietary changes, acute infection and inflammation can alter immunoregulation in the mucosa. Such events early in life may reduce the predisposition toward allergy later in life and, conversely, a reduction in acute infections and/or alterations of the microbiota in "more hygienic" lifestyles may promote disease (the "hygiene hypothesis"). The extent and mechanisms of the immune interaction between anatomically distant mucosal sites remains to be determined and the data from this proposal will begin to bridge the gap in our understanding of the mechanisms by which inflammatory changes in GI mucosa can promote or prevent allergic disease in the airways. This information will be critically useful for the future design of therapies to treat or prevent allergic diseases.