Mucosal Mechanisms Linking Pulmonary and Gastrointestinal Inflammation/Immunity

描述（由申请人提供）：粘膜表面经常暴露于抗原、感染因子和本地微生物群。序次感染越来越被认为是对不相关抗原/感染的免疫反应结果的决定性因素。此外，抗生素的使用、饮食的改变、急性感染和炎症对胃肠道微生物群的干扰可以改变粘膜的免疫调节。生命早期的这些事件可能会减少生命后期对特应性反应的易感性，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”）。虽然先前暴露于感染因子对炎症发展的影响已经在孤立的粘膜部位进行了研究，但解剖距离较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，但其机制尚不清楚。我们的假设是胃肠道炎症（急性或慢性）产生免疫调节变化，影响气道免疫反应的发展和/或表现，包括调节性T细胞反应和骨髓生成的变化。在本研究中，我们将探讨两种可能的机制，即对肠道限制性病原体（鼠Citrobacter rodentium，肠致病性大肠杆菌小鼠模型，诱导结肠限制性、th1偏向性免疫反应）的炎症反应如何调节th2介导的对肺部不相关过敏原（OVA）的免疫反应：1)鼻内过敏原刺激对肺、肺相关淋巴结和肠系膜淋巴结中过敏原特异性调节性和效应T细胞极化的影响；2)树突状细胞和嗜酸性粒细胞前体从骨髓经血液进入过敏原刺激的肺的动员和迁移的影响。

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.