Mucosal Mechanisms Linking Pulmonary and Gastrointestinal Inflammation/Immunity

描述(申请人提供)：粘膜表面经常暴露在抗原、感染剂和本土微生物群中。人们越来越认识到，顺序感染是对无关抗原/感染的免疫反应结果的决定因素。此外，通过抗生素使用、饮食变化、急性感染和炎症对胃肠道(GI)微生物区系的干扰可以改变粘膜中的免疫调节。生命早期的这些事件可能会降低晚年患特应性疾病的可能性，相反，急性感染的减少和/或“更卫生”的生活方式中微生物区系的改变可能会促进疾病(“卫生假说”)。虽然在孤立的粘膜部位已经研究了先前接触感染剂对炎症发展的影响，但解剖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。肠-肺免疫调节轴的证据开始积累，但其机制尚不清楚。我们的假设是，胃肠道炎症(急性或慢性)会产生免疫调节变化，影响呼吸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。在这项建议中，我们将研究两种潜在的机制，即对肠道限制性病原体(罗氏柠檬酸杆菌，肠道致病性大肠杆菌的小鼠模型，它诱导结肠限制性的，Th1偏向的免疫反应)的炎症反应如何调节Th2介导的对肺部无关变应原(OVA)的免疫反应：1)对鼻腔变应原攻击后肺、肺相关淋巴结和肠系膜淋巴结变应原特异性调节和效应器T细胞极化的影响；2)对树突状细胞和嗜酸性粒细胞前体细胞从骨髓通过血液动员和迁移到变应原挑战的肺部的影响。 公共卫生相关性顺序感染越来越多地被认为是对无关过敏原/感染的免疫反应结果的决定因素。此外，抗生素使用、饮食变化、急性感染和炎症对胃肠道微生物区系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降低晚年过敏的易感性，相反，急性感染的减少和/或“更卫生”的生活方式中微生物区系的改变可能会促进疾病(“卫生假说”)。解剖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，来自这一提议的数据将开始弥合我们对胃肠道粘膜炎症变化促进或预防呼吸道过敏性疾病的机制的理解上的差距。这些信息将对未来治疗或预防过敏性疾病的治疗方法的设计至关重要。

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.