Role of Helicobacter Pylori in the Pathogenesis of Childhood Asthma

描述（由申请人提供）：幽门螺杆菌通常感染人类的胃，在那里它会引起所有人的炎症（胃炎），并在一些人中引起消化性溃疡疾病或胃癌。幽门螺杆菌在发达国家儿童中的患病率不到10%，而在大多数发展中国家几乎普遍存在。随着幽门螺杆菌患病率的下降，一些疾病急剧增加，其中之一是儿童哮喘。最近的回顾性和病例对照研究表明，幽门螺杆菌感染，特别是带有促炎cag致病性岛的菌株，与哮喘呈负相关。幽门螺杆菌诱导儿童调节性T细胞（Treg）反应是一种生物学上合理的机制，可以解释这种关联。这项建议的主要目的是确定早期接触幽门螺杆菌是否可以预防儿童哮喘的发展。我们的总体假设是幽门螺杆菌促进儿童treg偏向的免疫反应，可以抑制促进过敏性炎症的肺部和全身细胞因子的合成，从而保护气道在早期生活中不发生反应性发展。这一假设是基于我们在恒河猴身上的初步发现，即室内尘螨气溶胶暴露会减弱成熟气道中的Treg细胞，以及已发表的幽门螺旋杆菌促进儿童胃粘膜Treg细胞发育的观察结果。因此，我们认为幽门螺杆菌感染对Treg细胞群的增强可能会阻止空气过敏原对这种免疫抑制淋巴细胞的抑制作用。加州国家灵长类动物研究中心（CNPRC）开发的幽门螺杆菌和哮喘恒河猴模型为研究幽门螺杆菌预防儿童哮喘的假设提供了一个独特的机会，我们将进行以下具体目的的测试：(1)确定实验性幽门螺杆菌感染是否可以预防儿童哮喘恒河猴模型中的哮喘表型。(2)检查幽门螺杆菌感染对儿童哮喘表型的全身、胃和肺部免疫相关因素的影响。这些具体目标的完成将为流行病学发现提供重要的实验支持，并可能直接推断出用于预防儿童哮喘和其他合并症的候选化合物。

DESCRIPTION (provided by applicant): Helicobacter pylori commonly infects the human stomach, where it causes inflammation (gastritis) in all individuals and peptic ulcer disease or gastric cancer in some. The prevalence of H. pylori in children in developed countries is less than 10%, while it is nearly universal in most developing countries. As the prevalence of H. pylori has declined, several diseases have dramatically increased, one of which is childhood asthma. Recent retrospective and case control studies suggest that infection with H. pylori, particularly strains bearing the proinflammatory cag pathogenicity island, is inversely associated with asthma. H. pylori induction of a regulatory T cell (Treg) response in children is a biologically plausible mechanism that may explain this association. The primary objective of this proposal is to determine if early life exposure to H. pylori can prevent the development of childhood asthma. Our overall hypothesis is that H. pylori promotes a Treg-biased immune response in children that can suppress synthesis of pulmonary and systemic cytokines that promote allergic inflammation, thereby protecting the airways from development of reactivity in early life. This hypothesis is based on our preliminary findings in rhesus macaques that Treg cells in maturing airways are attenuated by house dust mite aerosol exposure, and the published observation that H. pylori promotes development of gastric mucosal Treg cells in children. Thus, we propose that enhancement of Treg cell populations by H. pylori infection may prevent the inhibitory effects of aeroallergen on this immunosuppressive lymphocyte. The rhesus macaque models of H. pylori and asthma developed at the California National Primate Research Center (CNPRC) provide a unique opportunity to study the hypothesis that H. pylori protects against childhood asthma, which we will test with the following specific aims: (1) Determine if experimental H. pylori infection can prevent the asthma phenotype in the infant rhesus macaque model of childhood asthma. (2) Examine the effects of H. pylori infection on systemic, gastric, and pulmonary immune correlates of the childhood asthma phenotype. Completion of these Specific Aims will provide important experimental support for epidemiologic findings, and may be directly extrapolated towards identification of candidate compounds for the prevention of childhood asthma and other co-morbid conditions.