Immunologic Pathways to Childhood Asthma

卫生学假说假定，生命早期接触微生物提供了驱动免疫的关键刺激。 系统的成熟远离了过敏敏感性的发展。这一竞争性更新的目标是 研究三种似乎可以预防哮喘的免疫途径，以确定这些途径是否 通路为卫生假说提供了机制基础，并确定了哮喘易感性 基因可能与环境影响相互作用，以预防哮喘。该项目的具体目标是 目的：1)确定婴儿期产生干扰素的能力与随后发病风险之间的关系 哮喘的发生，并确定微生物暴露或单核苷酸多态(SNPs)的任何影响 模式识别受体对发育的影响；2)建立早期生命中IL-10产生对 过敏原特异性IgG4/IgE比值与哮喘后续发展的关系，并确定 天然免疫基因TLR4和CD14对IL-10产生的影响；3)建立了IL-10产生减少的生物学基础 与TLR4中特定SNP相关的哮喘患病率；以及4)单独和合并评估影响， TLR SNPs和家庭微生物暴露对生命早期外周血单核细胞TLRs表达的影响 该项目建立在成功的、正在进行的婴儿免疫研究的基础上，该研究跟踪了一名出生至8岁的儿童。 竞争性更新将招收足够统计能力所需的最后三分之一的婴儿，将 新评估早期微生物暴露、过敏原特异性IgG4和TLR表达，并将遵循已登记的 受试者至8岁。采集血液进行DNA和免疫学评估(细胞因子产生、总IgE、过敏原- 特异性IgE和IgG4)在出生后的头5年内6次；父母也会抽血。皮肤点刺试验是 给父母使用，在5岁时给孩子使用。经常获得呼吸系统问卷，以确定 哮喘症状的出现和复发，以及为确定哮喘的诊断和治疗而进行的病历审查 其他呼吸道疾病。在接种早期从家中获取粉尘样本，以评估接触内毒素的情况， 革兰氏阴性菌、革兰氏阳性菌和总细菌。该项目综合了流行病学、免疫学、遗传学和 综合研究环境因素和遗传易感性的分子方法 相互作用，改变免疫系统的成熟和随后的哮喘风险。对这些的理解 过程对于阐明哮喘的发病机制以及开发有效的治疗策略至关重要。 哮喘的一级预防。

The hygiene hypothesis postulates that exposure to microbes early in life provides critical stimuli that drive immune system maturation away from the development of allergic susceptibility. The objective of this competing renewal is to investigate three immunologic pathways that appear to protect against asthma, to determine whether these pathways provide a mechanistic basis for the hygiene hypothesis, and to determine how asthma susceptibility genes may interact with environmental influences to protect against asthma. The specific aims of the project are to: 1) determine the relation between the capacity to produce IFN-,/in infancy and the risk for the subsequent development of asthma, and to identify any influence of microbial exposure or single nucleofide polymorphisms (SNPs) in pattern recognition receptors on that development; 2) establish the influence of IL-10 production in early life on the ratio of allergen specific IgG4/IgE and the subsequent development of asthma, and to determine the influence of the innate immunity genes TLR4 and CD14 on IL-10 production; 3) establish the biologic basis for the decreased prevalence of asthma associated with a particular SNP in TLR4; and 4) assess the influence, separately and combined, of TLR SNPs and household microbial exposure on peripheral blood monocyte expression of TLRs in early life. The project builds on the successful, on-going Infant Immune Study, which is following a birth cohort to 8 years of age. The competing renewal will enroll the last third of the population of infants required for adequate statistical power, will newly assess early microbial exposures, allergen specific IgG4, and TLR expression, and will follow already enrolled subjects to age 8. Blood is obtained for DNA and immunologic assessments (cytokine production, total IgE, allergen- specific IgE and IgG4) six times in the first 5 years of life; blood is also drawn on parents. Skin prick tests are administered to parents and, at age 5, to the children. Respiratory questionnaires are obtained frequently to determine onset and recurrence of asthma symptoms, and medical record reviews conducted to identify diagnosis of asthma and other respiratory conditions. Dust samples are obtained from the home in early inthncy to assess exposure to endotoxin, and Gram-negative, Gram-positive and total bacteria. This project integrates epidemiologic, immunologic, genetic, and molecular approaches to study, in a comprehensive manner, how environmental factors and genetic susceptibility interact to alter the maturation of the immune system and subsequent risk of asthma. An understanding of these processes is critical to elucidating the pathogenesis of asthma, and the development of effective strategies for the primary prevention of asthma.