Immunologic Pathways to Childhood Asthma

描述(由申请人提供)：卫生学假说假设，生命早期接触微生物提供关键刺激，促使免疫系统成熟，使其远离过敏敏感性的发展。这一竞争更新的目的是研究三条似乎可以预防哮喘的免疫途径，确定这些途径是否为卫生学假说提供了机制基础，并确定哮喘易感基因如何与环境影响相互作用来预防哮喘。该项目的具体目标是：(1)确定婴儿期产生干扰素-γ的能力与随后发生哮喘的风险之间的关系，并确定微生物暴露或模式识别受体中单核苷酸多态(SNPs)对这一发展的任何影响；(2)建立生命早期产生IL-10对过敏原特异性IgG4/IgE比率和随后哮喘发生的影响，并确定先天免疫基因TLR4和CD14对IL-10产生的影响；(3)建立与TLR4中特定SNP相关的哮喘发病率降低的生物学基础；以及(4)单独和联合评估TLR SNPs和家庭微生物暴露对生命早期外周血单核细胞TLR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。竞争更新将招募足够统计能力所需的最后三分之一的婴儿，将重新评估早期微生物暴露、过敏原特异性IgG4和TLR表达，并将跟踪已登记的受试者至8岁。在出生的头5年内，将采集血液进行DNA和免疫学评估(细胞因子产生、总IgE、过敏原特异性IgE和IgG4)六次；父母也会抽血。对父母和5岁的孩子进行皮肤点刺试验。经常获得呼吸道问卷，以确定哮喘症状的发作和复发，并进行病历审查，以确定哮喘和其他呼吸道疾病的诊断。粉尘样本是在婴儿早期从家里获取的，以评估暴露于内毒素、革兰氏阴性、革兰氏阳性和细菌总数。该项目综合了流行病学、免疫学、遗传学和分子生物学的方法，以全面的方式研究环境因素和遗传易感性如何相互作用来改变免疫系统的成熟和随后的哮喘风险。对这些过程的了解对于阐明哮喘的发病机制和制定有效的哮喘一级预防策略至关重要。

DESCRIPTION (provided by applicant): 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-gamma 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, allergenspecific 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 infancy 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.