Immune Development Across the Life Course: Integrating Exposures and Multi-Omics in the Boston Birth Cohort

摘要 我们的首要目标是研究生命早期免疫反应对一系列广泛的免疫缺陷的影响。 病原微生物和真菌以及暴露于多种环境污染物对发育的影响 和从出生到18岁的过敏性疾病的预后及其潜在的分子途径。我们 越来越多的证据表明，在子宫内和生命的最初几年是关键的窗口， 免疫力的发展，并通过观察，早期生活暴露于微生物和环境 污染物可能对未来患过敏性疾病的风险产生深远影响。为了实现我们的目标，我们将利用 波士顿出生队列（BBC）的丰富资源，约有3,500对母婴在出生时登记 并进行前瞻性跟踪。通过我们之前在BBC的研究，我们已经建立了必要的临床， 实验室和计算基础设施，并获得纵向流行病学和临床数据， 多组学（基因组、表观基因组、代谢组）数据以及存档的生物标本。我们已经证明 英国广播公司是一个高风险的人口不利的环境暴露和英国广播公司的儿童有一个 免疫相关疾病的高患病率，包括食物过敏、幼儿期反复喘息和 儿童哮喘BBC数据和生物储存库的广度、深度和高质量一直受到人们的关注。 在120多篇同行评审的出版物中得到证实。我们还获得了令人信服的初步数据， 支持我们的研究目的和假设。具体来说，包括1,000个英国广播公司的母子二人组， 从出生到18岁的关键纵向数据元素和生物标本，我们的目的是调查：（1） 生命早期对微生物的免疫应答对儿童过敏表型的影响;（2）生命早期暴露的影响 环境污染物（例如，空气污染、有毒金属）对儿童过敏表型的影响;以及（3）分子 早期生活环境暴露和过敏性疾病之间的联系的潜在途径。我们将 利用先进的抗体分析技术（PhIP-Seq）在1,000个BBC中分析IgG和IgE抗体 儿童在三个重要的发展窗口（出生，1-2岁，15-18岁）。这将提供深入的 儿童抗体谱的表型分析，并确定产前，围产期， 以及出生后遗传和环境的相互作用。我们能够分析抗体库， 跨越关键发育窗口的变应性表型允许我们描绘它们的纵向轨迹， 暴露和结果之间的时间和剂量反应关系。成功完成 这项研究将有助于确定重要的早期生命风险和保护因素，沿着新的生物标志物， 预测或治疗目标。最终，我们希望高危新生儿能够被识别出来，并且有效 干预措施可以在最早的发育窗口期开始，那时它们可能有最长的寿命， 长期受益

Abstract Our overarching goal is to investigate the impact of early life immune response to a broad array of pathogenic and commensal microbes and exposure to multiple environmental pollutants on the development and prognosis of allergic diseases from birth up to age 18 years and their underlying molecular pathways. Our project is motivated by growing evidence that in-utero and the first few years of life are critical windows for the development of immunity, and by observations that early life exposures to microbes and environmental pollutants may have a profound impact on future risk of allergic diseases. To achieve our goal, we will leverage the rich resources of the Boston Birth Cohort (BBC), with ~3,500 mother-child pairs who were enrolled at birth and followed prospectively. Through our prior research in the BBC, we have established essential clinical, laboratory and computational infrastructures, and obtained longitudinal epidemiological and clinical data, and multi-omics (genome, epigenome, metabolome) data as well as archived biospecimens. We have shown that the BBC is a high-risk population for adverse environmental exposures and the children of the BBC have a high prevalence of immune-related disorders, including food allergies, early childhood recurrent wheezing and childhood asthma. The breadth, depth, and high quality of the BBC data and biorepository have been demonstrated in over 120 peer-reviewed publications. We also have generated compelling preliminary data to support our study aims and hypotheses. Specifically, by including 1,000 mother-child dyads of the BBC with key longitudinal data elements and biospecimens from birth up to age 18 years, we aim to investigate: (1) effects of early life immune response to microbes on child allergic phenotypes; (2) effects of early life exposure to environmental pollutants (e.g., air pollution, toxic metals) on child allergic phenotypes; and (3) molecular pathways underlying the link between early life environmental exposures and allergic diseases. We will harness cutting-edge antibody profiling technology (PhIP-Seq) to profile IgG and IgE antibodies in 1,000 BBC children at three important developmental windows (birth, 1-2 years, and 15-18 years). This will provide deep phenotyping of a child’s antibody profile and identify longitudinal changes in the context of prenatal, perinatal, and postnatal genetic and environmental interactions. Our ability to profile the antibody repertoire and define allergic phenotypes across critical developmental windows allow us to delineate their longitudinal trajectories, temporal and dose-response relationships between the exposures and outcomes. Successful completion of this study will help identify important early life risk and protective factors, along with novel biomarkers for prediction or therapeutic targets. Ultimately, we hope that high-risk newborns can be identified, and effective interventions can be initiated during the earliest developmental windows when they may have the greatest life- long benefit.