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早期免疫反应对广泛的 致病微生物和共生微生物与多种环境污染物接触对发育的影响 过敏性疾病从出生到18岁的预后及其潜在的分子途径。我们的 该项目的动机是越来越多的证据表明，宫内和生命的头几年是 免疫力的发展，以及早期生命接触微生物和环境的观察 污染物可能会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，出生时登记的母子对约3,500对 并前瞻性地进行了跟踪。通过我们之前在BBC的研究，我们已经建立了基本的临床， 实验室和计算基础设施，并获得纵向流行病学和临床数据，以及 多组学(基因组、表观基因组、代谢组)数据以及存档的生物谱系。我们已经证明了 BBC是有害环境暴露的高危人群，BBC的孩子们有 免疫相关疾病的高流行率，包括食物过敏、幼儿反复喘息和 儿童哮喘。BBC数据和生物信息库的广度、深度和高质量 在120多份同行评议的出版物中展示了这一点。我们还生成了令人信服的初步数据 支持我们的研究目标和假设。具体地说，通过将BBC的1000对母子二人组与 从出生到18岁的关键纵向数据元素和生物样本，我们的目标是调查：(1) 早期对微生物的免疫反应对儿童过敏表型的影响；(2)早期接触的影响 环境污染物(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联系的潜在途径。我们会 利用尖端抗体分析技术(PhIP-Seq)分析1,000个BBC的免疫球蛋白抗体和免疫球蛋白E抗体 儿童处于三个重要的发育窗口(出生、1-2岁和15-18岁)。这将为我们提供深度的 对儿童的抗体谱进行表型分型，并确定产前、围产期和 以及出生后遗传和环境的相互作用。我们分析抗体谱系和确定 通过关键发育窗口的过敏表型，我们可以描绘其纵向轨迹， 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，以及新的生物标志物 预测或治疗靶点。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，那时他们可能拥有最好的生活- 长期福利。

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.