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

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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.