Refining the Atopic March: Mechanisms of Progression in Black and White Children

项目摘要 近二十年来，描述特应性疾病的顺序发展的“特应性进行曲”概念， 皮炎（AD）、食物过敏（FA）、哮喘和过敏性鼻炎（AR）已经作为指导原则，然而， 最近的一次国家卫生研究所研讨会得出结论，只有大约3%的儿童遵循传统的特应性行进。他们表示 虽然早期AD仍然是任何特应性疾病发展的主要风险因素，但没有单一的 特应性行进的独特路径相反，存在显著异质性，包括时间和器官 受影响，游行需要修改，以包括这种异质性，并纳入各种 组合。我们设计了儿童特应性皮炎（AD）进展为哮喘的机制 （MPAACH）队列，第一个美国AD前瞻性纵向早期生命队列，以满足这一需求。MPAACH 包括65%的黑人儿童，是历史上唯一代表这一点的早期生活群体之一。 代表性不足和研究不足的人口。以前对特应性进行曲的研究大多是在白色人群中进行的 人口。我们从MPAACH的早期发现揭示了特应性行进概念的明显种族差异， 强调了当前关于特应性游行的范例中的种族偏见。黑人儿童不成比例 受哮喘患病率、发病率和死亡率的影响， 调整社会经济因素 这表明种族也可以作为一个关键生物因素的代表， 我们目前还不认识。我们的中心假设是，致敏作用的纵向轨迹和 变应性疾病的进展在白人和黑人之间是不同的，这是由于机制， 一是生物学差异。我们将进行皮肤转录组学，并将这些数据与纵向 免疫学、环境和临床数据，以构建过敏性疾病发展的发病机制， 进展、持续、缓解和消退。种族是一个复杂的概念， 社会经济因素，以及生物因素。因此，我们将使用自我报告的种族来定义黑人和白色， 遗传血统，以及量化皮肤中黑色素含量的生物学方法，从而识别连续体 除了种族的社会文化定义之外，还由于生物多样性。此应用程序将具有 重大公共卫生影响。通过提出的目标，我们将（1）定义纵向AD表型， 黑人和白色MPAACH儿童，（2）阐明皮肤转录组学特征和生物学途径， 黑人和白色MPAACH儿童的AD纵向表型和（3）定义纵向表型 黑人和白色儿童AD的免疫表型及按种族构建变应性疾病的发病机制 基于遗传学（来自项目2）-->皮肤转录组学-->免疫学环境-->纵向临床 内型

Project Summary For nearly two decades, the “atopic march” concept, which describes the sequential development of atopic dermatitis (AD), food allergy (FA), asthma, and allergic rhinitis (AR) has served as a guiding principle, however, a recent NIH workshop concluded that only about 3% of children follow the traditional atopic march. They stated that while early-life AD remains a major risk factor for the development of any atopic disease, there is no single unique pathway for the atopic march. Rather, there is significant heterogeneity including the timing and organ(s) affected, and the march needs to be revised to include this heterogeneity and incorporate the various combinations. We designed the Mechanisms of Progression of Atopic Dermatitis (AD) to Asthma in CHildren (MPAACH) cohort, the first US prospective longitudinal early life cohort of AD, to meet this need. MPAACH includes 65% Black children and is one of the only early life cohorts that represents this historically underrepresented and understudied population. Previous studies of the atopic march were done mostly in White populations. Our early findings from MPAACH reveal marked racial differences in the atopic march concept and underscore the racial bias in current paradigms around the atopic march. Black children are disproportionately impacted by asthma prevalence, morbidity, and mortality and this race-asthma association is not eliminated after adjusting for socioeconomic factors suggesting that race may also serve as a proxy for a critical biologic factor that we do not currently recognize. Our central hypothesis is that the longitudinal trajectories of sensitization and allergic disease progression are different between Whites and Blacks, and that this is mechanistically due, in part, to biologic differences. We will conduct skin transcriptomics and integrate this data with longitudinal immunologic, environmental, and clinical data to construct the pathogenesis of allergic disease development, progression, persistence, remission, and resolution. Race is a complex concept including sociocultural and socioeconomic, as well as biologic factors. As such, we will define Black and White using self-reported race, genetic ancestry, and biologic methods that quantify melanin content in the skin, thus recognizing the continuum resulting from biologic diversity in addition to the sociocultural definitions of race. This application will have significant public health impact. Through the proposed aims, we will (1) define longitudinal AD phenotypes in Black and White MPAACH children, (2) elucidate skin transcriptomic profiles and biologic pathways that predict AD longitudinal phenotypes for Black and White MPAACH children and (3) define longitudinal immunophenotypes of AD in Black and White children and construct the pathogenesis of allergic disease by race based on genetics (from Project 2)--> skin transcriptomics--> immunologic milieu--> longitudinal clinical endotypes.