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

项目摘要 近二十年来，特应性进行曲的概念，它描述了特应性疾病的顺序发展 皮炎(AD)、食物过敏(FA)、哮喘和过敏性鼻炎(AR)一直是指导原则，然而， 美国国立卫生研究院最近的一次研讨会得出结论，只有大约3%的儿童遵循传统的特应性进行曲。他们说 虽然早期阿尔茨海默病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 特应性进行曲的独特路径。相反，存在显著的异质性，包括时间和器官(S) 受影响，进行曲需要修改，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)向哮喘进展的机制 (MPAACH)队列，美国第一个AD的前瞻性纵向早期队列，以满足这一需求。MPAACH 包括65%的黑人儿童，是历史上仅有的代表这一点的早期儿童之一 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进行的 人口。我们来自MPAACH的早期发现显示，特应性进行症概念和特应性进行症的种族差异显著 强调目前围绕特应性进行曲的范式中的种族偏见。黑人儿童的比例不成比例 受哮喘患病率、发病率和死亡率的影响，这种种族与哮喘的关联在 对社会经济因素进行调整表明，种族也可能是一个关键生物因素的替代品 我们目前还不承认。我们的中心假设是敏化的纵向轨迹和 过敏性疾病的进展在白人和黑人之间是不同的，这是机械上的原因， 部分，与生物差异有关。我们将进行皮肤转录，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、坚持、缓解和解决。种族是一个复杂的概念，包括社会文化和 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人， 遗传祖先，以及量化皮肤中黑色素含量的生物方法，从而识别连续体 除了对种族的社会文化定义外，还有生物多样性造成的。此应用程序将具有 对公共卫生产生重大影响。通过提出的目标，我们将(1)定义纵向AD表型 黑人和白人MPAACH儿童，(2)阐明皮肤转录图谱和预测 黑人和白人MPAACH儿童的AD纵向表型和(3)定义纵向 黑人和白人儿童AD的免疫表型及其与过敏性疾病发病机制的关系 基于遗传学(来自项目2)？皮肤转录学？免疫环境？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.