Atopic dermatitis: mechanisms of disease progression

项目总结 特应性皮炎(AD)是一种慢性炎症性皮肤病，全世界高达20%的儿童受到影响。广告 已被强调为“特应性进行曲”的第一步，AD通常先于 其他过敏性疾病。据报道，特应性过敏和食物过敏是AD的先兆 进展为呼吸道过敏，然而，最近的数据表明，其机制要复杂得多。这个 美国国家过敏症和传染病研究所最近召开了一次题为``特应性皮炎和 特应性进行曲：机制和干预6他们得出结论，只有大约3%的儿童遵循 通常被称为特应性进行曲。他们表示，一项新的前瞻性队列研究表明 使用多参数方法定义AD的表型/内型亚组并预测AD结果 是必要的。作为我们U19哮喘和过敏性疾病合作研究中心(AADCRC)资助的一部分 在国家过敏和传染病研究所的帮助下，我们建立了第一个机械性纵向队列 儿童特应性皮炎(AD)、特应性皮炎向哮喘进展机制的研究 儿童(MPAACH)。MPAACH是美国和美国第一个AD儿童早期预期队列 包括对皮肤、肠道、呼吸道和外周血液的广泛评估，以及多参数的使用 确定阿尔茨海默病表型和内型亚群的方法。到目前为止，我们已经招收了537名儿童。这个 MPAACH队列的目标是定义AD表型和内型，剖析 有助于AD进展为其他过敏性疾病(食物过敏、过敏性鼻炎、哮喘)，以及 描述免疫、皮肤、生物群、遗传/表观遗传/基因组、生理和环境因素 促进AD儿童过敏性合并症的发展。为了实现机械性研究，广泛的 生物素采集自皮损和非皮损皮肤。我们有20年的经验和专业知识 在进行大型队列研究方面具有得天独厚的优势，能够为ADRN和SunBeam做出贡献 目前的队列和临床研究基础设施，以及我们经验丰富和多样化的大型员工，他们是 招聘、监管事务、进行访问、收集和加工生物检疫的专家，以及 执行和报告研究。基于我们来自MPAACH的强有力的初步数据，我们建议3 CRC特定的研究项目解决了我们的主要假设，即视觉正常的皮肤可能有皮肤 屏障功能障碍变得明显(皮损)或仍处于亚临床状态(无损害)，但在这两种情况下 皮肤屏障功能障碍加上皮肤微生物组的失调会触发警报，从而启动一种 促进包括食物过敏在内的过敏性疾病的后续发展的免疫级联反应， 哮喘和过敏性鼻炎。

PROJECT SUMMARY Atopic dermatitis (AD) is a chronic, inflammatory skin disorder that affects up to 20% of children worldwide. AD has been highlighted as the first step in the “atopic march”, whereby AD typically predates the development of other allergic disorders. Atopic sensitization and food allergy have been reported to be precursors of AD progression to respiratory allergy, however recent data indicate that the mechanisms are far more complex. The National Institute of Allergy and Infectious Diseases recently convened a workshop titled ``Atopic dermatitis and the atopic march: mechanisms and interventions''6 and they concluded that only about 3% of children follow what has been conventionally referred to as the atopic march. They stated that a new prospective cohort study that uses multiparameter approaches to define phenotypic/endotypic subgroups of AD and to predict AD outcomes is needed. As part of our U19 Asthma and Allergic Diseases Cooperative Research Center (AADCRC) funded by the National Institute of Allergy and Infectious Diseases, we have built the first mechanistic longitudinal cohort study of pediatric atopic dermatitis (AD), the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children (MPAACH). MPAACH is the first early life prospective cohort of children with AD in the US and incorporates extensive evaluations of skin, gut, airway and peripheral blood, as well as the use of multiparameter approaches to define phenotypic and endotypic subgroups of AD. Thus far, we have enrolled 537 children. The goals of the MPAACH cohort are to define AD phenotypes and endotypes, dissect the mechanisms that contribute to the progression of AD to other allergic disorders (food allergy, allergic rhinitis, asthma), and delineate the immunologic, skin, biome, genetic/epigenetic/genomic, physiologic, and environmental factors that promote the development of allergic comorbidities in children with AD. To enable mechanistic studies, extensive biospecimens are collected from lesional and non-lesional skin. We have 20 years of experience and expertise in conducting large cohort studies and are uniquely positioned to contribute to ADRN and SUNBEAM due to our current cohorts and clinical research infrastructure, as well as our experienced and diverse large staff, who are experts in recruitment, regulatory affairs, conducting visits, collection and processing of biospecimens, and execution and reporting of studies. Based on our strong preliminary data from MPAACH, we are proposing 3 CRC-specific research projects to address our overarching hypothesis is that visually normal skin may have skin barrier dysfunction that becomes clinically evident (lesional) or remains subclinical (no lesions), but in both cases the skin barrier dysfunction coupled with dysbiosis of skin microbiome triggers alarmins, which initiates an immunologic cascade that promotes the subsequent development of allergic disease including food allergy, asthma and allergic rhinitis.