Atopic dermatitis: mechanisms of disease progression

项目摘要 特应性皮炎（AD）是一种慢性炎症性皮肤病，影响全世界高达20%的儿童。AD 已经被强调为“特应性进军”的第一步，其中AD通常先于 其他过敏性疾病。特应性过敏和食物过敏是AD的先兆 然而，最近的数据表明，其机制要复杂得多。的 国家过敏和传染病研究所最近召开了一个题为"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指出，一项新的前瞻性队列研究， 使用多参数方法定义AD的表型/内型亚组并预测AD结局 是必要的。作为我们的U19哮喘和过敏性疾病合作研究中心（AADCRC）资助的一部分， 由国家过敏和传染病研究所，我们已经建立了第一个机械纵向队列， 儿童特应性皮炎（AD）的研究，特应性皮炎进展为哮喘的机制， 儿童（MPAACH）。MPAACH是美国首个AD儿童早期前瞻性队列， 包括皮肤、肠道、气道和外周血的广泛评价，以及多参数 方法来定义AD的表型和内型亚组。到目前为止，我们已经招收了537名儿童。的 MPAACH队列的目标是确定AD表型和内型，分析 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、生物群系、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。为了进行机械研究， 从损伤和非损伤皮肤收集生物样本。我们拥有20年的经验和专业知识 在进行大型队列研究，并具有独特的地位，有助于ADRN和SUNBEAM由于我们的 目前的队列和临床研究基础设施，以及我们经验丰富，多样化的大型工作人员，他们是 招募、法规事务、开展访视、收集和处理生物标本方面的专家，以及 研究的执行和报告。根据我们从MPAACH获得的强大的初步数据，我们建议3 CRC的具体研究项目，以解决我们的总体假设是，视觉正常的皮肤可能有皮肤 屏障功能障碍变得临床明显（病变）或保持亚临床（无病变），但在两种情况下 皮肤屏障功能障碍与皮肤微生物组的生态失调相结合触发警报素，其引发 免疫级联反应，促进过敏性疾病包括食物过敏的后续发展， 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.