Epidermal injury and TSLP

这个AADCRC项目的一个主要目标是确定上皮细胞屏障在 研究哮喘和过敏性疾病的发病机制，并开发新的预防策略。在这方面，这一点 该项目旨在研究阻止特应性皮炎进展为哮喘的方法(通常 称为特应性进行曲)。有严重特应性皮炎(AD)病史的患者表现出8至10倍的 患哮喘的几率更高。我们最近的观察表明，在小鼠身上，表皮来源的 胸腺间质淋巴生成素(TSLP)由AD皮肤分泌。此外，循环中的TSLP水平 足以使没有任何AD样病理的动物的肺部对吸入过敏原敏感， 先前存在的炎症，或以前接触过过敏原。在一项针对婴儿的初步研究中，我们发现了一种 血清TSLP与空气变应原的相关性基于对老鼠和人类的这些观察，我们 假设特应性进行曲的机制如下。(1)儿童早期的表皮缺陷/损伤 通过一种未知的机制启动角质形成细胞中TSLP的产生；(2)角质形成细胞 将TSLP分泌到血清中。(3)随后，循环中的TSLP通过促进Th2免疫应答 树突状细胞和T细胞对抗无害的过敏原(吸入或皮下注射)；和(4) 过度适应性Th2反应导致对空气变应原的超敏反应和随之而来的过敏 哮喘。我们进一步假设，在模型生物体中干扰其中一些事件将导致 阻断人类过敏性疾病和哮喘发展的策略。为了实现这一目标，我们 建议(I)检查表皮分化/屏障形成缺陷(内在因素)以及 过敏原或病原体(外在因素(S))推动TSLP过度表达；(Ii)在B和C核心的帮助下 在体外和患者体内，人类皮肤和肺细胞如何调节TSLP的分泌。接下来，(Iii)我们将询问是否 我们可以用小分子佐剂来钝化血清中TSLP的作用，这些佐剂能够操纵 免疫反应和(IV)分析皮肤微生物群对皮肤维护的贡献 屏障、TSLP表达和呼吸道高敏感性。最后，(V)我们将确认TSLP是以下项目的风险因素 出生队列中的哮喘(URECA)，并与项目1合作，比较其在呼吸道合胞病毒毛细支气管炎中的作用 早期生活中的队列(Rbel)。这些目标的实现将开辟新的治疗方法来预防 阿尔茨海默病患者的哮喘发生。

A major goal of the this AADCRC program is to define the role of the epithelial cell barrier in the pathogenesis of asthma and allergic disease and develop new preventative strategies. In that context, this project aims to investigate means by which to block progression from atopic dermatitis to asthma (often referred to as the atopic march). Patients with a history of severe atopic dermatitis (AD) exhibit a 8-to-10-fold greater incidence of developing asthma. Our recent observations demonstrated that in mice, epidermal-derived thymic stromal lymphopoietin (TSLP) was secreted by AD skin. Moreover, circulating levels of TSLP were sufficient to sensitize the lung airways to inhaled allergens in animals lacking any AD-like pathology, preexisting inflammation, or previous exposure to the allergen. In a pilot study in infants we uncovered a correlation between serum TSLP and aeroallergens. Based on these observations in mice and humans, we hypothesize the following mechanism for the atopic march. (1) Epidermal defect/injury during early childhood is sensed by an unknown mechanism that initiates production of TSLP in keratinocytes; (2) keratinocytes secrete TSLP into the serum. (3) Subsequently, circulating TSLP facilitates Th2 immune responses by dendritic cells and T-cells towards innocuous allergens (inhaled or introduced epicutaneously); and (4) this exaggerated adaptive Th2 response results in hypersensitivity to aeroallergens and consequent allergic asthma. We further hypothesize that interrupting some of these events in a model organism will lead to strategies for blocking the development of allergic disease and asthma in humans. To achieve this goal, we propose the to (I) examine how epidermal differentiation/barrier formation defects (intrinsic factors) as well as allergen or pathogens (extrinsic factor(s)) drive TSLP overexpression; (II) with the help of Cores B and C ask how TSLP secretion is regulated by human skin and lung cells in vitro and in patients. Next, (III) we will ask if we can blunt the effects of TSLP in the serum with small molecule adjuvants capable of manipulating the immune responses and (IV) analyze the contribution of the skin microbiome to the maintenance of skin barrier, TSLP expression, and airway hyper sensitivity. Finally, (V) we will confirm TSLP as a risk factor for asthma in a birth cohort (URECA) and, in collaboration with project1, compare its role in an RSV bronchiolitis in early life cohort (RBEL). Achievement of these aims will open up novel therapeutic approach to prevent asthma development in AD patients.