IL-13 Atopic Dermatitis and Its Relationship with the Development of Asthma

描述(申请人提供)：特应性皮炎(AD)被认为是一种全身性疾病的皮肤表现，该疾病还会引起哮喘和过敏性鼻炎，即所谓的“特应性进行曲”。AD和其他特应性疾病有重叠的发病机制和遗传基础。此外，AD和哮喘有一些共同的免疫学特征，包括IgE升高、外周和皮损嗜酸性粒细胞增多、Th2细胞因子升高、上皮功能障碍和相似的过敏原触发因素。Th2炎症是哮喘和AD发病机制中的重要组成部分。白介素13是一种主要的Th2细胞因子，被认为与AD的发病有关。然而，AD的确切分子机制仍然不清楚，AD和哮喘之间的关系也不太清楚。我们最近开发了一种外部可调控的过表达转基因模型系统，在该模型中，IL-13在小鼠皮肤中选择性表达。在我们的初步研究中，IL-13在皮肤中的表达导致一种慢性瘙痒性炎症性皮肤病，其许多特征与人类特应性皮炎非常相似。许多促炎细胞因子在皮肤中高度上调，包括IL-17和TSLP。IL-13诱导的慢性皮炎导致全身Th2倾向环境。此外，IL-13诱导的皮炎与肺部炎症增加、粘液化生和对变应原刺激的气道高反应性有关，这表明IL-13诱导的AD易患哮喘表型。从这些研究中，我们假设IL-13在特应性皮炎的发病机制中起重要作用，而IL-13诱导的特应性皮炎导致哮喘的发生。在这一应用中，我们建议：(1)进一步鉴定皮肤特异性的IL-13转基因AD模型，并确定IL-13诱导的AD的下游细胞、分子和免疫学机制；(2)确定IL-13诱导的AD是否导致肺内过敏表型发展的易感性增加，以及从AD到哮喘进展的免疫学机制；以及(3)确定TSLP在IL-13诱导的AD以及肺内对变应原过敏反应发展的敏感性增加中的作用。这些研究将有助于更好地了解IL-13在AD发病机制中的作用及其与哮喘发生发展的关系，以及这些相关疾病的细胞和分子机制。 公共卫生相关叙述：特应性皮炎和哮喘是密切相关的过敏性疾病，具有许多共同的免疫学特征，包括疾病过程中以Th2为主的免疫。我们已经建立了一种特应性皮炎的小鼠模型，其中IL-13靶向于皮肤，这种主要Th2细胞因子的表达导致小鼠特应性皮炎和哮喘样表型。在这个项目中，我们建议利用这个“特应性进行曲”模型来探索特应性皮炎发病的分子、细胞和免疫学机制，以及它与哮喘发生发展的关系。

DESCRIPTION (provided by applicant): Atopic dermatitis (AD) has been proposed as the cutaneous manifestation of a systemic disorder that also gives rise to asthma and allergic rhinitis, the so-called "atopic march". AD and other atopic disorders have an overlapping pathogenesis and genetic basis. In addition, AD and asthma share some common immunological features, including elevated IgE, peripheral and lesional eosinophilia, Th2 cytokine elevation, epithelial dysfunction and similar allergenic triggers. Th2 inflammation is an important component in the pathogenesis of both asthma and AD. Interleukin-13, a major Th2 cytokine, is believed to be involved in the pathogenesis of AD. However the precise molecular mechanisms underlying AD still remain elusive and the relationship between AD and asthma is poorly understood. We have recently developed an externally regulatable overexpression transgenic model system in which IL-13 is selectively expressed in the murine skin. In our preliminary studies, expression of IL-13 in the skin causes a chronic pruritic inflammatory skin disease with many characteristics closely resembling those of human atopic dermatitis. Many proinflammatory cytokines are highly upregulated, including IL-17 and TSLP, in the skin. IL-13-induced chronic dermatitis causes a systemic Th2-prone environment. Moreover, IL-13-induced dermatitis is associated with increased pulmonary inflammation, mucus metaplasia and airway hyperresponsiveness to allergen challenges, suggesting that IL-13 induced AD predisposes to an asthma phenotype. From these studies, we hypothesized that IL-13 plays an important role in the pathogenesis of atopic dermatitis and IL-13-induced atopic dermatitis leads to the development of asthma. In this application, we propose to: (1) Further characterize the skin-specific IL-13 transgenic model of AD and define the downstream cellular, molecular, and immunological mechanisms of IL-13-induced AD; (2) Determine if IL-13-induced AD leads to increased susceptibility to the development of allergic phenotype in the lung and the immunological mechanisms that underlie the progression from AD to asthma; and (3) Define the role of TSLP in IL-13 induced AD and in increased susceptibility to the development of allergic response to allergens in the lung. These studies will provide better understanding of the role of IL-13 in the pathogenesis of AD and its relationship with the development of asthma and the cellular and molecular mechanisms underlying these related disorders. PUBLIC HEALTH RELEVANCE Narrative: Atopic dermatitis and asthma are closely related allergic disorders that share many immunological features, including Th2-dominated immunity during the course of the disease. We have developed a mouse model of atopic dermatitis in which IL-13 is targeted to the skin and expression of this major Th2 cytokine causes both atopic dermatitis and asthma-like phenotypes in mice. We propose in this project to utilize this model of "atopic march" to explore the molecular, cellular, and immunological mechanisms that underlie the pathogenesis of atopic dermatitis and its relationship with the development of asthma.