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.
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.
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