Atopic dermatitis (AD) is a chronic, relapsing skin disease that affects 10-20% of children and 1-3% of adults and is estimated to cost over $3 billion a year in direct medical costs in the US alone. AD is associated with the development of T helper type 2 (TH2) cell responses characterized by increased expression of the cytokines interleukin (IL)-4, IL-5 and IL-13. Further, changes in the composition of beneficial commensal bacterial communities have been associated with increased susceptibility to TH2 cytokine-associated inflammation, suggesting that microbial signals could have a significant influence on diseases like AD. Despite our increased understanding of the factors that promote allergic inflammation, the cellular and molecular mechanisms that regulate the development of AD remain poorly defined. In recent studies, I identified a previously unrecognized population of group 2 innate lymphoid cells (ILC2s) that are present in healthy human skin and are enriched in the lesional skin of AD patients. ILC2s lack markers for a variety of well-described cell types such as T cells, B cells, dendritic cells, macrophages, natural killer cells and granulocytes, and therefore are referred to as lineage-negative (Lin-). However, they do express markers such as CD25 and IL-33R and can produce TH2 cell-associated cytokines following stimulation with the epithelial cell-derived cytokines thymic stromal lymphopoietin (TSLP), IL-25 or IL-33. Employing a murine model of AD, I identified that TSLP is required for the elicitation of ILC2s in the skin and that these TSLP-elicited ILC2s are essential for the development of AD-like disease in mice lacking T and B cells. In addition, when TSLP-elicited ILC2s were transferred into na?ve wild-type mice, AD-like disease and adaptive TH2 cell responses ensued. These studies provoked the hypothesis that TSLP-elicited skin-associated ILC2s are necessary for the progression of AD-like disease and that they may directly influence TH2 cell responses in lymphocyte-sufficient hosts. This hypothesis forms the basis of Aim 1, which will address how skin-associated ILC2s influence AD-like disease and TH2 cell responses in mice and how skin-resident ILC2s in humans may influence AD in patients. In new preliminary studies, I also found that depletion or deliberate alteration of commensal bacteria by treatment with broad- spectrum antibiotics (ABX) resulted in increased TSLP expression and elevated numbers of ILC2s in the skin- draining lymph nodes, provoking the hypothesis that commensal bacteria may influence TSLP-elicited ILC2 responses and susceptibility to AD. This hypothesis forms the basis of Aim 2, which will address how alterations in commensal bacteria may regulate ILC2 responses and murine AD-like inflammation.
These aims will be addressed employing the intellectual and scientific resources available to me in the Artis lab, novel TSLP-related reagents and the University of Pennsylvania Gnotobiotic Mouse Facility. As a board-certified dermatologist and a student in the Masters in Translational Research program at UPenn, I will directly accomplish the translational aspects of this project employing my clinical and translational skill sets.

Public Health Relevance

Atopic dermatitis (AD) is a common skin disease that affects both children and adults and has become a significant public health concern and economic burden in the US. Populations of innate immune cells called innate lymphoid cells (ILCs) and alterations in commensal microbiota have been associated with the development of AD. The proposed studies will investigate how ILCs and signals from commensal microbiota contribute to the disease pathogenesis of AD in order to aid in the identification of new pathways that could be targeted therapeutically to prevent or treat AD.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Clinical Investigator Award (CIA) (K08)
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Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
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Cibotti, Ricardo
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Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
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