Atopic dermatitis (AD) is a chronic, relapsing skin disease that affects 10-20% of children and 1-3% of adultsand is estimated to cost over $3 billion a year in direct medical costs in the US alone. AD is associated with thedevelopment of T helper type 2 (TH2) cell responses characterized by increased expression of the cytokinesinterleukin (IL)-4, IL-5 and IL-13. Further, changes in the composition of beneficial commensal bacterialcommunities 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 ourincreased understanding of the factors that promote allergic inflammation, the cellular and molecularmechanisms that regulate the development of AD remain poorly defined. In recent studies, I identified apreviously unrecognized population of group 2 innate lymphoid cells (ILC2s) that are present in healthy humanskin and are enriched in the lesional skin of AD patients. ILC2s lack markers for a variety of well-described celltypes such as T cells, B cells, dendritic cells, macrophages, natural killer cells and granulocytes, and thereforeare referred to as lineage-negative (Lin-). However, they do express markers such as CD25 and IL-33R andcan produce TH2 cell-associated cytokines following stimulation with the epithelial cell-derived cytokines thymicstromal lymphopoietin (TSLP), IL-25 or IL-33. Employing a murine model of AD, I identified that TSLP isrequired for the elicitation of ILC2s in the skin and that these TSLP-elicited ILC2s are essential for thedevelopment of AD-like disease in mice lacking T and B cells. In addition, when TSLP-elicited ILC2s weretransferred into na ve wild-type mice, AD-like disease and adaptive TH2 cell responses ensued. These studiesprovoked the hypothesis that TSLP-elicited skin-associated ILC2s are necessary for the progression of AD-likedisease and that they may directly influence TH2 cell responses in lymphocyte-sufficient hosts. This hypothesisforms the basis of Aim 1, which will address how skin-associated ILC2s influence AD-like disease and TH2 cellresponses in mice and how skin-resident ILC2s in humans may influence AD in patients. In new preliminarystudies, 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 ILC2responses and susceptibility to AD. This hypothesis forms the basis of Aim 2, which will address howalterations 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, novelTSLP-related reagents and the University of Pennsylvania Gnotobiotic Mouse Facility. As a board-certifieddermatologist and a student in the Masters in Translational Research program at UPenn, I will directlyaccomplish the translational aspects of this project employing my clinical and translational skill sets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08AR065577-01
Application #
8617382
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Cibotti, Ricardo
Project Start
2014-04-01
Project End
2019-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
Fiscal Year
2014
Total Cost
$128,358
Indirect Cost
$9,508
Name
University of Pennsylvania
Department
Dermatology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Kim, Brian S; Wang, Kelvin; Siracusa, Mark C et al. (2014) Basophils promote innate lymphoid cell responses in inflamed skin. J Immunol 193:3717-25