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.

Public Health Relevance

A preexisting skin condition in children is a strong risk factor for asthma in adulthood. This proposal aims directly at the mechanism linking hose allergic conditions issue by defining the elements controlling expression, secretion and function of TSLP, a secreted cytokine we show can explain the atopic march. At minimum, we expect to provide strategies that will help prevent atopic march in at-risk AD patients. In the best case scenario, we may uncover novel pathways to therapeutic intervention.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-PA-I (M1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Saint Louis
United States
Zip Code
Olias, Philipp; Etheridge, Ronald D; Zhang, Yong et al. (2016) Toxoplasma Effector Recruits the Mi-2/NuRD Complex to Repress STAT1 Transcription and Block IFN-γ-Dependent Gene Expression. Cell Host Microbe 20:72-82
Lu, Qun; Yokoyama, Christine C; Williams, Jesse W et al. (2016) Homeostatic Control of Innate Lung Inflammation by Vici Syndrome Gene Epg5 and Additional Autophagy Genes Promotes Influenza Pathogenesis. Cell Host Microbe 19:102-13
Dickinson, John D; Alevy, Yael; Malvin, Nicole P et al. (2016) IL13 activates autophagy to regulate secretion in airway epithelial cells. Autophagy 12:397-409
Kitcharoensakkul, Maleewan; Bacharier, Leonard B; Yin-Declue, Huiqing et al. (2016) Temporal biological variability in dendritic cells and regulatory T cells in peripheral blood of healthy adults. J Immunol Methods 431:63-5
Xu, Amy Z; Tripathi, Shivani V; Kau, Andrew L et al. (2016) Immune dysregulation underlies a subset of patients with chronic idiopathic pruritus. J Am Acad Dermatol 74:1017-20
Zhang, Yong; Mao, Dailing; Roswit, William T et al. (2015) PARP9-DTX3L ubiquitin ligase targets host histone H2BJ and viral 3C protease to enhance interferon signaling and control viral infection. Nat Immunol 16:1215-27
Morales, David J; Monte, Kristen; Sun, Lulu et al. (2015) Novel mode of ISG15-mediated protection against influenza A virus and Sendai virus in mice. J Virol 89:337-49
Wu, Kangyun; Byers, Derek E; Jin, Xiaohua et al. (2015) TREM-2 promotes macrophage survival and lung disease after respiratory viral infection. J Exp Med 212:681-97
Barrow, Alexander D; Palarasah, Yaseelan; Bugatti, Mattia et al. (2015) OSCAR is a receptor for surfactant protein D that activates TNF-α release from human CCR2+ inflammatory monocytes. J Immunol 194:3317-26
Sheshadri, Ajay; Rodriguez, Alfonso; Chen, Ryan et al. (2015) Effect of Reducing Field of View on Multidetector Quantitative Computed Tomography Parameters of Airway Wall Thickness in Asthma. J Comput Assist Tomogr 39:584-90

Showing the most recent 10 out of 64 publications