Asthma is the most frequent chronic disease in children, who are at high risk for adverse health consequences associated with ambient air pollution exposure. Recent studies have shown that the links between air pollution and asthma are complex and that air pollution may play a significant role in the etiology of asthma. The overall goal of this project is to further understand the link between exposure indicators and asthma outcomes by studying immune system changes in subjects exposed to elevated levels of polycyclic aromatic hydrocarbons (PAH). This application addresses an important gap in asthma immunopathogenesis by analyzing regulatory T cells (Treg), a cell type that inhibits effector T-cell responses, in asthmatic and non- asthmatic children concurrently with quantifying their in vivo exposure to ambient air pollution. This project's central hypothesis is that Treg function is impaired by PAH, which allows amplification of the T helper 2 (Th2) mediated inflammatory response and the promotion of asthma.
The specific aims are 1) to determine Treg subset function, including both suppressive function and chemotactic function to human bronchial epithelial cells, 2) to define Treg memory and naive phenotypes, which we predict will be associated with acute and chronic PAH exposure, respectively, and 3) to measure epigenetic modifications in the Foxp3 gene in purified Treg subsets in each of subject. We will then compare the resultant data from each specific aim to individual exposure estimates and health outcomes in the asthmatic and non-asthmatic children exposed to high levels vs. low levels of PAH. This work will build on a cohort that we have been studying to determine the in vivo effects of high levels of ambient air pollution in children, as part of P20 Children's Environmental Health Center/Fresno Asthmatic Children's Environment Study (FACES). FACES is a cohort in which multiple detailed environmental exposures and health outcomes have been measured over the past 9 years. Repeated measurements over time of individual estimate exposure levels, blood sample results, and health outcome data from each subject will be compared. Together, these studies will: i) define the extent to which Treg dysfunction in asthma is due to PAH, ii) test whether PAH can lead to subsequent Th2-mediated inflammation in asthma, and iii) determine if PAHs are associated with epigenetic changes in Foxp3, a key transcription factor involved in Treg function and development. If the aims of the study are met, we expect that immunological indicators linked to environmental exposure and health outcomes will elucidate the role and mechanism of air pollution in asthma. This link is theoretically understood, circumstantially clear but heretofore not yet proven. The results are expected to have real-time, public health relevance to environmental policy and risk management because when it is completed, the study will have helped to develop tools to assess the effects of air pollution on immunologic mechanisms that underlie asthma and to determine possible targets for new asthma therapy.

Public Health Relevance

Asthma is the leading serious chronic illness of children in the U.S. for which an estimated 6.8 million children under age 18 currently have asthma. Our proposed research findings could provide biologic plausibility to the association between the increase in asthma and ambient air pollution exposure.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
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Gray, Kimberly A
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Stanford University
Schools of Medicine
United States
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Padula, Amy M; Balmes, John R; Eisen, Ellen A et al. (2015) Ambient polycyclic aromatic hydrocarbons and pulmonary function in children. J Expo Sci Environ Epidemiol 25:295-302
Hew, K M; Walker, A I; Kohli, A et al. (2015) Childhood exposure to ambient polycyclic aromatic hydrocarbons is linked to epigenetic modifications and impaired systemic immunity in T cells. Clin Exp Allergy 45:238-48
Miller, Rachel L; Peden, David B (2014) Environmental effects on immune responses in patients with atopy and asthma. J Allergy Clin Immunol 134:1001-8
Klingbeil, E C; Hew, K M; Nygaard, U C et al. (2014) Polycyclic aromatic hydrocarbons, tobacco smoke, and epigenetic remodeling in asthma. Immunol Res 58:369-73
de Planell-Saguer, Mariangels; Lovinsky-Desir, Stephanie; Miller, Rachel L (2014) Epigenetic regulation: the interface between prenatal and early-life exposure and asthma susceptibility. Environ Mol Mutagen 55:231-43