Mechanisms of allergy and clinical immunology
Ambient air pollution impairs regulatory T-cell function in asthma

https://doi.org/10.1016/j.jaci.2010.08.008Get rights and content

Background

Asthma is the most frequent chronic disease in children, and children are at high risk for adverse health consequences associated with ambient air pollution (AAP) exposure. Regulatory T (Treg) cells are suppressors of immune responses involved in asthma pathogenesis. Treg-cell impairment is associated with increased DNA methylation of Forkhead box transcription factor 3 (Foxp3), a key transcription factor in Treg-cell activity. Because AAP exposure can induce epigenetic changes, we hypothesized that Treg-cell function would be impaired by AAP, allowing amplification of an inflammatory response.

Objectives

To assess whether exposure to AAP led to hypermethylation of the Foxp3 gene, causing impaired Treg-cell suppression and worsened asthma symptom scores.

Methods

Children with and without asthma from Fresno, Calif (high pollution, Fresno Asthma Group [FA], n = 71, and Fresno Non Asthmatic Group, n = 30, respectively), and from Stanford, Calif (low pollution, Stanford Asthma Group, n = 40, and Stanford Non Asthmatic Group, n = 40), were enrolled in a cross-sectional study. Peripheral blood Treg cells were used in functional and epigenetic studies. Asthma outcomes were assessed by Global Initiative in Asthma score.

Results

Fresno Asthma Group Treg-cell suppression was impaired and FA Treg-cell chemotaxis were reduced compared with other groups (P ≤ .05). Treg-cell dysfunction was associated with more pronounced decreases in asthma Global Initiative in Asthma score in FA versus the Stanford Asthma Group. Foxp3 was decreased in FA compared with the Fresno Non Asthmatic Group (P ≤ .05). FA also contained significantly higher levels of methylation at the Foxp3 locus (P ≤ .05).

Conclusion

Increased exposure to AAP is associated with hypermethylation of the Foxp3 locus, impairing Treg-cell function and increasing asthma morbidity. AAP could play a role in mediating epigenetic changes in Treg cells, which may worsen asthma by an immune mechanism.

Section snippets

Methods

All methods and procedures were approved by the University of California, Berkeley, and Stanford University Committees for the Protection of Human Subjects.

Subjects

Ambient air pollution data confirmed contrasts in pollution concentrations between Stanford and Fresno, CA (Table I). By design, all 4 groups (FA, SA, FNA, SNA) were similar in age distribution (Table II). The FNA group had a greater percentage of reported smokers at home (17%) than FA, SA, or SNA (all 10%). Overall, GINA scores were lower in the SA versus FA group, with 77.5% of SA and 32.4% of FA subjects having a score of 1 (Table II). Further demographics and health outcome data for each

Discussion

The results from this cross-sectional study provide support for our central hypothesis that ambient air pollution exposure may worsen asthma symptoms, at least in part, by epigenetic decrease of Foxp3 expression and impaired Treg-cell–mediated suppression of TH2 responses. Compared with children who live in a relatively low air pollution environment (Palo Alto, Calif), children who live in an environment with high levels of ambient air pollutants (Fresno/Clovis, Calif) have impaired function of

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    Supported by the McCormick Fund at Stanford, the American Academy of Allergy, Asthma, and Immunology Junior Faculty Fund, the Westly Foundation, the Global Health Research Foundation, NIEHS (R01 HL081521), CDC cooperative agreement 5U19EH000097-04, the California Air Resources Board (contract nos. 99-322, 99-323, and 01-346), the US EPA (PO no. 2A-0540-NASX), the Austin Memorial Fund, and the Mickey Leland National Urban Air Toxics Research Center (RFA 2005-01).

    Disclosure of potential conflict of interest: S. K. Hammond has received research support from the National Institutes of Health—National Heart, Lung, and Blood Institute and National Institute of Environmental Health Sciences, the National Institute for Occupational Safety and Health, the Flight Attendant Medical Research Institute, and the Environmental Protection Agency and has provided legal consultation or expert witness testimony on the topic of exposure to chemicals in semiconductor manufacturing. J. Balmes is a member of the California Air Resources Board and has received research support from the National Institutes of Health, Centers for Disease Control and Prevention, and the California Air Resource Board. The rest of the authors have declared that they have no conflict of interest.

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