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.
Bibliographical noteFunding Information:
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 ).
- Ambient air pollution
- immune system
- regulatory T cell