© 2008 American Thoracic Society
Epigenetic Studies Should Focus on Specific Cell TypesTo the Editor:We read with interest the pulmonary perspective by Drs. Miller and Ho, in which the authors called for future studies into the role of epigenetics in environmentally induced asthma (1). The authors provided an overview of this fast-paced field and included a useful list of unanswered questions, but we think one additional topic is worth further emphasis. We suggest that future studies should attempt to identify the lung cell types directly affected at the epigenetic level by environmental exposures. The identification of direct effects, as opposed to their indirect consequences, should enhance our understanding of how environmental exposures contribute to asthma pathophysiology. Studies of specific cell types should take into account their anatomic location and residence times in the lung. An epigenetic alteration that occurs in a granulocyte traversing the pulmonary vasculature will have less long-term impact on disease outcome than one that occurs in a mesenchymal stem cell. Although studies of primary lung cells are technically challenging, advances in cell isolation and imaging techniques, together with newer quantitative assays of chromatin structure, should enhance their feasibility in the coming years. The case of allergen-specific Th2 immune responses provides an illustrative example. As reviewed by Miller and Ho, T-cell activation and differentiation are accompanied by chromatin remodeling, which includes changes in histone structure and DNA methylation surrounding the IL-4 gene (2, 3). T-cell activation and differentiation occur via signals provided by dendritic cells (DCs) or other structural cells present in the local microenvironment (4). DCs have evolved to sense and rapidly respond to diverse environmental cues, and cannot only activate naive T cells in lung draining lymph nodes, but also can reactivate effector T cells within the lung (5). Because they are richly interdigitated throughout the lung epithelium, DCs are likely to be direct targets of inhaled particles or allergens and could thus indirectly imprint an epigenetic tag in responding T cells. For this reason, we proposed that the ability to induce chromatin remodeling at the IL-4 gene in responding T cells should be considered a defining feature of "pro-Th2" DCs (6). Although DCs are generally considered to be short-lived cells that do not possess long-term memory, our understanding of DC activation and persistence in asthma is still limited. Future studies determining the mechanisms by which environmental exposures directly induce chromatin remodeling in specific lung cell types in asthma should be insightful.
University of Rochester Medical Center FOOTNOTES Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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