Reviews and feature article
Environmental effects on immune responses in patients with atopy and asthma

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Despite attempts and some successes to improve air quality over the decades, current US national trends suggest that exposure to outdoor and indoor air pollution remains a significant risk factor for both the development of asthma and the triggering of asthma symptoms. Emerging science also suggests that environmental exposures during the prenatal period and early childhood years increase the risk of asthma. Multiple mechanisms mediate this risk because a wide range of deleterious air pollutants contribute to the pathogenesis of asthma across a variety of complex asthma phenotypes. In this review we will consider the role of altered innate and adaptive immune responses, gene-environment interactions, epigenetic regulation, and possibly gene-environment-epigene interactions. Gaining a greater understanding of the mechanisms that underlie the effect of exposure to air pollution on asthma, allergies, and other airway diseases can identify targets for therapy. Such interventions will include pollutant source reduction among those most exposed and most vulnerable and novel pharmaceutical strategies to reduce asthma morbidity.

Section snippets

Effect of time windows of susceptibility

Murine and human birth cohort studies suggest that the prenatal period is a time when the effects of ambient air pollution are heightened.7, 8 Studies from the Columbia Center for Children's Environmental Health (CCCEH) showed that prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) in association with exposure to secondhand smoke9, 10 or higher cockroach allergen levels11 was associated with asthma-related symptoms in children and cockroach allergic sensitization in urban children,

Effect of modifying factors

Susceptibility to the hazards of exposure to air pollution and its molecular and clinical consequences can be modified by the presence of atopy, stress, and obesity. Modification by atopy was well described in the Northeast Chinese Children's Health Study of more than 30,000 Chinese children aged 3 to 12 years selected in 2009, which examined associations by using multipollutant (PM10, sulfur dioxide, NO2, O3, and carbon monoxide) models.16 In contrast, in the New York City CCCEH birth cohort,

Update on pollutant effects on immune mechanisms

How do pollutants affect disease? Epidemiologic findings associating phenotypes such as atopy and obesity with greater susceptibility provide mechanistic clues. Also evident is that multiple mechanisms are involved, as would be expected given the range of deleterious air pollutants and complex asthma phenotypes. To date, the best supportive evidence implicates both heightened innate and adaptive immune responses, as described below.

Gene-environment interactions

Another emerging area of investigation into the mechanisms of air pollution exposure in asthmatic patients is in the identification of gene-environment interactions. Much of this work has been conducted in studies of oxidative stress genes, such as the GST genes, as well as genes associated with TLRs. In the Taiwan Children's Health Study, which used data derived from more than 4000 children and measures collected from the Taiwan Environmental Protection Agency's air-monitoring stations,

Epigenetic mechanisms

Newer mechanistic lines of investigation focus on epigenetic regulation, gene-environment-epigene interactions, and identification of asthma genes the imprinting of which might be disrupted by environmental exposures. Several air pollutants, such as diesel exhaust, PM, SO4, and PAHs, have been shown to induce epigenetic changes in asthma candidate genes. For example, DEP exposure combined with the allergen Aspergillus fumigatus induced DNA methylation changes in several CpG sites of the IFN-γ

Interventions

Because much of the pathobiology of pollutant-induced asthma is due to inflammation, it is also logical that standard anti-inflammatory agents would be useful in preventing acute exacerbations. Inhaled steroid use has been shown to decrease both neutrophilic and eosinophilic inflammation after experimental O3 challenge.79, 80 Epidemiologic studies indicate that pollutant-induced asthma exacerbation is less frequent in asthmatic patients using inhaled corticosteroids than in those not using

Conclusion

Air pollution remains a significant cause for exacerbation of allergic airway diseases, and there is increasing evidence that pollutants can modulate the incidence of disease as well. Pollutants have been shown to have a number of specific proinflammatory actions (summarized in Table I).∗ Interventions need to be tested in large clinical

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    Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, and William T. Shearer, MD, PhD

    Supported by National Institutes of Health grants 2R01ES13163-06A1 (to R.L.M.), RO1 ES020926 (to R.L.M.), and R01 ES023349 (to D.B.P.).

    Disclosure of potential conflict of interest: R. L. Miller has received research support from the National Institutes of Health and the Environmental Protection Agency. D. B. Peden declares that he has no relevant conflicts of interest.

    Terms in boldface and italics are defined in the glossary on page 1002.

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