Once Nadeau understood the role of the methyl groups in gene expression, all the dots began to connect. She believed that air pollution triggered asthma in her Fresno patients by tagging Foxp3 in immature T cells with methyl groups, switching off its expression. This prevents the cells from maturing into those police officer T-regs that hold T helper cells in check. More exposure to pollution, then, would mean more methyl groups.
As it turned out, Foxp3 bore the fewest methyl groups in Palo Alto children without asthma, and more in Palo Alto children with the disease. In Fresno children without asthma — who had grown up with more pollution — the gene had still more methyl groups. Foxp3 bore the most methyl groups in Fresno kids with asthma. “It seemed amazing for just one molecule to be standing out,” Nadeau says.
Nadeau and Tager published their results in the Journal of Allergy and Clinical Immunology in 2010. Meanwhile, researchers at Columbia University, the University of Cincinnati and other institutions began publishing similar findings. But the trend was troubling: Pollution’s imprint wasn’t unique to Fresno. Scientists were seeing the same effects in polluted cities across the country.
Nadeau’s findings revealed that pollution could cause asthma by altering our biology at a fundamental level, changing how our very genes behave. After the 2010 paper was published, she wondered, could secondhand smoke have a similar effect? It also can lead to asthma, and research had shown that children, especially those living in poor communities like Fresno, are especially vulnerable to secondhand smoke. Nadeau wanted to unravel how exposure to it affected methylation and gene expression. Scientists had already found that smoking could cause epigenetic changes. But what were those changes? And how might they trigger asthma?
In a small office in Nadeau’s clinic, Arunima Kohli, an undergraduate in her lab, was sifting through the questionnaire and pollution data that Nadeau and Tager collected. Since the questionnaires asked about participants’ secondhand smoke exposure, Nadeau asked Kohli to include the responses in the analysis of their immune cells. It’s right at our fingertips, Nadeau thought.
Nadeau wanted to examine how air pollution and secondhand smoke — both linked to asthma — spurred epigenetic changes to Foxp3. And if these stressors epigenetically altered Foxp3, they probably affected other genes regulating the allergic pathway, too. Since studies had shown that children in heavily polluted areas of the Central Valley had more infections, and pollution and secondhand smoke contain similar toxic compounds, Nadeau searched for genes that played a major role in fighting infection. Understanding how they worked might help point the way to therapies that treat them. She also sought out genes that controlled the switch for maturation of T helper cells, maintaining just the right balance of T helpers — between Th1 cells that suppress allergic responses and Th2 cells that trigger them.