To figure out why and how the effect lasts for years after someone smokes their last cigarette, Duffy’s team turned to their donors’ DNA. Seemingly everything from wildfire smoke to your parents’ trauma has been linked to epigenetic changes—physical manipulations of the DNA molecule that switch genes on or off. Sure enough, the long-term effect of smoking on the immune response also appears to be linked to epigenetics.

Duffy admits that interpreting these effects can get weird. It’s tempting to think of the more reactive immune system seen in smokers as “good”—when you’re injured or sick, short-term inflammation helps your body heal. But an overblown response that lingers once the threat is gone can lead to chronic inflammation or autoimmune disease.

Giving up smoking brings the inflammatory response back to where it would have been without cigarettes, but smoking-related epigenetic changes may be tougher to reverse, suspects Sheena Cruickshank, an immunologist at the University of Manchester. The affected immune cells are long-lived, sticking around in the bloodstream for years. Ex-smokers may have to carry traces of their past cigarettes with them until those cells die.

Of course, smoking behavior doesn’t happen in a vacuum. All 1,000 donors in this study live widely varied lives shaped by a dizzying number of things beyond cigarettes. “We’re exposed to so many different things that it’s difficult to tease them apart,” says Adam Lacy-Hulbert, an immunologist at the Benaroya Research Institute in Seattle, Washington. This study corrected for age and sex, but that certainly doesn’t account for everything. Cruickshank says that, while the effect of any individual environmental factor—smoking included—may be modest, these effects can pile on top of each other and lead to big changes to the immune system.

These results may have important implications for vaccine delivery. We already tailor vaccine recommendations to specific age groups because inflammation is known to increase as we get older (immunologists even have a term for this: “inflammaging”). Lacy-Hulbert wonders whether we ought to consider environmental factors like people’s smoking habits (past and present) when planning the timing or formulation of their vaccinations. “Immune age, like regular old age, just marches on—things get worse and worse over time,” Lacy-Hulbert says. If smoking is associated with roughly the same degree of change to the immune response as aging, he speculates, “You might imagine that smoking could add years to your immunological age.”

Duffy and his colleagues at the Milieu Intérieur project already have multiple follow-up projects underway, gathering data from donors in Africa and Asia as well as from children and adults over 75 years old. They’re also preparing a 10-year follow-up report with 415 of the original 1,000 donors sampled in the Nature study to see how changes to their lifestyle affected their immune response over that decade. Moving forward, Tsang hopes that future studies run specific experiments to test some of these associations in the lab, to dig into how our environment and behavior shapes our immune system.

In the meantime, Cruickshank says, the best way to keep your immune system healthy is to follow the basic advice you’ve probably been told a thousand times: eat a varied, minimally processed diet; move your body; destress; and get plenty of sleep. “In terms of being healthy, smoking is probably the worst thing you can do,” Duffy adds.

While we still don’t know exactly how long-lived the impact of smoking is, or whether it can be reversed, there’s some good news: After quitting, the effect of smoking on the immune response seems to fade with time. “The best time to stop smoking is now,” Duffy says. “It’s always a good time.”


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