It’s 2024—we know that cigarettes are bad for you. But scientists are still uncovering new and troubling ways that smoking changes you from the inside out. Today in Nature, a new study from the Institut Pasteur in Paris reports that smoking has a lingering effect on the immune system that persists long after taking your last drag.
The health of your immune system is defined by how well it responds to things. Like Goldilocks, the body prefers an immune response that’s not too big or too small, but just right: enough inflammation and antibodies to heal wounds and fight infections, but not so much that the body starts to attack itself.
But not all immune systems are created equal—there’s a lot of variability in how different people respond to the same microbes, and we still have a relatively limited understanding of where these differences stem from. “It’s a constant question,” says study author Darragh Duffy, who leads the translational immunology unit at the Institut Pasteur. “It’s really hard to disentangle cause and effect.”
Duffy’s research group at the Institut Pasteur is devoted to studying how factors like age, genetics, and the environment explain person-to-person variability in immune responses. As part of a broader ongoing study of the links between genetics and the environment, Duffy and his team at the institute’s Milieu Intérieur Consortium studied 500 French men and 500 French women, all of whom donated blood and answered 44 pages of questions about their demographics and lifestyle.
By stimulating blood samples from each person with different microbial triggers, the team was able to watch the immune response unfold. They measured levels of immune-signaling proteins called cytokines generated by each stimulation, which approximate how long and strong an immune response will be. Of the 136 environmental factors Duffy’s team looked into, 11 were associated with some degree of cytokine release—a sign that they altered the body’s response to infection.
Body mass index (BMI) and whether someone had been infected with cytomegalovirus (CMV, a very common and usually asymptomatic virus) were two major influences on the immune response. So was being a cigarette-smoker; the blood of smokers showed an unusually high inflammatory response to bacteria.
This boost in inflammation faded in ex-smokers—but other smoking-induced changes to the immune response persisted years after people quit. Some of the stimulants used in this experiment were chosen to target the adaptive immune response, where specialized cells and antibodies attack intruders and remember them. Some of these parts of the adaptive immune response exhibited long-lasting changes. For example, when triggered, blood samples from smokers (current and former) released more signaling proteins called interleukins than the blood of nonsmokers—a warning sign that their white blood cells were kicking into overdrive.
Cigarette smoke is a known health stressor, but the study of how it specifically impacts the immune system is relatively new, says John Tsang, a professor of systems immunology at Yale University. Yet the level of sway that smoking seems to have on the immune response roughly parallels that of age, sex, or genetics.
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.”
