Public health messages have told us for decades that if you smoke, you should quit. And if you don’t smoke, don’t start. But a new study suggests smoking may be even worse than we thought.
The study, published Wednesday in Nature, underscores the importance of never lighting up that first cigarette, based on its conclusion that smoking has much longer harmful effects on immune responses than previously understood.
People who quit smoking soon regained normal function of their immune system’s power to mount fast and general innate responses to bacteria or viruses. But researchers also found that slower, more targeted adaptive T cell defenses remembered from past pathogens did not come back so soon after that last cigarette.
“We could see that the effect of active smoking on inflammatory responses to bacterial stimulation were lost when individuals quit smoking,” senior study author Darragh Duffy of the Institut Pasteur said about the innate response on a call with reporters. “In contrast, the effect on the T cell response was maintained for many years after the individuals quit smoking.”
These results come from the Milieu Intérieur project, a long-term study of healthy people in France exploring the impact of environmental factors on immune responses. For this study, 1,000 participants answered questionnaires about 136 diet, lifestyle, demographic, and socioeconomic factors. They also gave blood samples for laboratory tests in which the scientists stimulated production of 13 cytokines, molecules involved in the body’s immune defense, in response to 12 proteins active in microbial and viral infections.
Three factors stood out as important in how immune responses varied: smoking, body mass index, and infection with cytomegalovirus (a member of the herpes family).
People who smoked had increased inflammatory responses, but those higher levels were transient, dropping after smoking cessation. But the effects on the adaptive response persisted for many years after quitting, changing the levels of cytokines released after infection or other immune challenges.
“We all know that smokers are predisposed to certain infections. This goes beyond that,” William Schaffner, a clinician, epidemiologist, and professor of infectious diseases at Vanderbilt University Medical Center, told STAT. He was not involved in the study, which he called “revelatory.”
“We have attributed that continuing risk to structural damage to the lungs,” he said. “That may be true, but here we have an additional reason that people are likely after a period of smoking to be at increased risk, namely their adaptive immune response.”
To explain their results, the Institut Pasteur researchers traced smoking to epigenetic changes, in which a process called methylation modifies DNA sequences in the nucleus, changing whether certain genes are activated or deactivated. In the study, smoking lowered DNA methylation at specific sites involved in signaling processes and metabolism, which had an impact on those cytokines and how they responded to immune challenges.
“This shows an example of how environmental factors can have long-term consequences through epigenetic modifications that may affect expression of specific genes on gene networks, only to alter the immune responses of exposed individuals,” study lead author Violaine Saint-André said on the press call. “It’s about the same level of the effect of age or sex or genetics on some of the disease risks. So it’s considerable.”
The researchers’ next step will be to follow this cohort of people further, to see how people who were healthy at the start of the current study have fared during the Covid-19 pandemic.
Schaffner said these laboratory findings fit with clinical observations, but confirming them would be a natural next step. “We know that they have an impaired response, at least physically,” he said of people who smoke. “Now we think their immune systems are somewhat impaired also. And so giving them as much protection as we can through vaccination becomes even more important.”
Duffy repeated the don’t-smoke message.
“We know smoking is bad in multiple ways. We’ve added a new layer of understanding of how it can have negative health consequences,” he said. “It’s never a good time to start smoking. But if you are a smoker, the best time to stop is now.”