An immense question, of course, but Violaine Saint-André and colleagues at The Milieu Intérieur Consortium have recently focussed on a particularly interesting bit — namely, what makes our immune responses so variable? There are two parts to the response: Innate immune defence — faster and more general — and the adaptive response, slower more targeted and sustained by memory T cells.
Almost anything can affect these responses — diet would be one obvious potential factor. But in Saint-André’s study it turned out that three things were the major causes of variation in immune responses. They pinned these down by measuring the levels of 13 cytokine proteins in the blood of 1,000 healthy individuals 22 hours after they’d been given one of 11 immune system stimulants. There were four categories of stimulant: T cell activators (e.g., anti-CD3/CD28 antibodies), microbes (e.g., E.coli), viruses (e.g., influenza), and specific cytokines (e.g., tumour necrosis factor (TNF)).
And the villains are …
Almost needless to say, smoking first with a significant effect on both types of immune responses (most notably increasing the levels of CXCL5, a ‘chemokine’ that recruits and activates leukocytes, in response to a shot of E.coli). The two other main contributors to variable immune responses are a dormant virus infection (cytomegalovirus) and weight (as measured by BMI — body mass index).
Immune system response to external challenge. (a): Innate and adaptive systems induce cytokine-based defences. (b) and (c): Two different stimulants induce abnormal levels of cytokines (CXCL5, IL-2 and IL-13) in current and ex-smokers. From Luo and Stent, 2024.
Important though smoking status is in shaping the immune response, Saint-André et al. noted that, in addition to latent viral infection and BMI, all the usual culprits contribute (age, sex, genetic variation, epigenetics (DNA methylation)).
Taking the CXCL5 response, it appears that smokers are ‘primed’ to make much larger amounts of this signalling protein than the rest of us in response to a challenge to their immune system. It seems most likely that this is due to epigenetic changes (DNA methylation) caused by chemicals in cigarette smoke. CXCL5 is known to have powerful cancer-promoting effects: it is an attractant for neutrophils, a type of white blood cell that has an essential role in cancer progression.
This study has shown a way of revealing the effects of environmental variables on immune responses as part of a picture that is complex and critical to cancer development. Not for the first time it highlights that what we do to ourselves is at least as important as what we’re born with. When will we learn?
References
Saint-André, V., Charbit, B., Biton, A. et al. Smoking changes adaptive immunity with persistent effects. Nature 626, 827–835 (2024). https://doi.org/10.1038/s41586-023-06968-8
Luo, Y. and Stent, S. 2024. Smoking’s lasting effect on the immune system. Nature. 2024 Feb;626(8000):724-725. doi: 10.1038/d41586-024-00232-3. PMID: 38355995.
Betrayed by Nature: The War on Cancer 