Immune responses are highly variable from one person to another, with this variability strongly impacting clinical outcome. Variable immunity can determine differential risks for infection, for development of autoimmunity, and for response to therapeutic interventions. A better understanding of the causes of such differences has huge potential to improve patient management through precision medicine strategies. Through the Milieu Interieur cohort of 1,000 well defined healthy donors we have characterized and quantified the contribution of age, sex, and host genetics on diverse immune phenotypes. More recently we have extended this approach to identify new environmental determinants of variable cytokine responses. Specifically, we identified how smoking influences both innate and adaptive immune responses. Interestingly the effect on innate responses is quickly lost upon smoking cessation and is associated with specific plasma proteins. In contrast, the effect on adaptive responses is persistent long after individuals stopped smoking and is associated with long-term epigenetic memory. This is supported by association of the smoking effect on cytokine responses with DNA methylation at specific signal transactivators and metabolism regulators. We are also applying our standardized whole blood stimulation approach to different disease settings and integrating an improved understanding of immune variability to biomarker discovery and application in infection and autoimmunity.

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