Rethinking immune studies: population-level immune variations and the path forward.

Abstract

Shifts in immune cell proportions underlie disease progression and immunotherapy response, positioning them as promising diagnostic biomarkers and therapeutic targets. However, these shifts also occur naturally across the lifespan and vary with demographic factors such as age and sex, which may complicate their interpretation and clinical utility. While demographic associations have been explored previously, there have been mixed results likely due to small sample sizes and cross-cohort population-specific differences. To address these limitations, we conducted a meta-analysis across 3 large, diverse cohort studies to evaluate associations between 20 immune cell subtypes, 3 informative cell ratios, and a range of sociodemographic variables such as age, sex, self-identified race and ethnicity (SIRE), and socioeconomic status. We find consistent and significant associations across all sociodemographic dimensions. Cytomegalovirus (CMV)-a key driver of immune senescence-emerged as a major contributor to variation in immune composition and CMV antibody levels were higher among women, individuals of lower socioeconomic status, and marginalized racial and ethnic groups. In addition, male sex showed similar patterns of association with immune profiles as aging, whereas race did not. These findings underscore the need to account for diverse sociodemographic factors in immunology study design and participant recruitment to avoid population-specific biases and ensure broadly generalizable results.