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

CMV antibody levels were higher among women, individuals of lower socioeconomic status, and marginalized racial and ethnic groups.

• CMV was identified as a key driver of immune senescence and a major contributor to variation in immune composition.
• CMV seroprevalence and antibody titers showed consistent associations with multiple sociodemographic dimensions across cohorts.
• These patterns suggest that sociodemographic disparities in CMV exposure may partially explain observed immune profile differences across demographic groups.

Male sex showed similar patterns of association with immune profiles as aging, whereas race did not.

• The study evaluated associations between 20 immune cell subtypes, 3 informative cell ratios, and sociodemographic variables.
• The parallel between male sex and aging in immune profiles was identified as a consistent finding across the 3 cohorts.
• Race and ethnicity showed distinct patterns of association with immune cell proportions compared to the age-sex relationship.
• The meta-analysis design across diverse cohorts allowed for more robust characterization of these differential patterns than prior single-cohort studies.

Consistent and significant associations were found across all sociodemographic dimensions examined, including age, sex, self-identified race and ethnicity (SIRE), and socioeconomic status.

• The meta-analysis included 3 large, diverse cohort studies to address limitations of prior studies including small sample sizes and cross-cohort population-specific differences.
• Twenty immune cell subtypes and 3 informative cell ratios were evaluated.
• Prior studies had yielded mixed results likely due to small sample sizes and cross-cohort population-specific differences.
• Associations were described as 'consistent and significant' across all sociodemographic dimensions examined.

Shifts in immune cell proportions occur naturally across the lifespan and vary with demographic factors, which may complicate their interpretation as diagnostic biomarkers and therapeutic targets.

• Immune cell proportion shifts underlie disease progression and immunotherapy response, positioning them as promising diagnostic biomarkers and therapeutic targets.
• Natural demographic variation in immune cell proportions poses a challenge to clinical utility of these biomarkers.
• The study was motivated by the need to disentangle disease-related immune shifts from demographic baseline variation.
• Age and sex were identified as key demographic factors affecting immune cell proportions.

The 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.

• The authors call for consideration of age, sex, race/ethnicity, and socioeconomic status in immunology study design.
• Population-specific biases are identified as a risk when sociodemographic factors are not adequately accounted for.
• The use of a diverse, multi-cohort meta-analysis approach was presented as a model for reducing these biases.
• Generalizability of immunological findings is highlighted as a primary concern motivating the study.