The impact of sex on the immune system explored at the single-cell level

Seyhan Yazar; José Alquicira-Hernández; Kristof Wing; Anne Senabouth; Stacey B. Andersen; Kirsten A. Fairfax; Alex William Hewitt; Joseph E. Powell; Sara Ballouz

doi:10.1016/j.ajhg.2026.04.003

ImmunologyThe American Journal of Human GeneticsMay 1, 2026

Peer-reviewed journal article

The impact of sex on the immune system explored at the single-cell level

Seyhan Yazar iD, José Alquicira-Hernández iD, Kristof Wing iD, Anne Senabouth iD, Stacey B. Andersen iD, Kirsten A. Fairfax iD, Alex William Hewitt iD, Joseph E. Powell iD, Sara Ballouz iD

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Abstract

Sex has a key role in disease susceptibility, in particular autoimmunity. Sex differences of the immune system stems from genes and their interactions with intrinsic and external factors. However, the cellular-level factors influencing sexual dimorphism is not fully understood. We thus examined immune sex differences at single-cell resolution to dissect the genetic impacts. Female-biased sex-differentially expressed genes (DEGs) in multiple immune cells were involved in TNF[a] signalling, whereas male DEGs were enriched for ribosomal-related functions. While cis-eQTLs were less common on sex chromosomes, we identified over 1000 sex-specific eQTLs and 51 sex-interacting eQTLs on autosomes. When we examined the effect of genetic control on sex-DEGs, we found genetic variants affecting the female-biased expression FCGR3A in NK cells (rs2099684) and ITGB2 in Monocytes (rs760462), both of which are associated with systemic lupus erythematosus. Our work reveals novel biases masked in bulk analyses and highlights sexually dimorphic genes and pathways at baseline.