Abstract
SummarySex differences in autoimmunity and infection suggest that a better understanding of molecular sex differences will improve the diagnosis and treatment of immune-related disease. We identified 144 differentially expressed genes, referred to as immune sex expression signature (iSEXS), between human males and females using an integrated multi-cohort analysis of blood transcriptome profiles from six discovery cohorts from five continents with 458 healthy individuals. We validated iSEXS in 11 additional cohorts of 524 peripheral blood samples. When we separated iSEXS into genes located on sex chromosomes (XY-iSEXS) or autosomes (autosomal-iSEXS), both modules distinguished males and females. iSEXS reflects sex differences in immune cell proportions, with female-associated genes showing higher expression by CD4+ T cells and male-associated genes showing higher expression by myeloid cells. Autosomal-iSEXS detected an increase in monocytes with age in females, reflected sex-differential immune cell dynamics during influenza infection, and predicted antibody response in males, but not females.
Highlights
Sex differences in immune responses lead to different risks for immunological diseases (Pennell et al, 2012)
X Chromosome Dosage Is Associated with AutosomaliSEXS Score we investigated whether XY-immune sex expression signature (iSEXS) and autosomal-iSEXS scores were associated with the number of X chromosomes present in an individual subject
In yet another independent cohort (ImmPort: SDY212), we found that the autosomal-iSEXS score was significantly higher in younger females than younger males (p = 4.5e-05), but there was no significant difference in the autosomal-iSEXS scores of older males and females (Figure S3B)
Summary
Sex differences in immune responses lead to different risks for immunological diseases (Pennell et al, 2012). Differences between male and female immune responses are mediated by both gender and sex. Gender encompasses the behaviors that a given society defines as masculine or feminine, whereas sex encompasses biological factors that differ between males and females, including hormonal milieu and chromosome complement (Klein and Flanagan, 2016). Female-like risk for SLE in XXY males with Klinefelter syndrome suggests that X chromosome dosage plays a role in autoimmunity risk (Souyris et al, 2018). Studies in SLE mouse models indicate that both hormonal milieu and chromosome complement play roles in disease risks, as XY-female mice have less severe SLE-like disease than XX-female mice (Sasidhar et al, 2012). Using a single homogeneous cohort makes it difficult to segregate effects of sex and gender or an interaction between the two in immune response
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