Abstract
Sexual dimorphism in the immune system is evidenced by a higher prevalence of autoimmune diseases in women and higher susceptibility to infectious diseases in men. However, the molecular basis of these sex-based differences is not fully understood. We have characterized the transcriptome profiles of peripheral blood monocytes from males and postmenopausal females with chronic low-grade inflammation. We identified 41 sexually differentially expressed genes [adjusted p value (FDR) < 0.1], including genes involved in immune cell activation (e.g., CEACAM1, FCGR2B, and SLAMF7) and antigen presentation (e.g., AIM2, CD1E, and UBA1) with a higher expression in females than males. Moreover, signaling pathways of immune or inflammatory responses, including interferon (IFN) signaling [z-score = 2.45, -log(p) = 3.88], were found to be more upregulated in female versus male monocytes, based on a set of genes exhibiting sex-biased expression (p < 0.03). The contribution of IFN signaling to the sexual transcriptional differences was further confirmed by direct comparisons of the monocyte sex-biased genes with IFN signature genes (ISGs) that were previously curated in mouse macrophages. ISGs showed a greater overlap with female-biased genes than male-biased genes and a higher overall expression in female than male monocytes, particularly for the genes of antiviral and inflammatory responses to IFN. Given the role of IFN in immune defense and autoimmunity, our results suggest that sexual dimorphism in immune functions may be associated with more priming of innate immune pathways in female than male monocytes. These findings highlight the role of sex on the human immune transcriptome.
Highlights
Sex dimorphism is one of the critical factors contributing to immunological variability among individuals and has been under-appreciated in the majority of immunology studies [1, 2]
Participant characteristics and measures of inflammation were similar between females and males, with the exception of diastolic blood pressure which was lower in females than in males
Monocyte-specific sex signature genes Monocyte transcriptional sex dimorphism was clearly observed, as shown in the separation of the samples based on sex in the principal component analysis (PCA) plot (Fig. 1A)
Summary
Sex dimorphism is one of the critical factors contributing to immunological variability among individuals and has been under-appreciated in the majority of immunology studies [1, 2]. Females, compared to males, show a stronger humoral and cell-mediated immunity [5, 6], as. Differences in sex steroid hormone concentrations [11] and sex chromosomes [12] play a prevailing role in genomic regulation of the immune system. Genes unique to the Y chromosome or additional copies of X chromosome genes that escape X-inactivation result in differential gene expression between males and females [12]. Some immune-related genes located on the X chromosome such as TLR7 and CD40LG are expressed at higher levels in females than males [14, 15], possibly as a result of imperfect X-silencing. Sexspecific genetic polymorphisms on autosomal genes and epigenetic controls may contribute to sexual differential gene expression [2]
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