Heterogeneous Escape from X Chromosome Inactivation Results in Sex Differences in Type I IFN Responses at the Single Human pDC Level

Sven Hendrik Hagen,Florian Henseling,Jana Hennesen,Hélène Savel,Solenne Delahaye,Laura Richert,Susanne Maria Ziegler,Marcus Altfeld

doi:10.1016/j.celrep.2020.108485

Sven Hendrik Hagen, Florian Henseling + Show 6 more

Open Access

https://doi.org/10.1016/j.celrep.2020.108485

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Abstract

Immune responses differ between women and men, and type I interferon (IFN) responses following Toll-like receptor 7 (TLR7) stimulation are higher in women. The precise mechanisms driving these sex differences in immunity are unknown. To investigate possible genetic factors, we quantify escape from X chromosome inactivation (XCI) for TLR7 and four other genes (RPS6KA3, CYBB, BTK, and IL13RA1) at the single plasmacytoid dendritic cell (pDC) level. We observe escape from XCI for all investigated genes, leading to biallelic expression patterns. pDCs with biallelic gene expression have significantly higher mRNA levels of the respective genes. Unstimulated pDCs with biallelic TLR7 expression exhibit significantly higher IFNα/β mRNA levels, and IFNα exposure results in significantly increased IFNα/β protein production by pDCs. These results identify unanticipated heterogeneity in escape from XCI of several genes in pDCs and highlight the important contribution of X chromosome factors to sex differences in type I IFN responses, which might explain observed sex differences in human diseases.

Highlights

Immune responses differ between women and men, resulting in sex-specific differences in the manifestations of infectious and autoimmune diseases
To investigate escape from X chromosome inactivation (XCI) at the single plasmacytoid dendritic cell (pDC) level, we took advantage of single nucleotide polymorphisms (SNPs) within the mature mRNA of genes encoded by the X chromosome, enabling differentiation of mRNA encoded by the two X chromosomes in heterozygous females (Berghofer et al, 2006; Souyris et al, 2018)
The percentage of pDCs with biallelic expression for the investigated genes ranged from 5.6% to 37.3%, with the broadest range in pDCs with escape from XCI observed for BTK and Toll-like receptor 7 (TLR7) (BTK: 5.6%–31.3%; TLR7: 19.0–37.3%; Figure 2C)

Summary

Introduction

Immune responses differ between women and men, resulting in sex-specific differences in the manifestations of infectious and autoimmune diseases. Immune responses toward vaccines differ between women and men, with most vaccines eliciting stronger immune responses in adult females (Flanagan et al, 2017). The prevalence of autoimmune diseases evidences a clear sex bias, with the majority of autoimmune diseases being more prevalent in females than in males (Amur et al, 2012; Markle and Fish 2014). These data show that the ramifications of a sex bias in immune responses are manifested in the incidence and severity of infectious and autoimmune diseases, as well as in differences in vaccine-induced immune responses

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