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

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/ß mRNA levels, and IFNα exposure results in significantly increased IFNα/ß 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.

Innate immune responses to toll-like receptor stimulation are altered during the course of pregnancy.

During pregnancy the maternal immune system has to develop tolerance towards the developing fetus. These changes in maternal immunity can result in increased severity of certain infections, but also in amelioration of autoimmune diseases. Pregnancy-related hormones have been suggested to play a central role in the adaptation of the maternal immune system, but their specific effects on innate immune function is not well understood. In a longitudinal study of pregnant women, we investigated innate immune cell function in response to toll-like receptors (TLR) 4 and 7 stimulation, two TLR pathways playing a critical role in early innate immune recognition of bacteria and viruses. IFNα production by TLR7-stimulated pDCs was decreased in early pregnancy, and increased towards the end of pregnancy. In contrast, pro-inflammatory TLR4-induced TNFα production by monocytes was increased during early pregnancy, but declined after the first trimester. Changes in cytokine production were associated with changes in pregnancy-related hormones and monocyte subpopulations over the course of pregnancy. These data demonstrating a significant association between pregnancy-related hormones and modulation of innate immune responses mediated by TLRs provide novel insights into the immunological adaptations occurring during pregnancy.

Human Immunodeficiency Virus 1 and Type I Interferons-Where Sex Makes a Difference.

The human immunodeficiency virus (HIV)-1 epidemic continues to represent a global health problem that is over-proportionally affecting women from sub-Saharan Africa. Besides social and environmental factors, the modulation of immunological pathways by sex hormones and gene dosage effects of X chromosomal-encoded genes have been suggested to lead to differential outcomes in HIV-1 disease. Women present with lower HIV-1 loads early in infection. However, the progression to AIDS for the same level of viremia is faster in women than in men. Type I interferons (IFNs) play a prominent role in the control of HIV-1 transmission and replication. Continuous stimulation of type I IFNs in chronic viral infections can lead to increased levels of immune activation, which can be higher in HIV-1-infected women than in men. A role of steroid hormone signaling in regulating viral replication has been postulated, which might further account for sex differences observed in HIV-1 infections. Here, we review recent findings and current knowledge on sex-specific differences in HIV-1 infections.