Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination

Abstract

Females have generally more robust immune responses than males for reasons that are not well-understood. Here we used a systems analysis to investigate these differences by analyzing the neutralizing antibody response to a trivalent inactivated seasonal influenza vaccine (TIV) and a large number of immune system components, including serum cytokines and chemokines, blood cell subset frequencies, genome-wide gene expression, and cellular responses to diverse in vitro stimuli, in 53 females and 34 males of different ages. We found elevated antibody responses to TIV and expression of inflammatory cytokines in the serum of females compared with males regardless of age. This inflammatory profile correlated with the levels of phosphorylated STAT3 proteins in monocytes but not with the serological response to the vaccine. In contrast, using a machine learning approach, we identified a cluster of genes involved in lipid biosynthesis and previously shown to be up-regulated by testosterone that correlated with poor virus-neutralizing activity in men. Moreover, men with elevated serum testosterone levels and associated gene signatures exhibited the lowest antibody responses to TIV. These results demonstrate a strong association between androgens and genes involved in lipid metabolism, suggesting that these could be important drivers of the differences in immune responses between males and females.

Relationship between sex hormones and RIG-I signaling in peripheral blood mononuclear cells of patients infected with hepatitis C virus

“…These results are consistent with studies in which men with elevated serum testosterone levels exhibited the lowest levels of antibody and inflammatory cytokines following viral infection (20,21). Among men infected with HCV, each 1 ng/ml increase in total serum testosterone has been associated with a 27% increase in risk of advanced fibrosis and 16% increase in risk of advanced inflammatory activity (22).…”

Androgens alter T-cell immunity by inhibiting T-helper 1 differentiation

“…In addition, there are a number of SNPs found in Ptpn1 that are associated with hypertension and obesity (25). One of the critical findings of a recent report demonstrating the negative correlation of testosterone and influenza vaccine efficacy was that testosterone altered lipid metabolism in the immune system (5). Given that Ptpn1 is a regulator of IGF signaling, it is rational to expect that testosterone induced expression of Ptpn1 may be associated with regulation of lipid metabolism, and therefore, could be one of the mechanisms that leads to reduced influenza vaccine efficacy by testosterone.…”

“…Why males need to be more protected from autoimmunity is unclear. Others have offered plausible speculation that the evolutionary role of testosterone-mediated immune suppression may be to protect men from pathogen exposure during traumatic injury, for which in many species the males are more likely to suffer (5). Our data suggest an additional possibility: that because the role of Ptpn1 is important in metabolism regulation and IGF1 signaling (31), testosterone regulation of Ptpn1 is more important for these processes, and the effect of testosterone on the immune system either directly or by altered lipid metabolism may be a bystander effect.…”

“…Recently, it was reported that testosterone levels negatively correlated with the antibody response to the trivalent inactivated seasonal influenza vaccine by interfering with lipid metabolism (5). Testosterone levels are also positively correlated with the viral load of Venezuelan equine encephalitis virus in macaques (6).…”

Influence of female sex and fertile age on neuromyelitis optica spectrum disorders

“…28,29 Women are known to show significantly stronger immune responses to infections and vaccination. 30 Immunological toler ance might be more strongly controlled by hormonal factors, especially before menopause and during pregnancy.…”