PNAS2014-01-15 9:16 PM

Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination 对性别差异的系统分析揭示睾丸激素在应对流感疫苗接种时的免疫抑制作用

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. 论文摘要 通常来说,女性有着比男性更加强大的免疫系统,但我们对其原因所知甚少。在一个由53个女性34个男性组成的不同年龄的受试群中, 我们使用了一种分析系统法来研究这些差别,通过分析了中和抗体对三价灭活的季节性流感疫苗(TIV)和大量的免疫系统组件, 包括血清细胞因子和趋化因子、血液细胞频率子集,全基因组基因表达和对多样化体外刺激的细胞反应的反应。 我们发现对TIV抗体反应的增强以及和男性相比,女性血清中较强的炎症细胞素的表达都和年龄无关。这一炎症的情况与单核细胞中磷酸化的STATS蛋白水平相关,但是和疫苗的血清应答无法。相比之下,使用机器研究方法,我们识别了一组参与脂类生物合成, 并且之前显示被睾丸酮激素上调的基因和男性体内较弱的病毒中和反应相关。 除此之外,拥有较高的血清睾丸酮水平和相关基因特征的男性表现出最低的对TIV的抗体反应。 这一结果证实了雄性激素和参与脂肪代谢的基因有着强大的联系,说明这也许是差异化男性和女性免疫反应的重要的驱动力。

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