Division of Pediatric Rheumatology, Department of Pediatrics, Washington University School of Medicine, St Louis, MO 63110, USA.
J Autoimmun. 2012 May;38(2-3):J245-53. doi: 10.1016/j.jaut.2011.12.003. Epub 2011 Dec 29.
Increased susceptibility to autoimmunity in females is often viewed as the consequence of enhanced immunoreactivity providing superior protection against infections. We paradoxically observed greater mortality in female compared to male mice during systemic viral infections with three large double-stranded DNA viruses (herpes simplex virus type I [HSV], murine cytomegalovirus [MCMV], and vaccinia virus [VV]). Indeed, female mice were 27-fold more susceptible to infection with HSV than male mice. Elimination of estrogen by ovariectomy in female mice or addition of estrogen to castrated male mice only partially eliminated the observed sex differences following HSV infection. However, the differences observed in survival between female and male mice were nearly abrogated in the absence of type I interferon receptor signaling and substantially mitigated in absence of DAP12 signaling. Interestingly, the sex-specific impact of type I interferon receptor and DAP12 signaling differentially influenced survival during systemic viral infections with type I interferon receptor signaling enhancing male survival and DAP12 signaling increasing the susceptibility of female mice. These results have potential implications for the sex disparities observed in human autoimmune disorders.
女性对自身免疫的易感性增加通常被认为是免疫反应增强的结果，这种增强提供了对感染的更好保护。然而，我们在系统性病毒感染中观察到，雌性小鼠比雄性小鼠的死亡率更高，这与上述观点相矛盾。在感染单纯疱疹病毒 I 型（HSV）、鼠巨细胞病毒（MCMV）和牛痘病毒（VV）这三种大型双链 DNA 病毒时，雌性小鼠的感染敏感性比雄性小鼠高 27 倍。通过卵巢切除术消除雌性小鼠中的雌激素或向去势雄性小鼠中添加雌激素，仅能部分消除 HSV 感染后观察到的性别差异。然而，在不存在 I 型干扰素受体信号的情况下，雌性和雄性小鼠之间的存活率差异几乎被消除，而在不存在 DAP12 信号的情况下，这种差异也大大减轻。有趣的是，I 型干扰素受体和 DAP12 信号的性别特异性影响在系统性病毒感染中对存活率的影响不同，I 型干扰素受体信号增强了雄性的存活率，而 DAP12 信号增加了雌性小鼠的易感性。这些结果可能对人类自身免疫性疾病中观察到的性别差异具有重要意义。
