Kotimaa Juha, Klar-Mohammad Ngaisah, Gueler Faikah, Schilders Geurt, Jansen Aswin, Rutjes Helma, Daha Mohamed R, van Kooten Cees
Leiden University Medical Center (LUMC), Department of Nephrology, Leiden, The Netherlands.
Department of Nephrology, Hannover Medical School, Hannover, Germany.
Mol Immunol. 2016 Aug;76:13-21. doi: 10.1016/j.molimm.2016.06.004. Epub 2016 Jun 20.
Experimental mouse models have been extensively used to elucidate the role of the complement system in different diseases and injuries. Contribution of gender has revealed an intriguing gender specific difference; female mice often show protection against most complement driven injuries such as ischemia/reperfusion injury, graft rejection and sepsis. Interestingly, early studies to the mouse complement system revealed that female mice have very low total complement activity (CH50), which is related to androgen regulation of hepatic complement synthesis. Here, our aim was to understand at which level the female specific differences in mouse complement resides. We have used recently developed complement assays to study the functional activities of female and male mice at the level of C3 and C9 activation, and furthermore assayed key complement factor levels in serum of age-matched female and male C57BL/6 mice. Our results show that the female mice have normal complement cascade functionality at the level of C3 activation, which was supported by determinations of early complement factors. However, all pathways are strongly reduced at the level of C9 activation, suggesting a terminal pathway specific difference. This was in line with C6 and C9 measurements, showing strongly decreased levels in females. Furthermore, similar gender differences were also found in BALB/cJ mice, but not in CD-1 mice. Our results clearly demonstrate that the complement system in females of frequently used mouse strains is restricted by the terminal pathway components and that the perceived female specific protection against experimental disease and injury might be in part explained by the inability promote inflammation through C5b-9.
实验小鼠模型已被广泛用于阐明补体系统在不同疾病和损伤中的作用。性别因素的影响揭示了一种有趣的性别特异性差异；雌性小鼠通常对大多数由补体驱动的损伤具有保护作用，如缺血/再灌注损伤、移植排斥和败血症。有趣的是，早期对小鼠补体系统的研究表明，雌性小鼠的总补体活性（CH50）非常低，这与雄激素对肝脏补体合成的调节有关。在此，我们的目的是了解小鼠补体中雌性特异性差异存在于哪个水平。我们使用了最近开发的补体检测方法，在C3和C9激活水平上研究雌性和雄性小鼠的功能活性，并进一步检测了年龄匹配的雌性和雄性C57BL/6小鼠血清中的关键补体因子水平。我们的结果表明，雌性小鼠在C3激活水平上具有正常的补体级联功能，这得到了早期补体因子测定的支持。然而，在C9激活水平上，所有途径都显著降低，表明存在终末途径特异性差异。这与C6和C9的测量结果一致，显示雌性水平显著降低。此外，在BALB/cJ小鼠中也发现了类似的性别差异，但在CD-1小鼠中未发现。我们的结果清楚地表明，常用小鼠品系雌性中的补体系统受到终末途径成分的限制，并且所观察到的雌性对实验性疾病和损伤的特异性保护可能部分是由于无法通过C5b-9促进炎症反应。
