Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany.
J Innate Immun. 2018;10(2):94-105. doi: 10.1159/000484257. Epub 2017 Dec 14.
The human plasma contact system is an immune surveillance system activated by the negatively charged surfaces of bacteria and fungi and includes the kallikrein-kinin, the coagulation, and the fibrinolytic systems. Previous work shows that the contact system also activates complement, and that plasma enzymes like kallikrein, plasmin, thrombin, and FXII are involved in the activation process. Here, we show for the first time that kallikrein cleaves the central complement component C3 directly to yield active components C3b and C3a. The cleavage site within C3 is identical to that recognized by the C3 convertase. Also, kallikrein-generated C3b forms C3 convertases, which trigger the C3 amplification loop. Since kallikrein also cleaves factor B to yield Bb and Ba, kallikrein alone can trigger complement activation. Kallikrein-generated C3 convertases are inhibited by factor H; thus, the kallikrein activation pathway merges with the amplification loop of the alternative pathway. Taken together, these data suggest that activation of the contact system locally enhances complement activation on cell surfaces. The human pathogenic microbe Candida albicans activates the contact system in normal human serum. However, C. albicans immediately recruits factor H to the surface, thereby evading the alternative and likely kallikrein-mediated complement pathways.
人体血浆接触系统是一个由细菌和真菌的负电荷表面激活的免疫监视系统，包括激肽释放酶-激肽系统、凝血系统和纤维蛋白溶解系统。先前的工作表明，接触系统还会激活补体，而血浆中的酶如激肽释放酶、纤溶酶、凝血酶和 FXII 参与了激活过程。在这里，我们首次表明激肽可直接切割补体的中心成分 C3，生成有活性的 C3b 和 C3a。C3 中的切割位点与 C3 转化酶识别的位点相同。此外，激肽生成的 C3b 形成 C3 转化酶，触发 C3 放大环。由于激肽还能将因子 B 裂解为 Bb 和 Ba，因此激肽本身就可以触发补体激活。激肽生成的 C3 转化酶被因子 H 抑制；因此，激肽激活途径与替代途径的放大环融合。综上所述，这些数据表明，接触系统的激活可局部增强细胞表面的补体激活。人类病原体白色念珠菌在正常人血清中激活接触系统。然而，白色念珠菌立即将因子 H 招募到表面，从而逃避替代途径和可能的激肽介导的补体途径。
