Xu Wei, Berger Stefan P, Trouw Leendert A, de Boer Hetty C, Schlagwein Nicole, Mutsaers Chantal, Daha Mohamed R, van Kooten Cees
Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.
J Immunol. 2008 Jun 1;180(11):7613-21. doi: 10.4049/jimmunol.180.11.7613.
Cells that undergo apoptosis or necrosis are promptly removed by phagocytes. Soluble opsonins such as complement can opsonize dying cells, thereby promoting their removal by phagocytes and modulating the immune response. The pivotal role of the complement system in the handling of dying cells has been demonstrated for the classical pathway (via C1q) and lectin pathway (via mannose-binding lectin and ficolin). Herein we report that the only known naturally occurring positive regulator of complement, properdin, binds predominantly to late apoptotic and necrotic cells, but not to early apoptotic cells. This binding occurs independently of C3b, which is additional to the standard model wherein properdin binds to preexisting clusters of C3b on targets and stabilizes the convertase C3bBb. By binding to late apoptotic or necrotic cells, properdin serves as a focal point for local amplification of alternative pathway complement activation. Furthermore, properdin exhibits a strong interaction with DNA that is exposed on the late stage of dying cells. Our data indicate that direct recognition of dying cells by properdin is essential to drive alternative pathway complement activation.
发生凋亡或坏死的细胞会迅速被吞噬细胞清除。可溶性调理素如补体可调理濒死细胞，从而促进吞噬细胞对其清除并调节免疫反应。补体系统在处理濒死细胞中的关键作用已在经典途径（通过C1q）和凝集素途径（通过甘露糖结合凝集素和纤维胶凝蛋白）中得到证实。在此我们报告，补体唯一已知的天然正向调节因子备解素主要结合晚期凋亡细胞和坏死细胞，而不结合早期凋亡细胞。这种结合独立于C3b发生，这是对标准模型的补充，在标准模型中备解素结合到靶标上预先存在的C3b簇并稳定转化酶C3bBb。通过结合晚期凋亡或坏死细胞，备解素成为旁路途径补体激活局部放大的焦点。此外，备解素与濒死细胞晚期暴露的DNA表现出强烈相互作用。我们的数据表明，备解素对濒死细胞的直接识别对于驱动旁路途径补体激活至关重要。
