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* Department of Nephrology,
Department of Rheumatology, and
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
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.
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1 This work was supported in part by a grant (C02.2015) from the Dutch Kidney Foundation.
2 W.X., M.R.D., and C.v.K. designed the study; W.X., N.S., and C.M. performed research; W.X., S.P.B., L.A.T., H.d.B., M.R.D., and C.v.K. analyzed data; and W.X., M.R.D., and C.v.K. wrote the paper. All authors reviewed and approved the paper.
3 Address correspondence and reprint requests to Dr. Cees van Kooten, Department of Nephrology, C3-P, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. E-mail address: kooten{at}lumc.nl
4 Abbreviations used in this paper: M
, macrophage; C4ds, C4-depleted serum; dsDNA, double-stranded DNA; EBV-LCL, Epstein-Barr virus-transformed B lymphoblastoid cell line; MBL, mannose-binding lectin; M-CSF, macrophage colony-stimulating factors; MFI, mean fluorescence intensity; NHS, normal human serum; Pds, properdin-depleted serum; PI, propidium iodide; SLE, systemic lupus erythematosus; ssDNA, single-stranded DNA; WT, wild type.
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