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J. Biol. Chem., Vol. 282, Issue 39, 28540-28548, September 28, 2007

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C4b-binding Protein and Factor H Compensate for the Loss of Membrane-bound Complement Inhibitors to Protect Apoptotic Cells against Excessive Complement Attack^*

Leendert A. Trouw¹, Anders A. Bengtsson, Kyra A. Gelderman^¶, Björn Dahlbäck, Gunnar Sturfelt, and Anna M. Blom²

From the Department of Laboratory Medicine, University Hospital Malmö, 5-20502 Malmö, Sweden and the Department of Clinical Science, Rheumatology and the ^¶Unit for Medical Inflammation Research, Lund University, 5-22184 Lund, Sweden

Apoptotic cells have been reported to down-regulate membrane-bound complement regulatory proteins (m-C-Reg) and to activate complement. Nonetheless, most apoptotic cells do not undergo complement-mediated lysis. Therefore, we hypothesized that fluid phase complement inhibitors would bind to apoptotic cells and compensate functionally for the loss of m-C-Reg. We observed that m-C-Reg are down-regulated rapidly upon apoptosis but that complement activation follows only after a gap of several hours. Coinciding with, but independent from, complement activation, fluid phase complement inhibitors C4b-binding protein (C4BP) and factor H (fH) bind to the cells. C4BP and fH do not entirely prevent complement activation but strongly limit C3 and C9 deposition. Late apoptotic cells, present in blood of healthy controls and systemic lupus erythematosus patients, are also positive for C4BP and fH. Upon culture, the percentage of late apoptotic cells increases, paralleled by increased C4BP binding. C4BP binds to dead cells mainly via phosphatidylserine, whereas fH binds via multiple interactions with CRP playing no major role for binding of C4BP or fH. In conclusion, during late apoptosis, cells acquire fluid phase complement inhibitors that compensate for the down-regulation of m-C-Reg and protect against excessive complement activation and lysis.

Received for publication, May 29, 2007 , and in revised form, July 23, 2007.

^* This work was supported by grants from the Foundations of Tore Nilsson and the Royal Physiographic Society in Lund (to L. A. T.) and Cancer-fonden, Swedish Research Council, Swedish Foundation for Strategic Research (INGVAR), Kock, Österlund, King Gustav V's 80^th anniversary, United States Immunodeficiency Network, Chronic Inflammation Program, Swedish Research Council and Cancer Fonden (to B. D.), and a research grant from the University Hospital in Malmö (to A. M. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of postdoctoral stipends from the Wenner-Gren and Anna-Greta Crafoord Foundations.

² To whom correspondence should be addressed: Lund University, Dept. of Laboratory Medicine, The Wallenberg Laboratory, MAS, Entrance 46, Floor 4, S-205 02, Malmö, Sweden. Tel.: 4640338233; E-mail: Anna.Blom{at}med.lu.se.

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