Original Article

A Hierarchical Role for Classical Pathway Complement Proteins in the Clearance of Apoptotic Cells In Vivo

Correspondence to: Mark J. Walport, Rheumatology Section, Div. of Medicine, Imperial College School of Medicine, Hammersmith Campus, Du Cane Rd., London W12 0NN, UK. Tel:44-20-8383-3299 Fax:44-20-8743-3109 E-mail:m.walport{at}ic.ac.uk.

The strongest susceptibility genes for the development of systemic lupus erythematosus (SLE) in humans are null mutants of classical pathway complement proteins. There is a hierarchy of disease susceptibility and severity according to the position of the missing protein in the activation pathway, with the severest disease associated with C1q deficiency. Here we demonstrate, using novel in vivo models of apoptotic cell clearance during sterile peritonitis, a similar hierarchical role for classical pathway complement proteins in vivo in the clearance of apoptotic cells by macrophages. Our results constitute the first demonstration of an impairment in the phagocytosis of apoptotic cells by macrophages in vivo in a mammalian system. Apoptotic cells are thought to be a major source of the autoantigens of SLE, and impairment of their removal by complement may explain the link between hereditary complement deficiency and the development of SLE.

Key Words: systemic lupus erythematosus, complement deficiency, C1q, transgenic mice, apoptosis

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• Robson, M. G., Cook, H. T., Botto, M., Taylor, P. R., Busso, N., Salvi, R., Pusey, C. D., Walport, M. J., Davies, K. A. (2001). Accelerated Nephrotoxic Nephritis Is Exacerbated in C1q-Deficient Mice. J. Immunol. 166: 6820-6828 [Abstract] [Full Text]  
• Leverrier, Y., Lorenzi, R., Blundell, M. P., Brickell, P., Kinnon, C., Ridley, A. J., Thrasher, A. J. (2001). Cutting Edge: The Wiskott-Aldrich Syndrome Protein Is Required for Efficient Phagocytosis of Apoptotic Cells. J. Immunol. 166: 4831-4834 [Abstract] [Full Text]  
• Walport, M. J. (2001). Complement- Second of Two Parts. NEJM 344: 1140-1144 [Full Text]  
• Ren, Y., Stuart, L., Lindberg, F. P., Rosenkranz, A. R., Chen, Y., Mayadas, T. N., Savill, J. (2001). Nonphlogistic Clearance of Late Apoptotic Neutrophils by Macrophages: Efficient Phagocytosis Independent of {{beta}}2 Integrins. J. Immunol. 166: 4743-4750 [Abstract] [Full Text]  
• Navratil, J. S., Watkins, S. C., Wisnieski, J. J., Ahearn, J. M. (2001). The Globular Heads of C1q Specifically Recognize Surface Blebs of Apoptotic Vascular Endothelial Cells. J. Immunol. 166: 3231-3239 [Abstract] [Full Text]  
• Chen, Z., Koralov, S. B., Kelsoe, G. (2000). Complement C4 Inhibits Systemic Autoimmunity through a Mechanism Independent of Complement Receptors CR1 and CR2. JEM 192: 1339-1352 [Abstract] [Full Text]  

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