Original Article

C-Reactive Protein Binds to Apoptotic Cells, Protects the Cells from Assembly of the Terminal Complement Components, and Sustains an Antiinflammatory Innate Immune Response: Implications for Systemic Autoimmunity

Correspondence to: Keith B. Elkon, Hospital for Special Surgery, 535 East 70th St., New York, NY 10021. Tel:212-606-1074 Fax:212-774-2337

C-reactive protein (CRP) is a serum protein that is massively induced as part of the innate immune response to infection and tissue injury. As CRP has been detected in damaged tissues and is known to activate complement, we assessed whether apoptotic lymphocytes bound CRP and determined the effect of binding on innate immunity. CRP bound to apoptotic cells in a Ca²⁺-dependent manner and augmented the classical pathway of complement activation but protected the cells from assembly of the terminal complement components. Furthermore, CRP enhanced opsonization and phagocytosis of apoptotic cells by macrophages associated with the expression of the antiinflammatory cytokine transforming growth factor ß. The antiinflammatory effects of CRP required C1q and factor H and were not effective once cells had become necrotic. These observations demonstrate that CRP and the classical complement components act in concert to promote noninflammatory clearance of apoptotic cells and may help to explain how deficiencies of the classical pathway and certain pentraxins lead to impaired handling of apoptotic cells and increased necrosis with the likelihood of immune response to self.

Key Words: apoptosis, C-reactive protein, complement, macrophages, autoimmunity

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• Shaw, P. X., Goodyear, C. S., Chang, M.-K., Witztum, J. L., Silverman34, G. J. (2003). The Autoreactivity of Anti-Phosphorylcholine Antibodies for Atherosclerosis-Associated Neo-Antigens and Apoptotic Cells. J. Immunol. 170: 6151-6157 [Abstract] [Full Text]  
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• Hart, S. P., Jackson, C., Kremmel, L. M., McNeill, M. S., Jersmann, H., Alexander, K. M., Ross, J. A., Dransfield, I. (2003). Specific Binding of an Antigen-Antibody Complex to Apoptotic Human Neutrophils. Am. J. Pathol. 162: 1011-1018 [Abstract] [Full Text]  
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• Khreiss, T., Jozsef, L., Hossain, S., Chan, J. S. D., Potempa, L. A., Filep, J. G. (2002). Loss of Pentameric Symmetry of C-reactive Protein Is Associated with Delayed Apoptosis of Human Neutrophils. J. Biol. Chem. 277: 40775-40781 [Abstract] [Full Text]  
• Chang, M.-K., Binder, C. J., Torzewski, M., Witztum, J. L. (2002). From the Cover: C-reactive protein binds to both oxidized LDL and apoptotic cells through recognition of a common ligand: Phosphorylcholine of oxidized phospholipids. Proc. Natl. Acad. Sci. USA 99: 13043-13048 [Abstract] [Full Text]  
• Agrawal, A., Simpson, M. J., Black, S., Carey, M. P., Samols, D. (2002). A C-Reactive Protein Mutant That Does Not Bind to Phosphocholine and Pneumococcal C-Polysaccharide. J. Immunol. 169: 3217-3222 [Abstract] [Full Text]  
• Kim, S. J., Gershov, D., Ma, X., Brot, N., Elkon, K. B. (2002). I-PLA2 Activation during Apoptosis Promotes the Exposure of Membrane Lysophosphatidylcholine Leading to Binding by Natural Immunoglobulin M Antibodies and Complement Activation. JEM 196: 655-665 [Abstract] [Full Text]  
• Webb, J. H., Blom, A. M., Dahlback, B. (2002). Vitamin K-Dependent Protein S Localizing Complement Regulator C4b-Binding Protein to the Surface of Apoptotic Cells. J. Immunol. 169: 2580-2586 [Abstract] [Full Text]  
• Cocca, B. A., Cline, A. M., Radic, M. Z. (2002). Blebs and Apoptotic Bodies Are B Cell Autoantigens. J. Immunol. 169: 159-166 [Abstract] [Full Text]  
• Szalai, A. J., Nataf, S., Hu, X.-Z., Barnum, S. R. (2002). Experimental Allergic Encephalomyelitis Is Inhibited in Transgenic Mice Expressing Human C-Reactive Protein. J. Immunol. 168: 5792-5797 [Abstract] [Full Text]  
• Kammerer, R., Stober, D., Riedl, P., Oehninger, C., Schirmbeck, R., Reimann, J. (2002). Noncovalent Association with Stress Protein Facilitates Cross-Priming of CD8+ T Cells to Tumor Cell Antigens by Dendritic Cells. J. Immunol. 168: 108-117 [Abstract] [Full Text]  
• Zouki, C., Haas, B., Chan, J. S. D., Potempa, L. A., Filep, J. G. (2001). Loss of Pentameric Symmetry of C-Reactive Protein Is Associated with Promotion of Neutrophil-Endothelial Cell Adhesion. J. Immunol. 167: 5355-5361 [Abstract] [Full Text]  
• Ogden, C. A., deCathelineau, A., Hoffmann, P. R., Bratton, D., Ghebrehiwet, B., Fadok, V. A., Henson, P. M. (2001). C1q and Mannose Binding Lectin Engagement of Cell Surface Calreticulin and CD91 Initiates Macropinocytosis and Uptake of Apoptotic Cells. JEM 194: 781-796 [Abstract] [Full Text]  
• Cairns, A P, Crockard, A D, Bell, A L (2001). CD36-mediated apoptotic cell clearance in SLE. Lupus 10: 656-657  
• Familian, A., Zwart, B., Huisman, H. G., Rensink, I., Roem, D., Hordijk, P. L., Aarden, L. A., Hack, C. E. (2001). Chromatin-Independent Binding of Serum Amyloid P Component to Apoptotic Cells. J. Immunol. 167: 647-654 [Abstract] [Full Text]  
• Walport, M. J. (2001). Complement- Second of Two Parts. NEJM 344: 1140-1144 [Full Text]  

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