Complement is activated by IgG hexamers assembled at the cell surface
Diebolder, Christoph A.; Beurskens, Frank J.; De Jong, Rob N.; Koning, Roman I.; Strumane, Kristin; Lindorfer, Margaret A.; Voorhorst, Marleen; Ugurlar, Deniz; Rosati, Sara; Heck, Albert J. R.; Van De Winkel, Jan G. J.; Wilson, Ian A.; Koster, Abraham J.; Taylor, Ronald P.; Saphire, Erica Ollmann; Burton, Dennis R.; Schuurman, Janine; Gros, Piet; Parren, Paul W. H. I.
(2014) Science, volume 343, issue 6176, pp. 1260 - 1263
(Article)
Abstract
Complement activation by antibodies bound to pathogens, tumors, and self antigens is a critical feature of natural immune defense, a number of disease processes, and immunotherapies. How antibodies activate the complement cascade, however, is poorly understood. We found that specific noncovalent interactions between Fc segments of immunoglobulin G (IgG) antibodies
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resulted in the formation of ordered antibody hexamers after antigen binding on cells. These hexamers recruited and activated C1, the first component of complement, thereby triggering the complement cascade. The interactions between neighboring Fc segments could be manipulated to block, reconstitute, and enhance complement activation and killing of target cells, using all four human IgG subclasses. We offer a general model for understanding antibody-mediated complement activation and the design of antibody therapeutics with enhanced efficacy.
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Keywords: antibody, antigen, complement component C1, immunoglobulin Fc fragment, immunoglobulin G, immunoglobulin G1, immunoglobulin G2, immunoglobulin G3, immunoglobulin G4, article, cell killing, cell surface, complement activation, human, immunotherapy, innate immunity, nonhuman, priority journal, target cell
ISSN: 0036-8075
Publisher: American Association for the Advancement of Science
(Peer reviewed)