Journal
SCIENCE
Volume 343, Issue 6176, Pages 1260-1263Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1248943
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Funding
- European Research Council [233229, FES0908]
- Netherlands Centre for Electron Nanoscopy (NeCEN), Leiden
- Netherlands Organization for Scientific Research [NWO 175.010.2009.001]
- European Regional Development Fund of the European Commission [21Z.014]
- National Institute of Allergy and Infectious Diseases (NIAID) [AI055332]
- NIAID [AI084817]
- Genmab
- European Research Council (ERC) [233229] Funding Source: European Research Council (ERC)
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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 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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