Complement is activated by IgG hexamers assembled at the cell surface

CA Diebolder, FJ Beurskens, RN De Jong, RI Koning… - Science, 2014 - science.org
CA Diebolder, FJ Beurskens, RN De Jong, RI Koning, K Strumane, MA Lindorfer…
Science, 2014science.org
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 …
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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