Complement Is Activated by IgG Hexamers Assembled at the Cell Surface
By C. Diebolder, F. Beurskens, R. D. de Jong, R. Koning, K. Strumane, M. Lindorfer, M. Voorhorst, D. Ugurlar, S. Rosati, Albert J. R. Heck and 9 more. Science, 2014
736 citations recorded by the source corpus.
Hexing Complement Complement activation is an immediate and potent immune defense mechanism, but how immunoglobulin G (IgG) antibodies activate complement at the molecular level is poorly understood. Using high-resolution crystallography, Diebolder et al. (p. 1260) show that human IgGs form hexameric structures by interacting with neighboring IgG molecules, and the complex then activates complement. Thus, IgG molecules and the complement system can coexist in the blood because complement activation will only be triggered after IgG senses a surface antigen and starts to aggregate. Hexameric platforms of antibodies on the cell surface trigger the complement cascade. 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.
Subfields: Immunology, Molecular Biology, Radiology, Nuclear Medicine and Imaging
View Paper: https://www.semanticscholar.org/paper/94e423eae98229241efb6de1b2afe4e87786fb3e
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Citations in the corpus
- Antibody Structure and Function: The Basis for Engineering Therapeutics (2019, background): “Combination mutations that result in antibodies with increased CDC can include K326A/E333A, K326W/E333A, H268F/S324T, S267E/H268F, S267E/S324T, E345R, and S267E/H268F/S324T [359,409,410].”
- Antibody distance from the cell membrane regulates antibody effector mechanisms (2017, background): “Although the formation of hexamers can be engineered via Fc modification (54), they can form naturally upon the surface of the target cell via lateral movement of the Ag:Ab complexes (7).”
- Complement System Part I – Molecular Mechanisms of Activation and Regulation (2015, background): “Diebolder and colleagues demonstrated that specific non-covalent interactions between Fc fragments of IgG and formation of ordered antibody hexamers on the antigen surface are needed for efficient C1q-binding (Figure 3A) (49).”
- IgG Subclasses and Allotypes: From Structure to Effector Functions (2014, background): “The residues most proximal to the hinge region in the CH2 domain of the Fc part are responsible for effector functions of antibodies as it contains a largely overlapping binding site for C1q (complement) and IgG-Fc receptors (FcγR) on effector cells of the innate immune system.”