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• W4247455740 abstract "New data reveal that IgG forms ordered hexameric complexes in order to optimally activate complement. New data reveal that IgG forms ordered hexameric complexes in order to optimally activate complement. CITATION: Diebolder CA, Beurskens FJ, de Jong RN, Koning RI, Strumane K, Lindorfer MA, et al. Complement is activated by IgG hexamers assembled at the cell surface. Science 2014; 343: 1260–1263. Complement activation by antibodies is a potent arm of protective immunity that unleashes a cascade of opsonins, anaphylaxatoxins, chemotactic agents and membrane attack complexes. Complement binding to donor-specific antibodies and deposition on donor tissue remains a major problem for long-term outcomes in transplantation, yet the mechanisms by which complement contributes to pathologic tissue injury are an ongoing area of investigation. Recently, Diebolder et al shed light on this area using high-resolution crystallography to reveal the formation of ordered antibody hexamers after antigen binding. An initial observation showing that IgG Fc segments within antigen-antibody complexes were arranged in hexameric rings, coupled with the precise spatial orientation of a residue known to be critical for C1q binding, led the authors to hypothesize that complement-dependent cytotoxicity is activated via specific Fc-Fc noncovalent interactions between neighboring IgG molecules. To test this, the Fc-Fc interface was blocked using a peptide known to bind within this region. The authors demonstrated that culture of human B cell lymphomas with the Fc-Fc blocking peptide resulted in dramatically reduced ability of an anti-CD20 mAb to lyse CD20-expressing tumor cells. Interestingly, the study also found that it was possible to experimentally augment complement-dependent cytotoxicity by making mutations within the IgG Fc region that enhance Fc-Fc–mediated IgG hexamer assembly at the cell surface. Taken together, these results demonstrate that hexameric IgG complexes efficiently recruit and activate C1, resulting in the initiation of the complement cascade. The model put forth by the authors suggests an evolutionary relationship between the mechanisms by which IgM and IgG trigger complement. It is well known that IgM is normally present in a polymeric state, and that C1q binding sites are sequestered under steady state and become exposed only upon antigen ligation. These new data suggest a related paradigm for IgG, one in which IgG exists in a monomeric state with C1q binding sites exposed, but that the affinity is too low to result in significant C1q binding and activation. Formation of IgG hexamers thus affords the ability to bind C1q with high avidity, resulting in optimal activation of the complement cascade. This finding solves a previously unexplained mystery in that it shows how IgG molecules and the complement system can coexist in the blood without initiating the cascade: Complement activation will only be optimally elicited after IgG recognizes cognate antigen, interacts with neighboring IgG molecules and starts to aggregate. Further, it has been suggested that one of the mechanisms of action of IVIg, used in transplantation and autoimmunity, is to inhibit initiation of the complement cascade by “soaking up” complement components and sequestering them away from allo- and/or auto-antibodies. However, this new insight demonstrating that IgG likely activates complement only in hexameric form following recognition of cognate antigen suggests that a complement-scavenging role is likely not a mechanism underlying the anti-inflammatory effects of IVIg. These findings have potential implications for transplantation in two respects. First, the study identifies a binding event that may be critical for the ability of donor-specific antibodies to elicit complement activation, leading to cytolysis of donor tissue and the release of soluble inflammatory mediators such as C5a. It is interesting to speculate that the formation of hexameric IgG complexes could be targeted therapeutically, for instance by delivery of a peptide that binds to and blocks the IgG Fc-Fc interface, similar to the one used in this study. Disruption of IgG hexamers may stymie the ability of alloantibodies to elicit complement activation and local inflammation within the allograft. Second, the observation that IgG hexamerization following antigen binding results in more efficient complement activation might be exploited therapeutically by artificially increasing Fc-Fc contact formation. Specifically, identification of IgG Fc mutations designed to enhance hexamer formation could pave the way for the engineering of reagents that more effectively deplete their target populations, potentially facilitating the design of better T cell– or B cell–depleting agents for use in transplantation." @default.
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• W4247455740 date "2015-05-01" @default.
• W4247455740 modified "2023-10-18" @default.
• W4247455740 title "AN IMMUNOLOGIC HEX: Novel Insights Into Mechanisms of Complement Activation" @default.
• W4247455740 doi "https://doi.org/10.1111/ajt.13332" @default.
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