IgG binding to cytoskeletal intermediate filaments activates the complement cascade.
The cellular plasma membrane becomes permeable to macromolecules during the cell injury process. This results in exposure of the interior of the cell to plasma proteins and to high-affinity binding of the Fc part of IgG to intermediate filaments (Hansson, G K, Starkebaum, G A, Benditt, E P & Schwartz, S M, Proc natl acad sci USA 81 (1984) 3103). Such IgG binding could be an early step in a process that serves to eliminate the injured cell. We have now identified its effect on the complement system. Intermediate filaments were reconstituted in vitro from purified vimentin, and incubated with plasma proteins. Cross-linker experiments showed binding of the heavy chain of IgG to vimentin, indicating that the vimentin protein carries an Fc-binding site. In contrast, no direct binding of complement factor Clq to vimentin could be detected. Binding of both IgG and Clq could, however, be detected by immunofluorescence when cytoskeletons of cultured endothelial cells were incubated with fresh serum. Therefore, IgG binding to filaments in the presence of serum is accompanied by Clq binding to IgG. This was in turn followed by fixation of C4 and C3 to intermediate filaments in a process that was dependent on both Ca2+, Mg2+ and Clq, indicating that it was part of a complement activation via the classical pathway. Exposure of fresh serum to intermediate filaments also resulted in production of the anaphylatoxic complement cleavage fragment. C3a, with a dose-response relationship between the amount of filaments present and the amount of C3a generated. Chemotactic activity towards granulocytes and monocytes was also generated by exposure of serum to intermediate filaments, and this activity was dependent on the presence of complement factor C5 and on the classical complement activation cascade, implying that it was due to the C5a peptide. Exposure of the interior of the cell to plasma proteins thus results in binding of IgG to intermediate filaments and activation of the complement cascade via the classical pathway. This, in turn generates bioactive mediators which may recruit leukocytes to the injured cell (C5a) and have profound effects on vascular permeability (C3a, C5a). We propose that this is part of a scavenger mechanism for the elimination of damaged cells.
D001665:Binding Sites; D002634:Chemotaxis, Leukocyte; D003166:Complement Activating Enzymes / Q000378:metabolism*; D003167:Complement Activation; D003172:Complement C1 / Q000378:metabolism*; D015922:Complement C1q; D003176:Complement C3 / Q000378:metabolism; D015932:Complement C3c; D003181:Complement C4 / Q000378:metabolism; D003182:Complement C5 / Q000378:metabolism; D015936:Complement C5a; D003171:Complement Pathway, Classical; D006801:Humans; D007127:Immunoglobulin Constant Regions / Q000378:metabolism; D007074:Immunoglobulin G / Q000502:physiology*; D011485:Protein Binding; D014746:Vimentin / Q000502:physiology*
D003172:Complement C1; D003176:Complement C3; D003181:Complement C4; D003182:Complement C5; D007127:Immunoglobulin Constant Regions; D007074:Immunoglobulin G; D014746:Vimentin; D015922:Complement C1q; D015932:Complement C3c; D015936:Complement C5a; D003166:Complement Activating Enzymes