Continual low-level activation of the classical complement pathway.
There is evidence that the classical complement pathway may be activated via a "C1-tickover" mechanism, analogous to the C3-tickover of the alternative pathway. We have quantitated and characterized this pathway of complement activation. Analysis of freshly collected mouse and human plasma revealed that spontaneous C3 activation rapidly occurred with the generation of C3 fragments in the plasma. By the use of complement- and Ig-deficient mice it was found that C1q, C4, C2, and plasma Ig were all required for this spontaneous C3 activation, with the alternative complement pathway further amplifying C3 fragment generation. Study of plasma from a human with C1q deficiency before and after therapeutic C1q infusion confirmed the existence of a similar pathway for complement activation in humans. Elevated levels of plasma C3 were detected in mice deficient in complement components required for activation of either the classical or alternative complement pathways, supporting the hypothesis that there is continuous complement activation and C3 consumption through both these pathways in vivo. Blood stasis was found to stimulate C3 activation by classical pathway tick-over. This antigen-independent mechanism for classical pathway activation may augment activation of the complement system at sites of inflammation and infarction.
Manderson
A P
AP
Division of Immunology and Cell Biology, John Curtin School of Medical Research, The Australian National University, Canberra ACT 2601, Australia.
Pickering
M C
MC
Botto
M
M
Walport
M J
MJ
Parish
C R
CR
D000818:Animals; D003167:Complement Activation / Q000276:immunology*; D015922:Complement C1q / Q000276:immunology; D003176:Complement C3 / Q000276:immunology*; D003181:Complement C4 / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018448:Models, Immunological; D014407:Tumor Cells, Cultured
D003176:Complement C3; D003181:Complement C4; D007074:Immunoglobulin G; D015922:Complement C1q