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Generation of C5a in the absence of C3: a new complement activation pathway


Complement-mediated tissue injury in humans occurs upon deposition of immune complexes, such as in autoimmune diseases and acute respiratory distress syndrome. Acute lung inflammatory injury in wild-type and C3−/− mice after deposition of IgG immune complexes was of equivalent intensity and was C5a dependent, but injury was greatly attenuated in Hc−/− mice (Hc encodes C5). Injury in lungs of C3−/− mice and C5a levels in bronchoalveolar lavage (BAL) fluids from these mice were greatly reduced in the presence of antithrombin III (ATIII) or hirudin but were not reduced in similarly treated C3+/+ mice. Plasma from C3−/− mice contained threefold higher levels of thrombin activity compared to plasma from C3+/+ mice. There were higher levels of F2 mRNA (encoding prothrombin) as well as prothrombin and thrombin protein in liver of C3−/− mice compared to C3+/+ mice. A potent solid-phase C5 convertase was generated using plasma from either C3+/+ or C3−/− mice. Human C5 incubated with thrombin generated C5a that was biologically active. These data suggest that, in the genetic absence of C3, thrombin substitutes for the C3-dependent C5 convertase. This linkage between the complement and coagulation pathways may represent a new pathway of complement activation.

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Figure 1: Immune complex–induced injury in C5 and C3 wild-type and knockout mice.
Figure 2: Lung injury in C3+/+ and C3−/− mice and protective effects of C5a-specific antibody (anti-C5a).
Figure 3: Generation of C5a activity in C3+/+ and C3−/− plasma and formation of a solid-phase C5 convertase.
Figure 4: Evidence for thrombin as a C5 convertase.


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This work was supported by US National Institutes of Health grants GM-29507, HL-31963 (to P.A.W.), GM-069438 (to J.G.Y.), DK-59422, AI-30040 and GM-069736 (to J.D.L.) and Deutsche Forschungsgemeinschaft grant HU823/2-2 (to M.H.-L.). We thank B. Schumann for secretarial assistance in preparation of the manuscript and R. Kunkel for assistance in preparing illustrations. We thank S. Albers for laboratory assistance. We thank A. Schmaier for suggestions regarding the prothrombin/thrombin studies and M. Carroll for supplying a second C3−/− strain of mice.

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M.H.-L., J.V.S., F.S.Z., S.M.D., R.L.W., M.A.F., D.R., L.M.H., R.A.W., S.R.M., T.A.N., J.G.Y. and P.A.W. contributed to animal models. J.V.S., F.S.Z., J.D.L. and T.A.N. contributed to ATIII and hirudin experiments. J.D.L. and F.G. contributed to thrombin experiments.

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Correspondence to Peter A Ward.

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Huber-Lang, M., Sarma, J., Zetoune, F. et al. Generation of C5a in the absence of C3: a new complement activation pathway. Nat Med 12, 682–687 (2006).

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