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.