C3(H2O) prevents rescue of complement-mediated C3 glomerulopathy in Cfh-/- Cfd-/- mice

Therapeutic complement inhibition is a major focus for novel drug development. Of upstream targets, factor Ell (FD) is appealing because it circulates in plasma at low concentrations and has a single function: to cleave factor B to generate C3 convertase of the alternative pathway (AP). Mice with a targeted deletion of factor H (FH; Cfh(-/-) mice) develop C3 glomerulopathy (C3G) due to uncontrolled AP activity. To assess the impact of FD inhibition, we studied Cfly(-/-) Cfd(-/-) mice. We show that C3G in Cfh(-/-) mice is not rescued by removing FD. We used serum from Cfh(-/-) Cld(-/-) mice to demonstrate that residual AP function occurs even when both FD and FH are missing and that hemolytic activity is present due to the action of C3(H2O). We propose that uncontrolled tickover leads to slow activation of the AP in Cfh(-/-) Cfd(-/-) mice and that a minimal threshold of FH is necessary if tissue deposition of C3 is to be prevented. The FD/FH ratio dictates serum C3 level and renal C3b deposition. In C3G patients with chronic renal disease, the FD/FH ratio correlates inversely with C3 and CS serum levels, suggesting that continuous AP control may be difficult to achieve by targeting FD.