Figure 7.

Model for mechanisms leading from fluid-phase impaired regulation of the alternative pathway to C3 glomerulopathies. Mutations in the factor H (FH) gene causing very low FH levels or impaired FH cofactor activity, or C3 nephritic factor (C3NeF) and C3 gain-of-function mutations that render the alternative pathway C3 convertase resistant to FH-mediated dissociation; all result in uncontrolled fluid-phase alternative pathway activation and finally in the formation of the fluid-phase terminal complement pathway complex (with vitronectin or clusterin bound; sC5b-9). The injury likely develops upon deposition in the subendothelial space of C3 activating products and the terminal complement complex after transfer through the fenestrated endothelium (dashed line). Abbreviations: FB, factor B; FI, factor I; MCP, membrane cofactor protein.