Abstract
C3 glomerulopathy is characterized by accumulation of complement C3 within glomeruli. Causes include, but are not limited to, abnormalities in factor H, the major negative regulator of the complement alternative pathway. Factor H-deficient (Cfh-/-) mice develop C3 glomerulopathy together with a reduction in plasma C3 levels. Using this model, we assessed the efficacy of two fusion proteins containing the factor H alternative pathway regulatory domains (FH1-5) linked to either a non-targeting mouse immunoglobulin (IgG-FH1-5) or to an anti-mouse properdin antibody (Anti-P-FH1-5). Both proteins increased plasma C3 and reduced glomerular C3 deposition to an equivalent extent, suggesting that properdin-targeting was not required for FH1-5 to alter C3 activation in either plasma or glomeruli. Following IgG-FH1-5 administration, plasma C3 levels temporally correlated with changes in factor B levels whereas plasma C5 levels correlated with changes in plasma properdin levels. Notably, the increases in plasma C5 and properdin levels persisted for longer than the increases in C3 and factor B. In Cfh-/- mice IgG-FH1-5 reduced kidney injury during accelerated serum nephrotoxic nephritis. Thus, our data demonstrate that IgG-FH1-5 restored circulating alternative pathway activity and reduced glomerular C3 deposition in Cfh-/- mice and that plasma properdin levels are a sensitive marker of C5 convertase activity in factor H deficiency. The immunoglobulin conjugated FH1-5 protein, through its comparatively long plasma half-life, may be a potential therapy for C3 glomerulopathy.
Highlights
Linked to either a non-targeting mouse immunoglobulin (IgG-FH1-5) or to an anti-mouse properdin antibody (Anti-PFH1-5)
Following IgG-FH1-5 administration, plasma C3 levels temporally correlated with changes in factor B levels whereas plasma C5 levels correlated with changes in plasma properdin levels
Both IgG-FH1-5 and anti-P-FH1-5 normalized C3, factor B (FB), and C5 levels in Cfh–/– mice. This finding is consistent with the fact that the complement regulatory domains of mouse factor H (FH) are located within short consensus repeat (SCR) domains 1 through 5
Summary
Fusion proteins were created by linking the first 5 short consensus repeat (SCR) domains of mouse FH (FH1-5) to either an anti-mouse properdin antibody (anti-P-FH1-5). Injection of antiP-FH1-5 protein into wild-type mice resulted in glomerular staining with anti-properdin, anti-FH/FHR, and anti-IgG antibodies at 96 hours (Supplementary Figure S3), indicating that this reagent interacts with normal glomeruli. When we injected the reagent into Cfh–/– mice that had been pretreated with anti-P to remove glomerular properdin, there was a reduction in the granular staining patterns using anti-properdin, anti-FH/FHR, and anti-IgG antibodies (Supplementary Figure S4). These observations indicate that the glomerular interaction of anti-P-FH1-5 protein in Cfh–/– mice is partly dependent on glomerular properdin.
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