Loss of Properdin Exacerbates C3 Glomerulopathy Resulting from Factor H Deficiency

Abstract

Complement factor H (CFH) is a negative regulator of the alternative pathway of complement, and properdin is the sole positive regulator. CFH-deficient mice (CFH 2/2 ) develop uncontrolled C3 activation and spontaneous renal disease characterized by accumulation of C3 along the glomerular basement membrane, but the role of properdin in the pathophysiology is unknown. Here, we studied mice deficient in both CFH and properdin (CFH 2/2 .P 2/2 ). Although CFH 2/2 mice had plasma depleted of both C3 and C5, CFH 2/2 .P 2/2 animals exhibited depletion of C3 predominantly, recapitulating the plasma complement profile observed in humans with properdin-independent C3 nephritic factors. Glomerular inflammation, thickening of the capillary wall, and glomerular C3 staining were significantly increased in CFH 2/2 .P 2/2 compared with CFH 2/2 mice. We previously reported that exogenous CFH ameliorates C3 staining of the glomerular basement membrane and triggers the appearance of mesangial C3 deposits in CFH 2/2 mice; here, we show that these effects require properdin. In summary, during uncontrolled activation of C3 driven by complete CFH deficiency, properdin influences the intraglomerular localization of C3, suggesting that therapeutic inhibition of properdin would be detrimental in this setting.

The role of the alternative pathway of complement activation in glomerular diseases

“…These results are consistent with the previously described role of FP in animal models deficient in CFH gene, where coexisting FP deficiency was associated with C3 depletion, whereas plasma C5 depletion was (at least in part) FP-dependent [91,92]. In CFH −/− mice, FP also influenced the intraglomerular distribution of C3, since only these mice injected with human CFH presented C3 mesangial deposition, while CFH −/− /P −/− mice did not show mesangial C3 staining [91].…”

“…Conversely, enhancing FP would cause more efficient AP activation. Unexpectedly, studies on murine models, designed to inhibit FP by producing animals deprived of CFH and FP genes [91] [91,92]. These studies emphasize the complexity of C3G pathogenesis.…”

Unexpected Role for Properdin in Complement C3 Glomerulopathies

“…10,11 Using comparable murine models, both Ruseva et al 10 and Lesher et al 11 come to the same unexpected findings, namely that fP deletion or depletion with mAbs, in contrast to what one would have expected, results in more severe renal pathology in fH 2/2 mice. The study by Ruseva et al…”

“…In this sense, the murine model of Ruseva et al 10 would be compatible with the fP-independent C3NeF patients. Together with the findings of Lesher et al, 11 it is clear that fP influences the intraglomerular fate of C3 during dysregulation of fluid phase C3 activation.…”

“…As pointed out by Ruseva et al, 10 DDD associates with uncontrolled activation of C3, most commonly due to C3NeF, an IgG antibody that stabilizes the AP C3 convertase. It was found that C3NeF activity is heterogeneous because some C3NeFs activate C3 without affecting terminal pathway activation while other C3NeFs clearly affect C5-9 activation.…”