Combination of Factor H Mutation and Properdin Deficiency Causes Severe C3 Glomerulonephritis

Abstract

Factor H (fH) and properdin both modulate complement; however, fH inhibits activation, and properdin promotes activation of the alternative pathway of complement. Mutations in fH associate with several human kidney diseases, but whether inhibiting properdin would be beneficial in these diseases is unknown. Here, we found that either genetic or pharmacological blockade of properdin, which we expected to be therapeutic, converted the mild C3 GN of an fH-mutant mouse to a lethal C3 GN with features of human dense deposit disease. We attributed this phenotypic change to a differential effect of properdin on the dynamics of alternative pathway complement activation in the fluid phase and the cell surface in the fHmutant mice. Thus, in fH mutation-related C3 glomerulopathy, additional factors that impact the activation of the alternative pathway of complement critically determine the nature and severity of kidney pathology. These results show that therapeutic manipulation of the complement system requires rigorous diseasespecific target validation.

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

“…The prevalence of C5Nef was higher in C3GN (72%), while C3Nef was more frequent in DDD (71%), suggesting that the type of nephritic factors may determine the biological phenotype of C3G [98]. 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

“…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. The most important conclusion from these two novel and elegant studies is that inhibition of fP in situations of uncontrolled fluid phase activation of complement may be disadvantageous to the host, whereas absence of fP in models of tissue-bound activation of the AP is favorable.…”

“…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…”

“…The study by Lesher et 11 also found that deletion of fP did not result in prevention of renal disease but in aggravation of disease activity. The investigators concluded that additional factors that affect the AP complement activation pathway critically determine the nature and severity of the kidney pathology.…”