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.

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 plasma protein properdin is the only known positive regulator of complement activation. Although regarded as an initiator of the alternative pathway of complement activation at the time of its discovery more than a half century ago, the role and mechanism of action of properdin in the complement cascade has undergone significant conceptual evolution since then. Despite the long history of research on properdin, however, new insight and unexpected findings on the role of properdin in complement activation, pathogen infection and host tissue injury are still being revealed by ongoing investigations. In this article, we provide a brief review on recent studies that shed new light on properdin biology, focusing on the following three topics: 1) its role as a pattern recognition molecule to direct and trigger complement activation, 2) its context-dependent requirement in complement activation on foreign and host cell surfaces, and 3) its involvement in alternative pathway complement-mediated immune disorders and considerations of properdin as a potential therapeutic target in human diseases.