The role of properdin in complement-mediated renal diseases: a new player in complement-inhibiting therapy?

Abstract

Properdin is known as the only positive regulator of the complement system. Properdin promotes the activity of this defense system by stabilizing its key enzymatic complexes: the complement alternative pathway (AP) convertases. Besides, some studies have indicated a role for properdin as an initiator of complement activity. Though the AP is a powerful activation route of the complement system, it is also involved in a wide variety of autoimmune and inflammatory diseases, many of which affect the kidneys. The role of properdin in regulating complement in health and disease has not received as much appraisal as the many negative AP regulators, such as factor H. Historically, properdin deficiency has been strongly associated with an increased risk for meningococcal disease. Yet only recently had studies begun to link properdin to other complement-related diseases, including renal diseases. In the light of the upcoming complement-inhibiting therapies, it is interesting whether properdin can be a therapeutic target to attenuate AP-mediated injury. A full understanding of the basic concepts of properdin biology is therefore needed. Here, we first provide an overview of the function of properdin in health and disease. Then, we explore its potential as a therapeutic target for the AP-associated renal diseases C3 glomerulopathy, atypical hemolytic uremic syndrome, and proteinuria-induced tubulointerstitial injury. Considering current knowledge, properdin-inhibiting therapy seems promising in certain cases. However, knowing the complexity of properdin's role in renal pathologies in vivo, further research is required to clarify the exact potential of properdin-targeted therapy in complement-mediated renal diseases.

Mycophenolate Mofetil in C3 Glomerulopathy and Pathogenic Drivers of the Disease

“…The number of patients who tested positive for autoantibodies was somewhat lower in our study, as compared with previous reports (6,20). We hypothesize that the determination of autoantibodies in some patients when they were already receiving immunosuppressive treatments could account for this discrepancy (24,25).…”

Complement Properdin Determines Disease Activity in MRL/lpr Mice

“…While the absence of Factors B or D abrogates the assembly of the convertase complexes C3bBb and C3b n Bb (Factor D cleaves Factor B to produce Bb), the absence of properdin leaves the enzyme complexes labile to decay. The therapeutic targeting of properdin in lupus nephritis would likely require vaccinations against meningococcal disease [ 39 ]. Previously, the therapeutic application of a soluble form of a complement receptor of the Immunoglobulin superfamily, which functions as an inhibitor of the alternative pathway, led to a reduction in lupus nephritis at a comparable endpoint (4 months) in MRL/ lpr mice, but, in contrast to our study, showed no effect on the levels of autoantibodies [ 40 ].…”

Effects of immunoadsorption combined with membrane filtration on complement markers – results of a randomized, controlled, crossover study

“…The role of properdin as a pattern‐recognition molecule and initiator of the AP has been extensively discussed: it seems that binding of properdin to complement activating surfaces depends on the initial C3b deposition . As the only known positive regulator of the CS, it has not been established whether properdin plays a role in complement‐mediated renal diseases, or whether properdin could be a therapeutic target . Properdin seems to be implicated in complement‐mediated diseases, such as in renal ischemia/reperfusion injury (IRI) lesions .…”