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

Marloes A H M Michels,Nicole C A J Van De Kar,Lambertus P W J Van Den Heuvel,Elena B Volokhina

doi:10.1007/s00467-018-4042-z

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.

Highlights

In the last decades, it has become evident that the complement system is involved in various diseases [1]
Almost two times lower in C3 glomerulonephritis (C3GN) compared with dense deposit disease (DDD), while soluble C5b-9 (sC5b-9) levels were elevated in C3GN compared with
C3GN was more frequent in the C3 nephritic factors (C3NeF)-negative group, but no difference in C3GN frequency between the groups with normal versus reduced P

Summary

Introduction

It has become evident that the complement system is involved in various diseases [1]. Confirming its potential as a direct pattern recognition molecule in different in vivo environments (Fig. 3(C)) demands for a critical evaluation of used properdin preparations and experimental setup Taking these conditions into account, the most important properdin-target interactions published so far can be summarized as follows: purified physiological properdin oligomers were shown to bind directly to zymosan [63, 64], necrotic, diseased B and T cell lines [64], Chlamydia pneumoniae [65], and activated platelets [67]; freshly secreted properdin was found to bind to apoptotic T cells [60] and activated platelets [67]; and properdin in C3-inactive serum has only been shown to bind to necrotic cells so far [17]. In cases of infection where complement is directed to the invading

Findings

Concluding remarks

Which statement about properdin is not true?

Compliance with ethical standards