Unexpected Role for Properdin in Complement C3 Glomerulopathies

Daha, Mohamed R.

doi:10.1681/asn.2012111110

Cited by 8 publications

(6 citation statements)

References 16 publications

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“…Thus, in fH −/− and fH m/m mice, C5 consumption was largely dependent on P whereas C3 consumption was not. These findings are reminiscent of the effects of P-dependent and P-independent C3NeFs discussed above, with fH −/− and fH m/m mice displaying a complement profile analogous to that caused by P-dependent C3NeFs and fH −/− /P −/− and fH m/m /P −/− mice that of C3-independent C3NeFs (Daha, 2013; Lesher et al, 2013; Ruseva et al, 2013). They also suggested that C3 GN exacerbation in the fH/P double mutant mouse strains may be caused by a change in plasma complement, especially C5 levels.…”

Section: Role Of Properdin In Complement-mediated Tissue Injurymentioning

confidence: 54%

“…While the studies described above pointed to a detrimental role of P in AP complement-mediated tissue injury, a pair of recent studies in murine models of C3 glomerulopathy surprisingly revealed a protective role of P and suggested that therapeutic targeting of P may not always be desirable (Daha, 2013; Lesher et al, 2013; Ruseva et al, 2013). The fluid phase complement regulator fH plays a key role in preventing AP complement activation in the fluid phase and on the cell surface (Pangburn, 2000; Thompson and Winterborn, 1981).…”

Section: Role Of Properdin In Complement-mediated Tissue Injurymentioning

confidence: 99%

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Properdin in complement activation and tissue injury

Lesher

Nilsson

Song

2013

Molecular Immunology

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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.

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Section: Role Of Properdin In Complement-mediated Tissue Injurymentioning

confidence: 54%

Section: Role Of Properdin In Complement-mediated Tissue Injurymentioning

confidence: 99%

Properdin in complement activation and tissue injury

Lesher

Nilsson

Song

2013

Molecular Immunology

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“…While there are numerous reports, including this study, that support the role of P in AP complement-mediated renal tubular damage, P-targeting therapy has also been evaluated [11,27,28]. P blockade may be a logical therapeutic target, and the accumulation of further research is required to decrease renal tubular damage.…”

Section: Discussionmentioning

confidence: 98%

Properdin has an ascendancy over factor H regulation in complement-mediated renal tubular damage

et al. 2014

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BackgroundUrinary (U)-complement components have been detected in patients with proteinuric renal diseases, and complement activation via the alternative pathway (AP) is believed to play a role in renal tubular damage. The present study aimed to examine the regulation of complement AP activation in patients with renal tubular damage by focusing on the balance between properdin (P) and factor H (fH).MethodsIn the in vivo studies, U concentrations of P, fH and membrane attack complex (MAC) were measured in patients with renal diseases using an enzyme-linked immunosorbent assay (ELISA), and their relationships with the clinical data were evaluated. In the in vitro studies, human proximal tubular epithelial cells (PTECs) were incubated with normal human serum (NHS), P-depleted serum (PDS), purified P and/or fH. Changes in cell morphology and phenotype were assessed by microscopy, real-time polymerase chain reaction (PCR), immunostaining and a cell viability assay.ResultsThe U-P, fH and MAC concentrations were significantly higher in patients with renal disease than in normal controls and correlated with the U-protein and tubular damage markers. Furthermore, multivariate analysis revealed a relationship between P levels and tubular damage markers. There were no significant changes in morphology and mRNA expression in the AP components (P, fH, fB, C3, C5 and C9) after the addition of up to 25% NHS. Dose-dependent depositions of P or fH were observed after the addition of P or fH on PTECs. Depositions of P were not inhibited by fH in a mixture of a fixed concentration of P and a variable concentration of fH, and vice versa. Preincubation with the fixed concentration of P before the addition of NHS or PDS increased the depositions of P, C3 and MAC compared with incubation with intact NHS or intact PDS only; the depositions of C3 and MAC showed a serum-dependent trend. Preincubation with P before NHS addition significantly suppressed cell viability without causing morphological changes.ConclusionsIn the pathogenesis of renal tubular damage, P can directly bind to PTECs and may accelerate AP activation by surpassing fH regulation.

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“…In addition, the consequences of properdin deficiency must be fully investigated before the general use of properdin-targeted therapy can be considered. (45) The hamster anti-mTSR5/6 MAbs we describe here are useful tools that, when employed with AP-dependent animal models, can help resolve these and other related issues.…”

Section: Figmentioning

confidence: 99%

Anti-Mouse Properdin TSR 5/6 Monoclonal Antibodies Block Complement Alternative Pathway-dependent Pathogenesis

Bertram

Akk

Zhou

et al. 2015

Monoclonal Antibodies in Immunodiagnosis and Immunotherapy

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The complement alternative pathway (AP) is a major contributor to a broad and growing spectrum of diseases that includes age-related macular degeneration, atypical hemolytic uremic syndrome, and preeclampsia. As a result, there is much interest in the therapeutic disruption of AP activity. Properdin, the only positive regulator of the AP, is a particularly promising AP target. Several issues need to be clarified before the potential for properdin-directed therapy can be realized. In this report we use a portion of the mouse properdin protein, expressed in a bacterial system, to raise rabbit polyclonal and hamster monoclonal antibodies that block properdin-dependent pathogenesis. These antibodies, when employed with AP-dependent mouse disease models, can help evaluate the feasibility of properdin-directed therapy.

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Unexpected Role for Properdin in Complement C3 Glomerulopathies

Cited by 8 publications

References 16 publications

Properdin in complement activation and tissue injury

Properdin in complement activation and tissue injury

Properdin has an ascendancy over factor H regulation in complement-mediated renal tubular damage

Anti-Mouse Properdin TSR 5/6 Monoclonal Antibodies Block Complement Alternative Pathway-dependent Pathogenesis

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