Properdin binding independent of complement activation in an in vivo model of anti-GBM disease

Juha Kotimaa, Joseph O'Flynn, Ria Faber-Krol, Karin Koekkoek, Ngaisah Klar-Mohamad, Angela Koudijs, Wilhelm J. Schwaeble, Cordula Stover, Mohamed R. Daha, Cees van Kooten

Research output: Conference materialsAbstractResearchpeer-review

Abstract

Properdin is the only known positive regulator of complement activation, stabilizing the alternative pathway (AP) convertase through C3 binding, thus prolonging its half-life and potentiating alternative pathway and complement amplification loop. Recent in vitro studies have suggested that in addition to the well understood interaction with C3, properdin (fP) may bind or deposit on to different surfaces and biomolecules, such as dying cells, LPS and heparan sulphates. To better understand the role of fP in vivo, we used an experimental model of acute anti-glomerular basement membrane (anti-GBM) nephritis which has been shown to have contribution by both classical (CP) and alternative (AP) pathways. It is characterized by severe proteinuria at 72–96 h, indicative of glomerular injury. Mice were sacrificed at different time points and analysed for complement activation. Activation of CP was confirmed by acute (2 h) and persistent glomerular C1q deposition (until 72 h). Also C3 deposition was observed from 2 h onwards. In contrast, deposition of fP and the terminal pathway components C6 and C9 were relatively late from 24 h onwards. Administration of anti-GBM in C3 and fP knockout (KO) showed trend for reduced proteinuria compared to wild-type (WT) mice. Importantly, fP deposition was also observed in the glomeruli of C3 KO mice. In some cases, there was co-localisation of fP with TUNEL positive apoptotic cells, both within WT and C3 KO mice glomeruli. Further analysis showed limited co-localisation of fP with infiltrating neutrophils and anti-GBM nephritis inducing IgG. Together our results establish for the first time a C3-independent deposition of properdin in vivo, possibly interacting with injured glomeruli and apoptotic cells, thereby further supporting a potential role of fP as pattern recognition molecule.
Original languageEnglish
Pages176-176
Number of pages1
Publication statusPublished - Oct 2018
MoE publication typeNot Eligible

Cite this

Kotimaa, J., O'Flynn, J., Faber-Krol, R., Koekkoek, K., Klar-Mohamad, N., Koudijs, A., ... van Kooten, C. (2018). Properdin binding independent of complement activation in an in vivo model of anti-GBM disease. 176-176.
Kotimaa, Juha ; O'Flynn, Joseph ; Faber-Krol, Ria ; Koekkoek, Karin ; Klar-Mohamad, Ngaisah ; Koudijs, Angela ; Schwaeble, Wilhelm J. ; Stover, Cordula ; Daha, Mohamed R. ; van Kooten, Cees. / Properdin binding independent of complement activation in an in vivo model of anti-GBM disease. 1 p.
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title = "Properdin binding independent of complement activation in an in vivo model of anti-GBM disease",
abstract = "Properdin is the only known positive regulator of complement activation, stabilizing the alternative pathway (AP) convertase through C3 binding, thus prolonging its half-life and potentiating alternative pathway and complement amplification loop. Recent in vitro studies have suggested that in addition to the well understood interaction with C3, properdin (fP) may bind or deposit on to different surfaces and biomolecules, such as dying cells, LPS and heparan sulphates. To better understand the role of fP in vivo, we used an experimental model of acute anti-glomerular basement membrane (anti-GBM) nephritis which has been shown to have contribution by both classical (CP) and alternative (AP) pathways. It is characterized by severe proteinuria at 72–96 h, indicative of glomerular injury. Mice were sacrificed at different time points and analysed for complement activation. Activation of CP was confirmed by acute (2 h) and persistent glomerular C1q deposition (until 72 h). Also C3 deposition was observed from 2 h onwards. In contrast, deposition of fP and the terminal pathway components C6 and C9 were relatively late from 24 h onwards. Administration of anti-GBM in C3 and fP knockout (KO) showed trend for reduced proteinuria compared to wild-type (WT) mice. Importantly, fP deposition was also observed in the glomeruli of C3 KO mice. In some cases, there was co-localisation of fP with TUNEL positive apoptotic cells, both within WT and C3 KO mice glomeruli. Further analysis showed limited co-localisation of fP with infiltrating neutrophils and anti-GBM nephritis inducing IgG. Together our results establish for the first time a C3-independent deposition of properdin in vivo, possibly interacting with injured glomeruli and apoptotic cells, thereby further supporting a potential role of fP as pattern recognition molecule.",
author = "Juha Kotimaa and Joseph O'Flynn and Ria Faber-Krol and Karin Koekkoek and Ngaisah Klar-Mohamad and Angela Koudijs and Schwaeble, {Wilhelm J.} and Cordula Stover and Daha, {Mohamed R.} and {van Kooten}, Cees",
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Kotimaa, J, O'Flynn, J, Faber-Krol, R, Koekkoek, K, Klar-Mohamad, N, Koudijs, A, Schwaeble, WJ, Stover, C, Daha, MR & van Kooten, C 2018, 'Properdin binding independent of complement activation in an in vivo model of anti-GBM disease' pp. 176-176.

Properdin binding independent of complement activation in an in vivo model of anti-GBM disease. / Kotimaa, Juha; O'Flynn, Joseph; Faber-Krol, Ria; Koekkoek, Karin; Klar-Mohamad, Ngaisah; Koudijs, Angela; Schwaeble, Wilhelm J.; Stover, Cordula; Daha, Mohamed R.; van Kooten, Cees.

2018. 176-176.

Research output: Conference materialsAbstractResearchpeer-review

TY - CONF

T1 - Properdin binding independent of complement activation in an in vivo model of anti-GBM disease

AU - Kotimaa, Juha

AU - O'Flynn, Joseph

AU - Faber-Krol, Ria

AU - Koekkoek, Karin

AU - Klar-Mohamad, Ngaisah

AU - Koudijs, Angela

AU - Schwaeble, Wilhelm J.

AU - Stover, Cordula

AU - Daha, Mohamed R.

AU - van Kooten, Cees

PY - 2018/10

Y1 - 2018/10

N2 - Properdin is the only known positive regulator of complement activation, stabilizing the alternative pathway (AP) convertase through C3 binding, thus prolonging its half-life and potentiating alternative pathway and complement amplification loop. Recent in vitro studies have suggested that in addition to the well understood interaction with C3, properdin (fP) may bind or deposit on to different surfaces and biomolecules, such as dying cells, LPS and heparan sulphates. To better understand the role of fP in vivo, we used an experimental model of acute anti-glomerular basement membrane (anti-GBM) nephritis which has been shown to have contribution by both classical (CP) and alternative (AP) pathways. It is characterized by severe proteinuria at 72–96 h, indicative of glomerular injury. Mice were sacrificed at different time points and analysed for complement activation. Activation of CP was confirmed by acute (2 h) and persistent glomerular C1q deposition (until 72 h). Also C3 deposition was observed from 2 h onwards. In contrast, deposition of fP and the terminal pathway components C6 and C9 were relatively late from 24 h onwards. Administration of anti-GBM in C3 and fP knockout (KO) showed trend for reduced proteinuria compared to wild-type (WT) mice. Importantly, fP deposition was also observed in the glomeruli of C3 KO mice. In some cases, there was co-localisation of fP with TUNEL positive apoptotic cells, both within WT and C3 KO mice glomeruli. Further analysis showed limited co-localisation of fP with infiltrating neutrophils and anti-GBM nephritis inducing IgG. Together our results establish for the first time a C3-independent deposition of properdin in vivo, possibly interacting with injured glomeruli and apoptotic cells, thereby further supporting a potential role of fP as pattern recognition molecule.

AB - Properdin is the only known positive regulator of complement activation, stabilizing the alternative pathway (AP) convertase through C3 binding, thus prolonging its half-life and potentiating alternative pathway and complement amplification loop. Recent in vitro studies have suggested that in addition to the well understood interaction with C3, properdin (fP) may bind or deposit on to different surfaces and biomolecules, such as dying cells, LPS and heparan sulphates. To better understand the role of fP in vivo, we used an experimental model of acute anti-glomerular basement membrane (anti-GBM) nephritis which has been shown to have contribution by both classical (CP) and alternative (AP) pathways. It is characterized by severe proteinuria at 72–96 h, indicative of glomerular injury. Mice were sacrificed at different time points and analysed for complement activation. Activation of CP was confirmed by acute (2 h) and persistent glomerular C1q deposition (until 72 h). Also C3 deposition was observed from 2 h onwards. In contrast, deposition of fP and the terminal pathway components C6 and C9 were relatively late from 24 h onwards. Administration of anti-GBM in C3 and fP knockout (KO) showed trend for reduced proteinuria compared to wild-type (WT) mice. Importantly, fP deposition was also observed in the glomeruli of C3 KO mice. In some cases, there was co-localisation of fP with TUNEL positive apoptotic cells, both within WT and C3 KO mice glomeruli. Further analysis showed limited co-localisation of fP with infiltrating neutrophils and anti-GBM nephritis inducing IgG. Together our results establish for the first time a C3-independent deposition of properdin in vivo, possibly interacting with injured glomeruli and apoptotic cells, thereby further supporting a potential role of fP as pattern recognition molecule.

M3 - Abstract

SP - 176

EP - 176

ER -

Kotimaa J, O'Flynn J, Faber-Krol R, Koekkoek K, Klar-Mohamad N, Koudijs A et al. Properdin binding independent of complement activation in an in vivo model of anti-GBM disease. 2018.