Abstract
Background and objects: In systemic lupus erythematosus, circulating immune complexes activate complement and, when trapped in renal capillaries, cause glomerulonephritis. Mouse models have been used in the preclinical assessment of targeting complement activation pathways to manage chronic inflammation in lupus. Properdin is the only known positive regulator of complement activation, but its role in the severity of lupus nephritis has not been studied yet. Materials and Methods: Fully characterized properdin-deficient mice were crossed with lupus prone MRL/lpr mice on C57Bl/6 background. Results: Compared to MRL/lpr properdin wildtype mice, MRL/lpr properdin-deficient mice had significantly lower anti-DNA antibody titres, TNFα and BAFF levels in serum. The qualitative glomerulonephritic score was less severe and there was significantly less serum creatinine in MRL/lpr properdin-deficient mice compared to MRL/lpr properdin wildtype littermate mice. Conclusion: Properdin plays a significant role in the severity of lupus overall and specifically in the extent of glomerulonephritis observed in MRL/lpr mice. Because MRL/lpr properdin-deficient mice had lower levels of anti-DNA antibodies, inflammatory mediators and markers of renal impairment, the study implies that properdin could constitute a novel therapy target in lupus disease.
Highlights
The complement system, a cascade of carefully regulated enzymatic reactions, bridges innate and adaptive immunity
The aim of this study was to determine whether, in the genetic absence of properdin, the systemic and organ specific inflammation was less severe, by using a novel mouse model generated by crossing the repository archived lupus-prone MRL/MpJ-Faslpr/J mice with our line of properdin knock-out mice to produce a strain of lupus-prone properdin-deficient (MRL/lpr PKO ) mice, and lupus-prone properdin-sufficient littermates (MRL/lpr PWT ) as controls
In a functional test of serum obtained from properdin deficient mice, we showed that properdin was the dominant factor in rabbit red blood cell lysis in buffers favouring alternative pathway activation [20]
Summary
The complement system, a cascade of carefully regulated enzymatic reactions, bridges innate and adaptive immunity. Complement activation is well controlled through the presence of regulators on the surface of host cells or in circulation [1]. The non-enzymatic formation of the membrane attack complex leads to pore formation, causing the rapid lytic destruction of damaged cells (or some Gram-negative microorganisms) but is detectable in a soluble form in systemic lupus erythematosus (SLE) [2]. In systemic lupus erythematosus, circulating immune complexes activate complement and, when trapped in renal capillaries, cause glomerulonephritis. Mouse models have been used in the preclinical assessment of targeting complement activation pathways to manage chronic inflammation in lupus. Properdin is the only known positive regulator of complement activation, but its role in the severity of lupus nephritis has not been studied yet.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
