Complement Properdin Determines Disease Activity in MRL/lpr Mice

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.

Exploring urine:serum fractional excretion ratios as potential biomarkers for lupus nephritis

“…Not surprisingly, targeting properdin, either genetically or pharmacologically, has been shown to effective in countering a number of renal diseases where properdin is elevated, including hemolytic uremic syndrome, ANCA-associated vasculitis, C3 glomerulopathy, IgA nephropathy, renal transplantation and murine model of acute anti-glomerular basement membrane disease ( 36 – 45 ). Recently, it has been shown that properdin-deficient MRL/lpr mice have reduced LN, again underscoring the pathogenic relevance of this molecule in this disease ( 46 ). Taken together with its outstanding diagnostic metrics, properdin warrants further study as a disease biomarker and potential therapeutic target in LN.…”