The dual role of complement in the progression of renal disease in NZB/W F1 mice and alternative pathway inhibition

Complement plays a dual role in the progression of systemic lupus erythematosus since it has important protective functions, such as the clearance of immune complexes and apoptotic cells, but is also a mediator of renal inflammation. To investigate this balance in a clinically relevant setting, we investigated how targeted inhibition of all complement pathways vs. targeted inhibition of only the alternative pathway impacts immune and therapeutic outcomes in NZB/W F1 mice. Following onset of proteinuria, mice were injected twice weekly with CR2-fH (inhibits alternative pathway), CR2-Crry (inhibits all pathways at C3 activation step), sCR2 (C3d targeting vehicle) or saline. Sera were analyzed every 2 weeks for anti-dsDNA antibody levels, and urinary albumin excretion was determined. Kidneys were collected for histological evaluation at 32 weeks. Compared to the control group, all CR2-fH, CR2-Crry and sCR2 treated groups showed significantly reduced serum anti-dsDNA antibody levels and strong trends towards reduced glomerular IgG deposition levels. Glomerular C3 deposition levels were also significantly reduced in all three-treated groups. However, significant reductions of disease activity (albuminuria and glomerulonephritis) were only seen in the CR2-fH treated group. These data highlight the dual role played by complement in the pathogenesis of lupus, and demonstrate a benefit of selectively inhibiting the alternative complement pathway, presumably because of protective contributions from the classical and/or lectin pathways. The sCR2 targeting moiety appears to be contributing to therapeutic outcome via modulation of autoimmunity. Furthermore, these results are largely consistent with our previous data using the MRL/lpr lupus model, thus broadening the significance of these findings.

► Complement plays a dual role in the pathogenesis of lupus. ► Selectively inhibiting the alternative complement pathway provides optimal protection from lupus nephritis. ► sCR2, the targeting moiety used to target deliver inhibitors to sites of complement activation, contributes to therapeutic outcome via modulation of autoimmunity.