Absence of functional alternative complement pathway alleviates lupus cerebritis

The complement inhibitor, Crry, which blocks both the classical and alternative pathways, alleviates CNS disease in the lupus model, MRLIMpJ-Tnfrsf6lpr (MRL/Ipr) mice. To understand the role of the alternative pathway, we studied mice deficient in a key alternative pathway protein, complement factor B (M). Immune deposits (IgG and C3) were reduced in the brains of MRL/lpr fB-deficient (fB(-/-)MRL/lpr) compared to fBsufficient (MRL/Ipr) mice, indicating reduced complement activation. Reduced neutrophil infiltration (22% of MRL/1pr mice) and apoptosis (caspase-3 activity was reduced to 33% of MRL/Ipr mice) in these mice indicates that the absence of the alternative pathway was neuroprotective. Furthermore, expression of phospho (p)-Akt (0.16 +/- 0.02 vs. 0.35 +/- 0.13, p < 0.03) was increased, while expression of p-PTEN (0.40 +/- 0.06 vs. 0.11 +/- 0.07, p < 0.05) was decreased in fB(-/-)MRL/lpr mice compared to their MRL/1pr counterparts. The expression of fibronectin, laminin and collagen I-V was significantly decreased in fB(-/-)MRL/Ipr mice compared to MRL/lpr mice, indicating that in the lupus setting, tissue integrity was maintained in the absence of the alternative pathway. Absence of fB reduced behavioral alterations in MRL/lpr mice. Our results suggest that in lupus, the alternative pathway may be the key mechanism through which complement activation occurs in brain, and therefore it might serve as a therapeutic target for lupus cerebritis.