Abstract
The complement inhibitor, Crry, which blocks both the classical and alternative pathways, alleviates CNS disease in the lupus model, MRL/MpJ‐Tnfrsf6lpr (MRL/lpr) mice. To understand the role of the alternative pathway, we studied mice deficient in a key alternative pathway protein, complement factor B (fB). Immune deposits (IgG and C3) were reduced in the brains of MRL__/lpr__ fB‐deficient (fB^–/–^MRL__/lpr__) compared to fB‐sufficient (MRL__/lpr__) mice, indicating reduced complement activation. Reduced neutrophil infiltration (22% of MRL__/lpr__ mice) and apoptosis (caspase‐3 activity was reduced to 33% of MRL__/lpr__ 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__/lpr__ counterparts. The expression of fibronectin, laminin and collagen IV was significantly decreased in fB^–/–^MRL__/lpr__ 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.