The complement cascade plays an important role in the pathogenesis of immune complex mediated diseases, including lupus nephritis. The alternative complement pathway is activated in lupus nephritis, though its role in the pathogenesis of disease is unclear. To provide insight into the role of the alternative pathway, and specifically the role of Factor B (Bf), in disease, mice deficient in Bf were derived. Bf deficient mice were found to have normal immune function despite being unable to activate the alternative pathway. To determine what role Bf and the alternative pathway play in autoimmune disease, we bred the Bf knockout genotype to the lupus prone MRL/lpr background. Compared to Bf expressing litter mates, the Bf deficient MRL/lpr mice developed significantly less proteinuria, pathologic renal disease, glomerular IgG immune deposits and vasculitis. Surprisingly, C3 levels were normal in the MRL/lpr Bf deficient mice in contrast to significantly, depressed levels in the Bf producing litter mates, typical of disease in MRL/lpr mice. These findings suggest Bf has a key pathogenic role in lupus nephritis in MRL/lpr mice and that the alternative pathway is an important mechanism for C3 activation and consumption in MRL/lpr disease. Our central hypothesis is that Factor B and the alternative pathway are pro-inflammatory in lupus and that blocking Factor B activity provides a novel approach to treating this disease. To further define the role of Factor B in immune complex mediated diseases and activation of C3, the following specific aims are proposed:
Aim 1 - Determine the mechanisms by which renal damage is diminished in Bf deficient MRL/lpr mice.
Aim 2 - Determine the mechanism for the maintenance of normal serum C3 levels in MRL/lpr Bf-/- mice .
Aim 3 - Identify the effects of Bf deficiency on autoimmune B cell function including isotype switching and tolerance as well as macrophage/mesangial cell function.
Aim 4 - Determine the potential for disease modification by inhibition of Bf activation using additional therapeutic strategies and models of glomerular injury. These studies will provide new insight into the role of the alternative pathway in disease and potentially provide a new therapeutic target (Factor B) in immune complex mediated diseases.
