Modulation of Renal Disease in MRL/lpr Mice Genetically Deficient in the Alternative Complement Pathway Factor B

Abstract

In systemic lupus erythematosus, the renal deposition of complement-containing immune complexes initiates an inflammatory cascade resulting in glomerulonephritis. Activation of the classical complement pathway with deposition of C3 is pathogenic in lupus nephritis. Although the alternative complement pathway is activated in lupus nephritis, its role in disease pathogenesis is unknown. To determine the role of the alternative pathway in lupus nephritis, complement factor B-deficient mice were backcrossed to MRL/lpr mice. MRL/lpr mice develop a spontaneous lupus-like disease characterized by immune complex glomerulonephritis. We derived complement factor B wild-type (B+/+), homozygous knockout (B−/−), and heterozygous (B+/−) MRL/lpr mice. Compared with B+/− or B+/+ mice, MRL/lpr B−/− mice developed significantly less proteinuria, less glomerular IgG deposition, and decreased renal scores as well as lower IgG3 cryoglobulin production and vasculitis. Serum C3 levels were normal in the B−/− mice compared with significantly decreased levels in the other two groups. These results suggest that: 1) factor B plays an important role in the pathogenesis of glomerulonephritis and vasculitis in MRL/lpr mice; and 2) activation of the alternative pathway, either by the amplification loop or by IgA immune complexes, has a prominent effect on serum C3 levels in this lupus model.

Absence of functional alternative complement pathway alleviates lupus cerebritis

“…IgM deposition was similar in the MRL/lpr mice both sufficient and deficient in fB with no apparent differences, while minimal deposition of IgA was observed in all the mice (data not shown). It was evident that the alternative pathway contributed to the increased deposits of IgG in MRL/lpr brains [7], since IgG (lower panel) was reduced in fB -/-MRL/lpr mice ( Fig. 2A, d) compared to the MRL/ lpr mice ( Fig.…”

“…Complement can be activated through classical, alternative and lectin pathways. Complement factor B (fB) is a key protein required for the activation of the alternative pathway [6] and is increased in circulation and in tissues of lupus mice [7][8][9]. In addition, fB solubilizes immune complexes, inhibits proliferation, acts as a B cell growth factor and activates monocytes 15].…”

“…In addition, fB solubilizes immune complexes, inhibits proliferation, acts as a B cell growth factor and activates monocytes 15]. Mice with targeted deletion of the fB gene (fB -/-) were protected from lupus nephritis and ischemiareperfusion injury [7,16]. However, the role of fB in the pathogenesis of lupus cerebritis has not been defined.…”

“…In light of these recent studies, breakdown of the BBB may give IgG access to the CNS and could activate complement proteins. This in turn could trigger neuronal damage, thereby contributing to the pathology observed in the lupus mouse models.To delineate the effects of the alternative and classical pathways and evaluate the role of the alternative pathway in lupus cerebritis, we studied the lupus mouse model, MRL/lpr mice [28,29], sufficient (MRL/lpr mice) and deficient in fB (fB -/-MRL/lpr mice) [7]. Circulating C3 levels were significantly higher in fB -/-MRL/lpr mice, while the circulating immune complexes remained unchanged.…”

“…Offspring of these matings were further backcrossed for twelve generations with MRL/lpr mice before use in this study. fB -/-mice on the MRL/lpr background have been characterized and were observed to be completely deficient in fB [7]. The mice were divided into two groups: the fB-deficient mice and littermate fB-sufficient mice that served as controls.…”