The role of the alternative pathway of complement in lupus nephritis

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the production of anti-nuclear antibodies, arthritis, vasculitis, and glomerulonephritis. Activation of the alternative pathway of complement (AP) is associated with the development of glomerulonephritis in individuals with SLE and in the murine model of SLE, the MRL/lpr mouse.We have shown that the lack of IgG3 in MR/lpr Bf-/- mice is not due to the lack of factor B but is linked to inheritance of the H-2b haplotype. MRL/lpr mice H-2b congenic mice also have a reduced IgG3 response to TI antigens. This response is further reduced in the MRL/lpr Bf-/- mice. MRL/lpr H-2b congenic mice also have a lower percentage of B-1 B cells in the spleen and in the peritoneum, showing the reduction in B-1 B cell populations is not due to the lack of factor B.To determine if the decreased incidence of renal disease in MRL/ lpr Bf-/- mice is due to the lack of AP activation or the H-2b haplotype, mice deficient in factor D (Df), another AP protein, were interbred with MRL/lpr mice for 4 generations. MRL/lpr Df-/- mice had no AP activation, produced factor B and are of the H-2k haplotype. MRL/lpr Df-/- mice produced similar serum levels of autoantibodies as Df+/+ and Df+/- littermates except for IgG rheumatoid factor, which was increased. Although glomerular IgG deposition was similar, the amount of C3 deposition in the glomeruli was significantly lower in Df-/- mice compared to wild type littermates. Serum creatinine levels in Df-/- mice did not increase with age and disease as occurred in Df+/+ and Df+/- littermates. Pathologic renal disease was also significantly reduced in Df-/- mice. Our results indicate the absence of factor D, and subsequently, the lack of AP activation, is protective against the development of pathologic renal disease in MRL/lpr mice. These findings provide further insight into the results obtained with the original MRL/lpr factor B deficient mice. The reduced serum levels of IgG3 in the MRL/ lpr Bf-/- mice was linked to the influence of the H-2 b haplotype on the MRL/lpr background and not the lack of factor B or AP activation. However, the protection from the development of pathologic renal disease seen in the MRL/lpr Bf-/- mice can be attributed, at least in part, to the lack of AP activation. (Abstract shortened by UMI.)...