Complement Component C3 Is Not Required for Full Expression of Immune Complex Glomerulonephritis in MRL/lprMice

Abstract

Complement activation and tissue deposition of complement fragments occur during disease progression in lupus nephritis. Genetic deficiency of some complement components (e.g., Factor B) and infusion of complement inhibitors (e.g., Crry, anti-C5 Ab) protect against inflammatory renal disease. Paradoxically, genetic deficiencies of early components of the classical complement pathway (e.g., C1q, C4, and C2) are associated with an increased incidence of lupus in humans and lupus-like disease in murine knockout strains. Complement protein C3 is the converging point for activation of all three complement pathways and thus plays a critical role in biologic processes mediated by complement activation. To define the role of C3 in lupus nephritis, mice rendered C3 deficient by targeted deletion were backcrossed for eight generations to MRL/lpr mice, a mouse strain that spontaneously develops lupus-like disease. We derived homozygous knockout (C3−/−), heterozygous (C3+/−), and C3 wild-type (C3+/+) MRL/lpr mice. Serum levels of autoantibodies and circulating immune complexes were similar among the three groups. However, there was earlier and significantly greater albuminuria in the C3−/− mice compared with the other two groups. Glomerular IgG deposition was also significantly greater in the C3−/− mice than in the other two groups, although overall pathologic renal scores were similar. These results indicate that C3 and/or activation of C3 is not required for full expression of immune complex renal disease in MRL/lpr mice and may in fact play a beneficial role via clearance of immune complexes.

C1q Deficiency and Autoimmunity: The Effects of Genetic Background on Disease Expression

“…Another study showed that homozygous deficiencies of C4 and CD21/CD35 (CR1/CR2) accelerated disease in C57BL/6.lpr/lpr mice, although paradoxically C3-deficient C57BL/6.lpr/lpr mice behaved in a similar fashion as controls (21). Furthermore, C3 deficiency in MRL/Mp-lpr/lpr mice has been shown to have minimal effects on disease expression (22). In light of all these observations, it can be speculated that the underlying explanation for these apparently conflicting reports may lie in the nature of the genetic background of the mice used for these various analyses or may reflect the complexity of the multiple biological roles of the complement system in inflammatory diseases.…”

Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

“…36,[38][39][40][41] To assess the effect of HSP90 inhibition on renal pathology, kidneys were taken from MRL/lpr mice at 18 weeks of age after being treated with 17-DMAG. For PAS staining, kidneys were formalin-fixed and sections were stained by the PAS method.…”

“…[32][33][34][35][36][37] Renal histological markers of glomerular lesions and glomerular deposition of IgG and C3 can also indicate disease. 36,[38][39][40][41] Splenocyte populations are often altered in autoimmune mice including differences in T-cell subtypes (including T regulatory cells (T REG )) and also alterations in B-cell subtypes. 36,37,42,43 HSP90 has been implicated in studies investigating similar autoimmune diseases and it has been reported that T cells respond to extracellular HSP90 by increasing their anti-inflammatory cytokines.…”

Role of MHC-Linked Genes in Autoantigen Selection and Renal Disease in a Murine Model of Systemic Lupus Erythematosus

“…Serum autoantibody levels against dsDNA and glomerular Ags (GA) were measured as described previously (27). For the anti-DNA ELISA, plates were coated overnight at 37°C with double-stranded calf thymus DNA (5 g/ml; Sigma-Aldrich) diluted in SSC buffer.…”