In Vivo Evidence of Complement Requirement for Mesangioproliferative Activity of Immune Complexes Containing Galactose-Deficient IgA1 in IgA Nephropathy

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Background: Patients with IgA nephropathy (IgAN) have distinctive immune complexes (IC) in the circulation containing IgA1 with some O-glycans deficient in galactose (Gd-IgA1) bound by IgG autoantibodies (AuAb) specific for Gd-IgA1. Additional serum proteins, such as complement components, often associate with these IC. Some of these Gd-IgA1-containing IC deposit in the glomeruli and induce kidney injury. Here we have tested the role of complement C3 in the pathogenicity of these IC by using our passive mouse model of IgAN in which the intravenous (i.v.) injection of pre-formed complexes containing human Gd-IgA1 and IgG AuAb induce mesangioproliferative glomerular injury. Methods: We used engineered IC (EIC) formed in vitro from recombinant human polymeric Gd-IgA1 and recombinant human IgG AuAb. The amount of Gd-IgA1, IgG, and IgG-IgA IC were determined by ELISA. Serum complement C3 was depleted by intraperitoneal (i.p.) injection of cobra venom factor (CVF). We have optimized the CVF dose and established the conditions in which C3 was <99% depleted from the circulation 1 day after CVF injection, and this depletion was maintained for at least 5 days. C3 was analyzed by SDS-PAGE and immunoblotting. One day after CVF injection that depleted C3, EIC were administered i.v. on three consecutive days to a group of nude mice and to another group without CVF treatment. A control group of mice received only CVF, and other control mice did not receive either EIC or CVF. The pathologic glomerular changes were evaluated by quantitative morphometry using H&E-stained sections of kidneys harvested one day after the last EIC dose. At least 25 glomeruli were analyzed for each mouse. Results: The results showed that EIC administration increased glomerular cellularity compared to control (P=0.0001) and that CVF blocked that effect (P=0.021). CVF alone did not alter glomerular cellularity. Our data indicate that CVF-mediated C3 depletion prevented mesangioproliferative changes induced by EIC in vivo. Conclusion: These results provide experimental evidence in vivo that complement C3 is required for the pathogenic activity of Gd-IgA1-containing IC in IgAN, confirming our in vitro findings with cultured human mesangial cells. Funding: NIDDK Support, Private Foundation Support

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