Complement analysis in children with idiopathic membranoproliferative glomerulonephritis: A long‐term follow‐up

Abstract

Fifty children with idiopathic membranoproliferative glomerulonephritis (MPGN), aged 2-14 years at apparent onset, were monitored for the presence of C3 nephritic factor (C3 NeF) and signs of complement activation in serum. In addition, C3 allotyping was performed in 32 patients. Observation time ranged from 2 to 20 (median 11) years. C3 NeF activity was detected at least once in 60% of the patients (in 11 of 26 with type I, in 15 of 17 with type II, and in four of seven with type III). C3 NeF-positive patients had significantly reduced levels of CH50 and C3 and elevated levels of C3dg/C3d. During follow-up, C3 levels were persistently normal in 62% of the patients with MPGN type I and in 43% with type III but in only 18% with type II. C3 allotype frequencies differed from those found in healthy controls with a significant shift to the C3F/C3FS variants in C3 NeF-positive patients. C3b(Bb)P as a marker for alternative pathway activation was not increased in C3 NeF-positive patients. Despite the presence of C3 NeF activity, C3 levels remained normal in six patients throughout the observation period. C3 NeF became undetectable in six patients, whereas seven developed C3 NeF activity during follow-up. There was no significant difference in renal survival probability in patients with or without C3 NeF activity. Neither C3 variants nor continuous low C3 or low CH50 levels had any prognostic value for the clinical outcome. No factor H deficiency was detected.

Anti-factor B autoantibody in dense deposit disease

“…By changing the balance of complement activation and inhibition C3NeF contributes to the disease, in line with the involvement of complement dysregulation in DDD (Appel et al, 2005). C3NeF, however, is also found in healthy persons and in other pathological conditions, and a clear causative relationship for C3NeF and DDD has not been demonstrated (Schwertz et al, 2001;Appel et al, 2005;Smith et al, 2007;Spitzer et al, 1990). The appearance of high-affinity C3NeF in the patients is possibly antigen-driven, due to neoepitopes exposed on activated complement components (Spitzer et al, 1992).…”

“…An anti-factor H miniantibody consisting of lambda light-chains, which inhibited factor H complement regulatory activity, was identified in a DDD patient (Meri et al, 1992;Jokiranta et al, 1999). C3 nephritic factor (C3NeF), an antibody against the C3bBb convertase (Spitzer et al, 1969), is found in 50-80% of DDD patients (Schwertz et al, 2001;Appel et al, 2005). C3NeF binds to a neoepitope on the newly assembled C3bBb, increases the half-life of the convertase against both intrinsic and extrinsic, factor H-mediated, decay and thus enhances C3 consumption (Daha et al, 1976).…”

The Central Role of the Alternative Complement Pathway in Human Disease

“…However, type II MPGN does not demonstrate immune complex or C4 deposition and shows preserved levels of C4 (62). Greater than 80% of the patients with type II MPGN have circulating autoantibodies, termed nephritic factors, that bind the alternative pathway convertase C3bBb (62)(63)(64). These nephritic factors stabilize the C3bBb complex and prolong its half-life.…”

A common haplotype in the complement regulatory gene factor H ( HF1/CFH ) predisposes individuals to age-related macular degeneration

“…In AMD and diseases such as Alzheimer's (17), atherosclerosis (18), and glomerulonephritis (19), characteristic lesions and deposits contribute to disease pathogenesis and progression. Although the molecular bases of these diseases may be diverse, the deposits contain many shared molecular constituents that are attributable, in part, to local inflammation and activation of the complement cascade, a key element of the innate immune system in host defense.…”