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Title: Testing the Activity of Complement Convertases in Serum/Plasma for Diagnosis of C4NeF-Mediated C3 Glomerulonephritis.
Authors: Blom, Anna M
Corvillo, Fernando
Magda, Michal
Stasiłojć, Grzegorz
Nozal, Pilar
Pérez-Valdivia, Miguel Ángel
Cabello-Chaves, Virginia
Rodríguez de Córdoba, Santiago
López-Trascasa, Margarita
Okrój, Marcin
Keywords: C3 glomerulonephritis;C4NeF;Complement system;complement convertase
metadata.dc.subject.mesh: Antigen-Antibody Complex
Blood Proteins
Complement Activation
Complement C3-C5 Convertases
Complement C4b
Complement Membrane Attack Complex
Complement System Proteins
DNA Mutational Analysis
Glomerulonephritis, Membranoproliferative
Middle Aged
Issue Date: 5-May-2016
Abstract: Autoantibodies termed C3-nephritic factor (C3NeF), which stabilize convertases of the alternative complement pathway, often stimulate autoinflammatory diseases. However, knowledge about analogous autoantibodies acting on the classical pathway (C4NeF) is limited to a few reports, which indicate association with kidney dysfunction, systemic lupus erythematous, and infections. C4NeF may appear independently from C3NeF, but the lack of a routine diagnostic method predisposes C4NeF for being an underestimated player in autoinflammatory episodes. We tested the activity of classical convertases directly in serum/plasma to screen samples from 13 patients with C3 glomerulopathies and identified one patient showing significantly prolonged half-life of these enzymes. Observed effect was reproduced by immunoglobulins purified from patient's plasma and additionally confirmed on classical convertase built from purified components. Isolated immunoglobulins protected classical convertases from both spontaneous and inhibitor-driven decay but not from C4b proteolysis. The patient had a decreased serum level of C3, elevated sC5b-9, and normal concentrations of factor B and C4. Neither C3NeF nor other autoantibodies directed against alternative pathway proteins (factor H, factor B, factor I, C3, and properdin) were found. Genetic analysis showed no mutations in C3, CFB, CFH, CFI, MCP, THBD, and DGKE genes. Renal biopsy revealed a membranoproliferative pattern with intense C3 deposits. Our results underline the importance of C4NeF as an independent pathogenic factor and a need for the implementation of routine examination of classical convertase activity. Proposed method may enable robust inspection of such atypical cases.
metadata.dc.identifier.doi: 10.1007/s10875-016-0290-5
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