Hyperfunctional C3 convertase leads to complement deposition on endothelial cells and contributes to atypical hemolytic uremic syndrome

LT Roumenina, M Jablonski, C Hue, J Blouin, JD Dimitrov, MA Dragon-Durey, M Cayla, WH Fridman, MA Macher, D Ribes, L Moulonquet, L Rostaing, SC Satchell, PW Mathieson, C Sautes-Fridman, C Loirat, CH Regnier, L Halbwachs-Mecarelli, V Fremeaux-Bacchi

Research output: Contribution to journalArticle (Academic Journal)peer-review

104 Citations (Scopus)

Abstract

Complement is a major innate immune defense against pathogens, tightly regulated to prevent host tissue damage. Atypical hemolytic uremic syndrome (aHUS) is characterized by endothelial damage leading to renal failure and is highly associated with abnormal alternative pathway regulation. We characterized the functional consequences of 2 aHUS-associated mutations (D(254)G and K(325)N) in factor B, a key participant in the alternative C3 convertase. Mutant proteins formed high-affinity C3-binding site, leading to a hyperfunctional C3 convertase, resistant to decay by factor H. This led to enhanced complement deposition on the surface of alternative pathway activator cells. In contrast to native factor B, the 2 mutants bound to inactivated C3 and induced formation of functional C3-convertase on iC3b-coated surface. We demonstrated for the first time that factor B mutations lead to enhanced C3-fragment deposition on quiescent and adherent human glomerular cells (GEnCs) and human umbilical vein endothelial cells (HUVECs), together with the formation of sC5b-9 complexes. These results could explain the occurrence of the disease, since excessive complement deposition on endothelial cells is a central event in the pathogenesis of aHUS. Therefore, risk factors for aHUS are not only mutations leading to loss of regulation, but also mutations, resulting in hyperactive C3 convertase.
Translated title of the contributionHyperfunctional C3 convertase leads to complement deposition on endothelial cells and contributes to atypical hemolytic uremic syndrome
Original languageEnglish
Pages (from-to)2837 - 2845
Number of pages9
JournalBlood
Volume114
Issue number13
DOIs
Publication statusPublished - 24 Sep 2009

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