title: Hyperfunctional C3 convertase leads to complement deposition on endothelial cells and contributes to atypical hemolytic uremic syndrome.
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.
authors: Cordeliers Research Center, Inserm, Unite Mixte de Recherche en Santé (UMRS) 872, Paris, France;
authors: Lubka T
authors: LT
authors: Roumenina
authors: Mathieu
authors: M
authors: Jablonski
authors: Christophe
authors: C
authors: Hue
authors: Jacques
authors: J
authors: Blouin
authors: Jordan D
authors: JD
authors: Dimitrov
authors: Marie-Agnes
authors: MA
authors: Dragon-Durey
authors: Mathieu
authors: M
authors: Cayla
authors: Wolf H
authors: WH
authors: Fridman
authors: Marie-Alice
authors: MA
authors: Macher
authors: David
authors: D
authors: Ribes
authors: Luc
authors: L
authors: Moulonguet
authors: Lionel
authors: L
authors: Rostaing
authors: Simon C
authors: SC
authors: Satchell
authors: Peter W
authors: PW
authors: Mathieson
authors: Catherine
authors: C
authors: Sautes-Fridman
authors: Chantal
authors: C
authors: Loirat
authors: Catherine H
authors: CH
authors: Regnier
authors: Lise
authors: L
authors: Halbwachs-Mecarelli
authors: Veronique
authors: V
authors: Fremeaux-Bacchi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003167:Complement Activation / Q000235:genetics; D050577:Complement C3-C5 Convertases / Q000235:genetics / Q000502:physiology*; D003165:Complement System Proteins / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D005190:Family; D005260:Female; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D050505:Mutant Proteins / Q000502:physiology; D010375:Pedigree; D055815:Young Adult
chemical_list: D050505:Mutant Proteins; D003165:Complement System Proteins; D050577:Complement C3-C5 Convertases