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Blood, 24 September 2009, Vol. 114, No. 13, pp. 2837-2845. Prepublished online as a Blood First Edition Paper on July 7, 2009; DOI 10.1182/blood-2009-01-197640. This Article Full Text Full Text (PDF) Supplemental Methods and Figures All Versions of this Article: blood-2009-01-197640v1 114/13/2837    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Google Scholar Articles by Roumenina, L. T. Articles by Fremeaux-Bacchi, V. PubMed PubMed Citation Articles by Roumenina, L. T. Articles by Fremeaux-Bacchi, V. Related Collections Vascular Biology Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  VASCULAR BIOLOGY Hyperfunctional C3 convertase leads to complement deposition on endothelial cells and contributes to atypical hemolytic uremic syndrome Lubka T. Roumenina13, Mathieu Jablonski13, Christophe Hue13, Jacques Blouin4, Jordan D. Dimitrov13, Marie-Agnes Dragon-Durey14, Mathieu Cayla13, Wolf H. Fridman14, Marie-Alice Macher5, David Ribes6, Luc Moulonguet7, Lionel Rostaing6, Simon C. Satchell8, Peter W. Mathieson8, Catherine Sautes-Fridman13, Chantal Loirat5, Catherine H. Regnier13, Lise Halbwachs-Mecarelli9, and Veronique Fremeaux-Bacchi14 1 Cordeliers Research Center, Inserm, Unite Mixte de Recherche en Santé (UMRS) 872, Paris, France; 2 Université Pierre et Marie Curie (UPMC-Paris-6), Paris, France; 3 Université Paris Descartes, Paris, France; 4 Assistance Publique-Hopitaux de Paris (AP-HP), Hopital Europeen Georges-Pompidou, Service d'Immunologie Biologique, Paris, France; 5 Service de Néphrologie Pédiatrique, Hôpital Robert-Debré, Paris, France; 6 Unité de Néphrologie, Centre Hospitalier de Toulouse, Toulouse, France; 7 Département de Médecine et de Nephrologie, Hôpital Ambroise Pare, Boulogne-Billancourt, France; 8 Academic Renal Unit, University of Bristol, Southmead Hospital, Bristol, United Kingdom; and 9 Inserm U845, Hôpital Necker, Paris, France 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 (D254G and K325N) 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Super factor B-gets atypical HUS Edward M. Conway Blood 2009 114: 2572-2574. [Full Text] [PDF] This article has been cited by other articles: E. M. Conway Super factor B-gets atypical HUS Blood, September 24, 2009; 114(13): 2572 - 2574. [Full Text] [PDF]

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