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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 (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 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 Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 5, 2009 Accepted May 21, 2009 Hyperfunctional C3 convertase leads to complement deposition on endothelial cells and contributes to atypical hemolytic uremic syndrome Lubka T. Roumenina, Mathieu Jablonski, Christophe Hue, Jacques Blouin, Jordan D. Dimitrov, Marie-Agnes Dragon-Durey, Mathieu Cayla, Wolf H. Fridman, Marie-Alice Macher, David Ribes, Luc Moulonguet, Lionel Rostaing, Simon C. Satchell, Peter W. Mathieson, Catherine Sautes-Fridman, Chantal Loirat, Catherine H. Regnier, Lise Halbwachs-Mecarelli, and Veronique Fremeaux-Bacchi* Cordeliers Research Center, INSERM UMRS 872, Paris, France Universite Pierre et Marie Curie (UPMC-Paris-6), Paris, France Universite Paris Descartes, Paris, France Assistance Publique-Hopitaux de Paris, Hopital Europeen Georges-Pompidou, Service d'Immunologie Biologique, Paris, France Universite Paris Descartes, Patis, France Service de Nephrologie Pediatrique, Hopital Robert-Debre, Paris, France Unite de Nephrologie, Centre Hospitalier de Toulouse, Toulouse, France Departement de Medecine et de Nephrologie, Hopital Ambroise Pare, Boulogne-Billancourt, France Academic Renal Unit, University of Bristol, Southmead Hospital, Bristol, United Kingdom INSERM U845, Hopital Necker, Paris, France * Corresponding author; email: veronique.fremeaux-bacchi{at}egp.aphp.fr. Complement is a major innate immune defense against pathogens, tightly regulated to prevent host tissue damage. The 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 two 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 two 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-fragments deposition on quiescent and adherent human glomerular (GEnC) and umbilical vein endothelial cells (HUVEC), 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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