aHUS caused by complement dysregulation: new therapies on the horizon

Atypical hemolytic uremic syndrome (aHUS) is a heterogeneous disease that is caused by defective complement regulation in over 50% of cases. Mutations have been identified in genes encoding both complement regulators [complement factor H (CFH), complement factor I (CFI), complement factor H-related proteins (CFHR), and membrane cofactor protein (MCP)], as well as complement activators [complement factor B (CFB) and C3]. More recently, mutations have also been identified in thrombomodulin (THBD), an anticoagulant glycoprotein that plays a role in the inactivation of C3a and C5a. Inhibitory autoantibodies to CFH account for an additional 5–10% of cases and can occur in isolation or in association with mutations in CFH, CFI, CFHR 1, 3, 4, and MCP. Plasma therapies are considered the mainstay of therapy in aHUS secondary to defective complement regulation and may be administered as plasma infusions or plasma exchange. However, in certain cases, despite initiation of plasma therapy, renal function continues to deteriorate with progression to end-stage renal disease and renal transplantation. Recently, eculizumab, a humanized monoclonal antibody against C5, has been described as an effective therapeutic strategy in the management of refractory aHUS that has failed to respond to plasma therapy. Clinical trials are now underway to further evaluate the efficacy of eculizumab in the management of both plasma-sensitive and plasma-resistant aHUS

Genetics and complement in atypical HUS

Central to the pathogenesis of atypical hemolytic uremic syndrome (aHUS) is over-activation of the alternative pathway of complement. Following the initial discovery of mutations in the complement regulatory protein, factor H, mutations have been described in factor I, membrane cofactor protein and thrombomodulin, which also result in decreased complement regulation. Autoantibodies to factor H have also been reported to impair complement regulation in aHUS. More recently, gain of function mutations in the complement components C3 and Factor B have been seen. This review focuses on the genetic causes of aHUS, their functional consequences, and clinical effect

Effet de la substitution d'essence sur le fonctionnement et la durabilité des écosystèmes forestiers : l'apport des travaux pluridisciplinaires menés en forêt de Breuil Chenue - Morvan

National audienceLe site-atelier de Breuil (Morvan), appartenant à l’Observatoire de Recherche sur l’Environnement F-ORE-T, est un support opérationnel des travaux actuels sur les cycles biogéochimiques en relation avec la diversité biologique du sol. De nombreux projets multidisciplinaires sont en cours sur ce site dont l’objectif commun est d’améliorer les connaissances sur les effets physiques, chimiques et biologiques des substitutions d’essences. Des travaux y sont menés à différentes échelles temporelles et spatiales, de l’instantané au pluriannuel, du microsystème fonctionnel jusqu’à l’écosystème complet. Les travaux développés à Breuil depuis 2001, montrent que les essences ont affecté les cycles clé du carbone et de l’azote avec les conséquences sur le fonctionnement des cycles de tous les autres éléments. Ces modifications sont entre autres liées à un contrôle des populations de micro-organismes du sol par les essences forestières qui les structurent. Les recherches en cours tentent d’élucider cette question pertinente d’écologie. Compte tenu de la longévité des essences forestières, ce site devra être suivi sur le long terme, vraisemblablement par une approche diachronique