AccueilAccueil>Research>Teams>Véronique FREMEAUX-BACCHI

Complement and Diseases

The complement system acts as an innate immune surveillance system, assuring a first line of defence against pathogens and serving as a guardian of the host homeostasis. Genetic abnormalities in and autoantibodies against complement proteins, leading to overactivity of the cascade are associated with different pathological conditions, comprising two rare and severe renal diseases – the atypical haemolytic uraemic syndrome (aHUS) and C3 glomerulopathies (C3G, dense deposit disease and C3 glomerulonephritis). Although the association of these diseases with excessive complement activation is well known, the molecular and cellular mechanisms behind it are still unclear. Additional, still not well understood, factors influence the diseases phenotype and severity. 

 

Our team focuses on fundamental and translational research linking complement to disease pathogenesis. Our ongoing projects cover four main axes of research:

  • Study of the structure-function relationship of disease-associated genetic abnormalities in complement proteins and their pathological relevance.

  • The pathophysiological role and mechanisms of complement-mediated cellular injury and the participation of complement to the intravascular cell-cell interactions in case of inflammation, hemolysis and thrombosis.

  • Identification of the mechanisms, leading to generation of auto-antibodies against complement proteins in aHUS and C3G as well as characterization of their functional consequences and disease relevance.

  • Identification of new diagnostic and prognostic markers for complement-mediated diseases and to improve the strategies or patients management.

    Our major achievements are :   

The milestones of aHUS, adapted from Malina et al., Press Med., 2012

 

  • One of the largest aHUS and C3G cohorts in the world (Fremeaux-Bacchi et al., Clin J Am Soc Nephrol. 2013; Servais et al., Kidney Int, 2012).

  • Discovery of Factor I (Fremeaux-Bacchi et al., J Med Genet. 2004) and C3 genetic abnormalities (Fremeaux-Bacchi et al., Blood, 2008) in aHUS patients.

  • The first description of a gene outside of the complement cascade, responsible for aHUS (Lemaire, Fremeaux-Bacchi et al., Nat Genet., 2013).

  • Characterization of the  functional consequences and pathogenic role of gain of functions mutations in C3 (Roumenina et al, Blood, 2012) and Factor B genes (Roumenina et al., Blood 2009, Marinozzi et al., 2014) and loss of function mutations in Factor I gene in aHUS (Bienaime et al., Kidney Int. 2010).

  • Establishment of a cellular model of aHUS and studies of the link between complement overactivation and the expression of a pro-thrombotic phenotype of the endothelium in the context of aHUS (Roumenina et al., Blood, 2009, 2012; Frimat et al., Blood, 2013).

  • Characterization of the molecular and cellular mechanisms of complement activation by heme and study of hemolysis as a secondary hit for the aHUS (Frimat et al., Blood, 2013).

  • First report of the autoimmune form of aHUS, related to anti-factor H auto-antibodies (Dragon-Durey et al., J Am Soc Nephrol. 2005), description of the clinical features of autoimmune aHUS (Dragon-Durey et al., J Am Soc Nephrol. 2010) and characterization of the functional consequences of the anti-factor H autoanobodies (Blanc et al., J. Immunol., 2012)

  • The first treatment of typical HUS with Eculizumab (Peyraque et al., NEJM, 2011) as well as establishment of the guidelines for application of this novel therapeutic strategy aHUS and C3G patients (Zuber et al., Nat Rev Nephrol., 2012).

  • New disease classification of C3 glomerulopathy (Fakhouri et al., Nat Rev Nephrol. 2010).
 Team Leader : Véronique FREMEAUX-BACCHI (Dr)

Team Members : Marie-Agnès DRAGON-DUREY (Dr), Lise HALBWACHS-MECARELLI (Dr), Lubka ROUMENINA (Dr),
Sophie CHAUVET (Eng), Samantha KNOCKAERT (Eng), Maria-Chiara MARINOZZI (Eng), Rémi NOE (Eng), Tania RYBKINE (Eng).
Marie DAUGAN (PhD), Nicolas MERLE (PhD).

Administration : Mehdi BENNACI, Esther PEROUMAL

Contact details: 33 1 44 27 91 00 / fax : 33 1 44 27 81 17

Email: mehdi.bennaci@crc.jusieu.fr

 

Selected Publications

  • Marinozzi, M. C., L. Vergoz, T. Rybkine, S. Ngo, S. Bettoni, A. Pashov, M. Cayla, F. Tabarin, M. Jablonski, C. Hue, R. J. Smith, M. Noris, L. Halbwachs-Mecarelli, R. Donadelli, V. Fremeaux-Bacchi, and L. T. Roumenina. 2014. Complement Factor B Mutations in Atypical Hemolytic Uremic Syndrome--Disease-Relevant or Benign? J Am Soc Nephrol.
  • Lemaire, M., V. Fremeaux-Bacchi, F. Schaefer, M. Choi, W. H. Tang, M. Le Quintrec, F. Fakhouri, S. Taque, F. Nobili, F. Martinez, W. Ji, J. D. Overton, S. M. Mane, G. Nurnberg, J. Altmuller, H. Thiele, D. Morin, G. Deschenes, V. Baudouin, B. Llanas, L. Collard, M. A. Majid, E. Simkova, P. Nurnberg, N. Rioux-Leclerc, G. W. Moeckel, M. C. Gubler, J. Hwa, C. Loirat, and R. P. Lifton. 2013. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat Genet 45:531-536.
  • Frimat, M., F. Tabarin, J. D. Dimitrov, C. Poitou, L. Halbwachs-Mecarelli, V. Fremeaux-Bacchi, and L. T. Roumenina. 2013. Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome. Blood 122:282-292.
  • Servais, A., L. H. Noel, L. T. Roumenina, M. Le Quintrec, S. Ngo, M. A. Dragon-Durey, M. A. Macher, J. Zuber, A. Karras, F. Provot, B. Moulin, J. P. Grunfeld, P. Niaudet, P. Lesavre, and V. Fremeaux-Bacchi. 2012. Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int 82:454-464.
  • Roumenina, L. T., M. Frimat, E. C. Miller, F. Provot, M. A. Dragon-Durey, P. Bordereau, S. Bigot, C. Hue, S. C. Satchell, P. W. Mathieson, C. Mousson, C. Noel, C. Sautes-Fridman, L. Halbwachs-Mecarelli, J. P. Atkinson, A. Lionet, and V. Fremeaux-Bacchi. 2012. A prevalent C3 mutation in aHUS patients causes a direct C3 convertase gain of function. Blood 119:4182-4191.
  • Blanc, C., L. T. Roumenina, Y. Ashraf, S. Hyvarinen, S. K. Sethi, B. Ranchin, P. Niaudet, C. Loirat, A. Gulati, A. Bagga, W. H. Fridman, C. Sautes-Fridman, T. S. Jokiranta, V. Fremeaux-Bacchi, and M. A. Dragon-Durey. 2012. Overall neutralization of complement factor H by autoantibodies in the acute phase of the autoimmune form of atypical hemolytic uremic syndrome. J Immunol 189:3528-3537.

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Link to PubMed

 

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