Glomerulonephritis & Immunoreceptors (GLOMI)
Team Monteiro / Flamant
Department Nephrology, Immunology and Hematology
Chronic kidney diseases (CKD) are a growing health problem worldwide as they lead to renal failure with so far limited treatment options. Approximately 10% of the general population have renal insufficiency, of which 5.6% at a light or moderate stage, 3.7% at a severe stage and 0.13% at the terminal stage needing dyalisis or transplantation as replacement therapy. CKD can be caused by disorders such as glomerulonephritis (GN). Among the GN, IgA nephropathy (IgAN), Lupus nephritis (LN) and idiopathic nephrotic syndrome (INS) are major causes of end-stage renal disease worldwide. Understanding mechanisms leading to IgAN, LN or INS are crucial to design new therapeutic strategies. Our team is one of the world leaders in IgAN field (www.iigann.com). We described that a soluble form of the CD89 (sCD89), an IgA Fc receptor, is part of nephritogenic mesangial IgA deposits and identified the Transferrin Receptor 1 (TfR1) as the IgA1 mesangial receptor in IgAN. We also showed that the TfR1 binds to IgA1 in a physiological way, promoting erythroblast proliferation. In IgAN physiopathology, TfR1 is overexpressed on mesangial cells with preferential affinity for deglycosylated IgA1 and induces proliferation of mesangial cells via the PI3K/Akt pathway, and production of inflammatory cytokines via the MAPK/Erk pathway. In other studies, we have shown that abnormalities of IgA1 glycosylation, a galactose-‐deficient (Gd) IgA1, also arise in alcoholic cirrhosis (AC), including mesangial IgA deposits with possible development of secondary IgAN indicating that common environmental factors (such as bacteria translocation at portal vein) may influence the IgAN development6. Moreover, we developed a new humanized mouse model of IgAN: alpha1KI-CD89Tg mice, in which sCD89 plays a pivotal role in IgAN inducing the formation of mesangial nephritogenic deposits, mesangial TfR1 and transglutaminase 2 (TG2) overexpression. Ablation of TG2 gene resulted in protection from the disease, showing for the first time that TG2 plays a crucial role in IgAN development. We have also studied the mechanisms involved in celiac disease (CD) and showed similarities with IgAN. In collaborative studies, we showed an increase of IgA complexes containing a gliadin peptide and apical expression of TfR1 on enterocytes in active CD patients. This overexpression could allow the retrograde transcytosis of gliadin peptide from apical to basal side of enterocytes. Moreover, we demonstrated that gluten sensitivity in mice leads to a CD phenotype, associated with overexpression of TfR1 and TG2, as well as overproduction of IgA and that it exacerbates IgAN.
Concerning our fundamental research on immunoregulation through Fc receptors (FcRs), we have shown, in a tight consortium with the team of U. Blank in the research unit, that CD89 (FcalphaRI), CD16 (FcgammaRIII) and CD32A (FcgammaRIIA), all receptors containing immunoreceptor tyrosine-based activation motifs (ITAM), are switch molecules which can induce either inhibition or cell activation, depending on their ligand configuration (mono/divalent versus multivalent) leading to inhibition (ITAMi) or activation (ITAMa), respectively. Targeting CD89 inhibited the appearance of inflammation in lungs, joints and kidneys. IVIg also induces ITAMi-mediated inhibition through CD16A and CD32A for IVIgG or through CD89 for IVIgA. In another hand, we have shown that E Coli is able to directly bind to CD16 and induce an ITAMi-mediated inhibition of phagocytosis, allowing E coli to escape the immune system. Our recent studies have shown that CD89 acts an innate receptor for bacteria that protects from sepsis through ITAMa-signaling pathway.
Our studies include 5 work-packages:
WP1. Understanding physiopathology of IgAN:
- To determine the role of the transglutaminase 2 in IgAN and
- To characterize the gut-kidney axis in IgAN;
WP2. Identification of autoantibodies in idiopathic nephrotic syndrome;
WP3. Src kinases as pronostic biomarkers in autoimmune GN:
- To establish Fyn effectors (phosphorylated SHP-1S591 and PKC-α) as prognostic biomarkers for autoimmune GN and
- To identify new specific prognostic markers for GN severity.
WP4. New therapeutic approaches for GN that are currently developped by targeting immunoreceptors as new anti-inflammatory therapeutic approaches in collaboration with an spinoff Inatherys (www.inatherys.com).
WP5. Studies on hypertension and lithium induced renal toxicity.
Team strengths are :
- Strong interaction with Bichat and Robert Debré hospitals (Nephrology, Physiology, Immunology).
- Available biobanks: 5 different cohorts of patients (Nephrotest, Henoch-Schonlein purpura, INS-nephrochain, GN Bichat, and MicrobIgAN cohorts).
- Mouse models of renal diseases (humanized model for IgAN, transgenic, KO mice), kidney-derived primary cells (mesangial cells, podocytes…).
- An active partner of the INFLAMEX Labex.
Publication date : 01 October 2019 More
Extracellular fluid volume is associated with incident end-stage kidney disease and mortality in patients with chronic kidney disease.
Authors : Faucon AL Flamant Martin Metzger M Boffa JJ Haymann JP Houillier P Thervet E Vrtovsnik François Stengel B Geri G Vidal-Petiot Emmanuelle NephroTest Study Group
Publication date : 01 July 2019 More
Modulation of the microbiota by oral antibiotics treats immunoglobulin A nephropathy in humanized mice.
Nephrol Dial Transplant.
Authors : Chemouny JM Gleeson PJ Abbad L Lauriero G Boedec Erwan Le Roux K Monot C Bredel M Bex-Coudrat Julie Sannier A Daugas Eric Vrtovsnik François Gesualdo L Leclerc M Berthelot L Ben Mkaddem Sanae Lepage P Monteiro Renato
Publication date : 16 April 2019 More
CD89 Is a Potent Innate Receptor for Bacteria and Mediates Host Protection from Sepsis.
Authors : De Tymowski Christian Heming N Correia MDT Abbad L Le Stang Marie-Bénédicte Flament Heloise Bex J Boedec Erwan Bounaix Carine Soler-Torronteras R Denamur E Galicier L Oksenhendler E Fehling HJ Pinheiro da Silva F Benhamou Marc Monteiro Renato Ben Mkaddem Sanae
Publication date : 01 December 2017 More
Serum Iron Protects from Renal Postischemic Injury.
J Am Soc Nephrol.
Authors : Vaugier C Amano MT Chemouny JM Dussiot M Berrou C Matignon M Ben Mkaddem Sanae Wang PHM Fricot A Maciel TT Grapton D Mathieu JRR Beaumont Carole Peraldi MN Peyssonnaux C Mesnard L Daugas Eric Vrtovsnik François Monteiro Renato Hermine O Ginzburg YZ Benhamou Marc Camara NOS Flamant Martin Moura IC
Publication date : 15 August 2017 More
Lyn and Fyn function as molecular switches that control antigen receptors directing homeostasis or inflammation
Nat Comm, in press.
Authors : Ben Mkaddem Sanae Murua Amaya Flament Heloise Titeca Dimitri Bounaix Carine Danelli Luca Launay Pierre Benhamou Marc Blank Ulrich Daugas Eric Charles Nicolas Monteiro Renato
Publication date : 01 September 2016 More
IgA1 Protease Treatment Reverses Mesangial Deposits and Hematuria in a Model of IgA Nephropathy.
J Am Soc Nephrol.
Authors : Lechner SM Abbad L Boedec Erwan Papista C Le Stang Marie-Bénédicte Moal C Maillard J Jamin A Bex-Coudrat Julie Wang Y Li A Martini PG Monteiro Renato Berthelot L.
Publication date : 26 August 2016 More
Cardiovascular event rates and mortality according to achieved systolic and diastolic blood pressure in patients with stable coronary artery disease: an international cohort study
Authors : Vidal-Petiot Emmanuelle Ford I Greenlaw N Ferrari R Fox KM Tardif JC Tendera M Tavazzi L Bhatt TL Steg PG CLARIFY Investigators
Publication date : 01 October 2015 More
Recurrent IgA nephropathy is predicted by altered glycosylated IgA, autoantibodies and soluble CD89 complexes.
Authors : Berthelot L Robert T Vuiblet V Tabary T Braconnier A Dramé M Toupance O Rieu P Monteiro Renato Touré F
Publication date : 01 August 2015 More
Gluten exacerbates IgA nephropathy in humanized mice through gliadin-CD89 interaction.
Authors : Papista C Lechner S Le Stang Marie-Bénédicte Ben Mkaddem Sanae Bex-Coudrat Julie Pillebout Evangéline Chemouny J Jablonski M Flamant Martin Daugas Eric Vrtovsnik François Yiangou M Berthelot L Monteiro Renato
Publication date : 25 July 2014 More
Shifting FcγRIIA-ITAM from activation to inhibitory configuration ameliorates arthritis
J Clin Invest.
Authors : Ben Mkaddem Sanae Hayem G Jönsson F Rossato E Boedec Erwan Boussetta T El Benna Jamel Launay Pierre Goujon JM Benhamou Marc Bruhns P Monteiro Renato
Publication date : 26 March 2012 More
Transglutaminase is essential for IgA nephropathy development acting through IgA receptors
J Exp Med.
Authors : Berthelot L Papista C Maciel TT Biarnes-Pelicot M Tissandie E Wang PH Tamouza H Jamin A Bex-Coudrat Julie Gestin A Boumediene A Arcos-Fajardo M England P Pillebout Evangéline Walker Francine Daugas Eric Vrtosvnik F Flamant Martin Benhamou Marc Cogné M Moura IC Monteiro Renato