Manager(s)
Team composition
Post-doctoral fellows
Chronic kidney disease (CKD) is a growing health problem worldwide because it leads to kidney failure with limited treatment options. Approximately 10% of the general population suffers from kidney failure, with 5.6% experiencing mild or moderate disease, 3.7% severe disease, and 0.13% end-stage renal disease requiring dialysis or transplantation as replacement therapy. CKD can be caused by disorders such as glomerulonephritis (GN). Among GN, IgA nephropathy (IgAN), lupus nephritis (LN), and idiopathic nephrotic syndrome (INS) are the leading causes of end-stage renal disease globally. Understanding the mechanisms leading to IgAN, LN, or INS is crucial for developing new therapeutic strategies. Our team is a world leader in the field of IgAN (www.iigann.com). We have described a soluble form of CD89 (sCD89), an IgA Fc receptor, as being part of nephritogenic mesangial IgA deposits and identified transferrin receptor 1 (TfR1) as the mesangial receptor for IgA1 in IgAN. We have also shown that TfR1 binds to IgA1 physiologically, thereby promoting erythroblast proliferation. In the pathophysiology of IgAN, TfR1 is overexpressed on mesangial cells with a preferential affinity for deglycosylated IgA1 and induces mesangial cell proliferation via the PI3K/Akt pathway and the production of inflammatory cytokines via the MAPK/Erk pathway. In other studies, we have shown that abnormalities in IgA1 glycosylation, specifically galactose-deficient (Gd) IgA1, also appear in alcoholic cirrhosis (AC), including mesangial IgA deposits with possible development of secondary IgAN, indicating that common environmental factors (such as bacterial translocation to the portal vein) can influence IgAN development. Furthermore, we have developed a novel humanized mouse model of IgAN: the alpha1KI-CD89Tg mouse, in which sCD89 plays a central role in IgAN, inducing the formation of mesangial nephritogenic deposits and the overexpression of mesangial TfR1 and transglutaminase 2 (TG2). Ablation of the TG2 gene resulted in protection against the disease, demonstrating for the first time that TG2 plays a crucial role in IgAN development. We also investigated the mechanisms involved in celiac disease and found similarities with IgAN. In collaborative studies, we demonstrated an increase in IgA complexes containing a gliadin peptide and apical expression of TfR1 on enterocytes in patients with active celiac disease. This overexpression could enable retrograde transcytosis of the gliadin peptide from the apical to the inferior side of enterocytes. Furthermore, we demonstrated that gluten sensitivity in mice resulted in a CD phenotype, associated with overexpression of TfR1 and TG2, as well as IgA overproduction, and that it exacerbated IgAN.
Regarding our fundamental research on immunoregulation by Fc receptors (FcR), we showed, in a close consortium with U. Blank’s team in the research unit, that CD89 (FcalphaRI), CD16 (FcgammaRIII), and CD32A (FcgammaRIIA), all receptors containing tyrosine-based immunoreceptor activation motifs (ITAMs), are switching molecules that can induce either inhibition or cell activation, depending on the configuration of their ligand (mono/divalent versus multivalent), leading to inhibition (ITAMi) or activation (ITAMa), respectively. Targeting CD89 inhibited the onset of inflammation in the lungs, joints, and kidneys. IVIG also induces ITAMi-mediated inhibition by CD16A and CD32A for IVIgG or by CD89 for IVIgA. Furthermore, we have shown that E. coli is capable of directly binding to CD16 and inducing ITAMi-mediated phagocytosis inhibition, thus allowing E. coli to evade the immune system. Our recent studies have shown that CD89 is an innate bacterial receptor that protects against sepsis via the ITAMa signaling pathway.
Our studies comprise 5 work packages:
WP1. Understanding the pathophysiology of IgAN:
WP2. Identification of autoantibodies in idiopathic nephrotic syndrome;
WP3. Src kinases as prognostic biomarkers in autoimmune GN:
WP4. Novel therapeutic approaches for GN currently being developed by targeting immunoreceptors as novel anti-inflammatory therapeutic approaches in collaboration with a spin-off company, Inatherys (www.inatherys.com).
WP5. Studies on hypertension and lithium-induced renal toxicity.
The team’s strengths are:
Strong interaction with Bichat and Robert Debré Hospitals (Nephrology, Physiology, Immunology).
Available biobanks: 5 different patient cohorts (Nephrotest, Henoch-Schönlein purpura, INS-nephrochain cohorts, GN Bichat, and MicrobIgAN).
Murine models of kidney disease (humanized model for IgAN, transgenic mice, knockout mice), primary kidney-derived cells (mesangial cells, podocytes, etc.).
An active partner of INFLAMEX Labex.