Physiopathology of IgA Nephropathy
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1 Physiopathology of IgA Nephropathy Renato C. Monteiro Center for Research on Inflammation - Inserm U1149 Paris Diderot Medical School & Bichat Hospital, Inflamex Laboratory of Excellence ACTUALITÉS NEPHROLOGIQUES JEAN HAMBURGER, PARIS 2018
2 IgA Nephropathy (IgA-N) Berger s disease IgA-N is the most prevalent GN One of the first cause of ESRD Hematuria & proteinuria Absence of specific treatment IgA1 complexes in the mesangium
3 Features IgA nephropathy Absence of symptoms Haematuria very common Deposits usually restricted to mesangium Deposits usually piga1 Variable systemic involvement - HSP Variable glomerular injury Transplant recurrence
4 IgA nephropathy Is IgAN a single disease? STEP 1 STEP 2 IgA deposit alone No disease? IgA deposit + altered function Disease Data from autopsies 5-15% of general pop Renal Biopsies
5 Is IgAN a multi-hit disease? General population IgA deposits 4-16% Hit 1: why? < 0.5% IgAN ESRD Hit 2: why? Hit 3: why?
6 SUSCEPTIBILITY TO IgA NEPHROPATHY Production of pathogenic IgA & complexes IgAN Abnormal Mucosal handling of Ag? Inflammatory phenotype Genetic influences
7 What leads to IgA1 deposits alone without renal alterations? What are the hits needed for disease development?
8 Polymeric IgA1 IgA1 IgA2 J-chain Polymeric IgA1 Secretory Secretory IgA IgA
9 Kidney eluates from patient biopsies revealed abnormal IgA containing immune complexes Negative charge of IgA1 piga complexes From «Charge and size of mesangial IgA in IgA Nephropathy» Monteiro,.., Berger, Lesavre. Kidney Int 1985
10 Galactose deficient IgA1 (Gd IgA1) From Robert et al Trends Mol Med 2015
11 4-hit pathogenesis model of IgA Nephropathy Oxidative stress (AOPP) Suzuki J et al. J Am Soc Nephrol 2011 Gharavi A et al. Nat Genet 2011
12 Why does Gd-pIgA1 deposit in the kidney? Is IgAN an IgA-immune complex disease?
13 Gd-IgA1 Possible mechanisms of mesangial deposition Complex formation Soluble CD89 IgG-IgA1 IgA1 as antigen Complex formation IgA1-IgA1 selfaggregation Mesangial Deposition
14 Role of the CD89 receptor in IgAN B Cell antibody production Macrophages, PMN, Eosinophils Dendritic cells, Platelets, Kupffer cells leukocyte IgA-N IgA IgA scd89 FcαRI (CD89) Launay et al J Exp Med 2000 Berthelot et al J Exp Med 2012 Dual role in immunoregulation Inhibition vs activation (Monteiro and Van De Winkel. Ann Rev Immunol, 2003) Cell effector functions Clearance Phagocytosis Mediators TNF IL-6 IL-1
15 Increased levels of Soluble CD89/IgA in IgA-N Soluble CD89 /IgA complexes in PEG precipitates: Sandwich Elisa: A3 anti-fcαri + Anti-IgA or IgG Ab Units 4 Units Co IgAN RA MC AC 0 Co Pat Pat Launay et al J Exp Med 2000 IgA IgG
16 Soluble CD89 /IgA complexes: a marker for disease progression? Sandwich Elisa: A3 anti-fcαri + Anti-IgA Ab Deposited in the mesangium? Vuong et al Kidney Int 2010
17 THE CHALLENGE OF ANIMAL STUDIES IN IgA NEPHROPATHY Two IgAs Fab IgA1 Human IgA2 One IgA Mouse Hinge region O-glycans Fc CD89 binding site N-glycans 90% monomers in blood IgA1 is highly glycosylated 80% polymers Poorly glycosylated IgA Fc receptor : CD89 No CD89 homolog
18 Expression of human CD89 induces mouse IgA deposits in mice Lines Non-Tg Lt Tg Construct 73 CD11b promotor Fc RI EGF 96 Fc RI Stop codon 83 Hematuria - + CD11b Launay et al J Exp Med 2000
19 IgA1 Knock-In/CD89 Tg: an humanized mouse model for IgAN Hematuria (x 10,000 RBC/ml) Protein / Creatinine (g/mmol) Serum Creatinine (mmol/l) IgA1KI mice (human IgA1) x CD89Tg mice (human CD89) Duchez et al Launay et al human mouse IgA1KI-CD89Tg CD89 induces mesangial IgA1 deposition and renal dysfunction Wt IgA1KI- CD89Tg ** 6 4 * * Berthelot et al. J Exp Med. 2012
20 IgAN is transferable by the serum Units 10 5 Co Tg Rag2 -/- 0 Adoptive transfer Fc RI Tg Serum IgAN Serum adsorbed by anti-fc RI mabs Hematuria + Rag2 -/- Launay et al J Exp Med 2000; Berthelot et al 2012 IgAN No disease
![40 20 0 IgA-sCD89 complexes AUC =0.76 [0.63-0.88] p=0.](/docs-images/89/97850286/images/21-4.jpg "001 20 40 60 80 100 Specificity (%) Anti-CD89 polyclonal Ab Berthelot")
21 Predictive power of circulating soluble CD89-IgA complexes: the case of recurrent IgA nephropathy Sensitivity (%) % IgA-sCD89 complexes % IgA-sCD89 complexes 100 *** *** ** * * ** R NR Ctr 0 PreTx M12-Tx R Recurrence M6-post Steroid pulse No Recurrence IgA-sCD89 complexes AUC =0.76 [ ] p= Specificity (%) Anti-CD89 polyclonal Ab Berthelot et al. Kidney Int 2015
22 From Robert et al Trends Mol Med 2015
23 IgA-CD89 complexes are nephrotoxics protease?? Fc RI/CD89 is shed from blood monocytes Receptor interaction on Mesangial cells
24 Mechanims for mesangial IgA1 deposition: Fp: podocyte, Mc: mesangial cell, En: endothelial cell, Ep: epithelial cell, CL: capillary, Bm: basement membrane Mesangial IgA1 receptors? Absence of classical IgA receptors (CD89, pigr, ASGPR, Fcα/μR)
25 The CD71 (Transferrin Receptor) is a mesangial IgA1 receptor Genes: Chromosome 3 from Lawrence et al Science 1999 Protein: Expression: Ligands: Physiological Functions: Pathology: TfR1 All mature cells but at low density +++Red cell precursors +++Mesangial cells from IgAN pat +++Enterocytes from Coeliac pat Low density: Transferrin High density : piga1 Transferrin: Iron uptake IgA1: erythropoeisis IgAN and Coeliac disease Increased affinity for GD IgA1 Moura et al. J Exp Med, 2001, JASN 2004 Matysiak-Budnik et al J Exp Med 2008 Coullon et al Nat Med 2011
26 Normal Upregulation of transferrin receptor (CD71) in the mesangium of patients with IgAN and HSP IgAN HSP Haddad et al J Am Soc Nephrol 2003
27 (F/F0)-1 (F/F0)-1 Differential signal by TfR ligands piga Fe-Tf i x x10 6 t (ms) x x10 6 t (ms) Tamouza et al Kidney Int : 0.5 µg/ml, 2 : 5 µg/ml, 3 : 50 µg/ml, 4 : 250 µg/ml,5 : 500 µg/ml, I : ionomycine
28 piga1 induces signal tranduction on mesangial cells Tamouza et al Kidney Int 2012 W: Wortmannin R: Rapamycin
29 Phosphorylated Erk is associated with severe IgAN Tamouza et al Kidney Int 2012
30 Phosphorylated ERK staining correlates with proteinuria and blood pressure Tamouza et al Kidney Int 2012
31 Cell Number Median Fluorescence Intensity Degalactosylation of IgA1 enhances binding to transferrin receptor Myeloma IgA1 Patient IgA 12 IgG desialylated & degalactosylated + stfr1 Non treated desialylated p<0.001 desialylated & degalactosylated Fluorescence Intensity (log) controls IgAN Moura et al J Am Soc Nephrol 2004
32 Proposed role of IgA receptors in IgAN IgA1 GD -soluble CD89 (with or w/o anti-iga1 Ab?) Proliferation IgA1 deposits on mesangial TfR perk activation Cytokines Chemokines Enhanced TfR expression TfR = transferrin receptor Inflammation Fibrosis Mesangiopathy An explanation for IgAN recurrence after transplantation?
33 What is the origin of the Gd-IgA1? Is IgAN an enteric (mucosal) disease?
34 Kidneys IgA-N IgA Skin HSP Dermatitis Intestin Celiac disease Crohn
35 Other similarities between IgAN and celiac disease IgA anti-gliadin Abs in both diseases (Coppo et al, J Am Soc Nephrol, 1992) Overexpression of TfR in enterocytes of celiac patients (Matiziak et al J Exp Med 2008) 4% of IgAN patients develop CD (vs 1% in gen. population) Decreased proteinuria in IgAN treated with gluten-free diet Altered intestinal functions (Coppo et al, Clin Nephrol 1990) Elevated intestinal permeability (Kovacs et al. Am J Nephrol, 1996) Symptoms of mucosal atrophy (Fornasiery et al. Br Med J, 1987) Protective effect of local action corticosteroids (Budesonide) (Fellström et al. Lancet, 2017)
36 Transglutaminase 2 (TG2): an enzyme linked to celiac disease TG2 is overexpressed in IgAN (Ikee et al, 2007, Berthelot 2012) (from Fesus and Piacentini, Trends in Biochemical Sciences, 2002) Hypothesis: TG2 mediates mesangial IgA1 deposits through TfR1
37 Mesangial TG2 overexpression in IgAN patients was confirmed Control IgAN patient Human TG2 Mesangial TG2 overexpression in IgA1-CD89 Tg mice WT IgA1KI IgA1KI-CD89Tg Mouse TG2
38 Hematuria (x 10,000 RBC/ml) Decreased IgA1 deposits and hematuria In IgA1KI-CD89Tg-TG2 -/- mice Anti-human IgA Ab x IgA1KI-CD89Tg TG2 -/- IgA1KI-CD89Tg IgA1KI-CD89Tg-TG2 -/- 50 ** IgA1KI-CD89Tg-TGase2 -/ Berthelot et al, J Exp Med, 2012
39 Working model for IgAN pathogenesis TG2 : an amplifier of IgA1-IC deposits Robert et al Trends Mol Med 2015
40 IgA1 AGA / OD at 405nm OD at 405nm Gliadin interacts with soluble CD89 scd89 binds to gliadin in a dose dependent way Albumin Gliadin CD89s-biot (µg/ml) IgA concentration x 10-3 IgA anti-gliadin Abs in α1ki-cd89tg mice ** 0 α1ki-cd89tg α1ki Papista et al Kidney Int 2015 Does gluten play a role in IgAN?
41 Marked / Glomerular area RBC / ml Early treatment by gluten-free diet prevents IgAN HEMATURIA Gluten-free diet Gluten-free diet Gluten-free diet Sacrifice 60 * ** *** * ** 40 α1ki-cd89tg: standard gluten diet 0 wk 3 wk 6 wk 10 wk 12 wk 9 weeks 6 weeks Treatment 2 weeks 20 0 IgA Standard gluten diet α1ki-cd89tg 2 weeks 6 weeks Treatment with Gluten-free diet 9 weeks 3 generations *** *** *** *** ** * New trials with gluten-free diet in IgAN: in patients with good renal function and antibodies to gliadin! 0
42 From Aaron & Monteiro J Clin & Cell Immunol in press
43 Hit 1: Genetic susceptibility GDIgA1 Hit 2: Aberrant IgA1 Hit 3 : IgA1-CIC formation GDIgA1-IgG GDIgA1-sCD89 GDIgA1-gliadin Hit 4 : Mesangial IgA1-CIC-CD71 in situ complex formation GDIgA1-CIC TfR1 (CD71) TG2
44 Genome-wide association study (GWAS) of IgAN 20,612 individuals of European and East Asian ancestry. Six new genome-wide significant associations, four in ITGAM- ITGAX, VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA. Most loci associated with risk of inflammatory bowel disease (IBD), maintenance of the intestinal epithelial barrier or response to mucosal pathogens. Genetic risk correlates strongly with variation in local pathogens, suggesting a possible role for host intestinal pathogen interactions in shaping the genetics of IgAN. Kiryluk, et al. Nature Genetics 2014
45 GUT KIDNEY AXIS Rationale: 1. Altered microbiota (De Angelis et al PloS One 2014), but studied in other CKD 2. Intestinal immunity gene linkage in IgAN patients (by GWAS Kiryluk et al. Nat Genet 2014) 3. Benefits of Budesonide, a corticosteroid with local intestinal action (Fellstrom et al Lancet 2017) Question: Role of microbiota dysbiosis in IgAN? Hypothesis: Microbiota dysbiosis induces dimeric Gd-IgA1 CD89 -
46 Intestinal dysbiosis in Italien IgAN patients (vs controls) De Angelis et al PLoS One 2014
47 But no evidence for commensals Streptococcus and IgAN J Immunol Jul 1;193(1): PLoS One Sep 29;9(9):e
48 Putative role of genetic factors, food, intestinal microbiota and MALT in the pathogenesis of IgAN ITGAM ITGAX, VAV3, CARD9 HLADQ B1 and DEFA Gluten, other food & evironmental factors Induction of nephrotoxic Gd IgA1 & Abs Circulation Formation of scd89- IgA1 complexes IgA1 depo sits Adapted from Levy et al Nat Rev Immunol 2017
49 Acknowledgments Christina Papista Laureline Berthelot Gabriella Lauriero Jonathan Chemouny James Gleeson Sanae Ben Mkaddem Martin Flamant Eric Daugas François Vrtovsnik CRI - INSERM U1149 COLLABORATORS France Michel Cogné Limoges Thomas Robert Fatouma Touré Philippe Rieu Reims Thank you for your attention!
50 T structure of IgA1 Long hinge region Binding site to Fc receptor in Cα2-Cα3 Hinge region: Heavily O-glycosilated 6% of M r
51 Berger s disease or IgA nephropathy Jean Berger et al Dépôts intercapillaires d IgA-IgG. J Urol Nephrol (Paris). Sept 1968; 74:694-5.
52 Main contributions of Prof. Jean Berger Neglected disease French food & environnement? Description by J. Berger in Paris Habib & Levy: Berger s disease Description by other groups: - Netherlands (Maintz and coll) - USA (West & Burkholder) - UK (Davies and coll) - Australia (Woodroffe & Clarkson) - Japan (Ueda and coll) Severe disease Recurrence after Tx Elution studies Negative Charge Polymeric IgA Immune complexes
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