PHYSIOPATHOLOGIE DES NEPHROPATHIES A DEPOTS D IgA

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1 PHYSIOPATHOLOGIE DES NEPHROPATHIES A DEPOTS D IgA Renato Monteiro Inserm U699, Hôpital Bichat, Paris Seminaire National de Néphrologie Juin 2010 Berger s disease or IgA nephropathy Jean Berger et Nicole Hinglais Dépôts intercapillaires d IgA-IgG. J Urol Nephrol (Paris). Sept 1968; 74: «The disease was first described in 1801 by Heberden (of "Heberden's nodes" fame) in a 5-year old child with abdominal pain, hematuria, and purpura of the legs. Then in 1837, Johann Schonlein and Eduard Henoch built upon these discoveries by further characterizing the disease in pediatric populations. It was not until 1968 that the pathogenic role of IgA depositions was revealed, based on the work of French pathologist Jean Berger (left). Prior to his discovery that mesangial IgA deposits are present in these patients, many had believed IgG to be the sole nephritogenic immunoglobulin.» 1

2 History French disease? Food & environnement? Description at Necker Hosp, 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 DIAGNOSIS OF IgAN: 1. Most of patients are asymptomatic 2. IgAN discovered during routine examination for jobs due to the presence of hematuria with or without proteinuria 3. Macroscopic hematuria following upper respiratory tract infection or after sport (back pain and hematuria). 4. Usually less than 40 years old 5. Definitive diagnosis is only made by kidney biopsy 2

3 Immunofluorescence IgG in 30-50% of cases IgM in 5-10% of cases (severity?) C3 in more than 60% of cases more λ than κ chains mesangial electrodense deposits IgA1 deposition in the mesangium Morphology Heterogeneity of lesions 3

4 The Oxford classification of IgA nephropathy Summary of four key pathological features 1. Mesangial Hypercellularity Score: 0.5 (M0) or < 0.5 (M1) 2. Segmental glomerulosclerosis: absent (S0) or present (S1) 3. Endocapillary hypercellularity: absent (E0) or present (E1) 4. Tubular atrophy/interstitial fibrosis : 25% (T0), 26-50% (T1), or > 50% (T2) International IgAN Network & Renal Pathology Society Cattran et al Kidney Int 76, , 2009 Roberts et al Kidney Int 76, , 2009 Correlation between Oxford classification and disease severity (examples) Glomerular lesions Definition Slope: ml/min per Criteria N of patients 1.73 m2 per year Minimal mesangial hypercellularity Without segmental sclerosis With segmental sclerosis M0, S0, E0 M0, S1, E ± ± 2.7 Mesangial hypercellularity Without segmental sclerosis With segmental sclerosis M1, S0, E0 M1, S1, E ± ± 7.6 Endocapillary proliferation Without segmental sclerosis With segmental sclerosis M0/1, S0, E1 M0/1, S1, E ± ± 10.0 Glomerular lesions Tubular atrophy/interstitial fibrosis Criteria N of patients Slope: ml/min per 1.73 m2 per year Minimal mesangial hypercellularity 25% < 26% M0, E0, T0 M0, E0,T ± ± 1.2 Mesangial hypercellularity 25% M1, E0, T ± 5.5 < 26% M1, E0, T ± 9.1 Endocapillary proliferation 25% -3.0 ± 1.9 < 26% M0/1, E1, T0 88 M0/1, E1, T ± 1.2 4

5 PREVALENCE: 1. South Europe, Asia, Australia, Finland: 20 to 40% of GN 2. UK, Canada, USA, Brazil: 5 to 15% of GN American indians (New Mexico): 38% of GN 3. Low prevalence in blacks CHARACTERISTICS: 1. More frequent between the 2 a or 3 a decade. 2. More frequent in males than females : 2:1 Japan; 6:1 Europe. GENETIC FACTORS IN IgAN Familial cases Several loci idenfied by genome-wide scan No gene has been identified yet Susceptibility Locus LOD Score Candidate Genes Reference 6q q q q SGK, VNN3 Gharavi, Nat Genet 2000 TRPC3, IL-2, IL-21 Bisceglia, Am J Hum Genet 2006 HD5 CCL20 Paterson, J Am Soc Nephrol

6 SUSCEPTIBILITY TO IgA NEPHROPATHY Production of pathogenic IgA complexes IgAN Abnormal mesangial IgA handling Inflammatory phenotype Genetic influences Physiopathogeny of IgA Nephropathy: 1. Abnormalities of IgA1 glycosylation and of immune system 2. Formation of IgA1 complexes: Role of IgA receptor type I 3. Defective clearance of IgA1 complexes 4. Mesangial deposition: Role of tranferrin receptor 5. Progression of IgAN towards renal failure 6

7 Circulation Mucosal fluids Monomeric IgA Polymeric IgA Secretory IgA J-chain 2 subclasses - IgA1 & IgA2 Human IgA System B cells MUCOSAL Secretory component piga SYSTEMIC B cells miga IgA1 = IgA2 BLOOD 95% miga1 IgA1 >> IgA2 7

8 Study with kidney tissues IgA complexes Negative charge «Charge and size of mesangial IgA in IgA Nephropathy» Monteiro et al Kidney Int 1985 Award of the French Society of Nephrology in 1986 Composition of IgA-immune complexes IgA1 IgA2 J-chain Polymeric IgA Secretory Secretory IgA IgA - Polymeric IgA1 - Components: Self-aggregated IgA1 (hypogalactosylated) IgG anti-iga antibodies (RF) Antigens: collagen, fibronectin soluble IgA receptors 8

9 Aberrant glycosylation of IgA1 in IgAN a VL CL b VH IgA1 Cα1 Cα2 Ser/Thr c d Cα3 e in IgAN Hypogalactosylation of IgA1 (Tomana et al Kidney Int 1997) IgA1 aggregates (Kokubo et al J Am Soc Nephrol 1997) Mesangial IgA1 is hypogalactosylated? (Allen et al Kidney Int 2001) Gal NeuAc GalNac IgA Nephropathy MUCOSAL SYSTEMIC piga piga1 h BLOOD piga1 h 9

10 Is increase in piga enough? NO, myeloma IgA has no IgAN STEP 1 STEP 2 IgA deposits No disease? Disease and Progression Estimates from autopsies: 10% of general population? 1 in 50 people with IgA deposits will have manifestations Abnormally O-glycosylated IgA1 Possible mechanisms of mesangial deposition Complex formation IgA1-receptor IgG-IgA1 IgA1 IgA1 as antigen Complex formation IgA1-IgA1 self- aggregation Mesangial Deposition 10

11 Soluble FcαRI in IgA-N Units 4 2 Co IgAN RA MC AC Launay et al J Exp Med 2000 Fc receptors: Cell based Systems for Humoral Immunity B Cell antibody production Macrophages, PMN, Eosinophils Dendritic cells, Platelets, Kupffer cells leukocyte IgA FcαRI (CD89) IgA-N IgA CD89 Regulation of immunity Inhibitory functions ITIM vs ITAM Cell effector function Clearance Phagocytosis Antigen Presentation Mediators TNF IL IL-6 IL IL-1 11

12 Humanized mouse model for IgAN Lines Non-Tg Lt Tg Construct 73 CD11b promotor FcαRI EGF 96 FcαRI Stop codon 83 Hematuria - + CD11b Launay et al J Exp Med 2000 Role of Soluble FcαRI in IgAN 10 Units 5 Co Tg Rag2 -/- 0 Adoptive transfer FcαRI Tg Serum IgAN Serum adsorbed by anti-fcαri mabs Hematuria + Rag2 -/- No IgAN disease 12

13 Man Mouse FcαRI (CD89) Yes No Polymeric IgA Monomeric IgA 10% 80% 90% 20% Polymeric IgA binds better to CD89 than monomeric IgA Can IgA/CD89 interaction induce IgAR expression on mesangial cells?? protease? FcαRI/CD89 on Blood monocytes Mesangial cells 13

14 Evidences in favor of IgA receptor(s) in the mesangium: IgA binding induces triggering of human mesangial cells: Ca++ mobilization, activation of PLCγ enhanced proliferation IL6, IL8, TNFα and TGFβ enhanced production of ECM (Gomes-guerrero et al 1994, Chen et al 1994, van den Dobbelsteen et al 1994, Lopez-Armada et al 1996, Amore et al 2001, Lai et al 2003) Absence of classical IgA receptors on mesangial cells Poly IgR Fcα/µR ASGP-R FcαRI (CD89) IgA/IgM IgA/IgM ASGP/IgA IgA Monteiro & Van de Winkel Ann. Rev. Immunol

15 Transferrin Receptor (TfR, CD71) binds IgA1 Genes: Chromosome 3 from Lawrence et al Science 1999 Proteins: Expression: Ligands: Functions: TfR1 and TfR2 All cells but heterogeneous Mesangial cells +++Immature cells Low density: Transferrin, HFE High density : piga1 Transferrin: Iron uptake IgA1: deleterious? Normal Upregulation of transferrin receptor in the mesangium of patients with IgAN and HSP IgAN HSP Haddad et al J Am Soc Nephrol

16 Enhanced expression of TfR is associated with disease severity. A new biomarker for diasese progression? Haddad et al J Am Soc Nephrol 2003 Can aberrantly glycosylated IgA1 bind to TfR? 16

17 Degalactosylation of piga1 promotes enhanced binding to transferrin receptor Myeloma IgA1 Patient IgA 12 Cell Number IgG desialylated & Degalactosyl ated + stfr1 Non treated desialylated desialylated & degalactosylated Median Fluorescence Intensity p< Fluorescence Intensity (log) controls IgAN Moura et al J Am Soc Nephrol 2004 Can IgA1-TfR interaction explain inflammation? 17

18 IgA1-induced cytokine production through TfR IL-6 TGF-β P < P < IL-6 (pg/ml) TGF β (pg/ml) % FCS - A % FCS A piga1 piga1 Proposed role of transferrin receptor in IgAN Aberrant IgA1 complexes Proliferation IgA1 deposits on mesangial TfR Enhanced TfR expression Cytokines Chemokines TfR = transferrin receptor Inflammation Fibrosis Mesangiopathy A possible explanation for recurrence of IgA deposits after transplantation 18

19 Role of transmembrane FcαRI-γ IgA complexes IgA complexes Soluble FcαRI γ chain (ITAM) Syk SHP-1 IgA recycling Cell activation Inhibition Inflammation IgA bound to FcαRI is correlated with glomerulosclerosis in IgAN patients Monocytes 5 p < Anti-IgA Ab (FI) Glomerulosclerosis Controls IgAN MC Grossetete et al Kidney Int 1998 Lai et al J Am Soc Nephrol

20 Crosslinking of FcαRI-γ induces proteinuria and macrophage infiltration Wild type Tg R Proteinuria (mg/dl) C57/BL6 FcαRI Tg γ-less FcαRI Tg * * * L Mutant R209L Tg γ chain days days A77 A77 * anti-fcαri F(ab ) 2 (Balb/c) IgA mac1 Kanamaru et al, Eur J Immunol Circulation Endothelium 2. Glomerulus Priming Defective clearance Fenestrated endothelium GBM Monocytes Renal interstitium 3. Activated Monocytes Chemotaxis Renal tubule Cytokines/ chemokines FcRγ adaptor Transmembrane FcαRI Soluble FcαRI IgA Activated Mesangial cells TfR (CD71) Moura et al Sem Nephrol

21 Future treatments for IgA Nephropathy MUCOSAL SYSTEMIC - Anti-CD20? - Proteases? Leukocytes piga piga1 BLOOD - Anti-CD89 piga1 - Anti-CD71 (A24) Developped by InatherYs - Rapamycin 21