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PHYSIOPATHOLOGIE DES NEPHROPATHIES A DEPOTS D’IgA

PHYSIOPATHOLOGIE DES NEPHROPATHIES A DEPOTS D’IgA. Renato Monteiro Inserm U699, Hôpital Bichat, Paris. Seminaire National de Néphrologie 20-22 Juin 2010. Berger’s disease or IgA nephropathy.

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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 20-22 Juin 2010

  2. Berger’s disease or IgA nephropathy « 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. » www.igan-world.org Jean Berger et Nicole Hinglais Dépôts intercapillaires d’IgA-IgG. J Urol Nephrol (Paris). Sept 1968; 74:694-5.

  3. History French disease ? Food & environnement? 1975 1968 1972-3 Description at Necker Hosp, Paris Severe disease. Recurrence after Tx 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)

  4. 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

  5. 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

  6. Morphology Heterogeneity of lesions

  7. 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, 534-545, 2009 Roberts et al Kidney Int 76, 546-556, 2009

  8. Correlation between Oxford classification and disease severity (examples) Slope: ml/min per 1.73 m2 per year Glomerular lesions Definition N° of patients Criteria Minimal mesangial hypercellularity Without segmental sclerosis With segmental sclerosis 0.7 ± 2.5 -1.5 ± 2.7 M0, S0, E0 M0, S1, E0 13 22 Mesangial hypercellularity Without segmental sclerosis With segmental sclerosis -2.2 ± 4.3 -4.7 ± 7.6 M1, S0, E0 M1, S1, E0 31 88 Endocapillary proliferation Without segmental sclerosis With segmental sclerosis 1.2 ± 1.2 -4.9 ± 10.0 M0/1, S0, E1 M0/1, S1, E1 21 90 Slope: ml/min per 1.73 m2 per year Glomerular lesions Tubular atrophy/interstitial fibrosis N° of patients Criteria Minimal mesangial hypercellularity ≤ 25% < 26% -0.6 ± 3.0 -1.0 ± 1.2 M0, E0, T0 M0, E0,T1-2 30 5 Mesangial hypercellularity ≤ 25% < 26% -2.7 ± 5.5 -7.9 ± 9.1 M1, E0, T0 M1, E0, T1-2 89 30 ≤ 25% < 26% Endocapillary proliferation -3.0 ± 1.9 -6.9 ± 1.2 M0/1, E1, T0 M0/1, E1, T1-2 88 23

  9. 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 2a or 3a decade. 2. More frequent in males than females : 2:1 Japan; 6:1 Europe.

  10. GENETIC FACTORS IN IgAN • Familial cases • Several loci idenfied by genome-wide scan • No gene has been identified yet LOD Score Susceptibility Locus Candidate Genes Reference 6q22-23 4q26-31 17q12-22 2q36 5.6 1.83 2.56 3.5 SGK, VNN3 TRPC3, IL-2, IL-21 HD5 CCL20 Gharavi, Nat Genet 2000 Bisceglia, Am J Hum Genet 2006 Paterson, J Am Soc Nephrol 2007

  11. SUSCEPTIBILITY TO IgA NEPHROPATHY Production of ‘pathogenic’ IgA complexes Abnormal mesangial IgA handling IgAN ‘Inflammatory phenotype’ Geneticinfluences

  12. 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

  13. J-chain Circulation Mucosal fluids Monomeric IgA Polymeric IgA Secretory IgA 2 subclasses - IgA1 & IgA2

  14. Human IgA System MUCOSAL SYSTEMIC B cells Secretory component mIgA pIgA B cells IgA1 = IgA2 IgA1 >> IgA2 BLOOD 95% mIgA1

  15. 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

  16. J-chain Composition of IgA-immune complexes IgA1 IgA2 Secretory IgA Polymeric IgA Secretory IgA - Polymeric IgA1 • Self-aggregated IgA1 (hypogalactosylated) • IgG anti-IgA antibodies (RF) • Antigens: collagen, fibronectin • soluble IgA receptors - Components:

  17. Aberrant glycosylation of IgA1 in IgAN a VL CL b VH c Ca1 Ser/Thr IgA1 Ca2 d Ca3 in IgAN e • 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

  18. IgA Nephropathy MUCOSAL SYSTEMIC pIgA pIgA1h BLOOD pIgA1h

  19. 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

  20. Abnormally O-glycosylated IgA1 Possible mechanisms of mesangial deposition Complex formation Complex formation IgG-IgA1 IgA1 as antigen IgA1-IgA1 self- aggregation IgA1-receptor Mesangial Deposition

  21. Soluble FcRI in IgA-N Units 4 2 Co IgAN RA MC AC Launay et al J Exp Med 2000

  22. Fc receptors: Cell based Systems for Humoral Immunity IgA IgA-N B Cell antibody production IgA CD89 FcαRI (CD89) Macrophages, PMN, Eosinophils Dendritic cells, Platelets, Kupffer cells leukocyte • Cell effector function • Clearance • Phagocytosis • Antigen Presentation • Mediators • TNF • IL-6 • IL-1 • Regulation of immunity • Inhibitory functions • ITIM vs ITAM

  23. Humanized mouse model for IgAN Non-Tg Lt Lines Tg Construct 73 CD11b promotor EGF FcRI FcaRI 96 Stop codon 83 - + CD11b Hematuria Launay et al J Exp Med 2000

  24. Rag2-/- Rag2-/- Adoptive transfer Serum FcaRI Tg IgAN Serum adsorbed by anti-FcRI mAbs Hematuria + Rag2-/- IgAN No disease Role of Soluble FcRI in IgAN Co 10 Tg Units 5 0

  25. Man Mouse Yes No FcRI (CD89) Polymeric IgA 10% 80% Monomeric IgA 90% 20% Polymeric IgA binds better to CD89 than monomeric IgA

  26. Can IgA/CD89 interaction induce IgAR expression on mesangial cells ? ? protease ? FcaRI/CD89 on Blood monocytes Mesangial cells

  27. 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, TNF and TGF • 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)

  28. Absence of classical IgA receptors on mesangial cells Poly IgR Fc/R ASGP-R FcRI (CD89) IgA/IgM IgA/IgM ASGP/IgA IgA Monteiro & Van de Winkel Ann. Rev. Immunol. 2003

  29. Transferrin Receptor (TfR, CD71) binds IgA1 Genes:Chromosome 3 Proteins:TfR1 and TfR2 Expression:All cells but heterogeneous Mesangial cells +++Immature cells Ligands:Low density:Transferrin, HFE High density : pIgA1 Functions: Transferrin: Iron uptake IgA1: deleterious? from Lawrence et al Science 1999

  30. Normal Upregulation of transferrin receptor in the mesangium of patients with IgAN and HSP IgAN HSP Haddad et al J Am Soc Nephrol 2003

  31. Enhanced expression of TfR is associated with disease severity. A new biomarker for diasese progression? Haddad et al J Am Soc Nephrol 2003

  32. Can aberrantly glycosylated IgA1 bind to TfR?

  33. desialylated & Degalactosyl ated + sTfR1 IgG Non treated desialylated Cell Number desialylated & degalactosylated Fluorescence Intensity (log) Degalactosylation of pIgA1 promotes enhanced binding to transferrin receptor Myeloma IgA1 Patient IgA 12 p<0.001 10 8 Median Fluorescence Intensity 6 4 2 0 controls IgAN Moura et al J Am Soc Nephrol 2004

  34. Can IgA1-TfR interaction explain inflammation ?

  35. IgA1-induced cytokine production through TfR IL-6 TGF-β 160 140 P < 0.05 P < 0.05 400 120 300 100 TGF  (pg/ml) IL-6 (pg/ml) 80 200 60 40 100 20 - 0 0 - 0.5% FCS A24 30.9 A24 30.9 0.5% FCS pIgA1 pIgA1

  36. Proposed role of transferrin receptor in IgAN Aberrant IgA1 complexes Enhanced TfR expression IgA1 deposits on mesangial TfR Proliferation TfR = transferrin receptor Cytokines Chemokines Inflammation Fibrosis Mesangiopathy • A possible explanation for recurrence of IgA deposits after transplantation

  37. Role of transmembrane FcRI- IgA complexes IgA complexes Soluble FcRI  chain (ITAM) SHP-1 Syk Cell activation IgA recycling Inhibition Inflammation

  38. p < 0 . 0 0 1 5 4 3 2 . 9 2 1 . 1 1 0 . 9 C o n t r o l s IgAN MC IgA bound to FcRI is correlated with glomerulosclerosis in IgAN patients Monocytes Glomerulosclerosis Anti-IgA Ab (FI) Grossetete et al Kidney Int 1998 Lai et al J Am Soc Nephrol 2002

  39. FcRI Tg 500 * Wild type Tg Proteinuria (mg/dl) 250 R L 0 0 1 2 3 5 6 7 4 days  chain Crosslinking of FcRI- induces proteinuria and macrophage infiltration C57/BL6 -less FcRI Tg Mutant R209L Tg * * 0 1 2 3 4 5 6 7 days A77 A77 anti-FcRI F(ab’)2 (Balb/c) * IgA mac1 Kanamaru et al, Eur J Immunol 2007

  40. Circulation Glomerulus Endothelium 1. 2. Fenestrated endothelium Defective clearance Priming GBM Monocytes 3. Cytokines/ chemokines Chemotaxis Activated Mesangial cells Activated Monocytes Renal interstitium Renal tubule FcR adaptor Transmembrane FcRI Soluble FcRI IgA TfR (CD71) Moura et al Sem Nephrol 2008

  41. Future treatments for IgA Nephropathy MUCOSAL SYSTEMIC • Anti-CD20 ? • Proteases ? pIgA pIgA1 Leukocytes BLOOD pIgA1 • Anti-CD89 • Anti-CD71 (A24) Developped by InatherYs • Rapamycin

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