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Semelhante a 5-2. C3 glomerulonephritis and Dense Deposit Disease. Francesco Emma (eng)
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5-2. C3 glomerulonephritis and Dense Deposit Disease. Francesco Emma (eng)
- 1. C3 glomerulonephritis and Dense Deposit Disease Francesco Emma Division of Nephrology and Dialysis Bambino Gesù Children’s Hospital, IRCCS Rome, Italy
- 2. The area of complement…. Leslie M., Science 2012
- 3. MPGN – “classic classification” MPGN Type I Subendothelial deposits West et al, J Pediatr 1965 MPGN Type II / DDD Intramembranous deposits Galle, Thesis 1962; Habib et al, Kidney Int 1975 MPGN Type III Subendothelial and subepithelial deposits Burkholder et al, Am J Pathol 1969 Anders et al, Virchows Arch A Pathol Anat Histol 1997 Strife et al, Clin Nephrol 1984
- 4. C3GN 19 patients with unusual glomerulonephritis and: - C3NeF positivity (7), CFH (3), CFI (2) or MCP (1) mutations - overt mesangial and epimembranous C3 deposits - absence of dense intramembranous deposits - no Ig deposition
- 5. Evidence for a role of complement in DDD/C3GN in humans • Proteomic profile of microdissected glomeruli: C3, C4, C5, C6, C7, C8, FHR1, FHR5…. • Very similar profile between DDD and C3GN Sethi et al Kidney Int 2009; Sethi S et al Clin J Am Soc Nephrol 2011
- 6. Histology in DDD and C3GN DDD Mesangial proliferation MPGN Crescentic / Exudative GN C3GN 45% 35% 10% 40% 55% 5% Servais A, J Med Genet 2007 Walker PD et al, Modern Pathol 2007 Fakhouri F et al, Nature Rev Nephrol 2010 Sethi S, Kidney Int 2012
- 7. Glomerular lesions in DDD MPGN Mesangial proliferation Crescentic Diffuse endocapillary proliferation Walker PD et al, Modern Pathol 2007
- 8. The diagnosis of DDD requires electron microscopy DDD Walker PD et al, Modern Pathol 2007 C3GN Sethi S et al, Clin J Am Soc Nephrol 2011
- 9. Glomerular lesions in C3GN Mesangial proliferation MPGN Diffuse endocapillary proliferation Sethi S, Kidney International (2012) 82, 465–473
- 10. Mesangial proliferative GN and MPGN represent a continuum Sethi S and Fervenza FC, Semin Nephrol 2011
- 11. New classification based on C3: MPGN1 / DDD / GN-C3
- 12. New classification based on the MPGN pattern * MPGN1 DDD C3GN Sethi S and Fervenza FC, Semin Nephrol 2011 Sethi S and Fervenza FC, NEJM 2012 *Servais et al, Kidney Int 2012; Dragon-Durey et al. JASN 2004; Vaziri-Sani et al. Kidney Int 2006; Leroy V et al. Ped Nephrol 2011
- 13. MPGN1 can also be secondary to dysregulation of the complement alternative pathway Servais et al, Kidney Int 2012
- 14. A simplified view of the complement system Zipfel and Skerka, Nat Rev Immunol 2009
- 15. Complement-mediated MPGN inflammation Sethi S, Fervenza FC NEJM 2012
- 16. C3 convertase C3bBb Sethi S, Fervenza FC NEJM 2012 Torreira et al, PNAS 2009
- 17. C3 convertase Rodríguez de Córdoba S et al., Biochem Biophys Acta, 2011
- 18. The C3 convertase can be activated in the fluid-phase or on cell surfaces
- 19. The C3 convertase can be activated in the fluid-phase or on cell surfaces Adapted from Rodríguez de Córdoba S et al., Biochem Biophys Acta, 2011
- 20. C3 mutations in DDD • Mutation in the C3 gene (923ΔDG) which lacks 2 amino acids • Generates an active C3-convertase that is: - normally regulated by DAF on the surface of endothelial cells - resistant to decay by factor H in the plasma Conclusion: fluid phase-restricted dysregulation of the AP
- 21. The C3 convertase can be activated in the fluid-phase or on cell surfaces C-terminal region surface binding (glycosaminoglycans/heparins) Rodríguez de Córdoba S et al., Biochem Biophys Acta, 2011
- 22. CFH domain mutations in aHUS and DDD C-terminal region surface binding (glycosaminoglycans/heparins) Rodríguez de Córdoba S et al., Biochem Biophys Acta, 2011
- 23. The role of C3 vs. C5 in MPGN Cfh-/- mice Cfh-/- FHD16-20 mice MPGN aHUS C3 Prevented if: Worsen if: Improved if: C3 Cfi-/- C5-/- or anti-C5 C3 activation C5-/- or anti-C5 Dependent on C3>>C5 Dependent on C5 Rose et al, J Clin Invest, 2008 Pickering et al. Nat Genet 2002 Pickering et al. PNAS 2006 Goicoechea de Jorge, JASN 2011
- 24. Complement dysregulation in kidney diseases
- 25. C3 levels in C3G Servais et al, Kidney Int 2012
- 27. Physiopathology of DDD/C3GN Adapted from Smith et al. Mol Immunol 2011
- 28. DDD / C3GN: autoimmune forms • C3 nephritic factor (C3NeF): - IgG binding to neoepitope on alternative C3 convertase (C3bBb) - Stabilizes C3bBb against intrinsic and extrinsic decay - Present in all MPGN subtypes (DDD: 55% adults and 80% children) - High degree of inter-/intraindividual variability – poor predictive value Schwertz et al, Acta Paediatr 1986; Schwertz et al, Pediatr Allergy Immunol 2001 • CFH (mini-)antibody: - Binds to CFH SCR3 and inhibits CFH cofactor activity - Phenotype DDD Meri et al, J Exp Med 1992; Jokiranta et al, J Immunol 1999 • CFB autoantibody: - Binds Bb - Similar effect as C3NeF - Enhances C3 conversion - Phenotype DDD Strobel et al, Mol Immunol 2010
- 29. C3NeF: still poorly understood… What epitopes do they bind and how tightly ? Do they all stabilize the convertase to the same extent ? Do they act on cell surface ? Do differences correlate with the phenotype ? Do they disappear spontaneously ?
- 30. DDD / C3GN: genetic forms Courtesy of Christoph Licth Gene / Protein Mutation / Variant Function CFH Mutations: - homo- / compound heterozygous - SCRs 1-4 (regulatory domain) - Cys residues (tertiary structure) - Intact surface binding - Reduced C3b binding - Loss of CFH cofactor and decay accelerating activity DDD C3GN CFH Polymorphisms: - Y402H (SCR 7) - Impaired C3b / heparin binding - Impaired CFH cofactor activity DDD CNV: - CFHR3-1 hybrid gene - Not tested - ?Dominant negative effect C3GN Malik, J Am Soc Nephrol 2012 CFHR5 CNV: - Duplication within CFHR5 exons 2/3 - Not tested - ?Dominant negative effect C3GN Gale, The Lancet 2010 CFHR5 Polymorphisms - Not tested DDD Abrera-Abeleda, J Med Genet 2006 Abrera-Abeleda, J Am Soc Nephrol 2011 C3 Mutations: - Heterozygous deletion - C3mut resistant to cleavage by C3bBb - C3mut convertase – resistant to CFH inactivation DDD Martinez-Barricarte, J Clin Invest 2010 C3 Polymorphisms - Not tested DDD Smith, J Am Soc Nephrol 2007 Abrera-Abeleda, J Am Soc Nephrol 2011 CFHR3-1 Phenotype Reference Levy, Kidney Int 1986 Meri, J Exp Med 1992 Vogt, Pediatr Nephrol 1995 Ault, J Biol Chem 1997 Dragon-Durey, J Am Soc Nephrol 2004 Licht, Kidney Int 2006 Habbig, Kidney Int 2009 Hageman, Proc Nat Acad Sci 2005 Abrera-Abeleda, J Med Genet 2006 Abrera-Abeleda, J Am Soc Nephrol 2011
- 31. Treatment of DDD / C3GN No established therapy Some cases may spontaneously improve Some patients have a relapsing course Immune-suppressive drugs (PDN, CsA, MMF) may be beneficial in some cases, in particular if evidence of renal inflammation: - anecdotal reports and retrospective cohort studies - generally partial responses Anti-C5 may be beneficial in some, but not all patients
- 32. Treatment of DDD with eculizumab NB: not all patients respond so well NB: expensive! Vivarelli et al, New England J Med 2012
- 33. Presenting symptom in C3G 2 7 9
- 35. Atypical APGN Kidney International 2012
- 36. Atypical APGN Kidney International 2012