Autoimmune Abnormalities of the Alternative Complement Pathway in Membranoproliferative Glomerulonephritis and C3 Glomerulopathy

Overview

Journal Pediatr Nephrol

Specialties Nephrology
Pediatrics

Date 2018 Jun 28

PMID 29948306

Citations 27

Authors

Marina Noris

Roberta Donadelli

Giuseppe Remuzzi

Affiliations

Soon will be listed here.

Abstract

Membranoproliferative glomerulonephritis (MPGN) is a rare chronic kidney disease associated with complement activation. Recent immunofluorescence-based classification distinguishes between immune complex (IC)-mediated MPGN, with glomerular IgG and C3 deposits, and C3 glomerulopathies (C3G), with predominant C3 deposits. Genetic and autoimmune abnormalities causing hyperactivation of the complement alternative pathway have been found as frequently in patients with immune complex-associated MPGN (IC-MPGN) as in those with C3G. In the last decade, there have been great advances in research into the autoimmune causes of IC-MPGN and C3G. The complement-activating autoantibodies called C3-nephritic factors (C3NeFs), which are present in 40-80% of patients, form a heterogeneous group of autoantibodies that stabilise the C3 convertase or the C5 convertase of the alternative pathway or both. A few patients, mainly with IC-MPGN, carry autoantibodies directed against the two components of the alternative pathway C3 convertase, factors B and C3b. Finally, autoantibodies against factor H, the main regulator of the alternative pathway, have been reported in a small proportion of patients with IC-MPGN or C3G. The identification of distinct pathogenetic patterns leading to kidney injury and of targets in the complement cascade may pave the way for tailored therapies for IC-MPGN and C3G, with specific complement inhibitors in the development pipeline.

Citing Articles

Acquired drivers of C3 glomerulopathy.

Welsh S, Zhang Y, Smith R Clin Kidney J. 2025; 18(3):sfaf022.

PMID: 40052168 PMC: 11883229. DOI: 10.1093/ckj/sfaf022.

Challenges in the Diagnosis and Management of Immune Complex-Mediated Membranoproliferative Glomerulonephritis and Complement 3 Glomerulopathy.

Bomback A, Charu V, Fakhouri F Kidney Int Rep. 2025; 10(1):17-28.

PMID: 39810761 PMC: 11725974. DOI: 10.1016/j.ekir.2024.09.017.

Functional Characterization of Anti-C3bBb Autoantibodies and C3 Glomerulopathy Phenotype.

Roquigny J, Meuleman M, El Sissy C, Cailliez M, Servais A, Roussey G J Am Soc Nephrol. 2024; 36(2):264-273.

PMID: 39325562 PMC: 11801764. DOI: 10.1681/ASN.0000000000000499.

First Successful Treatment of a Patient with a Primary Immune Complex-Membranoproliferative Glomerulonephritis with Iptacopan: A Case Report.

Arnold S, Nickler M, Dickenmann M, Menter T, Hopfer H, Hirt-Minkowski P Case Rep Nephrol Dial. 2024; 14(1):138-147.

PMID: 39118827 PMC: 11309753. DOI: 10.1159/000540013.

The ouroboros of autoimmunity.

Casanova J, Peel J, Donadieu J, Neehus A, Puel A, Bastard P Nat Immunol. 2024; 25(5):743-754.

PMID: 38698239 DOI: 10.1038/s41590-024-01815-y.

References

Schena F, Pertosa G, Stanziale P, Vox E, Pecoraro C, Andreucci V . Biological significance of the C3 nephritic factor in membranoproliferative glomerulonephritis. Clin Nephrol. 1982; 18(5):240-6. View

Iatropoulos P, Noris M, Mele C, Piras R, Valoti E, Bresin E . Complement gene variants determine the risk of immunoglobulin-associated MPGN and C3 glomerulopathy and predict long-term renal outcome. Mol Immunol. 2016; 71:131-142. DOI: 10.1016/j.molimm.2016.01.010. View

Berends E, Gorham Jr R, Ruyken M, Soppe J, Orhan H, Aerts P . Molecular insights into the surface-specific arrangement of complement C5 convertase enzymes. BMC Biol. 2015; 13:93. PMC: 4638095. DOI: 10.1186/s12915-015-0203-8. View

Appel G, Cook H, Hageman G, Jennette J, Kashgarian M, Kirschfink M . Membranoproliferative glomerulonephritis type II (dense deposit disease): an update. J Am Soc Nephrol. 2005; 16(5):1392-403. DOI: 10.1681/ASN.2005010078. View

Levy M, Gubler M, Sich M, Beziau A, Habib R . Immunopathology of membranoproliferative glomerulonephritis with subendothelial deposits (Type I MPGN). Clin Immunol Immunopathol. 1978; 10(4):477-92. DOI: 10.1016/0090-1229(78)90160-5. View

Servais A, Noel L, Roumenina L, le Quintrec M, Ngo S, Dragon-Durey M . Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int. 2012; 82(4):454-64. DOI: 10.1038/ki.2012.63. View

Delvaeye M, Noris M, de Vriese A, Esmon C, Esmon N, Ferrell G . Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med. 2009; 361(4):345-57. PMC: 3530919. DOI: 10.1056/NEJMoa0810739. View

Marinozzi M, Roumenina L, Chauvet S, Hertig A, Bertrand D, Olagne J . Anti-Factor B and Anti-C3b Autoantibodies in C3 Glomerulopathy and Ig-Associated Membranoproliferative GN. J Am Soc Nephrol. 2017; 28(5):1603-1613. PMC: 5407719. DOI: 10.1681/ASN.2016030343. View

Podack E, KOLB W, MULLER-EBERHARD H . The SC5b-7 complex: formation, isolation, properties, and subunit composition. J Immunol. 1977; 119(6):2024-9. View

10.

Sethi S, Gamez J, Vrana J, Theis J, Bergen 3rd H, Zipfel P . Glomeruli of Dense Deposit Disease contain components of the alternative and terminal complement pathway. Kidney Int. 2009; 75(9):952-60. PMC: 2738640. DOI: 10.1038/ki.2008.657. View

11.

Sethi S, Fervenza F . Membranoproliferative glomerulonephritis--a new look at an old entity. N Engl J Med. 2012; 366(12):1119-31. DOI: 10.1056/NEJMra1108178. View

12.

Mollnes T, Ng Y, PETERS D, Lea T, Tschopp J, HARBOE M . Effect of nephritic factor on C3 and on the terminal pathway of complement in vivo and in vitro. Clin Exp Immunol. 1986; 65(1):73-9. PMC: 1542267. View

13.

Ohi H, Yasugi T . Occurrence of C3 nephritic factor and C4 nephritic factor in membranoproliferative glomerulonephritis (MPGN). Clin Exp Immunol. 1994; 95(2):316-21. PMC: 1534915. DOI: 10.1111/j.1365-2249.1994.tb06530.x. View

14.

Zipfel P, Skerka C . Complement regulators and inhibitory proteins. Nat Rev Immunol. 2009; 9(10):729-40. DOI: 10.1038/nri2620. View

15.

Iatropoulos P, Daina E, Curreri M, Piras R, Valoti E, Mele C . Cluster Analysis Identifies Distinct Pathogenetic Patterns in C3 Glomerulopathies/Immune Complex-Mediated Membranoproliferative GN. J Am Soc Nephrol. 2017; 29(1):283-294. PMC: 5748907. DOI: 10.1681/ASN.2017030258. View

16.

Durey M, Sinha A, Togarsimalemath S, Bagga A . Anti-complement-factor H-associated glomerulopathies. Nat Rev Nephrol. 2016; 12(9):563-78. DOI: 10.1038/nrneph.2016.99. View

17.

Vernon K, Goicoechea de Jorge E, Hall A, Fremeaux-Bacchi V, Aitman T, Cook H . Acute presentation and persistent glomerulonephritis following streptococcal infection in a patient with heterozygous complement factor H-related protein 5 deficiency. Am J Kidney Dis. 2012; 60(1):121-5. PMC: 3382710. DOI: 10.1053/j.ajkd.2012.02.329. View

18.

Bhattacharjee A, Reuter S, Trojnar E, Kolodziejczyk R, Seeberger H, Hyvarinen S . The major autoantibody epitope on factor H in atypical hemolytic uremic syndrome is structurally different from its homologous site in factor H-related protein 1, supporting a novel model for induction of autoimmunity in this disease. J Biol Chem. 2015; 290(15):9500-10. PMC: 4392255. DOI: 10.1074/jbc.M114.630871. View

19.

Vivarelli M, Emma F . Treatment of C3 glomerulopathy with complement blockers. Semin Thromb Hemost. 2014; 40(4):472-7. DOI: 10.1055/s-0034-1375299. View

20.

Zhang Y, Meyer N, Wang K, Nishimura C, Frees K, Jones M . Causes of alternative pathway dysregulation in dense deposit disease. Clin J Am Soc Nephrol. 2012; 7(2):265-74. PMC: 3280037. DOI: 10.2215/CJN.07900811. View