The classical pathway triggers pathogenic complement activation in membranous nephropathy

Larissa Seifert, Gunther Zahner, Catherine Meyer-Schwesinger, Naemi Hickstein, Silke Dehde, Sonia Wulf, Sarah M. S. Köllner, Renke Lucas, Dominik Kylies, Sarah Froembling, Stephanie Zielinski, Oliver Kretz, Anna Borodovsky, Sergey Biniaminov, Yanyan Wang, Hong Cheng, Friedrich Koch-Nolte, Peter F. Zipfel, Helmut Hopfer, Victor G. Puelles, Ulf Panzer, Tobias B. Huber, Thorsten Wiech and Nicola M. Tomas ()
Additional contact information
Larissa Seifert: University Medical Center Hamburg-Eppendorf
Gunther Zahner: University Medical Center Hamburg-Eppendorf
Catherine Meyer-Schwesinger: University Medical Center Hamburg-Eppendorf
Naemi Hickstein: University Medical Center Hamburg-Eppendorf
Silke Dehde: University Medical Center Hamburg-Eppendorf
Sonia Wulf: University Medical Center Hamburg-Eppendorf
Sarah M. S. Köllner: University Medical Center Hamburg-Eppendorf
Renke Lucas: University Medical Center Hamburg-Eppendorf
Dominik Kylies: University Medical Center Hamburg-Eppendorf
Sarah Froembling: University Medical Center Hamburg-Eppendorf
Stephanie Zielinski: University Medical Center Hamburg-Eppendorf
Oliver Kretz: University Medical Center Hamburg-Eppendorf
Anna Borodovsky: Alnylam Pharmaceuticals
Sergey Biniaminov: HS Analysis GmbH
Yanyan Wang: Capital Medical University
Hong Cheng: Capital Medical University
Friedrich Koch-Nolte: University Medical Center Hamburg-Eppendorf
Peter F. Zipfel: Hans Knöll Institute
Helmut Hopfer: University Hospital Basel, University of Basel
Victor G. Puelles: University Medical Center Hamburg-Eppendorf
Ulf Panzer: University Medical Center Hamburg-Eppendorf
Tobias B. Huber: University Medical Center Hamburg-Eppendorf
Thorsten Wiech: University Medical Center Hamburg-Eppendorf
Nicola M. Tomas: University Medical Center Hamburg-Eppendorf

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Membranous nephropathy (MN) is an antibody-mediated autoimmune disease characterized by glomerular immune complexes containing complement components. However, both the initiation pathways and the pathogenic significance of complement activation in MN are poorly understood. Here, we show that components from all three complement pathways (alternative, classical and lectin) are found in renal biopsies from patients with MN. Proximity ligation assays to directly visualize complement assembly in the tissue reveal dominant activation via the classical pathway, with a close correlation to the degree of glomerular C1q-binding IgG subclasses. In an antigen-specific autoimmune mouse model of MN, glomerular damage and proteinuria are reduced in complement-deficient mice compared with wild-type littermates. Severe disease with progressive ascites, accompanied by extensive loss of the integral podocyte slit diaphragm proteins, nephrin and neph1, only occur in wild-type animals. Finally, targeted silencing of C3 using RNA interference after the onset of proteinuria significantly attenuates disease. Our study shows that, in MN, complement is primarily activated via the classical pathway and targeting complement components such as C3 may represent a promising therapeutic strategy.

Date: 2023
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DOI: 10.1038/s41467-023-36068-0

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