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; Nicola M. Tomas

doi:10.1038/s41467-023-36068-0

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. PuellesUlf Panzer, Tobias B. Huber, Thorsten Wiech, Nicola M. Tomas^*

^*Corresponding author for this work

Department of Clinical Medicine - The Department of Pathology

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

54 Citations (Scopus)

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.

Original language	English
Article number	473
Journal	Nature Communications
Volume	14
Issue	1
Number of pages	18
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-023-36068-0
Publication status	Published - 2023

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Seifert, L., Zahner, G., Meyer-Schwesinger, C., Hickstein, N., Dehde, S., Wulf, S., Köllner, S. M. S., Lucas, R., Kylies, D., Froembling, S., Zielinski, S., Kretz, O., Borodovsky, A., Biniaminov, S., Wang, Y., Cheng, H., Koch-Nolte, F., Zipfel, P. F., Hopfer, H., ... Tomas, N. M. (2023). The classical pathway triggers pathogenic complement activation in membranous nephropathy. Nature Communications, 14(1), Article 473. https://doi.org/10.1038/s41467-023-36068-0

@article{51adfac2c7b848f3b99312fbeb00ab13,

title = "The classical pathway triggers pathogenic complement activation in membranous nephropathy",

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.",

author = "Larissa Seifert and Gunther Zahner and Catherine Meyer-Schwesinger and Naemi Hickstein and Silke Dehde and Sonia Wulf and K{\"o}llner, {Sarah M.S.} and Renke Lucas and Dominik Kylies and Sarah Froembling and Stephanie Zielinski and Oliver Kretz and Anna Borodovsky and Sergey Biniaminov and Yanyan Wang and Hong Cheng and Friedrich Koch-Nolte and Zipfel, {Peter F.} and Helmut Hopfer and Puelles, {Victor G.} and Ulf Panzer and Huber, {Tobias B.} and Thorsten Wiech and Tomas, {Nicola M.}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

doi = "10.1038/s41467-023-36068-0",

language = "English",

volume = "14",

journal = "Nature Communications",

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Seifert, L, Zahner, G, Meyer-Schwesinger, C, Hickstein, N, Dehde, S, Wulf, S, Köllner, SMS, Lucas, R, Kylies, D, Froembling, S, Zielinski, S, Kretz, O, Borodovsky, A, Biniaminov, S, Wang, Y, Cheng, H, Koch-Nolte, F, Zipfel, PF, Hopfer, H, Puelles, VG, Panzer, U, Huber, TB, Wiech, T & Tomas, NM 2023, 'The classical pathway triggers pathogenic complement activation in membranous nephropathy', Nature Communications, vol. 14, no. 1, 473. https://doi.org/10.1038/s41467-023-36068-0

TY - JOUR

T1 - The classical pathway triggers pathogenic complement activation in membranous nephropathy

AU - Seifert, Larissa

AU - Zahner, Gunther

AU - Meyer-Schwesinger, Catherine

AU - Hickstein, Naemi

AU - Dehde, Silke

AU - Wulf, Sonia

AU - Köllner, Sarah M.S.

AU - Lucas, Renke

AU - Kylies, Dominik

AU - Froembling, Sarah

AU - Zielinski, Stephanie

AU - Kretz, Oliver

AU - Borodovsky, Anna

AU - Biniaminov, Sergey

AU - Wang, Yanyan

AU - Cheng, Hong

AU - Koch-Nolte, Friedrich

AU - Zipfel, Peter F.

AU - Hopfer, Helmut

AU - Puelles, Victor G.

AU - Panzer, Ulf

AU - Huber, Tobias B.

AU - Wiech, Thorsten

AU - Tomas, Nicola M.

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85146944779&partnerID=8YFLogxK

U2 - 10.1038/s41467-023-36068-0

DO - 10.1038/s41467-023-36068-0

M3 - Journal article

C2 - 36709213

AN - SCOPUS:85146944779

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 473

ER -

The classical pathway triggers pathogenic complement activation in membranous nephropathy

Abstract

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