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Peer-reviewedCC BY 4.0The Journal of Clinical Investigation

Anti-PLA2R autoantibodies induce complement activation via IgG subclass–dependent epitope pairings in membranous nephropathy

  • Tsai-Yi Wu1,2,3,4
  • Kun-Hua Tu1,4,5
  • Larissa Seifert2,3
  • Kung-Wei Lin1,6
  • Han-Po Shih1,7,8
  • Yu-Fang Lo1,7
  • Jhan-Jie Peng7,8
  • Gunther Zahner2,3
  • Oliver Kretz2,3,9
  • You-Ning Lin1,7
  • Chen-Xuan Kang1,4,7
  • Jing-Ya Ding1,7
8 more authors
  • Yi-Ran Tu5
  • Li-Yi Ma5
  • Ya-Ting Chuang10
  • Chia-Chi Lo1,7
  • Yu-Huan Tsai7,8,11,12
  • Chih-Wei Yang5
  • Nicola M. Tomas2,3,13
  • Cheng-Lung Ku1,5,7,14,15
15 affiliations
  1. 1Laboratory of Human Immunology and Infectious Disease, Institute of Immunology and Translational Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
  2. 2III. Department of Medicine, and
  3. 3Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  4. 4Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
  5. 5Kidney Research Center, Department of Nephrology, Chanα-g Gung Memorial Hospital, Taoyuan, Taiwan.
  6. 6Institute of Microbiology and Immunology, School of Life Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan.
  7. 7Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
  8. 8Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
  9. 9Core Facility for Electron Microscopy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  10. 10Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
  11. 11Laboratory of Host-Microbe Interactions and Cell Dynamics, Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan, Taiwan.
  12. 12Institute of Immunology and Translational Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
  13. 13Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  14. 14Division of Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
  15. 15Center for Drug Research and Development, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan.
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Abstract

Membranous nephropathy (MN) is an autoimmune kidney disease and a major cause of nephrotic syndrome in adults. Although autoantibodies against phospholipase A2 receptor 1 (PLA2R) and complement activation are central to disease pathogenesis, the mechanisms by which anti-PLA2R antibodies activate complement at the podocyte surface remain incompletely defined. Here, we cloned 14 patient-derived anti-PLA2R mAbs and found that they predominantly recognized the N-terminal cysteine-rich (CysR) and C-type lectin domain 1 (CTLD1) regions of PLA2R. Individual anti-PLA2R mAbs induced little or no complement-dependent cytotoxicity (CDC) of PLA2R-expressing podocytes in vitro. In contrast, paired mAbs targeting distinct epitopes, particularly CysR and CTLD1, markedly enhanced CDC. This effect was strongest for IgG1 and IgG3 antibodies, whereas IgG4 alone did not activate complement but modulated CDC in combination with IgG1. Purified IgG from patients with PLA2R-associated MN similarly induced CDC, which was augmented by addition of anti–PLA2R IgG1 and reduced by anti–PLA2R IgG4 or Fab fragments targeting CysR or CTLD1. In human PLA2R–expressing mice, paired anti-PLA2R antibodies increased glomerular complement deposition and induced albuminuria. These findings identify epitope pairing as a key determinant of complement activation in PLA2R-associated MN and support epitope-specific targeting strategies as a promising avenue for therapeutic intervention.

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Cite

BibTeXRIS
BibTeX
@article{wu2026antipla2r,
  title = {{Anti-PLA2R autoantibodies induce complement activation via IgG subclass–dependent epitope pairings in membranous nephropathy}},
  author = {Tsai-Yi Wu and Kun-Hua Tu and Larissa Seifert and Kung-Wei Lin and Han-Po Shih and Yu-Fang Lo and Jhan-Jie Peng and Gunther Zahner and Oliver Kretz and You-Ning Lin and Chen-Xuan Kang and Jing-Ya Ding and Yi-Ran Tu and Li-Yi Ma and Ya-Ting Chuang and Chia-Chi Lo and Yu-Huan Tsai and Chih-Wei Yang and Nicola M. Tomas and Cheng-Lung Ku},
  journal = {The Journal of Clinical Investigation},
  year = {2026},
  month = sep,
  doi = {10.1172/jci191995},
  url = {https://doi.org/10.1172/jci191995},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Anti-PLA2R autoantibodies induce complement activation via IgG subclass–dependent epitope pairings in membranous nephropathy
AU  - Tsai-Yi Wu
AU  - Kun-Hua Tu
AU  - Larissa Seifert
AU  - Kung-Wei Lin
AU  - Han-Po Shih
AU  - Yu-Fang Lo
AU  - Jhan-Jie Peng
AU  - Gunther Zahner
AU  - Oliver Kretz
AU  - You-Ning Lin
AU  - Chen-Xuan Kang
AU  - Jing-Ya Ding
AU  - Yi-Ran Tu
AU  - Li-Yi Ma
AU  - Ya-Ting Chuang
AU  - Chia-Chi Lo
AU  - Yu-Huan Tsai
AU  - Chih-Wei Yang
AU  - Nicola M. Tomas
AU  - Cheng-Lung Ku
PY  - 2026
DA  - 2026/09/08
JO  - The Journal of Clinical Investigation
DO  - 10.1172/jci191995
UR  - https://doi.org/10.1172/jci191995
AB  - Membranous nephropathy (MN) is an autoimmune kidney disease and a major cause of nephrotic syndrome in adults. Although autoantibodies against phospholipase A2 receptor 1 (PLA2R) and complement activation are central to disease pathogenesis, the mechanisms by which anti-PLA2R antibodies activate complement at the podocyte surface remain incompletely defined. Here, we cloned 14 patient-derived anti-PLA2R mAbs and found that they predominantly recognized the N-terminal cysteine-rich (CysR) and C-type lectin domain 1 (CTLD1) regions of PLA2R. Individual anti-PLA2R mAbs induced little or no complement-dependent cytotoxicity (CDC) of PLA2R-expressing podocytes in vitro. In contrast, paired mAbs targeting distinct epitopes, particularly CysR and CTLD1, markedly enhanced CDC. This effect was strongest for IgG1 and IgG3 antibodies, whereas IgG4 alone did not activate complement but modulated CDC in combination with IgG1. Purified IgG from patients with PLA2R-associated MN similarly induced CDC, which was augmented by addition of anti–PLA2R IgG1 and reduced by anti–PLA2R IgG4 or Fab fragments targeting CysR or CTLD1. In human PLA2R–expressing mice, paired anti-PLA2R antibodies increased glomerular complement deposition and induced albuminuria. These findings identify epitope pairing as a key determinant of complement activation in PLA2R-associated MN and support epitope-specific targeting strategies as a promising avenue for therapeutic intervention.
SN  - 0021-9738
SN  - 1558-8238
ER  -