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ResearchIn-Press PreviewAutoimmunityImmunologyNephrology Open Access | 10.1172/JCI191995

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

Tsai-Yi Wu,1 Kun-Hua Tu,1 Larissa Seifert,2 Kung-Wei Lin,1 Han-Po Shih,1 Yu-Fang Lo,1 Jhan-Jie Peng,3 Gunther Zahner,2 Oliver Kretz,2 You-Ning Lin,1 Chen-Xuan Kang,1 Jing-Ya Ding,1 Yi-Ran Tu,4 Li-Yi Ma,4 Ya-Ting Chuang,5 Chia-Chi Lo,1 Yu-Huan Tsai,3 Chih-Wei Yang,4 Nicola M. Tomas,2 and Cheng-Lung Ku1

1Laboratory of Human Immunology and Infectious Disease, Institute of Immunology and Translational Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan

2III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan

4Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan

5Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

Find articles by Wu, T. in: PubMed | Google Scholar

1Laboratory of Human Immunology and Infectious Disease, Institute of Immunology and Translational Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan

2III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan

4Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan

5Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

Find articles by Tu, K. in: PubMed | Google Scholar

1Laboratory of Human Immunology and Infectious Disease, Institute of Immunology and Translational Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan

2III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan

4Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan

5Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

Find articles by Seifert, L. in: PubMed | Google Scholar

1Laboratory of Human Immunology and Infectious Disease, Institute of Immunology and Translational Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan

2III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan

4Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan

5Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

Find articles by Lin, K. in: PubMed | Google Scholar

1Laboratory of Human Immunology and Infectious Disease, Institute of Immunology and Translational Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan

2III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan

4Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan

5Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

Find articles by Shih, H. in: PubMed | Google Scholar

1Laboratory of Human Immunology and Infectious Disease, Institute of Immunology and Translational Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan

2III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan

4Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan

5Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

Find articles by Lo, Y. in: PubMed | Google Scholar

1Laboratory of Human Immunology and Infectious Disease, Institute of Immunology and Translational Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan

2III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan

4Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan

5Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

Find articles by Peng, J. in: PubMed | Google Scholar

1Laboratory of Human Immunology and Infectious Disease, Institute of Immunology and Translational Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan

2III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan

4Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan

5Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

Find articles by Zahner, G. in: PubMed | Google Scholar

1Laboratory of Human Immunology and Infectious Disease, Institute of Immunology and Translational Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan

2III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan

4Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan

5Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

Find articles by Kretz, O. in: PubMed | Google Scholar

1Laboratory of Human Immunology and Infectious Disease, Institute of Immunology and Translational Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan

2III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan

4Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan

5Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

Find articles by Lin, Y. in: PubMed | Google Scholar

1Laboratory of Human Immunology and Infectious Disease, Institute of Immunology and Translational Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan

2III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan

4Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan

5Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

Find articles by Kang, C. in: PubMed | Google Scholar

1Laboratory of Human Immunology and Infectious Disease, Institute of Immunology and Translational Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan

2III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan

4Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan

5Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

Find articles by Ding, J. in: PubMed | Google Scholar

1Laboratory of Human Immunology and Infectious Disease, Institute of Immunology and Translational Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan

2III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan

4Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan

5Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

Find articles by Tu, Y. in: PubMed | Google Scholar

1Laboratory of Human Immunology and Infectious Disease, Institute of Immunology and Translational Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan

2III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan

4Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan

5Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

Find articles by Ma, L. in: PubMed | Google Scholar

1Laboratory of Human Immunology and Infectious Disease, Institute of Immunology and Translational Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan

2III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan

4Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan

5Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

Find articles by Chuang, Y. in: PubMed | Google Scholar

1Laboratory of Human Immunology and Infectious Disease, Institute of Immunology and Translational Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan

2III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan

4Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan

5Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

Find articles by Lo, C. in: PubMed | Google Scholar

1Laboratory of Human Immunology and Infectious Disease, Institute of Immunology and Translational Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan

2III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan

4Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan

5Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

Find articles by Tsai, Y. in: PubMed | Google Scholar

1Laboratory of Human Immunology and Infectious Disease, Institute of Immunology and Translational Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan

2III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan

4Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan

5Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

Find articles by Yang, C. in: PubMed | Google Scholar

1Laboratory of Human Immunology and Infectious Disease, Institute of Immunology and Translational Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan

2III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan

4Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan

5Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

Find articles by Tomas, N. in: PubMed | Google Scholar |

1Laboratory of Human Immunology and Infectious Disease, Institute of Immunology and Translational Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan

2III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan

4Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan

5Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

Find articles by Ku, C. in: PubMed | Google Scholar

Published September 8, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI191995.
Copyright © 2026, Wu et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published September 8, 2026 - Version history
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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 monoclonal antibodies (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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