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Peer-reviewedCC BYThe Journal of experimental medicine

Epitope-diverse autoantibodies induce neutrophil-epithelial niches driving kidney injury in ANCA-associated glomerulonephritis.

  • Masayuki Nishide1,2,3
  • Hiroaki Matsushita3,4,5
  • Yumiko Mizuno1,2
  • Kei Nishimura3,4,5
  • Patrick M Lelliott6
  • Shoji Kawada1,2,3
  • Takashi Fujii4
  • Shogo Kamikawaji4
  • Tatsuya Nonaka4
  • Daisuke Motooka7
  • Shoichi Metsugi3,4,5
  • Hiroshi Shimagami1,2,3
29 more authors
  • Atsuko Tsujii Miyamoto1,2,3
  • Yasuhiro Kato1,2,3
  • Kohei Tsujimoto1,2,3
  • Ryuya Edahiro1,8,9
  • Yuya Shirai1,8
  • Yuji Yamamoto1,8
  • Yujiro Naito1,2
  • Hachiro Konaka1,2
  • Mayuko Izumi1,2,3,10
  • Maiko Naito1,2
  • Yoshimitsu Nakanishi1,2,3,10
  • Tomoko Namba-Hamano11
  • Kazunori Inoue11
  • Atsushi Takahashi11
  • Masayuki Mizui11
  • Shigeaki Nakazawa12
  • Yoichi Kakuta12
  • Kenji Funakoshi13
  • Makoto Terada13
  • Machiko Irie4
  • Takuya Torizawa4
  • Ryusuke Omiya4,5
  • Nicolas I Smith6,10
  • Yoshitaka Isaka11
  • Norio Nonomura12
  • Yukinori Okada8,9,10,14,15,16
  • Kunihiro Hattori4,5
  • Masashi Narazaki1,2,3
  • Atsushi Kumanogoh1,2,10,16,17,18
18 affiliations
  1. 1Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka, Suita, Osaka, Japan.
  2. 2Department of Immunopathology, World Premier International Research Center Initiative (WPI), Immunology Frontier Research Center (IFReC), The University of Osaka, Suita, Osaka, Japan.
  3. 3Department of Advanced Clinical and Translational Immunology, Graduate School of Medicine, The University of Osaka, Suita, Osaka, Japan.
  4. 4Research Division, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan.
  5. 5Joint Research Chair of Innovative Drug Discovery in Immunology, World Premier International Research Center Initiative (WPI), Immunology Frontier Research Center (IFReC), The University of Osaka , Suita, Osaka, Japan.
  6. 6Biophotonics Laboratory, World Premier International Research Center Initiative (WPI), Immunology Frontier Research Center (IFReC), The University of Osaka, Suita, Osaka, Japan.
  7. 7NGS Core Facility, Bioinformatics Center, Research Institute for Microbial Diseases, The University of Osaka, Suita, Osaka, Japan.
  8. 8Department of Statistical Genetics, Graduate School of Medicine, The University of Osaka, Suita, Osaka, Japan.
  9. 9Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
  10. 10Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), The University of Osaka, Suita, Osaka, Japan.
  11. 11Department of Nephrology, Graduate School of Medicine, The University of Osaka, Suita, Osaka, Japan.
  12. 12Department of Urology, Graduate School of Medicine, The University of Osaka, Suita, Osaka, Japan.
  13. 13Itami City Hospital , Itami, Japan.
  14. 14Department of Statistical Immunology, World Premier International Research Center Initiative (WPI), Immunology Frontier Research Center (IFReC), The University of Osaka, Suita, Osaka, Japan.
  15. 15Department of Genome Informatics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  16. 16Japan Agency for Medical Research and Development - Core Research for Evolutional Science and Technology (AMED-CREST), The University of Osaka , Suita, Osaka, Japan.
  17. 17Center for Infectious Diseases for Education and Research (CiDER), The University of Osaka , Suita, Osaka, Japan.
  18. 18Center for Advanced Modalities and DDS (CAMaD), The University of Osaka , Suita, Osaka, Japan.
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Abstract

Autoantibody-mediated inflammation drives tissue injury in autoimmune diseases, yet how pathogenic antibodies evoke local immune activation remains poorly understood. Here, we show that spatially organized neutrophil-epithelial niches contribute to kidney injury in myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody-associated glomerulonephritis. Single-cell-resolved spatial transcriptomics of treatment-naïve patient kidney biopsies identified early-phase inflammatory niches enriched with HAVCR1+ injured proximal tubular epithelial cells, neutrophils, lymphocytes, and TREM2+ macrophages. Injured epithelial cells expressed chemokines including CXCL6 and CXCL16, defining a microenvironment associated with local immune cell accumulation. Neutrophils within these niches were characterized by transcriptional programs enriched for type II interferon and Fcγ receptor (FcγR)-related signaling. Mechanistically, combinations of monoclonal anti-MPO antibodies recognizing distinct epitopes enhanced neutrophil activation and induced pauci-immune crescentic glomerulonephritis in mice, recapitulating key aspects of epithelial injury observed in human kidneys. One-armed anti-MPO antibodies engineered to minimize FcγR engagement ameliorated kidney injury in mice. Together, these findings identify pathogenic neutrophil-epithelial niche formation as a driver of autoimmune kidney injury.

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Cite

BibTeXRIS
BibTeX
@article{nishide2026epitopediverse,
  title = {{Epitope-diverse autoantibodies induce neutrophil-epithelial niches driving kidney injury in ANCA-associated glomerulonephritis.}},
  author = {Masayuki Nishide and Hiroaki Matsushita and Yumiko Mizuno and Kei Nishimura and Patrick M Lelliott and Shoji Kawada and Takashi Fujii and Shogo Kamikawaji and Tatsuya Nonaka and Daisuke Motooka and Shoichi Metsugi and Hiroshi Shimagami and Atsuko Tsujii Miyamoto and Yasuhiro Kato and Kohei Tsujimoto and Ryuya Edahiro and Yuya Shirai and Yuji Yamamoto and Yujiro Naito and Hachiro Konaka and Mayuko Izumi and Maiko Naito and Yoshimitsu Nakanishi and Tomoko Namba-Hamano and Kazunori Inoue and Atsushi Takahashi and Masayuki Mizui and Shigeaki Nakazawa and Yoichi Kakuta and Kenji Funakoshi and Makoto Terada and Machiko Irie and Takuya Torizawa and Ryusuke Omiya and Nicolas I Smith and Yoshitaka Isaka and Norio Nonomura and Yukinori Okada and Kunihiro Hattori and Masashi Narazaki and Atsushi Kumanogoh},
  journal = {The Journal of experimental medicine},
  year = {2026},
  month = oct,
  doi = {10.1084/jem.20260506},
  url = {https://europepmc.org/article/MED/42895484},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Epitope-diverse autoantibodies induce neutrophil-epithelial niches driving kidney injury in ANCA-associated glomerulonephritis.
AU  - Masayuki Nishide
AU  - Hiroaki Matsushita
AU  - Yumiko Mizuno
AU  - Kei Nishimura
AU  - Patrick M Lelliott
AU  - Shoji Kawada
AU  - Takashi Fujii
AU  - Shogo Kamikawaji
AU  - Tatsuya Nonaka
AU  - Daisuke Motooka
AU  - Shoichi Metsugi
AU  - Hiroshi Shimagami
AU  - Atsuko Tsujii Miyamoto
AU  - Yasuhiro Kato
AU  - Kohei Tsujimoto
AU  - Ryuya Edahiro
AU  - Yuya Shirai
AU  - Yuji Yamamoto
AU  - Yujiro Naito
AU  - Hachiro Konaka
AU  - Mayuko Izumi
AU  - Maiko Naito
AU  - Yoshimitsu Nakanishi
AU  - Tomoko Namba-Hamano
AU  - Kazunori Inoue
AU  - Atsushi Takahashi
AU  - Masayuki Mizui
AU  - Shigeaki Nakazawa
AU  - Yoichi Kakuta
AU  - Kenji Funakoshi
AU  - Makoto Terada
AU  - Machiko Irie
AU  - Takuya Torizawa
AU  - Ryusuke Omiya
AU  - Nicolas I Smith
AU  - Yoshitaka Isaka
AU  - Norio Nonomura
AU  - Yukinori Okada
AU  - Kunihiro Hattori
AU  - Masashi Narazaki
AU  - Atsushi Kumanogoh
PY  - 2026
DA  - 2026/10/19
JO  - The Journal of experimental medicine
DO  - 10.1084/jem.20260506
UR  - https://europepmc.org/article/MED/42895484
AB  - Autoantibody-mediated inflammation drives tissue injury in autoimmune diseases, yet how pathogenic antibodies evoke local immune activation remains poorly understood. Here, we show that spatially organized neutrophil-epithelial niches contribute to kidney injury in myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody-associated glomerulonephritis. Single-cell-resolved spatial transcriptomics of treatment-naïve patient kidney biopsies identified early-phase inflammatory niches enriched with HAVCR1+ injured proximal tubular epithelial cells, neutrophils, lymphocytes, and TREM2+ macrophages. Injured epithelial cells expressed chemokines including CXCL6 and CXCL16, defining a microenvironment associated with local immune cell accumulation. Neutrophils within these niches were characterized by transcriptional programs enriched for type II interferon and Fcγ receptor (FcγR)-related signaling. Mechanistically, combinations of monoclonal anti-MPO antibodies recognizing distinct epitopes enhanced neutrophil activation and induced pauci-immune crescentic glomerulonephritis in mice, recapitulating key aspects of epithelial injury observed in human kidneys. One-armed anti-MPO antibodies engineered to minimize FcγR engagement ameliorated kidney injury in mice. Together, these findings identify pathogenic neutrophil-epithelial niche formation as a driver of autoimmune kidney injury.
SN  - 0022-1007
SN  - 1540-9538
ER  -