Epitope-diverse autoantibodies induce neutrophil–epithelial niches driving kidney injury in ANCA-associated glomerulonephritis
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.
Authors
- Daisuke Motooka (ORCID: https://orcid.org/0000-0002-4616-9608)
- Yuji Yamamoto (ORCID: https://orcid.org/0000-0002-5489-5079)
- Kazunori Inoue (ORCID: https://orcid.org/0000-0002-7149-6651)
- Kohei Tsujimoto (ORCID: https://orcid.org/0000-0001-6958-2983)
- Kunihiro Hattori
- Yoshitaka Isaka (ORCID: https://orcid.org/0000-0002-0820-7167)
- Ryusuke Omiya
- Atsushi Takahashi (ORCID: https://orcid.org/0000-0002-5182-4320)
- Yoichi Kakuta (ORCID: https://orcid.org/0000-0001-5339-4312)
- Hachiro Konaka
- Shoji Kawada (ORCID: https://orcid.org/0000-0001-9679-5925)
- Yoshimitsu Nakanishi (ORCID: https://orcid.org/0000-0001-6172-6364)
- Shoichi Metsugi
- Atsushi Kumanogoh (ORCID: https://orcid.org/0000-0003-4749-7117)
- Yujiro Naito (ORCID: https://orcid.org/0000-0003-0633-4936)
- Shogo Kamikawaji (ORCID: https://orcid.org/0009-0004-4075-4453)
- Takuya Torizawa (ORCID: https://orcid.org/0000-0001-7537-6123)
- Masayuki Nishide (ORCID: https://orcid.org/0000-0001-6060-1228)
- Yukinori Okada (ORCID: https://orcid.org/0000-0002-0311-8472)
- Masashi Narazaki (ORCID: https://orcid.org/0000-0002-5613-4409)
- Hiroshi Shimagami (ORCID: https://orcid.org/0000-0001-7820-364X)
- Makoto Terada (ORCID: https://orcid.org/0000-0002-6180-2854)
- Nicholas Isaac Smith (ORCID: https://orcid.org/0000-0002-7835-199X)
- Patrick M. Lelliott (ORCID: https://orcid.org/0000-0002-4666-1846)
- Kenji Funakoshi (ORCID: https://orcid.org/0000-0002-1757-6925)
- Ryuya Edahiro (ORCID: https://orcid.org/0000-0001-5009-6408)
- Maiko Naito (ORCID: https://orcid.org/0000-0002-4360-7043)
- Tomoko Namba‐Hamano (ORCID: https://orcid.org/0000-0002-6049-7616)
- Yuya Shirai (ORCID: https://orcid.org/0000-0002-0518-9020)
- Norio Nonomura (ORCID: https://orcid.org/0000-0002-6522-6233)
- Yasuhiro Kato (ORCID: https://orcid.org/0000-0002-4050-2350)
- Masayuki Mizui (ORCID: https://orcid.org/0000-0003-2543-8108)
- Shigeaki Nakazawa (ORCID: https://orcid.org/0000-0001-5857-3483)
- Kei Nishimura
- Hiroaki Matsushita (ORCID: https://orcid.org/0000-0003-2899-5313)
- Yumiko Mizuno
- Takashi Fujii (ORCID: https://orcid.org/0009-0007-5974-0635)
- Mayuko Izumi
- Machiko Irie
- Tatsuya Nonaka (ORCID: https://orcid.org/0009-0002-7384-3140)
- Atsuko Tsujii Miyamoto (ORCID: https://orcid.org/0009-0007-3216-4949)
Institutions
- Osaka Gakuin University (JP)
- Japan Agency for Medical Research and Development (JP)
- Chugai Pharma (United States) (US)
- Itami City Hospital (JP)
- RIKEN Center for Integrative Medical Sciences (JP)
- Osaka International University (JP)
- The University of Tokyo (JP)
- The University of Osaka (JP)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2026-10-19
- DOI
- https://doi.org/10.1084/jem.20260506
- Citations
- 1
- Primary Topic
- Vasculitis and related conditions
- Type
- article
- Field-Weighted Citation Impact
- 4.35