Epitope-diverse autoantibodies induce neutrophil–epithelial niches driving kidney injury in ANCA-associated glomerulonephritis
Masayuki Nishide, Hiroaki Matsushita, Yumiko Mizuno, Kei Nishimura, Patrick M. Lelliott, Shoji Kawada, Takashi Fujii, Shogo Kamikawaji, Tatsuya Nonaka, Daisuke Motooka, Shoichi Metsugi, Hiroshi Shimagami, Atsuko Tsujii Miyamoto, Yasuhiro Kato, Kohei Tsujimoto, Ryuya Edahiro, Yuya Shirai, Yuji Yamamoto, Yujiro Naito, Hachiro Konaka, Mayuko Izumi, Maiko Naito, Yoshimitsu Nakanishi, Tomoko Namba-Hamano, Kazunori Inoue, Atsushi Takahashi, Masayuki Mizui, Shigeaki Nakazawa, Yoichi Kakuta, Kenji Funakoshi, Makoto Terada, Machiko Irie, Takuya Torizawa, Ryusuke Omiya, Nicolas I. Smith, Yoshitaka Isaka, Norio Nonomura, Yukinori Okada, Kunihiro Hattori, Masashi Narazaki, Atsushi KumanogohAutoantibody-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.