The Journal of Experimental Medicine· 2026Q1
Epitope-diverse autoantibodies induce neutrophil–epithelial niches driving kidney injury in ANCA-associated glomerulonephritis
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- Q1SCImago
- 2026year
Short summary
In ANCA-associated glomerulonephritis, spatially organized neutrophil-epithelial niches, driven by injured epithelial cells expressing chemokines and activated neutrophils, promote kidney injury.
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Key points
- Neutrophil-epithelial niches are identified as a driver of kidney injury in ANCA-associated glomerulonephritis.
- Early-phase inflammatory niches in patient biopsies are enriched with HAVCR1+ injured proximal tubular epithelial cells, neutrophils, lymphocytes, and TREM2+ macrophages.
- Injured epithelial cells express chemokines (CXCL6, CXCL16) that recruit immune cells to form these niches.
- Neutrophils within these niches show transcriptional programs for type II interferon and FcγR signaling.
- Monoclonal anti-MPO antibodies induced kidney injury in mice, which was ameliorated by engineering antibodies to minimize FcγR engagement.
AI-generated from the title and abstract; the full text is not read.
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.
The authors' abstract, as published at the source. The Journal of Experimental Medicine, 2026 · DOI ↗
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Field: Pulmonary and Respiratory Medicine
Pulmonary and Respiratory MedicineMedicine