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

Autoantibody-induced neutrophil-epithelial niches are linked to kidney injury in MPO-associated glomerulonephritis, with anti-MPO antibodies recognizing multiple epitopes enhancing neutrophil activation.

• Why it matters: Understanding how pathogenic antibodies trigger local immune activation is crucial for developing targeted therapies for autoimmune kidney diseases, yet this mechanism remains poorly understood.
• What they did: Single-cell spatial transcriptomics of treatment-naïve patient kidney biopsies identified early inflammatory niches containing injured epithelial cells, neutrophils, lymphocytes, and macrophages, with injured epithelial cells expressing chemokines like CXCL6 and CXCL16. In mice, combinations of monoclonal anti-MPO antibodies recognizing different epitopes increased neutrophil activation and caused pauci-immune crescentic glomerulonephritis, mimicking human kidney injury; engineered anti-MPO antibodies with reduced FcγR engagement lessened damage.
• The result: Findings suggest that pathogenic neutrophil-epithelial niches drive autoimmune kidney injury, and modulating FcγR engagement on anti-MPO antibodies may offer therapeutic benefit.