B1 cells drive pulmonary emphysema progression through ADAM10

The pathogenic role of B cells in pulmonary emphysema remains incompletely understood. This study aimed to delineate the specific B cell subsets and molecular mechanisms driving disease progression. Using single-cell RNA sequencing (scRNA-seq), we characterized lung B cell heterogeneity in a murine model of emphysema induced by porcine pancreatic elastase (PPE). Functional roles were assessed via B cell depletion and pharmacological inhibition of a disintegrin and metalloprotease 10 (ADAM10). Emphysema triggered the formation of pulmonary tertiary lymphoid structures (TLS) enriched with proliferating BAFF⁺ B cells. scRNA-seq revealed a selective expansion of B1 cells, primarily the B1b subset, which was accompanied by increased ICOS expression on lung CD4⁺ T cells. B cell depletion attenuated alveolar destruction, abolished TLS, reduced serum autoantibody levels, and improved lung function. Mechanistically, ADAM10 was specifically upregulated in B1 cells. Functional studies demonstrated that ADAM10, through activation of the Notch signaling pathway, was essential for the proliferation of B1 cells and their capacity to activate CD4+ T cells. Pharmacological inhibition of ADAM10 recapitulated the therapeutic effects, reducing B1 cell numbers, suppressing TLS formation, diminishing ICOS⁺ CD4⁺ T cells and autoantibody titers, and ultimately ameliorating lung pathology and function. Our findings identify ADAM10 as a critical regulator of B1 cell-driven immunopathology in emphysema, highlighting the ADAM10-Notch axis in B1 cells as a potential therapeutic target.