Abstract
OBJECTIVE: Granulomatosis with polyangiitis (GPA) is a rare multisystem autoimmune vasculitis. 10-20% of patients suffer life-threatening obstruction of their proximal airways. Although progress has been made in the treatment of systemic disease, ameliorating airway disease in GPA remains an unmet need arising from limited understanding of disease pathogenesis. We sought to characterize the cellular constituents of the affected proximal airway mucosa in GPA airway scar. STUDY DESIGN: Basic/translational study. SETTING: Single tertiary care center. METHODS: Using single-cell RNA sequencing, we profiled the cellular constituents of proximal airway samples from GPA and disease comparators (GPA; n = 9, idiopathic subglottic stenosis: iSGS; n = 7, post-intubation proximal stenosis: PIPS; n = 5, and control; n = 10). We report transcriptomes for subglottic epithelial, immune, endothelial, and stromal cell types and map expression of GPA risk genes to tissue types present in the proximal airway. We compared differential gene expression across immune cell populations and performed pseudotime analysis using Monocle 3. RESULTS: Similar to iSGS and PIPS, the subglottic mucosa of GPA patients demonstrated an abundant immune infiltrate. 71% of the established GPA risk genes (10 of 14) localized to T cells and macrophages. Differential gene expression and pseudotime analysis revealed a sub-population of CD4-/CD8- inflammatory T cells that only originated from GPA. CONCLUSION: We characterized the cellular composition of GPA airway disease and demonstrated that the expression of GPA risk alleles is predominantly localized to immune cell populations. We also identified a subset of inflammatory T cells that is unique to GPA.