Airway immune profiles and therapeutic implications of IGF1 in eosinophilic granulomatosis with polyangiitis

Eosinophilic granulomatosis with polyangiitis (EGPA) and severe eosinophilic asthma (SEA) share a Type 2 (T2) inflammatory signature but exhibit distinct pathophysiology. We hypothesized that EGPA involves additional inflammatory mechanisms, beyond T2 immunity, that drive its systemic manifestations and treatment resistance. Using single-cell RNA sequencing, we identify interferon (IFN-I)-driven inflammation in EGPA, in contrast to TNF predominant pathway activation in SEA. IL1B+MX1+ neutrophils in EGPA express IFN-stimulated genes and promote tertiary lymphoid structure formation with autoantibody production. In addition, other IFN-activated granulocytes, including APOC1+ eosinophils, SCN7A+ mast cells, and basophils, further contribute to immune dysregulation in EGPA, unlike TNF activated granulocytes in SEA. Longitudinal single-cell analysis of EGPA reveals an IGF1+ macrophage population linked to EGPA relapse. In animal models of both conditions, IGF1 blockade attenuates T2 inflammation, mucin production, and goblet cell hyperplasia, highlighting IGF1 as a possible therapeutic target in T2 inflammation disease. There are similarities in airway inflammatory endotype between eosinophilic granulomatosis with polyangiitis (EGPA) and type 2 eosinophilic asthma. Here, the authors perform single-cell transcriptomics to compare EGPA with severe eosinophilic asthma and find differences in the innate immune cell populations and use mouse models to characterise the function and phenotype of these cells.