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.