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<p>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. <i>IL1B</i><sup>+</sup><i>MX1</i><sup>+</sup> neutrophils in EGPA express IFN-stimulated genes and promote tertiary lymphoid structure formation with autoantibody production. In addition, other IFN-activated granulocytes, including <i>APOC1</i><sup>+</sup> eosinophils, <i>SCN7A</i><sup>+</sup> 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 <i>IGF1</i><sup>+</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月7日

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  • Cong Dong,
  • Bingtai Lu,
  • Changhao Zhong,
  • Changxing Ou,
  • Xiaojing Yang,
  • Lingwei Wang,
  • Xiaoyu Zuo,
  • Lingna Xue,
  • Chenyang Lu,
  • Shang Wang,
  • Junjie Wen,
  • Jianjuan Ma,
  • Zhenan Deng,
  • Yiyi Liu,
  • Liuheyi Ma,
  • Ming Liu,
  • Andrew M. Lew,
  • Manali Mukherjee,
  • Parameswaran Nair,
  • Nanshan Zhong,
  • Rongchang Chen,
  • Zhanghua Chen,
  • Yuxia Zhang,
  • Qingling Zhang

摘要

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.