| Autor: |
Kotas ME; Division of Pulmonary, Critical Care, Allergy & Sleep Medicine, University of California, San Francisco, California, USA., Dion J; Department of Internal Medicine, National Referral Center for Rare and Systemic Autoimmune Diseases, Cochin Hospital, AP-HP, Paris, France., Van Dyken S; Department of Pathology & Immunology, Washington University School of Medicine in St. Louis, Missouri, USA., Ricardo-Gonzalez RR; Department of Dermatology, University of California, San Francisco, California, USA., Danel CJ; Department of Pathology and., Taillé C; Department of Pulmonology, Bichat Hospital, AP-HP, Paris, France., Mouthon L; Department of Internal Medicine, National Referral Center for Rare and Systemic Autoimmune Diseases, Cochin Hospital, AP-HP, Paris, France., Locksley RM; Howard Hughes Medical Institute, University of California, San Francisco, California, USA.; Department of Medicine, University of California, San Francisco, California, USA., Terrier B; Department of Internal Medicine, National Referral Center for Rare and Systemic Autoimmune Diseases, Cochin Hospital, AP-HP, Paris, France. |
| Abstrakt: |
Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare but serious disease with poorly understood mechanisms. Here, we report that patients with EGPA have elevated levels of TSLP, IL-25, and soluble ST2, which are well-characterized cytokine "alarmins" that activate or modulate type 2 innate lymphoid cells (ILC2s). Patients with active EGPA have a concurrent reduction in circulating ILC2s, suggesting a role for ILC2s in the pathogenesis of this disease. To explore the mechanism of these findings in patients, we established a model of EGPA in which active vasculitis and pulmonary hemorrhage were induced by IL-33 administration in predisposed, hypereosinophilic mice. In this model, induction of pulmonary hemorrhage and vasculitis was dependent on ILC2s and signaling through IL4Rα. In the absence of IL4Rα or STAT6, IL-33-treated mice had less vascular leak and pulmonary edema, less endothelial activation, and reduced eotaxin production, cumulatively leading to a reduction of pathologic eosinophil migration into the lung parenchyma. These results offer a mouse model for use in future mechanistic studies of EGPA, and they suggest that IL-33, ILC2s, and IL4Rα signaling may be potential targets for further study and therapeutic targeting in patients with EGPA. |
