| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Christianson, Christina A. Goplen, Nicholas P. Zafar, Iram Irvin, Chaoyu Good, James T. Rollins, Donald R. Gorentla, Balachandra Liu, Weimin Gorska, Magdalena M. Chu, HongWei Martin, Richard J. Alam, Rafeul |
| Description |
Author Affiliation: Christianson CA ( Division of Allergy and Immunology, National Jewish Health, Denver, Colo.); Goplen NP ( Division of Allergy and Immunology, National Jewish Health, Denver, Colo.); Zafar I ( Division of Allergy and Immunology, National Jewish Health, Denver, Colo.); Irvin C ( Division of Allergy and Immunology, National Jewish Health, Denver, Colo.); Good JT ( Division of Pulmonary Medicine, Department of Medicine, National Jewish Health, Denver, Colo.); Rollins DR ( Division of Pulmonary Medicine, Department of Medicine, National Jewish Health, Denver, Colo.); Gorentla B ( Division of Allergy and Immunology, National Jewish Health, Denver, Colo.); Liu W ( Division of Allergy and Immunology, National Jewish Health, Denver, Colo.); Gorska MM ( Division of Allergy and Immunology, National Jewish Health, Denver, Colo); Chu H ( Division of Pulmonary Medicine, Department of Medicine, National Jewish Health, Denver, Colo); Martin RJ ( Division of Pulmonary Medicine, Department of Medicine, National Jewish Health, Denver, Colo); Alam R ( Division of Allergy and Immunology, National Jewish Health, Denver, Colo) |
| Abstract |
BACKGROUND: Asthma in a mouse model spontaneously resolves after cessation of allergen exposure. We developed a mouse model in which asthma features persisted for 6 months after cessation of allergen exposure. OBJECTIVE: We sought to elucidate factors contributing to the persistence of asthma. METHODS: We used a combination of immunologic, genetic, microarray, and pharmacologic approaches to dissect the mechanism of asthma persistence. RESULTS: Elimination of T cells though antibody-mediated depletion or lethal irradiation and transplantation of recombination-activating gene (Rag1)(-/-) bone marrow in mice with chronic asthma resulted in resolution of airway inflammation but not airway hyperreactivity or remodeling. Elimination of T cells and type 2 innate lymphoid cells (ILC2s) through lethal irradiation and transplantation of Rag2(-/-)γc(-/-) bone marrow or blockade of IL-33 resulted in resolution of airway inflammation and hyperreactivity. Persistence of asthma required multiple interconnected feedback and feed-forward circuits between ILC2s and epithelial cells. Epithelial IL-33 induced ILC2s, a rich source of IL-13. The latter directly induced epithelial IL-33, establishing a positive feedback circuit. IL-33 autoinduced, generating another feedback circuit. IL-13 upregulated IL-33 receptors and facilitated IL-33 autoinduction, thus establishing a feed-forward circuit. Elimination of any component of these circuits resulted in resolution of chronic asthma. In agreement with the foregoing, IL-33 and ILC2 levels were increased in the airways of asthmatic patients. IL-33 levels correlated with disease severity. CONCLUSIONS: We present a critical network of feedback and feed-forward interactions between epithelial cells and ILC2s involved in maintaining chronic asthma. Although T cells contributed to the severity of chronic asthma, they were redundant in maintaining airway hyperreactivity and remodeling. |
| File Format |
HTM / HTML |
| ISSN |
00916749 |
| e-ISSN |
10976825 |
| DOI |
10.1016/j.jaci.2014.11.037 |
| Journal |
Journal of Allergy and Clinical Immunology |
| Issue Number |
1 |
| Volume Number |
136 |
| Language |
English |
| Publisher |
Elsevier |
| Publisher Date |
2015-07-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Discipline Immunology Antibodies, Blocking Administration & Dosage Asthma Immunology Interleukins Lymphocytes Th2 Cells Adoptive Transfer Airway Remodeling Drug Effects Genetics Allergens Animals Bone Marrow Transplantation Bronchial Hyperreactivity Chronic Disease Disease Models, Animal Disease Progression Feedback, Physiological Immunity, Innate Interleukin-13 Metabolism Interleukin-33 Lymphocyte Depletion Mice Mice, Inbred Balb C Mice, Inbred C57bl Mice, Knockout Research Support, N.i.h., Extramural |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Immunology and Allergy Immunology |
