Increased frequency of dual-positive TH2/TH17 cells in bronchoalveolar lavage fluid characterizes a population of patients with severe asthma

被引：270
作者：
Irvin, Chaoyu [1 ,2 ]
Zafar, Iram [1 ,2 ]
Good, James [1 ,2 ,3 ]
Rollins, Donald [1 ,2 ,3 ]
Christianson, Christina [1 ,2 ]
Gorska, Magdalena M. [1 ,2 ,3 ]
Martin, Richard J. [1 ,2 ,3 ]
Alam, Rafeul [1 ,2 ,3 ]
机构：
[1] Natl Jewish Hlth, Dept Med, Div Allergy & Immunol, Denver, CO 80206 USA
[2] Natl Jewish Hlth, Div Pulm & Crit Care Med, Denver, CO 80206 USA
[3] Univ Colorado, Sch Med, Denver, CO USA
来源：
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY | 2014年 / 134卷 / 05期
基金：
美国国家卫生研究院;
关键词：
Dual-positive T(H)2/T(H)17 cells; asthma; bronchoalveolar lavage; glucocorticoid resistance; MEK; SEGMENTAL ALLERGEN CHALLENGE; STEROID-RESISTANT ASTHMA; CD4(+) T-CELLS; AIRWAY HYPERRESPONSIVENESS; CYTOKINE EXPRESSION; EPITHELIAL-CELLS; MESSENGER-RNA; ATOPIC ASTHMA; INFLAMMATION; IL-4;
D O I：
10.1016/j.jaci.2014.05.038
中图分类号：
R392 [医学免疫学];
学科分类号：
100102 ;
摘要：
Background: T(H)2 cells can further differentiate into dual-positive T(H)2/T(H)17 cells. The presence of dual-positive T(H)2/T(H)17 cells in the airways and their effect on asthma severity are unknown. Objective: We sought to study dual-positive T(H)2/T(H)17 cells in bronchoalveolar lavage (BAL) fluid from asthmatic patients, examine their response to glucocorticoids, and define their relevance for disease severity. Methods: Bronchoscopy and lavage were performed in 52 asthmatic patients and 25 disease control subjects. T(H)2 and T(H)2/T(H)17 cells were analyzed by using multicolor flow cytometry and confocal immunofluorescence microscopy. Cytokines were assayed by means of ELISA. Results: Dual-positive T(H)2/T(H)17 cells were present at a higher frequency in BAL fluid from asthmatic patients compared with numbers seen in disease control subjects. High-level IL-4 production was typically accompanied by high-level IL-17 production and coexpression of GATA3 and retinoic acid receptor-related orphan receptor gamma t. Increased presence of T(H)2/T(H)17 cells was associated with increased IL-17 production in lavage fluid. T(H)2/T(H)17 cell counts and IL-17 production correlated with PC20 for methacholine, eosinophil counts, and FEV1. T(H)2/T(H)17 cells, unlike T(H)2 cells, were resistant to dexamethasone-induced cell death. They expressed higher levels of mitogen-activated protein-extracellular signal-regulated kinase kinase 1, a molecule that induces glucocorticoid resistance. On the basis of the dominance of BAL fluid T(H)2 or T(H)2/T(H)17 cells, we identified 3 subgroups of asthma: T(H)2(predominant), T(H)2/T(H)17(predominant), and T(H)2/T(H)17(low). The T(H)2/T(H)17(predominant) subgroup manifested the most severe form of asthma, whereas the T(H)2/T(H)17(low) subgroup had the mildest asthma. Conclusion: Asthma is associated with a higher frequency of dual-positive T(H)2/T(H)17 cells in BAL fluid. The T(H)2/T(H)17(predominant) subgroup of asthmatic patients manifested glucocorticoid resistance in vitro. They also had the greatest airway obstruction and hyperreactivity compared with the T(H)2(predominant) and T(H)2/T(H)17(low) subgroups.
引用
收藏
页码：1175 / +
页数：19
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