Duvall Melody G, Barnig Cindy, Cernadas Manuela, Ricklefs Isabell, Krishnamoorthy Nandini, Grossman Nicole L, Bhakta Nirav R, Fahy John V, Bleecker Eugene R, Castro Mario, Erzurum Serpil C, Gaston Benjamin M, Jarjour Nizar N, Mauger David T, Wenzel Sally E, Comhair Suzy A, Coverstone Andrea M, Fajt Merritt L, Hastie Annette T, Johansson Mats W, Peters Michael C, Phillips Brenda R, Israel Elliot, Levy Bruce D
Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Division of Critical Care Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Sci Immunol. 2017 Mar 10;2(9). doi: 10.1126/sciimmunol.aam5446.
Severe asthma is typically characterized by chronic airway inflammation that is refractory to corticosteroids and associated with excess morbidity. Patients were recruited into the National Heart, Lung, and Blood Institute-sponsored Severe Asthma Research Program and comprehensively phenotyped by bronchoscopy. Bronchoalveolar lavage (BAL) cells were analyzed by flow cytometry. Compared with healthy individuals ( = 21), patients with asthma ( = 53) had fewer BAL natural killer (NK) cells. Patients with severe asthma ( = 29) had a marked increase in the ratios of CD4 T cells to NK cells and neutrophils to NK cells. BAL NK cells in severe asthma were skewed toward the cytotoxic CD56 subset, with significantly increased BAL fluid levels of the cytotoxic mediator granzyme A. The numbers of BAL CD56 NK cells and CCR6CCR4 T helper 1-enriched CD4 T cells correlated inversely with lung function [forced expiratory volume in 1 s (FEV) % predicted] in asthma. Relative to cells from healthy controls, peripheral blood NK cells from asthmatic patients had impaired killing of K562 myeloid target cells despite releasing more cytotoxic mediators. Ex vivo exposure to dexamethasone markedly decreased blood NK cell lysis of target cells and cytotoxic mediator release. NK cells expressed airway lipoxin A/formyl peptide receptor 2 receptors, and in contrast to dexamethasone, lipoxin A-exposed NK cells had preserved functional responses. Together, our findings indicate that the immunology of the severe asthma airway is characterized by decreased NK cell cytotoxicity with increased numbers of target leukocytes, which is exacerbated by corticosteroids that further disable NK cell function. These failed resolution mechanisms likely contribute to persistent airway inflammation in severe asthma.
重度哮喘的典型特征是慢性气道炎症，这种炎症对皮质类固醇难治，并伴有过高的发病率。患者被纳入美国国立心肺血液研究所资助的重度哮喘研究项目，并通过支气管镜检查进行全面的表型分析。通过流式细胞术分析支气管肺泡灌洗（BAL）细胞。与健康个体（n = 21）相比，哮喘患者（n = 53）的BAL自然杀伤（NK）细胞较少。重度哮喘患者（n = 29）的CD4 T细胞与NK细胞以及中性粒细胞与NK细胞的比例显著增加。重度哮喘患者的BAL NK细胞倾向于细胞毒性CD56亚群，细胞毒性介质颗粒酶A的BAL液水平显著升高。哮喘患者BAL CD56 NK细胞和CCR6⁺CCR4⁺辅助性T细胞1富集的CD4 T细胞数量与肺功能[1秒用力呼气量（FEV）占预计值的百分比]呈负相关。相对于健康对照的细胞，哮喘患者外周血NK细胞尽管释放了更多的细胞毒性介质，但对K562髓系靶细胞的杀伤能力受损。体外暴露于地塞米松显著降低了血液NK细胞对靶细胞的裂解和细胞毒性介质的释放。NK细胞表达气道脂氧素A/甲酰肽受体2受体，与地塞米松不同，暴露于脂氧素A的NK细胞保留了功能反应。总之，我们的研究结果表明，重度哮喘气道的免疫学特征是NK细胞细胞毒性降低，靶白细胞数量增加，皮质类固醇会加剧这种情况，进一步损害NK细胞功能。这些未能解决的机制可能导致重度哮喘患者气道炎症持续存在。
