Jia Yi, Fang Xu, Zhu Xuehua, Bai Chunxue, Zhu Lei, Jin Meiling, Wang Xiangdong, Hu Min, Tang Renhong, Chen Zhihong
1 Asia & Emerging Markets iMed, AstraZeneca Innovative Medicine and Early Development, Shanghai, China; and.
2 Respiratory Division of Zhongshan Hospital, Shanghai Institute of Respiratory Disease, and.
Am J Respir Cell Mol Biol. 2016 Nov;55(5):675-683. doi: 10.1165/rcmb.2016-0099OC.
Type 2 innate lymphoid cells (ILC2s) have been shown to produce large amounts of type 2 cytokines in a non-antigen-specific manner. These cytokines act upstream and downstream of ILC2 and are increasingly common in asthma drug development, thus warranting a closer investigation of the mechanism-related clinical manifestations of ILC2 in the selection of patients with asthma. We hypothesized that IL-13ILC2s in the circulation might correlate with asthma control status as a result of persistent T-helper cell type 2 (Th2) inflammation in the lung. Furthermore, we aimed to explore ILC2s' responsiveness to glucocorticoid. The percentages of ILC2s and IL-13ILC2s in different asthma subgroups were checked, and correlation analyses between ILC2s and asthma-related clinical parameters were performed. Dexamethasone treatments in ILC2s and Th2 cells were performed to clarify their response properties. ILC2s were identified as a LinCD45IL-7RαCRTH2 cell population distinct from human peripheral blood mononuclear cells. Frequencies of ILC2s were increased dramatically in those with asthma (0.04 ± 0.02%) compared with healthy donors (0.025 ± 0.011%). The percentages of IL-13ILC2s were significantly higher in patients in the uncontrolled group (49.7 ± 16.9%) and partly controlled groups (30.8 ± 13.1%) than in those in the well-controlled group (16.7 ± 5.9%) and healthy control subjects (18.7 ± 8.7%). Effective treatment of uncontrolled IL-13ILC2-positive patients with asthma resulted in dynamic modulation of IL-13ILC2 levels back to baseline. ILC2s were more resistant to glucocorticoid than Th2 cells in vitro. ILC2s are strong responders to IL-25/IL-33 stimulation. IL-13ILC2s show a positive correlation with patient asthma control status and are more resistant to glucocorticoid than Th2 cells in humans.
2型固有淋巴细胞（ILC2s）已被证明能以非抗原特异性方式产生大量2型细胞因子。这些细胞因子在ILC2的上下游发挥作用，在哮喘药物研发中越来越常见，因此在哮喘患者的选择中，有必要更深入地研究与ILC2机制相关的临床表现。我们推测，由于肺部持续存在2型辅助性T细胞（Th2）炎症，循环中的IL-13⁺ILC2s可能与哮喘控制状态相关。此外，我们旨在探索ILC2s对糖皮质激素的反应性。检查了不同哮喘亚组中ILC2s和IL-13⁺ILC2s的百分比，并对ILC2s与哮喘相关临床参数进行了相关性分析。对ILC2s和Th2细胞进行地塞米松处理，以阐明它们的反应特性。ILC2s被鉴定为与人类外周血单个核细胞不同的Lin⁻CD45⁺IL-7Rα⁺CRTH2⁺细胞群体。与健康供体（0.025±0.011%）相比，哮喘患者中ILC2s的频率显著增加（0.04±0.02%）。未控制组（49.7±16.9%）和部分控制组（30.8±13.1%）患者中IL-13⁺ILC2s的百分比显著高于良好控制组（16.7±5.9%）和健康对照受试者（18.7±8.7%）。对未控制的IL-13⁺ILC2s阳性哮喘患者进行有效治疗后，IL-13⁺ILC2水平会动态调节至基线水平。在体外，ILC2s比Th2细胞对糖皮质激素更具抗性。ILC2s对IL-25/IL-33刺激反应强烈。在人类中，IL-13⁺ILC2s与患者哮喘控制状态呈正相关，且比Th2细胞对糖皮质激素更具抗性。
