重症哮喘及持续性气道嗜酸性粒细胞增多患者气道中活化的2型固有淋巴样细胞计数增加
2015/12/31
摘要
背景：在重度嗜酸细胞性哮喘患者中，可能是局部分化成熟而不是全身成熟细胞的募集导致了持续性气道嗜酸性粒细胞增多。2型固有淋巴样细胞（Group 2 innate lymphoid cells：ILC2s）是2型细胞因子（IL-5与IL-13）的一个主要来源，并且在CD4+ 淋巴细胞缺乏的哮喘小鼠模型中可以促进嗜酸性粒细胞性炎症反应。本研究探索在规律使用大剂量口服糖皮质激素治疗基础上，ILC2s在重症哮喘患者中推动慢性气道嗜酸性粒细胞增多的潜在作用。
方法：这项横断面研究纳入了重症哮喘患者（n = 25）、激素敏感的轻度过敏性哮喘患者（n = 9）以及非过敏性对照组（n = 5）；对受试者血和痰中ILC2s (lin-CD45+127+ST2+)的数量及其细胞内IL-5与IL-13的水平进行计数。其结果与CD4+ 淋巴细胞、嗜酸性粒系定向祖细胞（嗜酸性粒细胞生成祖细胞[EoPs]）和成熟的嗜酸粒细胞进行比较。
结果：与轻度哮喘患者比较，检测到重症哮喘患者的血和痰中，ILC2s的细胞总数以及产生2型细胞因子的ILC2s的数量显著升高。相反，两组哮喘患者间，气道内CD4细胞与EoPs表达的细胞内细胞因子并无差别。在重症哮喘患者中，尽管痰中CD4+细胞比ILC2s和EoPs更加丰富，但按比例来看，ILC2s是2型细胞因子的主要来源。此外，尽管血嗜酸粒细胞计数正常（<300/mL），但气道嗜酸粒细胞大于3%的重症哮喘患者，其IL-5+IL-13+ILC2s的数量显著增加。
结论：我们的研究表明，重症患者尽管使用了大剂量口服糖皮质激素治疗，ILC2s仍可通过局部产生不受控制的2型细胞因子IL-5与IL-13，从而促进持续性气道嗜酸粒细胞增多。
Increased numbers of activated group 2 innate lymphoid cells in the airways of patients with severe asthma and persistent airway eosinophilia
Smith SG, Chen RC, Kjarsgaard M, Huang C, Oliveria JP, O’Byrne PM, Gauvreau GM, Boulet LP, Lemiere C, Martin J, Nair P, and Sehmi R
J Allergy Clin Immunol 2015 Jul 17. pii: S0091-6749(15)00789-7
ABSTRACT
Background ：In patients with severe eosinophilic asthma, local maturation rather than systemic recruitment of mature cells might contribute to persistent airway eosinophilia. Group 2 innate lymphoid cells (ILC2s) are a major source of type 2 cytokines (IL-5 and IL-13) and can facilitate eosinophilic inflammatory responses in mouse models of asthma in the absence of CD4+ lymphocytes. This study investigated the potential role of ILC2s in driving chronic airway eosinophilia in patients with severe asthma, despite regular high-dose oral corticosteroid therapy.
Methods：In a cross-sectional study we enumerated blood and sputum ILC2s (lin-CD45+127+ST2+) and levels of intracellular IL-5 and IL-13 in patients with severe asthma (n = 25), patients with steroid-naive mild atopic asthma (n = 19), and nonatopic control subjects (n = 5). Results were compared with numbers of CD4+ lymphocytes, eosinophil lineage–committed progenitors (eosinophilopoietic progenitor cells [EoPs]), and mature eosinophils.
Results：Significantly greater numbers of total and type 2 cytokine–producing ILC2s were detected in blood and sputum of patients with severe asthma compared to mild asthmatics. In contrast, intracellular cytokine expression by CD4 cells and EoPs within the airways did not differ between the asthmatic groups. In patients with severe asthma, although sputum CD4+ cells were more abundant than ILC2s and EoPs, proportionally, ILC2s were the predominant source of type 2 cytokines. In addition, there were significantly greater numbers of sputum IL-5+IL-13+ILC2s in patients with severe asthma whose airway eosinophilia was greater than 3%, despite normal blood eosinophil numbers (<300/mL).
Conclusions：Our findings suggest that ILC2s can promote the persistence of airway eosinophilia in patients with severe asthma through uncontrolled localized production of the type 2 cytokines IL-5 and IL-13, despite high-dose oral corticosteroid therapy.
背景：在重度嗜酸细胞性哮喘患者中，可能是局部分化成熟而不是全身成熟细胞的募集导致了持续性气道嗜酸性粒细胞增多。2型固有淋巴样细胞（Group 2 innate lymphoid cells：ILC2s）是2型细胞因子（IL-5与IL-13）的一个主要来源，并且在CD4+ 淋巴细胞缺乏的哮喘小鼠模型中可以促进嗜酸性粒细胞性炎症反应。本研究探索在规律使用大剂量口服糖皮质激素治疗基础上，ILC2s在重症哮喘患者中推动慢性气道嗜酸性粒细胞增多的潜在作用。
方法：这项横断面研究纳入了重症哮喘患者（n = 25）、激素敏感的轻度过敏性哮喘患者（n = 9）以及非过敏性对照组（n = 5）；对受试者血和痰中ILC2s (lin-CD45+127+ST2+)的数量及其细胞内IL-5与IL-13的水平进行计数。其结果与CD4+ 淋巴细胞、嗜酸性粒系定向祖细胞（嗜酸性粒细胞生成祖细胞[EoPs]）和成熟的嗜酸粒细胞进行比较。
结果：与轻度哮喘患者比较，检测到重症哮喘患者的血和痰中，ILC2s的细胞总数以及产生2型细胞因子的ILC2s的数量显著升高。相反，两组哮喘患者间，气道内CD4细胞与EoPs表达的细胞内细胞因子并无差别。在重症哮喘患者中，尽管痰中CD4+细胞比ILC2s和EoPs更加丰富，但按比例来看，ILC2s是2型细胞因子的主要来源。此外，尽管血嗜酸粒细胞计数正常（<300/mL），但气道嗜酸粒细胞大于3%的重症哮喘患者，其IL-5+IL-13+ILC2s的数量显著增加。
结论：我们的研究表明，重症患者尽管使用了大剂量口服糖皮质激素治疗，ILC2s仍可通过局部产生不受控制的2型细胞因子IL-5与IL-13，从而促进持续性气道嗜酸粒细胞增多。
(刘影 张红萍 王刚 四川大学华西医院中西医结合科呼吸病组 610041 摘译)
（J Allergy Clin Immunol 2015 Jul 17. pii: S0091-6749(15)00789-7）
（J Allergy Clin Immunol 2015 Jul 17. pii: S0091-6749(15)00789-7）
Increased numbers of activated group 2 innate lymphoid cells in the airways of patients with severe asthma and persistent airway eosinophilia
Smith SG, Chen RC, Kjarsgaard M, Huang C, Oliveria JP, O’Byrne PM, Gauvreau GM, Boulet LP, Lemiere C, Martin J, Nair P, and Sehmi R
J Allergy Clin Immunol 2015 Jul 17. pii: S0091-6749(15)00789-7
ABSTRACT
Background ：In patients with severe eosinophilic asthma, local maturation rather than systemic recruitment of mature cells might contribute to persistent airway eosinophilia. Group 2 innate lymphoid cells (ILC2s) are a major source of type 2 cytokines (IL-5 and IL-13) and can facilitate eosinophilic inflammatory responses in mouse models of asthma in the absence of CD4+ lymphocytes. This study investigated the potential role of ILC2s in driving chronic airway eosinophilia in patients with severe asthma, despite regular high-dose oral corticosteroid therapy.
Methods：In a cross-sectional study we enumerated blood and sputum ILC2s (lin-CD45+127+ST2+) and levels of intracellular IL-5 and IL-13 in patients with severe asthma (n = 25), patients with steroid-naive mild atopic asthma (n = 19), and nonatopic control subjects (n = 5). Results were compared with numbers of CD4+ lymphocytes, eosinophil lineage–committed progenitors (eosinophilopoietic progenitor cells [EoPs]), and mature eosinophils.
Results：Significantly greater numbers of total and type 2 cytokine–producing ILC2s were detected in blood and sputum of patients with severe asthma compared to mild asthmatics. In contrast, intracellular cytokine expression by CD4 cells and EoPs within the airways did not differ between the asthmatic groups. In patients with severe asthma, although sputum CD4+ cells were more abundant than ILC2s and EoPs, proportionally, ILC2s were the predominant source of type 2 cytokines. In addition, there were significantly greater numbers of sputum IL-5+IL-13+ILC2s in patients with severe asthma whose airway eosinophilia was greater than 3%, despite normal blood eosinophil numbers (<300/mL).
Conclusions：Our findings suggest that ILC2s can promote the persistence of airway eosinophilia in patients with severe asthma through uncontrolled localized production of the type 2 cytokines IL-5 and IL-13, despite high-dose oral corticosteroid therapy.
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