重症嗜酸粒细胞性哮喘患者中的痰自身抗体
2018/10/31
摘要
背景：尽管使用了大剂量皮质类固醇激素，哮喘患者痰液中嗜酸性粒细胞仍然持续存在，且与疾病严重程度相关。随着时间推移，存在慢性炎症的气道会失去对嗜酸性粒细胞频繁脱颗粒释放的免疫原性物质的耐受性，这进一步加重了疾病的严重程度，且导致患者需要增加皮质类固醇激素的维持剂量。
目的：我们旨在探索哮喘患者气道中多克隆自身免疫事件的可能性，并确定相关的临床和分子特征。
方法：纳入需要吸入大剂量皮质类固醇激素或/和口服泼尼松维持治疗的嗜酸性粒细胞性哮喘患者，探索其抗嗜酸粒细胞过氧化物酶（eosinophil peroxidase， EPX）自身抗体和抗核抗体。评估痰免疫球蛋白在体外诱导嗜酸性粒细胞脱颗粒的能力。此外，检测存在自身抗体患者的相关炎性微环境。
结果：在泼尼松依赖性哮喘患者气道中发生了“多克隆”自身免疫事件，这些患者具有嗜酸性粒细胞活性增加和/或反复发生肺部感染的特征，痰抗体同时存在抗EPX抗体和IgG亚型的抗核抗体。多重痰液细胞因子分析揭示出TH2主导的微环境（嗜酸性粒细胞趋化因子-2，IL-5，IL-18和IL-13），增加的信号分子（B细胞激活因子和B细胞 - 吸引趋化因子1），导致了异位淋巴结构形成。自身抗体水平增加的患者，其免疫共沉淀的痰液免疫球蛋白在体外可诱导嗜酸性粒细胞脱颗粒，释放出较多富含组蛋白的胞外网，它不能被地塞米松抑制，很可能导致了这些嗜酸粒细胞哮喘患者出现糖皮质激素不敏感。
结论：本研究鉴定了重症哮喘的免疫内型，其可通过出现针对EPX与自体细胞组分的痰自身抗体来鉴定。
Sputum autoantibodies in patients with severe eosinophilic asthma
Manali Mukherjee, David C. Bulir, Katherine Radford,MSc, Melanie Kjarsgaard, RRT, et,al
J Allergy Clin Immunol. 2018;141(4):1269-1279.
Abstract
Background: The persistence of eosinophils in sputum despite high doses of corticosteroids indicates disease severity in asthmatic patients. Chronic inflamed airways can lose tolerance over time to immunogenic entities released on frequent eosinophil degranulation, which further contributes to disease severity and necessitates an increase in maintenance corticosteroids.
Objectives: We sought to investigate the possibility of a polyclonal autoimmune event in the airways of asthmatic patients and to identify associated clinical and molecular characteristics.
Methods: The presence of autoantibodies against eosinophil peroxidase (EPX) and anti-nuclear antibodies was investigated in patients with eosinophilic asthma maintained on high-dose corticosteroids, prednisone, or both. The ability of sputum immunoglobulins to induce eosinophil degranulation in vitro was assessed. In addition, the associated inflammatory microenvironment in patients with detectable autoantibodies was examined.
Results: We report a ‘‘polyclonal’’ autoimmune event occurring in the airways of prednisone-dependent asthmatic patients with increased eosinophil activity, recurrent pulmonary infections, or both, as evident by the concomitant presence of sputum anti-
EPX and anti-nuclear antibodies of the IgG subtype. Extensive cytokine profiling of sputum revealed a TH2-dominated microenvironment (eotaxin-2, IL-5, IL-18, and IL-13) and increased signalling molecules that support the formation of ectopic lymphoid structures (B-cell activating factor and B cell–attracting chemokine 1). Immunoprecipitated sputum immunoglobulins from patients with increased autoantibody
levels triggered eosinophil degranulation in vitro, with release of extensive histone-rich extracellular traps, an event unsuppressed by dexamethasone and possibly contributing to
the steroid-unresponsive nature of these eosinophilic patients.
Conclusion: This study identifies an autoimmune endotype of severe asthma that can be identified by the presence of sputum autoantibodies against EPX and autologous cellularcomponents.
背景：尽管使用了大剂量皮质类固醇激素，哮喘患者痰液中嗜酸性粒细胞仍然持续存在，且与疾病严重程度相关。随着时间推移，存在慢性炎症的气道会失去对嗜酸性粒细胞频繁脱颗粒释放的免疫原性物质的耐受性，这进一步加重了疾病的严重程度，且导致患者需要增加皮质类固醇激素的维持剂量。
目的：我们旨在探索哮喘患者气道中多克隆自身免疫事件的可能性，并确定相关的临床和分子特征。
方法：纳入需要吸入大剂量皮质类固醇激素或/和口服泼尼松维持治疗的嗜酸性粒细胞性哮喘患者，探索其抗嗜酸粒细胞过氧化物酶（eosinophil peroxidase， EPX）自身抗体和抗核抗体。评估痰免疫球蛋白在体外诱导嗜酸性粒细胞脱颗粒的能力。此外，检测存在自身抗体患者的相关炎性微环境。
结果：在泼尼松依赖性哮喘患者气道中发生了“多克隆”自身免疫事件，这些患者具有嗜酸性粒细胞活性增加和/或反复发生肺部感染的特征，痰抗体同时存在抗EPX抗体和IgG亚型的抗核抗体。多重痰液细胞因子分析揭示出TH2主导的微环境（嗜酸性粒细胞趋化因子-2，IL-5，IL-18和IL-13），增加的信号分子（B细胞激活因子和B细胞 - 吸引趋化因子1），导致了异位淋巴结构形成。自身抗体水平增加的患者，其免疫共沉淀的痰液免疫球蛋白在体外可诱导嗜酸性粒细胞脱颗粒，释放出较多富含组蛋白的胞外网，它不能被地塞米松抑制，很可能导致了这些嗜酸粒细胞哮喘患者出现糖皮质激素不敏感。
结论：本研究鉴定了重症哮喘的免疫内型，其可通过出现针对EPX与自体细胞组分的痰自身抗体来鉴定。
(袁雨来1 张欣1 张红萍1 王刚2 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. 2018;141(4):1269-1279.）
（J Allergy Clin Immunol. 2018;141(4):1269-1279.）
Sputum autoantibodies in patients with severe eosinophilic asthma
Manali Mukherjee, David C. Bulir, Katherine Radford,MSc, Melanie Kjarsgaard, RRT, et,al
J Allergy Clin Immunol. 2018;141(4):1269-1279.
Abstract
Background: The persistence of eosinophils in sputum despite high doses of corticosteroids indicates disease severity in asthmatic patients. Chronic inflamed airways can lose tolerance over time to immunogenic entities released on frequent eosinophil degranulation, which further contributes to disease severity and necessitates an increase in maintenance corticosteroids.
Objectives: We sought to investigate the possibility of a polyclonal autoimmune event in the airways of asthmatic patients and to identify associated clinical and molecular characteristics.
Methods: The presence of autoantibodies against eosinophil peroxidase (EPX) and anti-nuclear antibodies was investigated in patients with eosinophilic asthma maintained on high-dose corticosteroids, prednisone, or both. The ability of sputum immunoglobulins to induce eosinophil degranulation in vitro was assessed. In addition, the associated inflammatory microenvironment in patients with detectable autoantibodies was examined.
Results: We report a ‘‘polyclonal’’ autoimmune event occurring in the airways of prednisone-dependent asthmatic patients with increased eosinophil activity, recurrent pulmonary infections, or both, as evident by the concomitant presence of sputum anti-
EPX and anti-nuclear antibodies of the IgG subtype. Extensive cytokine profiling of sputum revealed a TH2-dominated microenvironment (eotaxin-2, IL-5, IL-18, and IL-13) and increased signalling molecules that support the formation of ectopic lymphoid structures (B-cell activating factor and B cell–attracting chemokine 1). Immunoprecipitated sputum immunoglobulins from patients with increased autoantibody
levels triggered eosinophil degranulation in vitro, with release of extensive histone-rich extracellular traps, an event unsuppressed by dexamethasone and possibly contributing to
the steroid-unresponsive nature of these eosinophilic patients.
Conclusion: This study identifies an autoimmune endotype of severe asthma that can be identified by the presence of sputum autoantibodies against EPX and autologous cellularcomponents.
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