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 T_H2-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 cellular components.

中文翻译：

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严重嗜酸性粒细胞性哮喘患者的痰中自身抗体

背景

尽管有高剂量的皮质类固醇，但痰液中嗜酸性粒细胞的持续存在表明哮喘患者的疾病严重程度。慢性发炎的气道可能会随着时间的流逝而失去对因频繁嗜酸性粒细胞脱粒而释放的免疫原性实体的耐受力，这进一步加剧了疾病的严重性，并需要增加维持糖皮质激素的剂量。

目标

我们试图调查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

在维持大剂量皮质类固醇，泼尼松或两者同时服用的嗜酸性哮喘患者中，研究了针对嗜酸性粒细胞过氧化物酶（EPX）和抗核抗体的自身抗体的存在。评估了痰液免疫球蛋白在体外诱导嗜酸性粒细胞脱粒的能力。此外，检查了可检测自身抗体患者的相关炎症微环境。

结果

我们报道了在泼尼松依赖的哮喘患者中，嗜酸性粒细胞活性增加，肺部反复感染或两者兼而有之的“多克隆”自身免疫事件，如痰中同时存在抗-EPX和IgG亚型抗核抗体所证实。广泛的细胞因子谱痰的揭示为T _ħ 2为主的微环境（eotaxin的-2，IL-5，IL-18，和IL-13）和增加的信令支持异位淋巴结构（B细胞活化因子的形成分子和吸引B细胞的趋化因子1）。来自自身抗体水平升高的患者的免疫沉淀痰免疫球蛋白在体外触发了嗜酸性粒细胞脱粒随着大量组蛋白丰富的细胞外陷阱的释放，地塞米松无法抑制这一事件，并可能导致这些嗜酸性粒细胞患者的类固醇无反应性。

结论

这项研究确定了严重哮喘的自身免疫内型，可以通过针对EPX和自体细胞成分的痰自身抗体的存在来鉴定。