The Circulating Proteinase Inhibitor α-1 Antitrypsin Regulates Neutrophil Degranulation and Autoimmunity
The Circulating Proteinase Inhibitor α-1 Antitrypsin Regulates Neutrophil Degranulation and Autoimmunity
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DOI：
10.1126/scitranslmed.3007116
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发表时间：
2014-01-01
影响因子：
17.1
通讯作者：
McElvaney, Noel G.
中科院分区：
文献类型：
--
作者：
Bergin, David A.;Reeves, Emer P.;McElvaney, Noel G.
病理性炎症和自身免疫性疾病常常涉及在没有传染源的情况下中性粒细胞活性升高。肿瘤坏死因子-a (TNF-α) 会导致许多与自身免疫性疾病相关的问题。我们研究了血清 α-1 抗胰蛋白酶 (AAT) 控制中性粒细胞中 TNF-α 生物合成和信号传导的能力，并评估了 AAT 缺乏症 (AATD) 是否是一种 TNF-α 相关疾病。体外研究表明，血清 AAT 通过调节配体-受体相互作用来协调 TNF-α 细胞内信号传导以及中性粒细胞的三级和二级颗粒脱颗粒。 Z 等位基因纯合的 AATD 患者的特征是 TNF-α 系统的激活增加，这通过膜 TNF-α 水平增加和 TNF 受体 1 以及中性粒细胞释放的二级和三级颗粒蛋白的血浆浓度增加来证明。在 ZZ-AATD 中，针对脱颗粒乳铁蛋白和这些抗体可接触的表面蛋白的自身抗体的发生率增加，导致中性粒细胞活性氧产生率增加。使用 AAT 增强疗法治疗 ZZ-AATD 个体会导致膜 TNF-α 表达以及颗粒抗原蛋白和免疫球蛋白 G 类自身抗体的血浆水平降低。这些结果提供了 AAT 增强疗法影响循环中性粒细胞中 TNF-α 信号传导的机制，表明该疗法在治疗其他 TNF-α 相关疾病方面具有广阔的前景。
Pathological inflammation and autoimmune disease frequently involve elevated neutrophil activity in the absence of infectious agents. Tumor necrosis factor-a (TNF-alpha) contributes to many of the problems associated with autoimmune diseases. We investigated the ability of serum alpha-1 antitrypsin (AAT) to control TNF-alpha biosynthesis and signaling in neutrophils and assessed whether AAT deficiency (AATD) is a TNF-alpha-related disease. In vitro studies demonstrate that serum AAT coordinates TNF-alpha intracellular signaling and neutrophil degranulation of tertiary and secondary granules via modulation of ligand-receptor interactions. AATD patients homozygous for the Z allele were characterized by increased activation of the TNF-alpha system, as demonstrated by increased membrane TNF-alpha levels and increased plasma concentrations of TNF receptor 1 and neutrophil-released secondary and tertiary granule proteins. The incidence of autoantibodies directed against degranulated lactoferrin and surface protein accessible to these antibodies was increased in ZZ-AATD, leading to an enhanced rate of neutrophil reactive oxygen species production. Treatment of ZZ-AATD individuals with AAT augmentation therapy resulted in decreased membrane TNF-alpha expression and plasma levels of granule antigenic proteins and immunoglobulin G class autoantibodies. These results provide a mechanism by which AAT augmentation therapy affects TNF-alpha signaling in the circulating neutrophil, indicating promising potential of this therapy for other TNF-alpha-related diseases.