Introduction Alpha-1 antitrypsin (AAT) deficiency (AATD) is associated with early onset emphysema. The aim of this study was to investigate whether AAT binding to plasma constituents could regulate their activation, and in AATD, exploit this binding event to better understand the condition and uncover novel biomarkers of therapeutic efficacy. Methods To isolate AAT linker proteins, plasma samples were separated by size exclusion chromatography, followed by co-immunoprecipitation. AAT binding proteins were identified by mass spectrometry. Complement turnover and activation was determined by ELISA measurement of C3, C3a and C3d levels in plasma of healthy controls (n=15), AATD (n=51), non-AATD patients with obstructive airway disease (n=10) and AATD patients post AAT augmentation therapy (n=5). Results Direct binding of complement C3 to AAT was identified in vivo and in vitro. Compared with healthy controls, a breakdown product of C3, C3d, was increased in AATD (0.04 µg/mL vs 1.96 µg/mL, p=0.0002), with a significant correlation between radiographic pulmonary emphysema and plasma levels of C3d (R2=0.37, p=0.001). In vivo, AAT augmentation therapy significantly reduced plasma levels of C3d in comparison to patients not receiving AAT therapy (0.15 µg/mL vs 2.18 µg/mL, respectively, p=0.001). Discussion Results highlight the immune-modulatory impact of AAT on the complement system, involving an important potential role for complement activation in disease pathogenesis in AATD. The association between plasma C3d levels and pulmonary disease severity, that decrease in response to AAT augmentation therapy, supports the exploration of C3d as a candidate biomarker of therapeutic efficacy in AATD.

中文翻译：

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补体成分 3 的激活与 α-1 抗胰蛋白酶缺乏症中的气道疾病和肺气肿有关

介绍 Alpha-1 抗胰蛋白酶 (AAT) 缺乏症 (AATD) 与早发性肺气肿有关。本研究的目的是调查 AAT 与血浆成分的结合是否可以调节它们的激活，并在 AATD 中利用这种结合事件来更好地了解病情并发现治疗功效的新生物标志物。方法 为了分离 AAT 接头蛋白，通过尺寸排阻色谱分离血浆样品，然后进行免疫共沉淀。AAT结合蛋白通过质谱法鉴定。通过 ELISA 测量健康对照 (n=15)、AATD (n=51)、非 AATD 阻塞性气道疾病患者 (n=10) 和 AATD 患者血浆中的 C3、C3a 和 C3d 水平，确定补体转换和激活AAT 增强治疗后 (n=5)。结果在体内和体外鉴定了补体C3与AAT的直接结合。与健康对照相比，ATD 中 C3 的分解产物 C3d 增加（0.04 µg/mL 对 1.96 µg/mL，p=0.0002），放射照相肺气肿与 C3d 血浆水平之间存在显着相关性（R2=0.37 ，p=0.001）。在体内，与未接受 AAT 治疗的患者相比，AAT 增强治疗显着降低了 C3d 的血浆水平（分别为 0.15 µg/mL 和 2.18 µg/mL，p=0.001）。讨论结果突出了 AAT 对补体系统的免疫调节影响，涉及补体激活在 AATD 疾病发病机制中的重要潜在作用。血浆 C3d 水平与肺部疾病严重程度之间的关联，对 AAT 增强治疗的反应降低，