The role for neutrophil extracellular traps in cystic fibrosis autoimmunity
The role for neutrophil extracellular traps in cystic fibrosis autoimmunity
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中性粒细胞胞外陷阱在囊性纤维化自身免疫中的作用
DOI：
10.1172/jci.insight.88912
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发表时间：
2016-10-20
期刊：
影响因子：
8
通讯作者：
Rigby, William F. C.
中科院分区：
文献类型：
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作者：
Skopelja, Sladjana;Hamilton, B. JoNell;Rigby, William F. C.
虽然囊性纤维化（CF）的呼吸衰竭经常与铜绿假单胞菌的慢性感染有关，但没有单一因素预测CF的肺损伤程度。为了阐明其他原因，我们研究了CF和类风湿性关节炎（RA）患者的自身抗体谱，因为RA患者的气道炎症和自身免疫具有相似的相关性。尽管我们观察到杀菌渗透性增加蛋白（BPI），氨甲酰化蛋白和瓜氨酸化蛋白都定位于中性粒细胞胞外陷阱（NET），这与自身免疫的发展有关，但我们的研究表明CF中具有惊人的自身抗体特异性。特别是，CF患者产生抗BPI自身抗体，但几乎没有任何抗瓜氨酸化蛋白自身抗体（ACPA）。相反，ACPA阳性RA患者对BPI无反应。有趣的是，在两个队列中均发现了抗氨甲酰化蛋白自身抗体（ACarPA），但未与BPI发生交叉反应。与ACPA和ACarPA相反，抗BPI自身抗体在没有翻译后修饰的情况下识别BPI C-末端。事实上，我们发现铜绿假单胞菌介导的NET形成导致BPI被铜绿假单胞菌弹性蛋白酶切割，这表明对BPI的自身免疫发展中的新机制。根据该模型，自身抗体与痰培养物上铜绿假单胞菌的存在相关。最后，我们的研究结果提供了自身免疫在CF疾病严重程度中的作用，因为自身抗体水平与肺功能减弱相关。
While respiratory failure in cystic fibrosis (CF) frequently associates with chronic infection by Pseudomonas aeruginosa, no single factor predicts the extent of lung damage in CF. To elucidate other causes, we studied the autoantibody profile in CF and rheumatoid arthritis (RA) patients, given the similar association of airway inflammation and autoimmunity in RA. Even though we observed that bactericidal permeability-increasing protein (BPI), carbamylated proteins, and citrullinated proteins all localized to the neutrophil extracellular traps (NETs), which are implicated in the development of autoimmunity, our study demonstrates striking autoantibody specificity in CF. Particularly, CF patients developed anti-BPI autoantibodies but hardly any anti-citrullinated protein autoantibodies (ACPA). In contrast, ACPA-positive RA patients exhibited no reactivity with BPI. Interestingly, anti-carbamylated protein autoantibodies (ACarPA) were found in both cohorts but did not cross-react with BPI. Contrary to ACPA and ACarPA, anti-BPI autoantibodies recognized the BPI C-terminus in the absence of posttranslational modifications. In fact, we discovered that P. aeruginosa-mediated NET formation results in BPI cleavage by P. aeruginosa elastase, which suggests a novel mechanism in the development of autoimmunity to BPI. In accordance with this model, autoantibodies associated with presence of P. aeruginosa on sputum culture. Finally, our results provide a role for autoimmunity in CF disease severity, as autoantibody levels associate with diminished lung function.