Department of Microbiology and Immunology and.
Division of Rheumatology, Department of Medicine, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.
JCI Insight. 2016 Oct 20;1(17):e88912. doi: 10.1172/jci.insight.88912.
While respiratory failure in cystic fibrosis (CF) frequently associates with chronic infection by , 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 . -mediated NET formation results in BPI cleavage by . elastase, which suggests a novel mechanism in the development of autoimmunity to BPI. In accordance with this model, autoantibodies associated with presence of . on sputum culture. Finally, our results provide a role for autoimmunity in CF disease severity, as autoantibody levels associate with diminished lung function.
在囊性纤维化 (CF) 中，呼吸衰竭通常与 慢性感染相关，但没有单一因素可以预测 CF 中的肺损伤程度。为了阐明其他原因，我们研究了 CF 和类风湿关节炎 (RA) 患者的自身抗体谱，因为 RA 中气道炎症和自身免疫之间存在相似的关联。尽管我们观察到杀菌/通透性增加蛋白 (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 (NETs) 中，而 NETs 与自身免疫的发展有关，但我们的研究表明 CF 具有显著的自身抗体特异性。特别是，CF 患者产生抗 BPI 自身抗体，但几乎没有抗瓜氨酸化蛋白自身抗体 (ACPA)。相比之下，ACPA 阳性的 RA 患者对 BPI 没有反应。有趣的是，两种患者群体均存在抗氨甲酰化蛋白自身抗体 (ACarPA)，但它们与 BPI 没有交叉反应。与 ACPA 和 ACarPA 不同，抗 BPI 自身抗体在没有翻译后修饰的情况下识别 BPI 的 C 末端。事实上，我们发现 弹性蛋白酶介导的 NET 形成导致 BPI 被切割，这表明 BPI 自身免疫发生的一种新机制。根据该模型，与痰培养中存在 相关的自身抗体。最后，我们的结果为自身免疫在 CF 疾病严重程度中的作用提供了依据，因为自身抗体水平与肺功能下降相关。
