BACKGROUND Respiratory viral infections can increase the risk of chronic lung allograft dysfunction after lung transplantation, but the mechanisms are unknown. In this study, we determined whether symptomatic respiratory viral infections after lung transplantation induce circulating exosomes that contain lung-associated self-antigens and assessed whether these exosomes activate immune responses to self-antigens. METHODS Serum samples were collected from lung transplant recipients with symptomatic lower- and upper-tract respiratory viral infections and from non-symptomatic stable recipients. Exosomes were isolated via ultracentrifugation; purity was determined using sucrose cushion; and presence of lung self-antigens, 20S proteasome, and viral antigens for rhinovirus, coronavirus, and respiratory syncytial virus were determined using immunoblot. Mice were immunized with circulating exosomes from each group and resulting differential immune responses and lung histology were analyzed. RESULTS Exosomes containing self-antigens, 20S proteasome, and viral antigens were detected at significantly higher levels (p < 0.05) in serum of recipients with symptomatic respiratory viral infections (n = 35) as compared with stable controls (n = 32). Mice immunized with exosomes from recipients with respiratory viral infections developed immune responses to self-antigens, fibrosis, small airway occlusion, and significant cellular infiltration; mice immunized with exosomes from controls did not (p < 0.05). CONCLUSIONS Circulating exosomes isolated from lung transplant recipients diagnosed with respiratory viral infections contained lung self-antigens, viral antigens, and 20S proteasome and elicited immune responses to lung self-antigens that resulted in development of chronic lung allograft dysfunction in immunized mice.

中文翻译：

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肺移植中的呼吸道病毒感染会诱导外来体，从而触发慢性排斥反应。

背景技术呼吸道病毒感染可增加肺移植后慢性同种异体移植功能障碍的风险，但其机制尚不清楚。在这项研究中，我们确定了肺移植后有症状的呼吸道病毒感染是否诱导了循环外来体，这些外来体含有与肺相关的自身抗原，并评估了这些外体是否激活了对自身抗原的免疫反应。方法从有症状的上下呼吸道病毒感染的肺移植接受者和无症状的稳定接受者中收集血清样品。通过超速离心分离外泌体；使用蔗糖垫测定纯度；使用免疫印迹法测定鼻病毒，鼻病毒，冠状病毒和呼吸道合胞病毒的肺自身抗原，20S蛋白酶体和病毒抗原的存在。用来自各组的循环外来体免疫小鼠，并分析产生的不同的免疫应答和肺组织学。结果与有症状的呼吸道病毒感染患者（n = 35）相比，在有症状呼吸道病毒感染的接受者血清中检出的含有自身抗原，20S蛋白酶体和病毒抗原的外泌体水平显着更高（p <0.05）。接受呼吸道病毒感染的接受者的外来体免疫的小鼠对自身抗原，纤维化，小气道阻塞和明显的细胞浸润产生了免疫反应。用来自对照的外来体免疫的小鼠没有（p ＜0.05）。结论从诊断为呼吸道病毒感染的肺移植受者中分离出的循环外泌体包含肺自身抗原，病毒抗原，