National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY UK.
Am J Respir Crit Care Med. 2011 Oct 1;184(7):796-802. doi: 10.1164/rccm.201010-1605OC.
There is increasing evidence for the presence of autoantibodies in chronic obstructive pulmonary disease (COPD). Chronic oxidative stress is an essential component in COPD pathogenesis and can lead to increased levels of highly reactive carbonyls in the lung, which could result in the formation of highly immunogenic carbonyl adducts on "self" proteins.
To determine the presence of autoantibodies to carbonyl-modified protein in patients with COPD and in a murine model of chronic ozone exposure. To assess the extent of activated immune responses toward carbonyl-modified proteins.
Blood and peripheral lung were taken from patients with COPD, age-matched smokers, and nonsmokers with normal lung function, as well as patients with severe persistent asthma. Mice were exposed to ambient air or ozone for 6 weeks. Antibody titers were measured by ELISA, activated compliment deposition by immunohistochemistry, and cellular activation by ELISA and fluorescence-activated cell sorter.
Antibody titer against carbonyl-modified self-protein was significantly increased in patients with Global Initiative for Chronic Obstructive Lung Disease stage III COPD compared with control subjects. Antibody levels inversely correlated with disease severity and showed a prevalence toward an IgG1 isotype. Deposition of activated complement in the vessels of COPD lung as well as autoantibodies against endothelial cells were also observed. Ozone-exposed mice similarly exhibited increased antibody titers to carbonyl-modified protein, as well as activated antigen-presenting cells in lung tissue and splenocytes sensitized to activation by carbonyl-modified protein.
Carbonyl-modified proteins, arising as a result of oxidative stress, promote antibody production, providing a link by which oxidative stress could drive an autoimmune response in COPD.
慢性阻塞性肺疾病（COPD）患者体内存在自身抗体已得到越来越多的证实。慢性氧化应激是 COPD 发病机制的一个重要组成部分，可导致肺部高反应性羰基水平升高，从而导致“自身”蛋白上形成高度免疫原性的羰基加合物。
确定 COPD 患者和慢性臭氧暴露的小鼠模型中是否存在针对羰基修饰蛋白的自身抗体。评估针对羰基修饰蛋白的激活免疫反应的程度。
从 COPD 患者、年龄匹配的吸烟者、肺功能正常的不吸烟者以及严重持续性哮喘患者中采集血液和外周肺组织。将小鼠暴露于环境空气或臭氧中 6 周。通过 ELISA 测定抗体滴度，通过免疫组织化学测定激活补体沉积，通过 ELISA 和荧光激活细胞分选测定细胞激活。
与对照组相比，全球慢性阻塞性肺病倡议 III 期 COPD 患者针对羰基修饰自身蛋白的抗体滴度显著增加。抗体水平与疾病严重程度呈负相关，且呈现 IgG1 同种型的流行趋势。COPD 肺部血管中也观察到激活补体的沉积以及针对内皮细胞的自身抗体。臭氧暴露的小鼠同样表现出针对羰基修饰蛋白的抗体滴度增加，以及对羰基修饰蛋白激活敏感的肺组织和脾细胞中的抗原呈递细胞激活。
氧化应激导致的羰基修饰蛋白促进抗体产生，为氧化应激如何在 COPD 中引发自身免疫反应提供了一种联系。
