Oxidative Stress-induced Antibodies to Carbonyl-modified Protein Correlate with Severity of Chronic Obstructive Pulmonary Disease
Oxidative Stress-induced Antibodies to Carbonyl-modified Protein Correlate with Severity of Chronic Obstructive Pulmonary Disease
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DOI：
10.1164/rccm.201010-1605oc
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发表时间：
2011-10-01
影响因子：
24.7
通讯作者：
Adcock, Ian M.
中科院分区：
文献类型：
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作者：
Kirkham, Paul A.;Caramori, Gaetano;Adcock, Ian M.
理由：越来越多的证据表明慢性阻塞性肺疾病（COPD）中存在自身抗体。慢性氧化应激是COPD发病机制的重要组成部分，可导致肺部高活性羰基水平升高，这可能导致“自身”蛋白上形成高度免疫原性的羰基加合物。目的：确定慢性阻塞性肺病患者和慢性臭氧暴露小鼠模型中羰基修饰蛋白自身抗体的存在。评估对羰基修饰蛋白激活免疫反应的程度。方法：采集COPD患者、年龄匹配的吸烟者、肺功能正常的不吸烟者以及重度持续性哮喘患者的血液和肺外周。小鼠暴露于环境空气或臭氧中6周。ELISA检测抗体滴度，免疫组织化学检测激活补体沉积，ELISA和荧光活化细胞分选仪检测细胞活化。测量结果和主要结果：与对照组相比，全球慢性阻塞性肺疾病III期COPD患者抗羰基修饰自身蛋白的抗体滴度显著升高。抗体水平与疾病严重程度呈负相关，并显示出IgG1同型的患病率。活化补体在COPD肺血管中的沉积以及针对内皮细胞的自身抗体也被观察到。暴露于臭氧的小鼠同样表现出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活化的抗原呈递细胞。结论：氧化应激产生的羰基修饰蛋白促进抗体产生，提供了氧化应激驱动COPD自身免疫反应的一个环节。
Rationale: 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.Objectives: 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.Methods: 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.Measurements and Main Results: 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.Conclusions: 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.