Autoreactive T Cells in Human Smokers is Predictive of Clinical Outcome.
Autoreactive T Cells in Human Smokers is Predictive of Clinical Outcome.
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DOI：
10.3389/fimmu.2012.00267
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发表时间：
2012
影响因子：
7.3
通讯作者：
Kheradmand F
中科院分区：
文献类型：
--
作者：
Xu C;Hesselbacher S;Tsai CL;Shan M;Spitz M;Scheurer M;Roberts L;Perusich S;Zarinkamar N;Coxson H;Krowchuk N;Corry DB;Kheradmand F
横断面研究表明，肺气肿吸烟者的适应性免疫激活具有一定作用，但这些发现的临床应用尚未得到探索。在这里，我们研究了检测自身反应性 T 细胞作为高危吸烟者群体肺气肿筛查工具的实用性。我们对 156 名曾经吸烟者和现在吸烟者进行了 2 年的跟踪，以评估外周血 CD4 T 细胞细胞因子对肺弹性蛋白片段 (EF) 的反应是否可以区分患有和不患有肺气肿的人，并评估自身反应性 T 细胞在预测随访期间肺部生理参数变化的相关性。志愿者接受了基线完整表型评估，包括肺功能测试、定量胸部 CT、每年 6 分钟步行距离 (6MWD) 测试以及每年测量 CD4 T 细胞细胞因子对 EF 的反应。预测干扰素 γ (IFN-γ) 和白细胞介素 6 (IL-6) 对 EF 反应的肺气肿的受试者工作特征曲线下面积分别为 0.81（95% CI 0.74-0.88）和 0.79（95% CI 0.72-0.86）。我们开发了一种双细胞因子酶联免疫细胞斑点测定法 γ-6 Spot，利用 CD4 T 细胞 IFN-γ 和 IL-6 反应，发现它能够以 90% 的灵敏度区分肺气肿。调整潜在的混杂因素后，自身反应性 T 细胞的存在预示着 6MWD 在 2 年内的下降（6MWD 下降，IFN-γ 每倍变化 -19 m；P = = 0.026；IL-6 每倍变化 -26 m；P = > 0.003）。为了支持人类关联研究，我们在患有肺气肿的吸烟者的外周血中克隆了具有特征性 T 辅助细胞 (Th)1 和 Th17 对 EF 反应的 CD4 T 细胞，证实了该人群中肺弹性蛋白的抗原性。这些发现共同表明，EF 特异性自身反应性 CD4 T 细胞测定 γ-6 Spot 可以提供一种非侵入性诊断工具，有可能应用于大规模筛查，以区分曾经吸烟者的肺气肿，并预测高危人群的早期相关生理结果。
Cross-sectional studies have suggested a role for activation of adaptive immunity in smokers with emphysema, but the clinical application of these findings has not been explored. Here we examined the utility of detecting autoreactive T cells as a screening tool for emphysema in an at-risk population of smokers. We followed 156 former and current (ever)-smokers for 2 years to assess whether peripheral blood CD4 T cell cytokine responses to lung elastin fragments (EFs) could discriminate between those with and without emphysema, and to evaluate the relevance of autoreactive T cells to predict changes during follow-up in lung physiological parameters. Volunteers underwent baseline complete phenotypic assessment with pulmonary function tests, quantitative chest CT, yearly 6-min walk distance (6MWD) testing, and annual measurement of CD4 T cell cytokine responses to EFs. The areas under the receiver operating characteristic curve to predict emphysema for interferon gamma (IFN-γ), and interleukin 6 (IL-6) responses to EFs were 0.81 (95% CI of 0.74–0.88) and 0.79 (95% CI of 0.72–0.86) respectively. We developed a dual cytokine enzyme-linked immunocell spot assay, the γ-6 Spot, using CD4 T cell IFN-γ and IL-6 responses and found that it discriminated emphysema with 90% sensitivity. After adjusting for potential confounders, the presence of autoreactive T cells was predictive of a decrease in 6MWD over 2 years (decline in 6MWD, −19 m per fold change in IFN-γ; P = 0.026, and −26 m per fold change in IL-6; P = 0.003). In support of the human association studies, we cloned CD4 T cells with characteristic T helper (Th)1 and Th17 responses to EFs in the peripheral blood of ever-smokers with emphysema, confirming antigenicity of lung elastin in this population. These findings collectively suggest that the EF-specific autoreactive CD4 T cell assay, γ-6 Spot, could provide a non-invasive diagnostic tool with potential application to large-scale screening to discriminate emphysema in ever-smokers, and predict early relevant physiological outcomes in those at risk.