Baylor College of Medicine Houston, TX, USA.
Front Immunol. 2012 Aug 27;3:267. doi: 10.3389/fimmu.2012.00267. eCollection 2012.
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.
横断面研究表明，适应性免疫的激活在肺气肿吸烟者中起作用，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 细胞作为一种筛选工具在有风险的吸烟人群中用于肺气肿的效用。我们对 156 名既往和当前（曾经）吸烟者进行了为期 2 年的随访，以评估外周血 CD4 T 细胞对肺弹力蛋白片段（EFs）的细胞因子反应是否可以区分肺气肿患者和非肺气肿患者，并评估自身反应性 T 细胞对预测随访期间肺生理参数变化的相关性。志愿者接受了肺功能测试、定量胸部 CT、每年 6 分钟步行距离（6MWD）测试和每年测量 CD4 T 细胞对 EFs 的细胞因子反应的完整表型评估。预测干扰素 γ（IFN-γ）和白细胞介素 6（IL-6）对 EFs 反应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）。我们使用 CD4 T 细胞 IFN-γ和 IL-6 反应开发了一种双细胞因子酶联免疫斑点测定法，即γ-6 斑点，并发现它具有 90%的敏感性来区分肺气肿。在校正潜在混杂因素后，自身反应性 T 细胞的存在可预测 2 年内 6MWD 的下降（6MWD 下降，IFN-γ每增加 1 倍变化 19 米；P=0.026，IL-6 每增加 1 倍变化 26 米；P=0.003）。支持人类关联研究，我们在肺气肿的既往吸烟者的外周血中克隆了对 EFs 具有特征性 Th1 和 Th17 反应的 CD4 T 细胞，证实了该人群中肺弹力蛋白的抗原性。这些发现共同表明，EF 特异性自身反应性 CD4 T 细胞测定法，γ-6 斑点，可以提供一种非侵入性诊断工具，具有潜在的应用价值，可用于大规模筛选以区分既往吸烟者的肺气肿，并预测处于危险中的人群中早期相关的生理结果。
