CD28 down-regulation on circulating CD4 T-cells is associated with poor prognoses of patients with idiopathic pulmonary fibrosis.
CD28 down-regulation on circulating CD4 T-cells is associated with poor prognoses of patients with idiopathic pulmonary fibrosis.
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DOI：
10.1371/journal.pone.0008959
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发表时间：
2010-01-29
期刊：
影响因子：
3.7
通讯作者：
Duncan SR
中科院分区：
文献类型：
--
作者：
Gilani SR;Vuga LJ;Lindell KO;Gibson KF;Xue J;Kaminski N;Valentine VG;Lindsay EK;George MP;Steele C;Duncan SR
尽管特发性肺纤维化（IPF）的病因仍然令人困惑，但在许多患病患者中适应性免疫激活是明显的。抗原诱导的增殖的重复循环导致 T 细胞失去 CD28 的表面表达，我们假设这个过程也可能发生在 IPF 中。通过流式细胞术和细胞因子多重检测分析了 89 名 IPF 患者的外周血 CD4 T 细胞，并将其与临床事件相关联。与自体 CD4+CD28+ 细胞相比，许多 IPF 患者中发现的异常 CD4+CD28null 淋巴细胞的激活标记物表达不一致，更频繁地产生细胞毒性介质穿孔素（2.4±0.8% vs. 60.0±7.4%，p<0.0001）和颗粒酶 B（4.5±2.8%） 与 74.9±6.5%，p<0.0001）相比，产生更多量的许多促炎细胞因子，并且较少表达调节性 T 细胞标记物 FoxP3（12.9±1.1% 与 3.3±0.6% p<0.0001）。通过共聚焦显微镜证实了 IPF 肺中 CD4+CD28null T 细胞的浸润。进行重复研究的受试者中CD28表达的间隔变化与其用力肺活量的连续变化相关（rs = 0.49，p = 0.012）。最重要的是，在 78 名 CD4+CD28+/CD4total ≥ 82% 的 IPF 患者中，一年内无重大不良临床事件（死亡或肺移植）的率为 56±6%，而 CD28 广泛下调（CD4+CD28+/CD4total<82%）的患者为 9±9%（p = 0.0004）。 CD28 下调最广泛的患者中，主要不良事件的比值比为 13.0，95% 置信区间为 1.6-111.1。由于反复抗原驱动的增殖，循环 CD4 T 细胞上 CD28 的显着下调与 IPF 患者的不良预后相关。这些患者的 CD4+CD28null 细胞可能具有增强的致病特征，包括细胞毒性介质和促炎细胞因子的产生增加。这些发现表明，导致 CD28 下调的抗原增殖性 T 细胞反应与 IPF 的进展和表现相关，并表明循环 CD4 T 细胞的检测可以识别临床恶化风险最大的患者。
Although the etiology of idiopathic pulmonary fibrosis (IPF) remains perplexing, adaptive immune activation is evident among many afflicted patients. Repeated cycles of antigen-induced proliferation cause T-cells to lose surface expression of CD28, and we hypothesized this process might also occur in IPF. Peripheral blood CD4 T-cells from 89 IPF patients were analyzed by flow cytometry and cytokine multiplex assays, and correlated with clinical events. In comparison to autologous CD4+CD28+cells, the unusual CD4+CD28null lymphocytes seen in many IPF patients had discordant expressions of activation markers, more frequently produced cytotoxic mediators perforin (2.4±0.8% vs. 60.0±7.4%, p<0.0001) and granzyme B (4.5±2.8% vs.74.9±6.5%, p<0.0001), produced greater amounts of many pro-inflammatory cytokines, and less frequently expressed the regulatory T-cell marker FoxP3 (12.9±1.1% vs. 3.3±0.6% p<0.0001). Infiltration of CD4+CD28null T-cells in IPF lungs was confirmed by confocal microscopy. Interval changes of CD28 expression among subjects who had replicate studies were correlated with conterminous changes of their forced vital capacities (rs = 0.49, p = 0.012). Most importantly, one-year freedom from major adverse clinical events (either death or lung transplantation) was 56±6% among 78 IPF patients with CD4+CD28+/CD4total≥82%, compared to 9±9% among those with more extensive CD28 down-regulation (CD4+CD28+/CD4total<82%) (p = 0.0004). The odds ratio for major adverse events among those with the most extensive CD28 down-regulation was 13.0, with 95% confidence intervals 1.6-111.1. Marked down-regulation of CD28 on circulating CD4 T-cells, a result of repeated antigen-driven proliferations, is associated with poor outcomes in IPF patients. The CD4+CD28null cells of these patients have potentially enhanced pathogenic characteristics, including increased productions of cytotoxic mediators and pro-inflammatory cytokines. These findings show proliferative T-cell responses to antigen(s) resulting in CD28 down-regulation are associated with progression and manifestations of IPF, and suggest assays of circulating CD4 T-cells may identify patients at greatest risk for clinical deterioration.
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