Biomedical Research Networking Center on Respiratory Diseases (CIBERES), Madrid, Spain.
Respiratory Diseases Group, Respiratory Service, La Paz University Hospital, IdiPAZ, Madrid, Spain.
Respirology. 2019 Jul;24(7):684-692. doi: 10.1111/resp.13470. Epub 2019 Jan 17.
In obstructive sleep apnoea (OSA), intermittent hypoxia (IH) compromises immune surveillance through the upregulation of the programmed cell death-1 (PD-1) receptor and its ligand (PD-L1). Because the risk of OSA-related cancer depends on age, we assessed PD-L1/PD-1 expression in middle-aged and older patients with OSA as well as in a murine model.
PD-L1 expression was studied in 41 patients with severe OSA and 40 healthy volunteers (HV), divided into two groups (≤55 and >55 years of age). We used flow cytometry, quantitative PCR (qPCR) and ELISA to determine PD-L1 expression on monocytes and plasma PD-L1 protein levels. Moreover, we analysed PD-L1 expression on an in vivo IH model with old and young mice.
In subjects up to 55 years of age, severe OSA increased PD-L1 surface protein and mRNA level expression on monocytes and soluble-PD-L1 protein concentration in plasma compared to HV. PD-L1 and hypoxia-induced factor (HIF)-1α expression correlated with age in HV, whereas in patients with OSA there was a negative relationship. In the mice exposed to IH, PD-L1 expression on F4/80+ splenocytes was also only increased in young animals. HIF-1α expression was significantly higher in patients with OSA than in HV in subjects up to 55 years of age, while PD-L1 expression in monocytes was related to HIF-1α expression in young patients with OSA.
PD-L1 upregulation in patients with OSA as a consequence of HIF-1α activation occurs mainly in young patients. In older patients with OSA, upregulation was not detected, possibly due to impaired oxygen sensitivity.
在阻塞性睡眠呼吸暂停（OSA）中，间歇性低氧（IH）通过上调程序性细胞死亡-1（PD-1）受体及其配体（PD-L1）来损害免疫监视。由于 OSA 相关癌症的风险取决于年龄，我们评估了 OSA 中中年和老年患者以及在小鼠模型中 PD-L1/PD-1 的表达。
研究了 41 例严重 OSA 患者和 40 例健康志愿者（HV）的 PD-L1 表达，分为两组（≤55 岁和>55 岁）。我们使用流式细胞术、定量 PCR（qPCR）和 ELISA 来确定单核细胞上的 PD-L1 表达和血浆中 PD-L1 蛋白水平。此外，我们分析了老年和年轻小鼠体内 IH 模型中的 PD-L1 表达。
在 55 岁以下的受试者中，与 HV 相比，严重 OSA 增加了单核细胞上 PD-L1 表面蛋白和 mRNA 水平表达以及血浆中可溶性 PD-L1 蛋白浓度。在 HV 中，PD-L1 和低氧诱导因子（HIF）-1α的表达与年龄相关，而在 OSA 患者中则呈负相关。在暴露于 IH 的小鼠中，F4/80+脾细胞上的 PD-L1 表达也仅在年轻动物中增加。在 55 岁以下的患者中，与 HV 相比，OSA 患者中 HIF-1α的表达显著更高，而年轻 OSA 患者中单核细胞上的 PD-L1 表达与 HIF-1α表达相关。
由于 HIF-1α 的激活，OSA 患者中 PD-L1 的上调主要发生在年轻患者中。在年龄较大的 OSA 患者中，未检测到上调，可能是由于氧敏感性受损所致。
