Department of Pulmonary Medicine, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands.
Department of Cardiology, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands.
Int J Mol Sci. 2022 Jun 10;23(12):6508. doi: 10.3390/ijms23126508.
Pulmonary arterial hypertension (PAH) is rare disease that is categorized as idiopathic (IPAH) when no underlying cause can be identified. Lungs of most patients with IPAH contain increased numbers of T cells and dendritic cells (DCs), suggesting involvement of the immune system in its pathophysiology. However, our knowledge on circulating immune cells in IPAH is rather limited. We used flow cytometry to characterize peripheral blood DCs and T cells in treatment-naive IPAH patients, compared with connective-tissue disease-PAH (CTD-PAH) patients and healthy controls (HCs). At diagnosis, T-helper (Th) cells of IPAH patients were less capable of producing TNFα, IFNγ, IL-4 and IL-17 compared to HCs. IPAH patients showed a decreased frequency of Th2 cells and significantly enhanced expression of the CTLA4 checkpoint molecule in naive CD4 T cells and both naive and memory CD8 T cells. Frequencies and surface marker expression of circulating DCs and monocytes were essentially comparable between IPAH patients and HCs. Principal component analysis (PCA) separated IPAH patients-but not CTD-PAH patients-from HCs, based on T-cell cytokine profiles. At 1-year follow-up, the frequencies of IL-17 production by memory CD4 T cells were increased in IPAH patients and accompanied by increased proportions of Th17 and Tc17 cells, as well as decreased CTLA4 expression. Treatment-naive IPAH patients displayed a unique T-cell phenotype that was different from CTD-PAH patients and was characterized by reduced cytokine-producing capacity. These findings point to involvement of adaptive immune responses in IPAH, which may have an implication for the development of therapeutic interventions.
特发性肺动脉高压（PAH）是一种罕见疾病，当无法确定潜在病因时，将其归类为特发性（IPAH）。大多数 IPAH 患者的肺部含有数量增加的 T 细胞和树突状细胞（DC），这表明免疫系统参与了其病理生理学过程。然而，我们对 IPAH 中循环免疫细胞的了解相当有限。我们使用流式细胞术来描述未经治疗的 IPAH 患者、结缔组织病相关 PAH（CTD-PAH）患者和健康对照（HC）的外周血 DC 和 T 细胞。在诊断时，与 HCs 相比，IPAH 患者的辅助性 T（Th）细胞产生 TNFα、IFNγ、IL-4 和 IL-17 的能力较低。IPAH 患者的 Th2 细胞频率降低，并且在幼稚 CD4 T 细胞以及幼稚和记忆 CD8 T 细胞中，CTLA4 检查点分子的表达显著增强。IPA 患者和 HCs 之间循环 DC 和单核细胞的频率和表面标记表达基本相当。基于 T 细胞细胞因子谱，主成分分析（PCA）将 IPAH 患者-而非 CTD-PAH 患者-与 HCs 区分开来。在 1 年的随访中，记忆 CD4 T 细胞产生 IL-17 的频率在 IPAH 患者中增加，同时 Th17 和 Tc17 细胞的比例增加，而 CTLA4 表达降低。未经治疗的 IPAH 患者表现出一种独特的 T 细胞表型，与 CTD-PAH 患者不同，其特征是细胞因子产生能力降低。这些发现表明适应性免疫反应参与了 IPAH，这可能对治疗干预的发展具有重要意义。
