Department of Nephrology, First Affiliated Hospital of ChongQing University of Medical Sciences, ChongQing, China.
Nephrology (Carlton). 2010 Feb;15(1):33-41. doi: 10.1111/j.1440-1797.2009.01172.x.
Adverse cardiovascular events resulting from accelerated atherosclerosis are the leading cause of mortality in uraemic patients on maintenance haemodialysis (MHD). Chronic inflammation due to antigen-specific responses is an important factor in the acceleration of atherosclerosis. The balance between CD4(+) CD25(+) forkhead/winged helix transcription factor (Foxp3)(+) regulatory T cells (Treg) and T helper (Th)17 cells has been reported to play an important role in the development of inflammatory and autoimmune diseases. The aim of the present study was to assess the Treg/Th17 pattern in uraemic patients on MHD and to explore the significance of Treg/Th17 imbalance in the development and outcome of acute cardiovascular events.
A total of 42 uraemic patients on MHD were evaluated. Of the 42, 22 patients with a history of acute cardiovascular events served as the MHD1 group and 20 patients without acute cardiovascular events served as the MHD2 group. Thirty patients with advanced chronic kidney disease (CKD) without acute cardiovascular events just before haemodialysis therapy served as the CKD control group and 30 healthy volunteers as the normal control group. The Treg and Th17 frequencies were measured by flow cytometry. The retinoic acid receptor-related orphan receptor gammat (RORgammat) and Foxp3 expressions were measured by real-time reverse transcription polymerase chain reaction. Serum cytokines and C-reactive protein were detected by enzyme-linked immunosorbent assay and immunoturbidimetry.
Patients with uraemia exhibited an obvious imbalance of Treg/Th17 function when compared to the normal control group, displaying increased peripheral Th17 frequency, Th17-related cytokines (interleukin [IL]-17, IL-6 and IL-23) and RORgammat mRNA levels. These patients also displayed decreased Treg frequency, Treg-related cytokines (IL-10, transforming growth factor-beta1) and Foxp3 mRNA levels. This imbalance was more pronounced in the MHD2 group, while there was no significant difference between the MHD1 and CKD control group (P < 0.01 between normal control and uraemic patients; P > 0.05 between CKD control and MHD1; and P < 0.05 between MHD1 and MHD2). It was also observed that the imbalance of Treg/Th17 was not only consistent with the cardiovascular disease but also correlated with a microinflammatory state.
The Treg/Th17 balance was disturbed by uraemia, especially in patients with adverse cardiovascular events. This Th17/Treg imbalance might act synergistically with microinflammation on immune-mediated atherosclerosis and contribute to the high incidence of adverse cardiovascular events.
由加速动脉粥样硬化引起的不良心血管事件是维持性血液透析（MHD）尿毒症患者死亡的主要原因。由于抗原特异性反应引起的慢性炎症是加速动脉粥样硬化的一个重要因素。CD4+CD25+叉头/翅膀状螺旋转录因子（Foxp3）+调节性 T 细胞（Treg）和辅助性 T 细胞 17（Th17）之间的平衡被报道在炎症和自身免疫性疾病的发展中发挥重要作用。本研究旨在评估 MHD 尿毒症患者的 Treg/Th17 模式，并探讨 Treg/Th17 失衡在急性心血管事件发展和结局中的意义。
评估了 42 名 MHD 尿毒症患者。其中，22 例有急性心血管事件史的患者作为 MHD1 组，20 例无急性心血管事件史的患者作为 MHD2 组。30 例接受血液透析治疗前有晚期慢性肾脏病（CKD）但无急性心血管事件的患者作为 CKD 对照组，30 名健康志愿者作为正常对照组。通过流式细胞术测定 Treg 和 Th17 频率。通过实时逆转录聚合酶链反应测定视黄酸受体相关孤儿受体γt（RORγt）和 Foxp3 的表达。通过酶联免疫吸附试验和免疫比浊法检测血清细胞因子和 C 反应蛋白。
与正常对照组相比，尿毒症患者 Treg/Th17 功能明显失衡，外周 Th17 频率、Th17 相关细胞因子（白细胞介素[IL]-17、IL-6 和 IL-23）和 RORγt mRNA 水平升高。这些患者的 Treg 频率、Treg 相关细胞因子（IL-10、转化生长因子-β1）和 Foxp3 mRNA 水平也降低。MHD2 组这种失衡更为明显，而 MHD1 组和 CKD 对照组之间无显著差异（正常对照组与尿毒症患者之间 P < 0.01；CKD 对照组与 MHD1 组之间 P > 0.05；MHD1 组与 MHD2 组之间 P < 0.05）。还观察到 Treg/Th17 的失衡不仅与心血管疾病一致，而且与微炎症状态相关。
尿毒症导致 Treg/Th17 平衡失调，尤其是在发生不良心血管事件的患者中。这种 Th17/Treg 失衡可能与微炎症协同作用于免疫介导的动脉粥样硬化，导致不良心血管事件的高发生率。
