Regulatory T cells/T-helper cell 17 functional imbalance in uraemic patients on maintenance haemodialysis: a pivotal link between microinflammation and adverse cardiovascular events.

AIM: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSION: 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.