Background The imbalance of T help 17 cells (Th17)/regulatory T cells (Tregs) is considered to be a pivotal cause of autoimmune diseases1, including systemic lupus erythematosus (SLE). However, previous reports1,2 describing the respective changes of Tregs and Th17 cells in SLE patients were controversial because a few samples or diverse markers were used to identify Tregs with little consensus.
Objectives To clarify the status of Tregs and Th17 in SLE, we investigated the frequencies of Tregs and Th17 cells on a large scale and whether those defects can be corrected by the supplementation of low-dose human recombinant interleukin-2 (IL-2).
Methods Two hundred and thirty-five SLE patients (219 women and 16 men), with mean age of 37.80±14.00 years, were enrolled. The disease activity using European League Against Rheumatism (EULAR) criteria was judged for SLE patients with erythrocyte sedimentation rate (ESR) and SLEDAI scores. The frequencies of CD3+CD4+FOXP3+Treg cells and Th17 cells in peripheral blood from these patients were measured by flow cytometry. And low-dose IL-2 was used among 127 patients at a dosage of fifty WIU every day for five days. Immunological and clinical assessments were performed again at the end of IL-2 treatment. Ninety healthy volunteers, matched for patients' age and gender, were also included for the estimation of CD4+ T cell subsets.
Results As compared to healthy controls (median of Treg cells: 33.09 cells/ul), the frequencies of circulating CD4+CD25+FOXP3+Treg cells were significantly decreased in SLE patients (median: 15.49 cells/ul, P<0.001). The median ratios of Th17/Tregs cells in patients were greatly higher than those of healthy volunteers [0.42 (0.19, 0.88) vs. 0.21 (0.15, 0.34), P<0.001]. There was not significantly different in circulating Th17 cell between two groups. Moreover, CD4+CD25+FOXP3+Treg cells were negatively correlated with ESR and SLEDAI score (r=-0.198, P=0.01; r=-0.25, P=0.002).While no obvious correlation was seen between Th17 cells and SLEDAI score. After IL-2 therapy in SLE, there was a four-fold increase in circulating CD4+CD25+FOXP3+Treg cells [43.73 (24.08,74.22) vs. 11.95 (7.51,20.34),P<0.001], whereas Th17 cells were increased slightly. The ratio of Th17/Tregs was decreased significantly in patients with IL-2 treatment [0.19 (0.09,0.41) vs. 0.52 (0.23,0.95),P<0.001], tended to balance and had no difference with healthy individual (P=0.275).
Conclusions With the increase of disease activity,CD4+CD25+FOXP3+Treg cells were gradually reducing, while Th17 cells did not show a significant change, indicating that the reduction of Tregs but not the elevation of Th17 cells may be the major reason for imbalance of Th17/Tregs. It is speculated that SLE is an autoimmune disease triggered by the defect of immunotolerance. More importantly, low-dose IL-2 selectively modulated the abundance of Tregs, which effectively induced autoimmune tolerance and further improved clinical symptoms.
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Steinmetz OM, Turner JE, Paust HJ et al. CXCR3 mediates renal Th1 and Th17 immune response in murine lupus nephritis[J]. J Immunol 2009;183:4693–704.
Disclosure of Interest None declared