Background:Behcet’s disease (BD) is a chronic multisystemic disease. Several studies have shown that immune mechanisms play an important role in the development of the disease and limited options of therapeutic medicines for BD. Low dose IL-2 has been reported to selectively promote the expansion of Treg.Objectives:To evaluate the significance of Treg cells and cytokines in the pathogenesis and the changes of peripheral lymphocyte subsets and clinical indexes in patients with BD after low dose IL-2 therapy.Methods:Absolute number of CD4+CD25+FOXP3+Treg, CD4+IL17+T (Th17) and other subsets in peripheral blood (PB) from 177 patients with BD and 160 healthy donors were characterized by flow cytometry combined with an internal microsphere counting standard. And cytokines were analyzed by cytometric beads array. Thirty-nine patients were treated with daily subcutaneous injections of 0.5 million IU of human IL-2 for five consecutive days, and then its effects were analyzed.Results:As compared to healthy controls, the number of Treg cells were significantly decreased in BD patients (median:22.32 cells/ul VS median:33.12 cells/ul,P<0.001), while there was no difference about Th1, Th2 and Th17 cells. Accordingly, the median ratios of Th17/Tregs cells in patients were greatly higher than those of healthy volunteers. Besides, the circulating NK cells in the patients appeared to be lower than the proportion in the healthy donors. While no difference was observed for that of T, B, CD4+T, CD8+T cells between groups. Further, the correlation analysis showed that circulating Treg levels were negatively correlated with ESR, CRP and BDCAF respectively, suggesting an important role of Tregs in sustained high disease activity. While no obvious correlation was seen in Th1, Th2, Th17 and NK cells. Then the results showed there was a statistically significant decrease in the secretion of IL-10 in the BD patients (P= 0.004), not for IFN-γ, IL-4, IL-17 and IL-6.To evaluate the effects of IL-2 on lymphocytes in vivo, we examined 39 inpatients who received daily low-dose IL-2 at the dosage of 50 WIU for 5 days. It showed that, besides NK cells, total T cells, B cells, CD4+ T cells, CD8+ T cells, Th1 cells, Th2 cells, and Th17 cells were all increased after IL-2 treatment. But only Treg cells were amplified more dramatically, with the four-fold increase. Accordingly, the ratio of Th17/Treg was decreased significantly in patients with IL-2 treatment, tended to balance and had no difference with healthy individuals. At the same time, we found that the symptom were mitigated obviously and disease activity including ESR and CRP were both decreased distinctly without observed side effects.Conclusion:Absolute decrease of PB Tregs in patients with BD was associated with disease activity,which might be the major reason for imbalance of Th17/Tregs. It is speculated that BD is an autoimmune disease triggered by the defect of immunotolerance. More importantly, low-dose IL-2 proposes a selective biological treatment strategy by restoring immune tolerance and promoting rapidly remission.References:[1]Lopalco G, Lucherini OM, Lopalco A, et al. Cytokine signatures in mucocutaneous and ocular Behçet’s disease. Front Immunol. 2017;8:200.[2]Lucherini OM, Lopalco G, Cantarini L, et al. Critical regulation of Th17 cell differentiation by serum amyloid-A signalling in Behcet’s disease. Immunol Lett. 2018;201:38-44.[3]Noack M, Miossec P. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases[J]. Autoimmun Rev,2014,13(6):668-677.Figure 1.The ratios of Th17/Treg among Healthy controls(HC), Before treatment and After treatment.Figure 2.The changes of disease activity in BD patients after low-dose IL-2 treatment.Acknowledgments: :We would like to express our sincere gratitude to all our coworkers and collaborators, to Jing Luo, Xiangcong Zhao, Chen Zhang, Qi Wu, Congcong Liang, and Rui Fu for their technical support.Disclosure of Interests:None declared
Decreased expression of Sirt1 contributes to ocular Behcet’s disease progression via Th17 and Th22 response