Zhang Jizhou, Wu Qingqing, Shi Jun, Ge Meili, Li Xingxin, Shao Yingqi, Yao Jianfeng, Zheng Yizhou
Severe Aplastic Anemia Studying Program, State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, China.
Eur J Haematol. 2015 Jul;95(1):44-51. doi: 10.1111/ejh.12471. Epub 2015 Mar 12.
Recently enhanced T-helper type 17 (Th17) immune responses and deficient CD4(+) CD25(hi) FoxP3(+) regulatory T cells (Tregs) have been reported in acquired aplastic anemia (AA). Interleukin-21 (IL-21), a CD4(+) T-cell-derived proinflammatory cytokine, modulates the balance between Th17 cells and Tregs. However, its role in AA remains unclear.
IL-21 gene expression was examined by quantitative real-time PCR. Cytokines in plasma and cell culture supernatants were detected by ELISA. Cytokines-producing T cells and Tregs were evaluated by flow cytometry.
IL-21 mRNA levels in circulating CD4(+) T cells and IL-21 levels in blood plasma were markedly increased in patients with newly diagnosed AA. Moreover, elevated IL-21-producing CD4(+) T cells were accompanied by Th17 cells accumulation and Tregs decrease, and correlated with AA activity. In vitro, IL-21 not only inhibited the expression of FoxP3, but also induced the expression of IL-17 in CD4(+) T cells of AA patients. More importantly, we found that T cells within the bone marrow (BM) of AA patients were in a heightened activation state, which may be related to IL-21.
Our data suggested a critical role of IL-21 in breaking immune homeostasis in AA by promoting Th17 cells, activating BM T cells and suppressing Tregs.
最近有报道称，获得性再生障碍性贫血（AA）患者存在辅助性T细胞17（Th17）免疫反应增强及CD4(+) CD25(hi) FoxP3(+)调节性T细胞（Tregs）缺乏的情况。白细胞介素-21（IL-21）是一种由CD4(+) T细胞产生的促炎细胞因子，可调节Th17细胞与Tregs之间的平衡。然而，其在AA中的作用仍不清楚。
通过定量实时PCR检测IL-21基因表达。采用酶联免疫吸附测定法检测血浆和细胞培养上清液中的细胞因子。通过流式细胞术评估产生细胞因子的T细胞和Tregs。
新诊断AA患者循环CD4(+) T细胞中的IL-21 mRNA水平及血浆中的IL-21水平显著升高。此外，产生IL-21的CD4(+) T细胞升高伴随着Th17细胞积聚和Tregs减少，且与AA病情活动相关。在体外，IL-21不仅抑制FoxP3的表达，还诱导AA患者CD4(+) T细胞中IL-17的表达。更重要的是，我们发现AA患者骨髓（BM）中的T细胞处于高度激活状态，这可能与IL-21有关。
我们的数据表明，IL-21通过促进Th17细胞、激活BM T细胞和抑制Tregs，在破坏AA免疫稳态中起关键作用。
