白细胞介素-21在再生障碍性贫血病理生理学中的作用。

Involvement of interleukin-21 in the pathophysiology of aplastic anemia.

作者信息

Zhang Jizhou, Wu Qingqing, Shi Jun, Ge Meili, Li Xingxin, Shao Yingqi, Yao Jianfeng, Zheng Yizhou

机构信息

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.

出版信息

Eur J Haematol. 2015 Jul;95(1):44-51. doi: 10.1111/ejh.12471. Epub 2015 Mar 12.

DOI:10.1111/ejh.12471

PMID:25784172

Abstract

OBJECTIVE

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.

METHODS

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.

RESULTS

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.

CONCLUSION

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.

摘要

目的

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。

方法

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。

结果

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。