CD8(+) T cells and IFN-gamma induce autoimmune myelofibrosis in mice
CD8(+) T cells and IFN-gamma induce autoimmune myelofibrosis in mice
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CD8(+) T 细胞和 IFN-γ 诱导小鼠自身免疫性骨髓纤维化。
DOI：
10.1016/j.jaut.2017.12.011
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发表时间：
2018
影响因子：
12.8
通讯作者：
Lian Zhe-Xiong
中科院分区：
文献类型：
--
作者：
Yao Yuan;Li Liang;Yang Shu-Han;Gao Cai-Yue;Liao Liang-Huan;Xie Yu-Qing;Yin Xue-Ying;Yang Yan-Qing;Fei Yun-Yun;Lian Zhe-Xiong
骨髓纤维化通常作为骨髓增生异常综合征的一部分或与肿瘤一起发生。它通常不被认为是一种自身免疫性疾病。我们报道了p40−/−IL-2 R α−/−（白细胞介素-12p40和白细胞介素-2受体α双敲除）小鼠，一种人类原发性胆管炎的小鼠模型，表现出与自身免疫性骨髓纤维化一致的特征，包括与骨髓纤维化相关的贫血，以及髓外造血（EMH），包括脾脏、肝脏和外周血中的LSK（Lineage-c-Kit+Sca-1+）细胞。骨髓中LSK细胞也增加，但表现出造血功能受损。重要的是，渗透到p40−/−IL-2 R α−/−小鼠骨髓中的效应记忆T细胞表现出更高的产生IFN-γ的能力。已知CD 8 +T细胞在门静脉炎症中起主导作用，也是骨髓失调和EMH的关键。IFN-γ是诱导骨髓纤维化、骨髓衰竭和EMH的关键细胞因子。最后，抗CD 8 α抗体治疗完全保护p40−/−IL-2 R α−/−小鼠免受自身免疫性骨髓纤维化。总之，我们的结果表明CD 8 +T细胞和IFN-γ与自身免疫性骨髓纤维化有关，这一发现可能允许将CD 8 +T细胞和IFN-γ作为治疗靶点。
Myelofibrosis usually occurs either as a part of a myelodysplastic syndrome or in conjunction with neoplasia. It is not commonly thought of an autoimmune disease. We reported that p40−/−IL-2Rα−/−(interleukin-12p40 and interleukin-2 receptor alpha double knockout) mice, a mouse model of human primary biliary cholangitis, exhibited features consistent with autoimmune myelofibrosis, including anemia associated with bone marrow fibrosis, and extramedullary hematopoiesis (EMH) including LSK (Lineage-c-Kit+Sca-1+) cells in spleen, liver and peripheral blood. There were also increased LSK cells in bone marrow but they demonstrated impaired hematopoiesis. Importantly effector memory T cells that infiltrated the bone marrow of p40−/−IL-2Rα−/−mice manifested a higher ability to produce IFN-γ. CD8+T cells, already known to play a dominate role in portal inflammation, were also key for bone marrow dysregulation and EMH. IFN-γ was the key cytokine that induced bone marrow fibrosis, bone marrow failure and EMH. Finally anti-CD8α antibody therapy fully protected p40−/−IL-2Rα−/−mice from autoimmune myelofibrosis. In conclusion, our results demonstrate that CD8+T cells and IFN-γ are associated with autoimmune myelofibrosis, a finding that may allow targeting of CD8+T cells and IFN-γ as a therapeutic targets.