SHIP-1 Deficiency in AID+ B Cells Leads to the Impaired Function of B10 Cells with Spontaneous Autoimmunity
SHIP-1 Deficiency in AID+ B Cells Leads to the Impaired Function of B10 Cells with Spontaneous Autoimmunity
复制标题
DOI：
10.4049/jimmunol.1700138
复制
发表时间：
2017-11-01
影响因子：
4.4
通讯作者：
Liu, Wanli
中科院分区：
文献类型：
--
作者：
Chen, Yingjia;Hu, Fanlei;Liu, Wanli
与传统 B 细胞不同，调节性 B 细胞具有免疫抑制功能，可通过产生 IL-10 来下调炎症。然而，调节IL-10产生的分子机制尚不完全清楚。在本研究中，我们报告了以下发现：Innp5d(fl/fl) Aicda(Cre/+) 小鼠的 IL-10 感受态 B 细胞 (B10) 细胞中激活诱导的胞苷脱氨酶 (AID) 高度上调，而 5' 肌醇磷酸酶 SHIP-1 下调。值得注意的是，AID(+) B 细胞中的 SHIP-1 缺陷会导致细胞计数减少和 B10 细胞产生 IL-10 受损。此外，Innp5d(fl/fl) Aicda(Cre/+)小鼠模型显示出B细胞依赖性自身免疫性狼疮样表型，例如IgG血清抗体升高、自发生发中心形成、抗dsDNA和抗核抗体的产生以及随着年龄的增长IgG免疫复合物在肾脏中的明显沉积。我们观察到，这些狼疮样表型可以通过从对照 Innp5d(fl/fl) 小鼠中过继转移 B10 细胞来逆转，但不能从 Innp5d(fl/fl) Aicda(Cre/+) 小鼠中过继转移。这一发现强调了 Innp5d(fl/fl) Aicda(Cre/+) 小鼠中有缺陷的 B10 细胞的重要性。虽然 p-Akt 显着上调，但 Innp5d(fl/fl) Aicda(Cre/+) 小鼠的 B10 细胞中 MAPK 和 AP-1 激活受损，导致 IL-10 产生减少。这些结果表明SHIP-1是维持B10细胞和产生IL-10所必需的，并且共同表明SHIP-1可能成为治疗自身免疫性疾病的新的潜在治疗靶点。
Unlike conventional B cells, regulatory B cells exhibit immunosuppressive functions to downregulate inflammation via IL-10 production. However, the molecular mechanism regulating the production of IL-10 is not fully understood. In this study, we report the finding that activation-induced cytidine deaminase (AID) is highly upregulated in the IL-10-competent B cell (B10) cell from Innp5d(fl/fl) Aicda(Cre/+) mice, whereas the 5 ' inositol phosphatase SHIP-1 is downregulated. Notably, SHIP-1 deficiency in AID(+) B cells leads to a reduction in cell count and impaired IL-10 production by B10 cells. Furthermore, the Innp5d(fl/fl) Aicda(Cre/+) mouse model shows B cell-dependent autoimmune lupus-like phenotypes, such as elevated IgG serum Abs, formation of spontaneous germinal centers, production of anti-dsDNA and anti-nuclear Abs, and the obvious deposition of IgG immune complexes in the kidney with age. We observe that these lupus-like phenotypes can be reversed by the adoptive transfer of B10 cells from control Innp5d(fl/fl) mice, but not from the Innp5d(fl/fl) Aicda(Cre/+) mice. This finding highlights the importance of defective B10 cells in Innp5d(fl/fl) Aicda(Cre/+) mice. Whereas p-Akt is significantly upregulated, MAPK and AP-1 activation is impaired in B10 cells from Innp5d(fl/fl) Aicda(Cre/+) mice, resulting in the reduced production of IL-10. These results show that SHIP-1 is required for the maintenance of B10 cells and production of IL-10, and collectively suggests that SHIP-1 could be a new potential therapeutic target for the treatment of autoimmune diseases.