Dendritic cell-associated B7-H3 suppresses the production of autoantibodies and renal inflammation in a mouse model of systemic lupus erythematosus
Dendritic cell-associated B7-H3 suppresses the production of autoantibodies and renal inflammation in a mouse model of systemic lupus erythematosus
复制标题
DOI：
10.1038/s41419-019-1623-0
复制
发表时间：
2019-05
影响因子：
9
通讯作者：
Xu Zheng;Z. Xiao;Li Hu;X. Fang;Liqun Luo;Lieping Chen
中科院分区：
文献类型：
--
作者：
Xu Zheng;Z. Xiao;Li Hu;X. Fang;Liqun Luo;Lieping Chen
B7-H3免疫调节分子参与了自身免疫性疾病的发生和发病，其作用机制尚不清楚。我们探讨了B7-H3在小鼠系统性红斑狼疮（SLE）模型中诱导自身抗体和器官定向炎症中的作用，在该模型中，用从活化T细胞中提取的DNA免疫诱导抗DNA自身抗体的产生和随后的肾小球肾炎，这是人类SLE的两个标志。与野生型小鼠相比，缺乏B7-H3或用B7-H3特异性抗体处理的小鼠产生显著更高水平的抗DNA自身抗体和更严重的肾小球肾炎，表明B7-H3在该模型中的抑制功能。有趣的是，用DNA脉冲的树突状细胞免疫小鼠诱导严重的SLE症状，而树突状细胞上的B7-H3在这个过程中是必需的。重要的是，用重组B7-H3 Ig融合蛋白治疗小鼠有效地改善了小鼠SLE的进展，伴随着抗DNA自身抗体水平的降低，减轻了肾小球肾炎，减少了肾脏中自身抗体沉积和补体沉积。我们的研究结果暗示B7-H3对树突状细胞在诱导SLE中的潜在作用，并作为治疗自身免疫性疾病的潜在靶点。
B7-H3 immune modulatory molecule has been implicated in the generation and pathogenesis of autoimmune diseases, the mechanism of action is less known. We explored the role of B7-H3 in the induction of autoantibodies and organ-directed inflammation in a murine systemic lupus erythematosus (SLE) model in which the immunization with DNA extracted from activated T cells induced the production of anti-DNA autoantibodies and subsequent glomerulonephritis, two hallmarks of human SLE. Mice deficient of B7-H3 or treated with a B7-H3 specific antibody produced significantly higher levels of anti-DNA autoantibodies and more severe glomerulonephritis than wild-type mice, indicating an inhibitory function of B7-H3 in this model. Interestingly, immunization of mice with DNA-pulsed dendritic cells induced severe SLE symptoms while B7-H3 on dendritic cells is required in this process. Importantly, treatment of mice with recombinant B7-H3Ig fusion protein effectively ameliorated progression of murine SLE, accompanied with decreased level of anti-DNA autoantibodies and alleviated glomerulonephritis, decreased autoantibody deposition and complement deposition in kidney. Our findings implicate a potential role of B7-H3 on dendritic cells in the induction of SLE and as a potential target for the treatment of autoimmune diseases.