Impaired TLR9 responses in B cells from patients with systemic lupus erythematosus
Impaired TLR9 responses in B cells from patients with systemic lupus erythematosus
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DOI：
10.1172/jci.insight.96795
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发表时间：
2018-03-08
期刊：
影响因子：
8
通讯作者：
Korganow, Anne-Sophie
中科院分区：
文献类型：
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作者：
Gies, Vincent;Schickel, Jean-Nicolas;Korganow, Anne-Sophie
B细胞在系统性红斑狼疮(SLE)的病理生理学中起着核心作用，但导致B细胞耐受性打破的失调途径尚不清楚。由于Toll样受体9(TLR9)有助于清除外周自身反应性B细胞，我们通过分析健康供者和患者分离的B细胞和浆细胞样树突状细胞(PDC)对TLR9激动剂CpG刺激后的反应来评估TLR9在SLE中的功能。我们发现，没有接受羟氯喹治疗的患者的SLE B细胞在体外表现出缺陷的TLR9反应，这表现为B细胞激活分子的上调受损，以及包括抗炎IL-10在内的各种细胞因子的产生减少。与CD19控制B细胞的TLR9反应一致，SLE B细胞上CD19/CD21复合体的表达降低早在过渡B细胞期就已检测到。相反，TLR7功能在SLE B细胞中保持不变，而SLE患者的PDCs对TLR9刺激反应正常，从而表明SLE患者TLR9功能受损仅限于B细胞。结论SLE患者B细胞CD19表达异常和TLR9耐受功能异常可能是导致B细胞耐受破坏的原因之一。
B cells play a central role in systemic lupus erythematosus (SLE) pathophysiology but dysregulated pathways leading to a break in B cell tolerance remain unclear. Since Toll-like receptor 9 (TLR9) favors the elimination of autoreactive B cells in the periphery, we assessed TLR9 function in SLE by analyzing the responses of B cells and plasmacytoid dendritic cells (pDCs) isolated from healthy donors and patients after stimulation with CpG, a TLR9 agonist. We found that SLE B cells from patients without hydroxychloroquine treatment displayed defective in vitro TLR9 responses, as illustrated by the impaired upregulation of B cell activation molecules and the diminished production of various cytokines including antiinflammatory IL-10. In agreement with CD19 controlling TLR9 responses in B cells, decreased expression of the CD19/CD21 complex on SLE B cells was detected as early as the transitional B cell stage. In contrast, TLR7 function was preserved in SLE B cells, whereas pDCs from SLE patients properly responded to TLR9 stimulation, thereby revealing that impaired TLR9 function in SLE was restricted to B cells. We conclude that abnormal CD19 expression and TLR9 tolerogenic function in SLE B cells may contribute to the break of B cell tolerance in these patients.