Immunology Program, Benaroya Research Institute, Seattle, WA 98109.
Department of Immunology, University of Washington, Seattle, WA 98109; and.
J Immunol. 2019 May 1;202(9):2529-2534. doi: 10.4049/jimmunol.1801267. Epub 2019 Apr 1.
Systemic lupus erythematosus severity correlates with elevated serum levels of type I IFNs, cytokines produced in large quantities by plasmacytoid dendritic cells (pDC) in response to engagement of TLR7 and TLR9 with endocytosed nucleic acids. B cell adaptor for PI3K (BCAP) promoted many aspects of TLR7-driven lupus-like disease, including and expression in blood and an immature pDC phenotype associated with higher IFN production. BCAP mice produced significantly less serum IFN-α than wild-type mice after injection of TLR9 agonist, and BCAP promoted TLR7 and TLR9-induced IFN-α production specifically in pDC. TLR-induced IFN-α production in pDC requires DOCK2-mediated activation of Rac1 leading to activation of IKKα, a mechanism we show was dependent on BCAP. BCAP pDC had decreased actin polymerization and Rac1 activation and reduced IKKα phosphorylation upon TLR9 stimulation. We show a novel role for BCAP in promoting TLR-induced IFN-α production in pDC and in systemic lupus erythematosus pathogenesis.
系统性红斑狼疮的严重程度与 I 型干扰素（IFN）血清水平升高相关，这种细胞因子是浆细胞样树突状细胞（pDC）在 TLR7 和 TLR9 与内吞核酸结合后大量产生的。PI3K 的 B 细胞衔接蛋白（BCAP）促进了许多 TLR7 驱动的狼疮样疾病的发生，包括血液中 和 的表达，以及与更高 IFN 产生相关的不成熟 pDC 表型。与野生型小鼠相比，BCAP 小鼠在注射 TLR9 激动剂后产生的血清 IFN-α 明显减少，BCAP 特异性促进 pDC 中 TLR7 和 TLR9 诱导的 IFN-α 产生。pDC 中 TLR 诱导的 IFN-α 产生需要 DOCK2 介导的 Rac1 激活，从而导致 IKKα 的激活，我们的研究表明该机制依赖于 BCAP。BCAP pDC 在 TLR9 刺激下，其肌动蛋白聚合和 Rac1 激活减少，IKKα 磷酸化减少。我们证明了 BCAP 在促进 pDC 中 TLR 诱导的 IFN-α 产生和系统性红斑狼疮发病机制中的新作用。
