PDF(Pubmed)
Abstract：
The pathogenesis of systemic lupus erythematosus (SLE) is linked to the differential roles of toll-like receptors (TLRs), particularly TLR7, TLR8, and TLR9. TLR7 overexpression or gene duplication, as seen with the Y-linked autoimmune accelerator (Yaa) locus or TLR7 agonist imiquimod, correlates with increased SLE severity, and specific TLR7 polymorphisms and gain-of-function variants are associated with enhanced SLE susceptibility and severity. In addition, the X-chromosome location of TLR7 and its escape from X-chromosome inactivation provide a genetic basis for female predominance in SLE. The absence of TLR8 and TLR9 have been shown to exacerbate the detrimental effects of TLR7, leading to upregulated TLR7 activity and increased disease severity in mouse models of SLE. The regulatory functions of TLR8 and TLR9 have been proposed to involve competition for the endosomal trafficking chaperone UNC93B1. However, recent evidence implies more direct, regulatory functions of TLR9 on TLR7 activity. The association between age-associated B cells (ABCs) and autoantibody production positions these cells as potential targets for treatment in SLE, but the lack of specific markers necessitates further research for precise therapeutic intervention. Therapeutically, targeting TLRs is a promising strategy for SLE treatment, with drugs like hydroxychloroquine already in clinical use.
摘要：
系统性红斑狼疮（SLE）的发病机制与toll样受体（TLRs）的不同作用有关，特别是TLR7、TLR8和TLR9。TLR7过表达或基因重复,如Y连接的自身免疫促进剂（Yaa）基因座或TLR7激动剂咪喹莫特所见，与SLE严重程度增加相关，而特定的TLR7多态性和功能获得变异与SLE易感性和严重性增强相关。此外,TLR7的X染色体位置及其从X染色体失活中的逃逸为女性在SLE中的优势提供了遗传基础。TLR8和TLR9的不存在已显示加剧TLR7的有害作用,导致SLE小鼠模型中TLR7活性上调和疾病严重程度增加。已经提出TLR8和TLR9的调节功能涉及对内体运输伴侣UNC93B1的竞争。然而,最近的证据暗示更直接，TLR9对TLR7活性的调节功能。年龄相关的B细胞（ABCs）与自身抗体产生之间的关联将这些细胞定位为SLE治疗的潜在靶标，但是缺乏特异性标志物需要进一步研究以进行精确的治疗干预。治疗学上,靶向TLRs是SLE治疗的一种有前途的策略，羟氯喹等药物已经在临床使用。
