Targeting Toll-like receptor signaling in plasmacytoid dendritic cells and autoreactive B cells as a therapy for lupus.
Targeting Toll-like receptor signaling in plasmacytoid dendritic cells and autoreactive B cells as a therapy for lupus.
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DOI：
10.1186/ar1888
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发表时间：
2006
影响因子：
4.9
通讯作者：
Lenert, Petar S
中科院分区：
文献类型：
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作者：
Lenert, Petar S
本综述重点关注 Toll 样受体 (TLR) 在狼疮中的作用以及使用 TLR 调节抑制性寡脱氧核苷酸 (INH-ODN) 治疗狼疮的可能性。 TLR 连接先天性和适应性免疫反应，可能在系统性红斑狼疮的发病机制中发挥重要作用。特别感兴趣的是位于细胞内的 TLR3、-7、-8 和 -9。这些 TLR 识别单链或双链 RNA 或低甲基化的 CpG-DNA。暴露于高阶 CpG-DNA 配体或免疫复合的自身 RNA 会触发自身反应性 B 细胞和浆细胞样树突状细胞的激活。最近开发的 INH-ODN 可以阻断 TLR9 反应细胞中的所有下游信号传导事件。其中一些 INH-ODN 还可以靶向 TLR7 信号通路。根据其优先的细胞反应性，我们将 INH-ODN 分为 B 类和 R 类。B 类（“广泛反应性”）INH-ODN 靶向广泛的 TLR 表达细胞。 R 类（“限制性”）INH-ODN 很容易形成 DNA 双链体或更高阶结构，并且优先被自身反应性 B 细胞和浆细胞样树突状细胞识别，而不是被非 DNA 特异性滤泡 B 细胞识别。两类 INH-ODN 都可以阻断动物狼疮。因此，这些新型 INH-ODN，特别是 R 类 INH-ODN 在人类狼疮中的治疗应用，可能会导致更具选择性和疾病特异性的免疫抑制。
This review focuses on the role of Toll-like receptors (TLRs) in lupus and on possibilities to treat lupus using TLR modulating inhibitory oligodeoxynucleotides (INH-ODNs). TLRs bridge innate and adaptive immune responses and may play an important role in the pathogenesis of systemic lupus erythematosus. Of particular interest are TLR3, -7, -8, and -9, which are localized intracellularly. These TLRs recognize single-stranded or double-stranded RNA or hypomethylated CpG-DNA. Exposure to higher order CpG-DNA ligands or to immune complexed self-RNA triggers activation of autoreactive B cells and plasmacytoid dendritic cells. INH-ODNs were recently developed that block all downstream signaling events in TLR9-responsive cells. Some of these INH-ODNs can also target TLR7 signaling pathways. Based on their preferential cell reactivity, we classify INH-ODNs into class B and class R. Class B ('broadly reactive') INH-ODNs target a broad range of TLR-expressing cells. Class R ('restricted') INH-ODNs easily form DNA duplexes or higher order structures, and are preferentially recognized by autoreactive B cells and plasmacytoid dendritic cells, rather than by non-DNA specific follicular B cells. Both classes of INH-ODNs can block animal lupus. Hence, therapeutic application of these novel INH-ODNs in human lupus, particularly class R INH-ODNs, may result in more selective and disease-specific immunosuppression.