Department of Internal Medicine, Division of Rheumatology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA.
Mediators Inflamm. 2010;2010:986596. doi: 10.1155/2010/986596. Epub 2010 May 18.
Our immune defense depends on two specialized armed forces. The innate force acts as an alarm mechanism that senses changes in the microenvironment through the recognition of common microbial patterns by Toll-like receptors (TLR) and NOD proteins. It rapidly generates an inflammatory response aimed at neutralizing the intruder at the mucosal checkpoint. The innate arm also communicates this message with more specialized adaptive forces represented by pathogen-specific B cells and T cells. Interestingly, B cells also express some innate sensors, like TLR7 and TLR9, and may respond to bacterial hypomethylated CpG motifs and single-stranded RNA viruses. Intracellular nucleic acid sensing TLRs play an important role in the pathogenesis of Systemic Lupus Erythematosus (SLE). In this review, we describe recent achievements in the development of oligonucleotide-(ODN)-based inhibitors of TLR9 and/or TLR7 signaling. We categorize these novel therapeutics into Classes G, R, and B based on their cellular and molecular targets. Several short ODNs have already shown promise as pathway-specific therapeutics for animal lupus. We envision their future use in human SLE, microbial DNA-dependent sepsis, and in other autoinflammatory diseases.
我们的免疫防御依赖于两支专业化的武装力量。先天免疫系统作为一个警报机制，通过 Toll 样受体 (TLR) 和 NOD 蛋白识别常见的微生物模式，感知微环境的变化。它会迅速产生炎症反应，旨在在黏膜检查点中和入侵物。先天免疫系统还通过病原体特异性 B 细胞和 T 细胞等更专业化的适应性免疫力量传递这一信息。有趣的是，B 细胞也表达一些先天传感器，如 TLR7 和 TLR9，并可能对细菌低甲基化 CpG 基序和单链 RNA 病毒产生反应。细胞内核酸感应 TLR 在系统性红斑狼疮 (SLE) 的发病机制中发挥着重要作用。在这篇综述中，我们描述了 TLR9 和/或 TLR7 信号通路的基于寡核苷酸 (ODN) 的抑制剂的最新进展。我们根据它们的细胞和分子靶点将这些新型治疗药物归类为 G、R 和 B 类。一些短的 ODN 已经显示出作为动物狼疮的特定途径治疗药物的潜力。我们设想它们未来在人类 SLE、微生物 DNA 依赖性败血症和其他自身炎症性疾病中的应用。
