Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus.
Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus.
复制标题
DOI：
10.1084/jem.20050914
复制
发表时间：
2005-10-17
影响因子：
15.3
通讯作者：
Coffman, Robert L
中科院分区：
文献类型：
--
作者：
Barrat, Franck J;Meeker, Thea;Gregorio, Josh;Chan, Jean H;Uematsu, Satoshi;Akira, Shizuo;Chang, Bonnie;Duramad, Omar;Coffman, Robert L
在系统性红斑狼疮（SLE）患者中观察到血清干扰素(IFN)-α水平升高，并且这些水平与疾病活动性和严重程度相关。IFN-α的起源尚不清楚，但越来越多的证据表明，活化的浆细胞样前树突状细胞（PDCs）的关键参与。在SLE患者中，DNA和RNA病毒以及由自身DNA和RNA蛋白颗粒特异性自身抗体组成的免疫复合物（ic）可以刺激IFN-α的产生。我们开发了三种基于寡核苷酸（ODN）的toll样受体（TLR）信号抑制剂系列。这些odn包括TLR9的抑制剂，TLR7的抑制剂但不包括TLR9，以及同时抑制TLR7和TLR9的序列。这些抑制剂的特异性是通过PDCs对DNA或RNA病毒的反应抑制IFN-α的产生来证实的。我们发现哺乳动物的DNA和RNA，以ic的形式，分别是TLR9和TLR7的有效自身抗原，并诱导PDCs产生IFN-α。这项工作表明，tlr可能通过PDCs诱导IFN-α在狼疮的促进中起关键作用。因此，这些TLR信号的抑制剂代表了治疗狼疮的新药物。
Raised serum levels of interferon (IFN)-α have been observed in systemic lupus erythematosus (SLE) patients, and these levels are correlated with both disease activity and severity. The origin of this IFN-α is still unclear, but increasing evidence suggests the critical involvement of activated plasmacytoid predendritic cells (PDCs). In SLE patients, DNA and RNA viruses, as well as immune complexes (ICs), that consist of autoantibodies specific to self-DNA and RNA protein particles can stimulate production of IFN-α. We have developed three series of oligonucleotide (ODN)-based inhibitors of Toll-like receptor (TLR) signaling. These ODNs include inhibitors of TLR9, inhibitors of TLR7 but not TLR9, and sequences that inhibit both TLR7 and TLR9. Specificity of these inhibitors is confirmed by inhibition of IFN-α production by PDCs in response to DNA or RNA viruses. We show that mammalian DNA and RNA, in the form of ICs, are potent self-antigens for TLR9 and TLR7, respectively, and induce IFN-α production by PDCs. This work suggests that TLRs may have a critical role in the promotion of lupus through the induction of IFN-α by PDCs. These inhibitors of TLR signaling thus represent novel therapeutic agents with potential for the treatment of lupus.