Nucleic acid sensing receptors in systemic lupus erythematosus: development of novel DNA- and/or RNA-like analogues for treating lupus.
Nucleic acid sensing receptors in systemic lupus erythematosus: development of novel DNA- and/or RNA-like analogues for treating lupus.
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DOI：
10.1111/j.1365-2249.2010.04176.x
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发表时间：
2010-08
影响因子：
4.6
通讯作者：
Lenert P
中科院分区：
文献类型：
--
作者：
Lenert P
双链（ds）DNA、DNA或RNA相关核蛋白是SLE的主要自身免疫靶点，但它们相对无法在实验动物中引发类似的自身免疫反应，这几十年来一直让科学家们着迷。虽然许多细胞蛋白质非特异性地结合带负电荷的核酸，但直到最近才发现，几种细胞内蛋白质直接参与外源DNA或RNA或胞质溶胶驻留的DNA或RNA病毒的先天识别。因此，内体Toll样受体（TLR）介导对双链RNA（TLR 3）、单链RNA（TLR 7/8）或未甲基化的细菌CpG-DNA（TLR 9）的应答，而DAI/ZBP 1、HIN-200（p202）、AIM 2、RNA聚合酶III、RIG-1和MDA 5分别介导对胞质dsDNA或dsRNA的应答。TLR诱导的应答比胞质DNA或RNA传感器诱导的应答更稳健，后者通常限于IRF 3依赖性I型IFN诱导和NF-κB活化。有趣的是，AIM 2不能诱导I型IFN，而是在caspase I活化中起作用。已经开发了DNA或RNA样合成寡核苷酸（INH-ODN），其在低纳摩尔浓度下拮抗自身免疫B细胞和I型IFN产生树突细胞中TLR 7和/或TLR 9诱导的活化。目前尚不清楚这些INH-ODN是否对细胞溶质DNA或RNA传感器具有任何激动或拮抗作用。虽然这仍有待于在未来确定，但体内研究已经显示了它们在各种狼疮动物模型中预防自发性狼疮的潜力。几个研究小组正在探索将这些INH-ODNs转化为人类治疗剂用于治疗SLE和细菌DNA诱导的脓毒症的可能性。
Double-stranded (ds) DNA, DNA- or RNA-associated nucleoproteins are the primary autoimmune targets in SLE, yet their relative inability to trigger similar autoimmune responses in experimental animals has fascinated scientists for decades. While many cellular proteins non-specifically bind negatively charged nucleic acids, it was only recently discovered that several intracellular proteins are directly involved in innate recognition of exogenous DNA or RNA, or cytosol-residing DNA or RNA viruses. So, endosomal Toll-like receptors (TLR) mediate responses to double-stranded RNA (TLR3), single-stranded RNA (TLR 7/8) or unmethylated bacterial CpG-DNA (TLR9), while DAI/ZBP1, HIN-200 (p202), AIM2, RNA polymerase III, RIG-I and MDA5 mediate responses to cytosolic dsDNA or dsRNA, respectively. TLR-induced responses are more robust than those induced by cytosolic DNA- or RNA- sensors, the later usually being limited to IRF3-dependent type I IFN induction and NF-κB activation. Interestingly, AIM2 is not capable of inducing type I IFN, but rather plays a role in caspase I activation. DNA- or RNA-like synthetic oligonucleotides (INH-ODN) have been developed that antagonize TLR7- and/or TLR9-induced activation in autoimmune B cells and in type I IFN-producing dendritic cells at low nanomolar concentrations. It is not known whether these INH-ODNs have any agonistic or antagonistic effects on cytosolic DNA or RNA sensors. While this remains to be determined in the future, in vivo studies have already shown their potential for preventing spontaneous lupus in various animal models of lupus. Several groups are exploring the possibility of translating these INH-ODNs into human therapeutics for treating SLE and bacterial DNA-induced sepsis.
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影响因子：
64.8
作者：
Alexopoulou, L;Holt, AC;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
4.4
作者：
Agrawal, Hemant;Jacob, Noam;Jacob, Chaim O.
通讯作者：
Jacob, Chaim O.
影响因子：
5.4
作者：
Allam, Ramanjaneyulu;Pawar, Rahul D.;Anders, Hans-Joachim
通讯作者：
Anders, Hans-Joachim
影响因子：
30.5
作者：
通讯作者：
--
DOI：
10.1084/jem.20021553
发表时间：
2003-03-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Bennett L;Palucka AK;Arce E;Cantrell V;Borvak J;Banchereau J;Pascual V
通讯作者：
Pascual V