Histidyl-transfer RNA synthetase: a key participant in idiopathic inflammatory myopathies.
Histidyl-transfer RNA synthetase: a key participant in idiopathic inflammatory myopathies.
复制标题
组氨酰转移 RNA 合成酶：特发性炎症性肌病的关键参与者。
DOI：
10.1002/art.30110
复制
发表时间：
2011
影响因子：
--
通讯作者：
Casciola-Rosen,Livia
中科院分区：
文献类型：
--
作者：
Casciola-Rosen,Livia
系统性自身免疫性疾病的不同临床表型通常与不同的自身抗体谱相关。一个显著的例子是特发性炎症性肌病（IIM；肌炎），其中氨基酰基转移RNA合成酶是自身免疫反应的目标。在这些抗原中，抗组氨酸转移RNA合成酶（HisRS，也称为Jo-1）的抗体是迄今为止最突出的；在15-20%的肌炎患者中发现，更引人注目的是，在70%的肌炎和间质性肺疾病患者中发现。HisRS属于古老的，普遍表达的蛋白质家族，执行将遗传信息翻译成蛋白质的关键细胞功能。1999年，Wakasugi和Schimmel(1)发表了一项开创性的研究，表明人酪氨酸转移RNA合成酶可以在凋亡条件下分泌，随后被细胞外白细胞弹性酶切割，产生两个具有不同细胞因子活性的片段。在肌炎中，作为适应性免疫反应靶点的分子能够启动先天免疫反应，这向Plotz(2)表明，先天免疫反应的激活可能是决定一个特定分子是否从数千种可能的自身抗原中被选择用于自身免疫反应的关键特性。Howard等人(3)证明氨基末端的HisRS结构域可以作为一种趋化因子，通过ccr5介导的相互作用吸引幼稚淋巴细胞和未成熟树突状细胞。这种经常靶向的自身抗原在先天和适应性免疫反应之间架起桥梁的能力似乎是许多自身免疫性疾病中自身抗原的共同特征（4,5）。虽然先前已经证明，用含有HisRS的佐剂（含有激活toll样受体[TLRs]和其他先天免疫受体的信号）免疫小鼠会引起对HisRS的免疫反应，并在一些小鼠品系中引起肌肉和肺部炎症(6)，但使用这种方法无法揭示HisRS的内在佐剂特性。Soejima和他的同事们(7)现在着手解决这个问题，在没有佐剂的情况下，用可溶性小鼠HisRS（以一种融合蛋白的形式，由小鼠HisRS的氨基酸1-151与麦芽糖结合蛋白（MBP）的c端连接组成）肌内免疫多种先天性和敲除小鼠菌株。他们的研究结果发表在本期《关节炎与风湿病》（Arthritis & Rheumatism）杂志上(7)，提供了证据表明，小鼠无佐剂的HisRS可以诱导持续的肌肉炎症和对HisRS的适应性免疫反应。用MBP融合伴侣和类似制备的对照免疫没有这种效果。炎症反应在刺激后1周检测到，并持续7周（检测时间最长）。在缺乏重组激活基因2的小鼠和缺乏TLR-4的小鼠中进行的类似研究表明，小鼠HisRS产生肌肉炎症的能力不需要TLR-4信号，也不依赖于B细胞和T细胞受体的识别。值得注意的是，在报告的实验中，动力学特性没有得到解决，研究也没有超过7周；因此，如果研究这些更广泛的特征，则可能存在诱导模型各方面不同的可能性。
Different clinical phenotypes of systemic autoimmune diseases are typically associated with distinct autoantibody profiles. A striking example of this is idiopathic inflammatory myopathy (IIM; myositis), in which the aminoacyl–transfer RNA synthetases are targets of the autoimmune response. Among these antigens, antibodies against histidyl–transfer RNA synthetase (HisRS; also known as Jo-1) are by far the most prominent; these are found in 15–20% of myositis patients, and more strikingly, are detected in 70% of patients with myositis and interstitial lung disease. HisRS belongs to the family of ancient, ubiquitously expressed proteins performing the critical cellular function of translating genetic information into proteins. In 1999, Wakasugi and Schimmel (1) published a seminal study showing that human tyrosyl–transfer RNA synthetase can be secreted under apoptotic conditions and subsequently cleaved by extracellular leukocyte elastase, generating two fragments with distinct cytokine activities. The ability of a molecule that is a target of an adaptive immune response in myositis to initiate an innate immune response suggested to Plotz (2) that activation of the innate immune response might be a critical property that determines whether a specific molecule is selected—from among thousands of possible self antigens—for an autoimmune response. Howard et al (3) demonstrated that the amino-terminal HisRS domain could function as a chemokine, attracting naive lymphocytes and immature dendritic cells through CCR5-mediated interactions. This ability of frequently targeted autoantigens to bridge the innate and adaptive immune responses appears to be a shared feature of many autoantigens in the systemic autoimmune diseases (4, 5). While immunization of mice with HisRS in adjuvant (which contains signals for activating Toll-like receptors [TLRs] and other innate immune receptors) has previously been shown to cause an immune response to HisRS, along with inflammation of muscle and lung in some mouse strains (6), the intrinsic adjuvant properties of HisRS could not be revealed using this approach. Soejima and colleagues (7) now set out to address this by immunizing a variety of congenic and knockout mouse strains intramuscularly with soluble mouse HisRS (in the form of a fusion protein consisting of amino acids 1–151 of mouse HisRS linked to the C-terminus of maltose binding protein [MBP]) in the absence of adjuvant. Their findings, which are reported in this issue of Arthritis & Rheumatism (7), provide evidence that mouse HisRS without adjuvant can induce sustained muscle inflammation and an adaptive immune response to HisRS. Control immunizations performed with the MBP fusion partner and prepared similarly do not have this effect. The inflammatory response was detected 1 week postimmunization and remained present for 7 weeks (the longest time examined). Similar studies performed in mice lacking recombination-activating gene 2 and in mice lacking TLR-4 showed that the ability of mouse HisRS to produce muscle inflammation did not require TLR-4 signaling, nor was it dependent on recognition of B cell and T cell receptors. It should be noted that in the reported experiments, kinetic characteristics were not addressed, nor were the studies extended beyond 7 weeks; thus, the potential exists for aspects of the induced model to differ if these broader features were studied.
影响因子：
32.4
作者：
Herlands, Robin A.;Christensen, Sean R.;Sweet, Rebecca A.;Hershberg, Uri;Shlomchik, Mark J.
通讯作者：
Shlomchik, Mark J.
影响因子：
56.9
作者：
Wakasugi, K;Schimmel, P
通讯作者：
Schimmel, P