A new autoantibody to valyl transfer RNA synthetase associated with anti-synthetase syndrome.
A new autoantibody to valyl transfer RNA synthetase associated with anti-synthetase syndrome.
复制标题
一种新的与抗合成酶综合征相关的缬氨酰转移 RNA 合成酶自身抗体。
DOI：
10.1093/rheumatology/keac569
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Morinobu A.
中科院分区：
文献类型：
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作者：
Sasai T;Nakashima R;Shirakashi M;Hiwa R;Tsuji H;Kitagori K;Akizuki S;Yoshifuji H;Mimori T;Morinobu A.
亲爱的编辑，氨酰tRNA合成酶（ARS）抗体是特发性炎性肌病中最常见的肌炎特异性自身抗体[1]。ARS抗体阳性的患者经常有肌炎，以及间质性肺病（ILD），多关节炎，RP，发烧和技工的手。这些症状共同定义了抗合成酶综合征（ASSD）[2]。ARS在三磷酸腺苷存在下将氨基酸结合到tRNA上，并催化氨酰tRNA的合成。在人类中，有20种不同类型的ARS，每种氨基酸一种。这些tRNA合成酶中有8种已被报道为肌炎特异性自身抗原[3][Jo-1（组氨酰基）、PL-7（苏氨酰基）、PL-12（丙氨酰基）、EJ（甘氨酰基）、OJ（异亮氨酰基）、KS（天冬酰胺酰基）、Zo（苯丙氨酰基）和Ha（酪氨酰基）]，并且与ASSD表型相关，后两种最不常见[4，5]。在这项研究中，我们确定了一个新的抗ARS针对缬氨酰tRNA合成酶（VRS）的患者与ASSD的典型特征。一位43岁男性因偶发性发烧、肌肉痛及关节痛持续2个月而入院。他还报告了RP。体格检查发现手指肿胀，三角肌和四头肌无力。实验室研究显示：乳酸脱氢酶，732 U/l;肌酸磷酸激酶（CK），2472 U/l;醛缩酶，46.4 IU/l; CRP，1.5 mg/dl; Krebs von den Lungen-6，396 U/ml。荧光ANA也呈阳性（滴度1：640，具有核仁和胞质模式），但疾病特异性自身抗体呈阴性。胸部CT显示ILD，模式分类为非特异性间质性肺炎。脂肪饱和T2加权MRI显示三角肌和髂腰肌弥漫性高强度信号，这些肌肉的针肌电图显示肌源性变化。左股四头肌的肌肉活检显示坏死的肌纤维和单核细胞的肌内膜浸润，与肌炎一致。根据这些发现，患者被临床诊断为ASSD。CT还显示了一个肿胀的纵隔淋巴结，病理诊断为未分化癌。淋巴结的免疫组织化学分析未将其鉴定为淋巴瘤、肉瘤或特定类型的癌。18F-氟脱氧葡萄糖PET未显示除纵隔淋巴结肿胀外的任何病变。因此，该患者被诊断为ASSD与不明原因的癌症共存。该患者接受了化疗（卡铂和紫杉醇）和同步放射治疗。CK值在化疗开始时达到峰值，并随着癌症治疗而逐渐下降。他在第一次入院后8个月死于癌症。该病例与ASSD一致，但患者的血清未显示任何已知的疾病特异性自身抗体。然而，我们发现血清沉淀的RNA免疫沉淀（IP）和蛋白IP的一些自身抗原。用尿素-10%聚丙烯酰胺凝胶电泳和银染色分析HeLa细胞提取物的RNA IP，显示出对应于tRNA的条带，其不同于先前报道的ARS抗体沉淀的条带（图1A）。用十二烷基硫酸钠-8%聚丙烯酰胺凝胶电泳从35 S标记的HeLa细胞中提取蛋白质，对蛋白质IP进行分析，发现沉淀的140-kDa蛋白质，与先前报道的蛋白质不同，例如黑素瘤分化相关基因5（图1B）。在20种ARS酶中，VRS因其分子量大小而被列为候选抗原，因此我们对VRS进行了初步的研究。
DEAR EDITOR, The aminoacyl tRNA synthetase (ARS) antibody is the most frequently detected myositis-specific autoantibody in idiopathic inflammatory myopathy [1]. ARS antibody-positive patients frequently have myositis, as well as interstitial lung disease (ILD), polyarthritis, RP, fever and mechanic’s hands. Together, these symptoms define antisynthetase syndrome (ASSD)[2]. ARS binds amino acids to tRNA in the presence of adenosine triphosphate and catalyses the synthesis of aminoacyl tRNA. In humans, there are 20 different types of ARSs, one for each amino acid. Eight of these tRNA synthetases have been reported as myositis-specific autoantigens [3][Jo-1 (histidyl), PL-7 (threonyl), PL-12 (alanyl), EJ (glycyl), OJ (isoleucyl), KS (asparaginyl), Zo (phenylalanyl), and Ha (tyrosyl)] and are associated with the ASSD phenotype, with the latter two being the least commonly involved [4, 5]. In this study we identified a new anti-ARS directed against valyl tRNA synthetase (VRS) in a patient with typical features of ASSD. A 43-year-old man was admitted to our hospital with occasional fever, myalgia and arthralgia lasting 2months. He also reported RP. Physical examination revealed swollen fingers and weakness of the deltoid and quadriceps muscles. Laboratory studies revealed the following: lactate dehydrogenase, 732 U/l; creatine phosphokinase (CK), 2472 U/l; aldolase, 46.4 IU/l; CRP, 1.5 mg/dl; and Krebs von den Lungen-6, 396 U/ml. Fluorescent ANA was also positive (titre 1: 640, with a nucleolar and cytoplasmic pattern) but disease-specific autoantibodies were negative. Chest CT revealed ILD, with a pattern classified as a non-specific interstitial pneumonia. Fat-saturated T2-weighted MRI revealed diffuse high-intensity signals in the deltoid and iliopsoas muscles and needle electromyography of these muscles revealed myogenic changes. A muscle biopsy of the left quadriceps femoris showed necrotic muscle fibres and endomysial infiltration of mononuclear cells, consistent with myositis. Based on these findings, the patient was clinically diagnosed with ASSD. CT also revealed a swollen mediastinal lymph node that was pathologically diagnosed as an undifferentiated carcinoma. Immunohistochemical analysis of the lymph node did not identify it as a lymphoma, sarcoma or specific type of carcinoma. 18F-fluorodeoxyglucose PET did not reveal any lesions other than the swollen mediastinal lymph node. Thus the patient was diagnosed with ASSD coexisting with a cancer of unknown origin.The patient was treated for cancer of unknown origin with chemotherapy (carboplatin and paclitaxel) and concurrent radiotherapy. The CK value peaked at the beginning of chemotherapy and gradually decreased with cancer treatment. He died of cancer 8 months after the first admission. This case was consistent with ASSD, but the patient’s serum did not show any known disease-specific autoantibodies. However, we found that the serum precipitated some autoantigens by RNA immunoprecipitation (IP) and protein IP. Analysis of RNA IP from HeLa cell extracts with urea–10% polyacrylamide gel electrophoresis and silver staining showed a band corresponding to tRNA, which differed from those precipitated by previously reported ARS antibodies (Fig. 1A). Analysis of protein IP using proteins extracted from 35S-labelled HeLa cells with sodium dodecyl sulphate–8% polyacrylamide gel electrophoresis revealed a 140-kDa protein precipitated, different from those reported previously, such as melanoma differentiation-associated gene 5 (Fig. 1B). Among the 20 ARS enzymes, VRS was listed as a candidate antigen based on its molecular weight, therefore we …