抗Jo-1抗体调控细胞间粘附分子（ICAM-1）在多发性肌炎/皮肌炎左室舒张功能不全的机制研究

Heart failure (HF) constitutes a major cause of death in polymyositis /dermatomyositis (PM/DM). However, the clinical significance is not always attractive. Approximately 34.5% of patients with PM/DM had left ventricular diastolic dysfunction (LVDD), which often reslut in HF. Myocardial fibrosis is the most important cause of LVDD in PM/DM. It has been reported that anti-Jo-1 antibody , the most specific antibody, can regrelate intercellular adhesion molecule-1 leading to tissure fibrosis, independent of other cytokines. Our preliminary studies have confirmed the high prelacent of LVDD in PM/DM,and PM/DM with positive Jo-1 antibody had abnormal parameters of left ventricylar diastolic function compared with negative Jo-1 antibody patients. In the present study, we will 1) to investigate whether sera from positive anti-Jo-1 antibody patients or purified Jo-1 in PM/DM can activate intercellular adhesion molecule-1 in cardiac muscle cell; 2) to construct the murine model of Jo-1-mediated myositis and explore the pathogenesis of LVDD in PM/DM; 3) to assess the association among anti-Jo-1 antibody, ICAM-1 and LVDD in PM/DM patients. The study not only supplies important siginificance for early intervention and lowering mortality in PM/DM patients with LVDD, but also gives a novel method for drug intervention.

心力衰竭是多发性肌炎/皮肌炎(PM/DM)最重要的死亡原因之一，但易被临床忽视。大约34.5%左右的PM/DM存在左室舒张功能不全（LVDD）,常发展为心力衰竭。PM/DM患者LVDD最重要的原因是心肌纤维化。据报道，抗Jo-1抗体是PM/DM最常见、最独特的抗体，可不依赖于其他炎症因子，单独调控细胞间粘附分子-1（ICAM-1）引起组织细胞纤维化。前期工作发现：PM/DM中LVDD患病率高达58%，与抗Jo-1抗体阴性PM/DM患者相比，阳性患者多项LVDD指标异常。因此，本课题拟以抗Jo-1抗体阳性PM/DM患者血清及纯化抗原刺激C57BL/6小鼠心肌细胞、构建PM/DM 小鼠模型及临床研究等方面探讨抗Jo-1抗体与ICAM-1、LVDD的相关性，阐明PM/DM患者LVDD的发病机制。此项目不仅对PM/DM合并LVDD的早期干预、降低死亡率有重要意义，还为药物干预治疗提供一条新的途径。

心力衰竭是多发性肌炎/皮肌炎最重要的死亡原因，左心室舒张功能不全是心力衰竭的前驱形式。通过我们的研究，多发性肌炎/皮肌炎左心室舒张功能不全发生率可高达70%左右，与细胞间粘附分子-1及抗Jo-1抗体密切相关，尤其是后者。本研究也通过构建多发性肌炎/皮肌炎模型小鼠，结果发现抗Jo-1抗体的靶点hisRS在心肌细胞细胞膜定位，而且模型小鼠心脏组织及血液中多个炎症分子(细胞间粘附分子-1/白细胞介素-6/肿瘤坏死因子)的表达明显升高，进一步的研究说明，血液中总的IgG可能与炎症分子分泌相关。以上结果提示我们在临床工作中，必须重视多发性肌炎/皮肌炎心脏损伤的筛查，另外，阻断炎症分子的分泌可能是早期预防多发性肌炎/皮肌炎心力衰竭的一个途径。