特发性炎性肌病是一种主要累及骨骼肌组织的非感染炎性自身免疫性疾病，病因与发病机制不明确。多发性肌炎和皮肌炎是最常见的两个疾病亚型。患者临床表现为肌力呈进行性降低、肌酶谱升高明显（尤其是肌酸磷酸激酶）、肌炎特异性及非特异性抗体出现，肌肉组织大量炎性细胞浸润。研究表明固有免疫、获得性免疫、以及非免疫学机制共同作用，导致特发性炎性肌病患者骨骼肌的病理损伤。

巨噬细胞迁移抑制因子（MIF）是一种多功能炎症因子，通过结合并活化CD74、CD44、CXCR2/4等受体，参与多种细胞病理生理的调控。在多种自身免疫性疾病如类风湿关节炎、硬皮病、系统性红斑狼疮中MIF表达异常，提示MIF在自身免疫病中可能具有重要的作用。但是，MIF与多发性肌炎和皮肌炎患者临床特征相关性仍不清楚。本次研究分为两部分，第一部分探讨分析血清MIF在多发性肌炎和皮肌炎发病机制中的可能作用。本课题检测了多发性肌炎和皮肌炎患者血清中MIF的表达水平，并分析了MIF与多发性肌炎/皮肌炎实验室检查指标、临床特征间的相关性，还比较了高、中、低糖皮质激素治疗量之间及有无加其他免疫抑制剂血清MIF水平的表达差异。为阐明MIF在多发性肌炎和皮肌炎中的致病作用及临床意义提供实验证据。同时，发现了多发性肌炎和皮肌炎患者血清MIF浓度和皮肌炎患者发生肿瘤并发症之间的相关性，并首次提出了血清MIF作为皮肌炎患者合并肿瘤并发症的早期诊断指标；第二部分系统分析MIF在风湿免疫疾病中的研究进展，包括相应已报道的分子机制、相关信号通路以及MIF与糖皮质激素抵抗机制的研究进展，探讨MIF在风湿免疫病发病机制中的可能作用，希望可以为IIM发病机制、临床诊断、个性化治疗用药、提高预后提供一些理论线索，为今后IIM的深入研究打下基础。

方法   第一部分采用ELISA方法检测135例PM/DM患者血清MIF表达水平,并分析其与PM/DM临床特征、实验室检查、疾病活动度的关系。第二部分检索并筛选MIF在风湿免疫病系统性红斑狼疮（SLE）、类风湿性关节炎（RA）、硬皮病（SSc）、免疫炎性肌病(IIM)领域的相关文献，进行系统分析比较MIF在不同风湿病中的发病机制及临床意义。

结果  

第一部分：

血清MIF在IIM 患者、疾病对照组RA、SLE、SSc患者中升高，血清MIF分别为11622.43pg/ml (IQR 2216.00-95968.00 pg/ml)、13686 pg/ml（IQR10142～17486 pg/ml）、4408 pg/ml（IQR 3133～5 208 pg/ml）、24251 pg/ml (IQR 19807～29604 pg/ml),均明显高于健康对照组1472.67 pg/ml (IQR 805.25 ~1940.25),P < 0.001)。

与实验室检查相关性：DM血清MIF水平与T总淋巴细胞百分比、CD3+ T淋巴细胞百分比弱正相关，与CD3+CD4+ T淋巴细胞百分比弱负相关。

病程及疾病进展中作用：比较46例新发病患者和已接受过治疗患者，血清MIF浓度在新发患者中有较高水平。疾病进展阶段（病程大于6个月）患者MIF水平高于早期阶段（病程小于6个月）。对疾病活动度评分结果进行分析，统计显示，疾病活动性评分和患者血清MIF水平没有相关性。

并发症的预测价值：有吞咽困难IIM患者血清MIF水平明显高于无吞咽困难的患者(P = 0.024)；合并肿瘤的IIM患者血清MIF水平高于未合并肿瘤的患者（P=0.013），尤其是DM 抗录中介因子(TIF)1-γ抗体（P<0.001）阳性患者。

糖皮质激素治疗剂量高的患者血清MIF水平高于低激素剂量患者组。单独使用糖皮质激素治疗组与糖皮质激素加其他免疫抑制剂组，患者血清MIF水平无显著变化。

随访研究。由于部分门诊随访患者资料不全，本次仅纳入7名资料完整的皮肌炎患者进行随访，随访的时间间隔不等，但均大于6个月，最多3年。收集随访患者的血清标本于-80^oC冻存。对随访研究中收集到的血清标本和对应的其他实验室检查和临床指标进行相关性分析，结果显示治疗之后，虽然患者血清MIF水平下降趋势不明显，但是血清CD3+、CD4+、CD8+淋巴细胞数量均显著下降，下降值具有显著统计学相关性（P<0.01）。

第二部分：分析了从1973年至今85篇关于MIF在RA、SLE、SSc、IIM中文献报道。MIF在RA、SLE、SSc、IIM患者外周血清中表达均增高，并且在RA滑液、RA外周血PBMC中、SLE的PBMC中表达水平升高。MIF可促进RA患者T细胞活化，活化Th1、Th2细胞进而分泌更多的MIF。

结论 第一部分：在我国多发性肌炎/皮肌炎患者人群中血清MIF水平升高，血清MIF可做为DM/PM疾病病程进展的标志。它还可与抗TIF1-γ抗体联合用于DM合并肿瘤的早期诊断。第二部分：MIF在风湿免疫病患者血清、外周血T淋巴细胞及组织中均不同程度表达增高，可通过多条信号通路参与调节疾病的发病和进展，为风湿免疫病发病机制的研究提供了可能的新方向。

Abstract

Idiopathic inflammatory myopathy is a non - infectious inflammatory autoimmune disease of skeletal muscle tissue. The etiology and pathogenesis are not clear.Multiple myositis and dermatomyositis are the two most common subtypes.Patients have clinical manifestations of  continuously decreasing muscle strength, rapidlyascending muscle enzymes, especially creatine phosphokinase, myositis specific or nonspecific antibody, muscle tissue of inflammatory cell infiltration.Studies have shown that innate immunity, acquired immunity, and non-immunological mechanisms all probably contribute to the pathological damage of skeletal muscle in idiopathic inflammatory myopathypatients.

Macrophage migration inhibitory factor (MIF) is a multifunctional inflammatory factor that participates in the regulation of various cell pathophysiology by binding and activating CD74, CD44 and CXCR2/4 receptors.The MIF expression in multiple autoimmune diseases such as rheumatoid arthritis, scleroderma and systemic lupus erythematosus is abnormal, suggesting that MIF may play an important role in autoimmune diseases.However, the correlation between MIF and patients with multiple myositis and dermatomyositis is not clear.

This study is divided into two parts. The first part is to reseachthe possible role of serum MIF in the pathogenesis of multiple myositis and dermatomyositis.we tested serum MIF expression level of multiple myositis and dermatomyositis patients , and analyzed the correlationbetween MIF and laboratory examination index, clinical features of  dermatomyositis and multiple myositis patients, and also compared the high, medium and low therapeutic dose of glucocorticoid and whether other immunosuppressantsor not. Meantime, we found a markablecorrelation between serum MIF in multiple myositis and tumor complications occurred in dermatomyositispatients, and we  put forward the idea thaserum MIF as biomarker of dermatomyositis in the early diagnosis oftumor complicationsfor the first time.

In the second part we systematacially review researcheson MIF possiblemolecular mechanism and Clinical significance in rheumatic immune diseases.To explore the possible role of MIF in the pathogenesis of rheumatic immune diseases, we hope to provide some clues for the theoretical research of IIM pathogenesis.

Methods: In the first part, serum MIF expression level of 135 PM/DM patients was detected by ELISA method, and its relationship with PM/DM clinical features, laboratory examination and disease activity wereanalyzed.The second part retrieval and screening of MIF in rheumatic autoimmune disease systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), scleroderma (SSc), immune inflammatory myopathy (IIM) in the field of literature, systematic analysis and comparison thedifferences of MIF in rheumatism pathogenesis and clinical significance.

Results

Part I:1. Serum MIF was found  elevatedin patients IIMpatients, and in disease control groups RA, SLE and SLE.Serum MIF concentrationrespectively were 11622.43pg/ml (IQR 2216.00-95968.00 pg/ml), 13686 pg/ml (IQR 10142 ~ 17486 pg/ml), 4408 pg/ml (IQR 3133 ~ 5 208 pg/ml), 24251pg/ml (IQR 19807~29604 pg/ml).All significantly higher than healthy control group concentration of 1472.67pg /ml (IQR 805.25~1940.25), P <0.01).

2. The relationship with laboratory examination: Level of MIF in DM serum was positively correlated with the percentage of T total lymphocytes and the percentage of CD3+ T lymphocytes, and was negatively correlated with the percentage of CD3+CD4+ T lymphocytes.

3. Effects of disease progression: compared with 46 new patients and those who had received treatment, serum MIF concentration was higher in the new patients.The level of MIF in patients with disease progression (duration > 6 months) was higher than that in the early stage (the duration was less than 6 months).The disease activity score was analyzed and the results showed that there was no correlation between the activity score of patients and serum MIF level after treatment.

4. Predictive value of complications: Serum MIF in IIM patients with dysphagia was significantly higher than that without dysphagia (P = 0.024);The level of MIF in dermatomyositis and malignant tumors was higher than that of the patients without tumor (P=0.013), especially the DM anti-transcription factor (TIF)-1 (P<0.001) positive patients.

5.The serum MIF level of patients treated with high dose of glucocorticoidc was higher than that in patients with low hormone dose.There was no significant MIF level change in patients pure treated with glucocorticoidcreferring to patients treated with glucocorticoid and other immunosuppressive groups.

6. Follow-up study.Assome information about outpatientis not complete ,follow-up study only included 7 patients with dermatomyositis, per follow-up time intervals ranging from 6 months to 3 years, serum specimens were collected patients at a time.Comparinglaboratory tests、clinical index and serum MIF, the results show that after treatment, although the level of serum MIF decline is not obvious, serum levels of CD3+, CD4+, CD8+ lymphocytes number were significantly decline, having significant statistical correlation (P < 0.01).

Keywords    Idiopathic inflammatory myopathies；Polymyositis ; Dermatomyositis；Macrophage Migration-Inhibitory Factors.