多发性肌炎(PM)/皮肌炎(DM)相关的肺间质病变发(ILD)病机制的研究进展

张 立(综述) 王 强(审校)

(复旦大学附属中山医院皮肤科 上海 200032)

多发性肌炎(PM)/皮肌炎(DM)相关的肺间质病变发(ILD)病机制的研究进展

张 立(综述) 王 强△(审校)

(复旦大学附属中山医院皮肤科 上海 200032)

肺间质病变(interstitial lung disease,ILD)是多发性肌炎(polymyositis,PM )/皮肌炎(dermatomyositis,DM)的常见并发症,预后不良且死亡率高,是PM/DM患者住院和死亡的重要原因。PM/DM相关ILD发病机制目前仍不清楚;治疗上仍以激素为主,尚缺乏有效的治疗方法,近年来,对ILD的发病机制和治疗已成为一个研究热点。本文就参与发病的自身抗体、免疫细胞、细胞因子、组织蛋白酶、遗传因素学等方面对PM/DM相关的ILD的发病机制研究作一简要综述。

多发性肌炎(PM); 皮肌炎(DM); 肺间质病变(ILD); 发病机制

特发性炎性肌病(idiopathic inflammatory myopathies,IIM)是一组以不同程度骨骼肌炎症为特征的结缔组织病,主要包括多发性肌炎(polymyositis,PM)、皮肌炎(dermatomyositis,DM)和包涵体性肌炎(inclusion body myositis,IBM)。在PM/DM中肺间质病变(interstitial lung disease,ILD)的发生率约19.9%～78%[1],ILD会导致更严重的肺纤维化和肺动脉高压,甚至呼衰;也是PM/DM患者住院和死亡的重要原因,严重威胁患者的健康。一些患者常会发生不可预测且致命性的急性发作,至今尚无有效的防治措施。近年来,ILD的发病机制和治疗已成为一个研究热点。

PM/DM-ILD发病机制相关的血清标记物

MDA5(melanoma differentiation-associated protein 5)蛋白 无肌病性皮肌炎(amyopathic dermatomyositis,ADM)在亚洲多发,特点为有典型的DM皮损而无肌炎的客观体征。临床无肌病性皮肌炎(dinical ADM,CADM)常发展为急性进行性ILD(RP-ILD)[2]。Sato等[3]于2005年用蛋氨酸标记的免疫沉淀技术和K562细胞标记的免疫印迹技术,在CADM患者中发现了一种重要自身抗体(相对分子质量140 000),命名为抗CADM-140抗体。MDA5,又称IFIHl(IFN induced with helicase C domain protein 1),是RIG-I样受体家族中一员,能识别胞质内的双链核糖核酸(dsRNA)并诱导炎性因子和细胞表面分子的产生,是针对抗CADM-140抗体的特异性抗原[4]。与“金标准”免疫沉淀法相比,其敏感性为85%,特异性为100%,对诊断 CADM或RP-ILD很有意义[5]。抗MDA5抗体阳性的DM患者易出现皮肤溃疡、Gottron丘疹、肌无力、RP-ILD、纵隔气肿等,提示DM预后不良,发展为致死性ILD的风险增加[6]。研究发现,干扰素α(IFN-α)和血清铁蛋白(ferritin)在抗MDA5阳性的DM患者血清中浓度明显增高[7]。Gono等[8]发现高浓度的血清铁蛋白与急性ILD有关,并可作为抗MDA5抗体阳性的DM患者预后不良的指标。Muro等[9]指出,抗MDA5抗体在CADM合并ILD患者的恢复期消失,并提出联合抗MDA5抗体和血清铁蛋白、IL-18 评价DM的预后更科学。

根据日本一项1994年至2010年的流行病学调查,CADM和抗MDA5抗体阳性出现相关度有增加趋势,且抗MDA5阳性的DM患者表型在日本的分布有地域差异,表明环境因素影响抗MDA5抗体的产生[10]。而对地中海DM患者调查发现,抗MDA5抗体阳性的ILD患者比抗合成酶抗体阳性的ILD患者生存期少70个月[11]。

KL-6(Krebs von den Lungen-6)蛋白 KL-6是1985年首次发现并命名的高分子量糖蛋白,属于黏蛋白家族,主要表达于Ⅱ型肺泡上皮细胞(alveolar epithelial cell,AEC)和细支气管上皮细胞,是一种对于ILD诊断有重要价值的血清学指标。研究表明,KL-6是包含sulfo-Gal/Gal的黏蛋白型O-聚糖[12],对肺成纤维细胞有促纤维化和抗凋亡作用[13]。Fathi等[14]发现,在PM-ILD患者中KL-6水平显著升高,且KL-6的升高程度与FEV1、VC、TLC、FVC、MVV40及DLco升高相关,能反映ILD的严重程度。血清KL-6浓度可作为诊断PM/DM-ILD非创伤性的有效方法,也是评估临床疗效的重要血清学指标。血清KL-6对ILD诊断的敏感性是100%,对PM/DM-ILD的特异性是83%。血清KL-6可作为PM/DM-ILD预后不良的诊断依据之一[15]。

肺表面活性蛋白D(surfactant protein D,SP-D) 多数ILD是由肺内T淋巴细胞和自身抗原引起的炎性反应造成AEC的损伤而引起。当I型肺泡上皮细胞(AECI)凋亡时,导致大量Ⅱ型肺泡上皮细胞(AECII)增殖,从而产生大量细胞因子、生长因子和肺泡表面活性蛋白和黏蛋白。其中,KL-6、SP-D和SP-A成为诊断严重ILD(特别是特发性肺纤维化IPF)的血清学指标[16]。Ihn等[17]指出,血清SP-D浓度在PM/DM-ILD患者中显著升高,检测准确度为93%,且其升高程度伴随着肺活量和肺弥散功能的下降,说明SP-D可作为评价PM/DM-ILD的特异性标志物。研究表明,同时检测SP-D和KL-6可提高诊断PM/DM-ILD的灵敏度[15]。

Jo-1抗体 抗氨基酰tRNA合成酶抗体包括抗Jo-1抗体,抗PL-7抗体,抗PL-12抗体,抗EJ抗体,抗OJ抗体和抗KS抗体。抗合成酶综合征(antisynthetase syndrome,AS)以肌炎、雷诺现象、关节炎和技工手为典型症状,常并发严重的ILD。最常见的抗氨基酰tRNA合成酶抗体是抗Jo-1抗体,在20%的肌炎患者中出现,更易并发普通ILD[18]。

免疫细胞

T淋巴细胞 在PM/DM肌肉组织中出现大量炎性细胞。PM由CD8+T淋巴细胞介导,与肌纤维细胞表达的I型主要组织相容性免疫复合体刺激相关细胞免疫[19];DM是炎性细胞浸润在肌肉组织血管周边部位,主要由CD4+T淋巴细胞和B淋巴细胞介导[20]。同样,T细胞也参与PM/DM-ILD的发病。研究发现激活的T细胞,特别是CD8+T淋巴细胞,在PM/DM-ILD中起重要作用。在PM/DM-ILD中出现外周血T细胞总数减少和CD4+T淋巴细胞比例降低[21]。Sauty等[22]发现PM/DM-ILD血清中抗Jo-1抗体与肺泡灌洗液(bronchoalveolar lavage fluid,BALF)中CD8+T淋巴细胞增多有关。Kurasawa等[23]检测22例ILD患者BALF,发现对激素治疗敏感的患者CD8+和CD25+T淋巴细胞显著增加。近期,CX3CL1及其受体 CX3CR1参与肌肉和肺组织的炎症浸润,CX3CL1在绝大多数CD8+T淋巴细胞和巨噬细胞及少数CD4+T淋巴细胞[24]中有所表达。

B淋巴细胞 DM患者肌肉局部血管周围可见B细胞浸润;包涵体肌炎患者肌肉中出现浆细胞浸润。B细胞活化因子(B-cell activating factor,BAFF)是肿瘤坏死因子(tumor necrosis factor,TNF)家族中的一员,对B细胞的成熟和存活十分重要。BAFF在自身抗体的产生过程和T细胞的激活和分化过程中起重要作用[25]。传统的激素和细胞抑制剂对AS合并严重ILD治疗无效,最近研究表明抗B细胞免疫抑制治疗有一定效果[26]。

巨噬细胞 巨噬细胞主要分为M1和M2型,前者由脂多糖(LPS)诱导产生,并能产生大量的炎性细胞因子,如IL-1β、IL-12、TNF-α 和iNOS[27];后者由TH2分泌的细胞因子(如IL-4、IL-13)诱导产生,并能产生IL-10、ARG-1、FIZZ-1和CCL17[28]。MMP28(基质金属蛋白酶28,又称上皮水解素)是蛋白酶的家族成员之一,参与巨噬细胞引起的ILD。MMP28由巨噬细胞产生,并能促进巨噬细胞趋化至肺组织。MMP28能抑制M1型巨噬细胞,促使其向M2型巨噬细胞极化,进而发生肺纤维化[29]。Yamashita等[30]研究认为,大量CD68巨噬细胞参与肺泡损伤机制,并由CCL19和CCR7介导趋化,大量聚集在肺泡纤维化区域。CHI3L1(chitinase 3-like 1)具有促肺泡炎症和细胞凋亡的作用,其通过促进M2型巨噬细胞、成纤维细胞增殖和细胞外基质(extracellular matrix,ECM)沉积而促进纤维化进程[31]。 巨噬细胞的集聚和活化与增高的TGF-β和IFN 共同促进肺纤维化[32]。

细胞因子 转化生长因子-β(transforming growth factorβ,TGF-β)是一种具有调节细胞增殖、分化、迁移和存活的多功能细胞因子,其中TGF-β1是免疫细胞表达的主要类型。TGF-β1能促进蛋白酶抑制肽C对组织蛋白酶的抑制作用,使ECM的降解减少[33]。TGF-β1能促进成纤维细胞的活化,并增殖分化为表达α平滑肌肌动蛋白的成肌纤维细胞。成肌纤维细胞分泌大量的ECM,其累积和长时间作用被认为是导致纤维化进展的重要因素[34]。研究发现,TGF-β信号促进巨噬细胞向M2型极化。TβRII功能缺陷的小鼠由于缺乏TβRII信号,肺组织中巨噬细胞无法向具有抗炎作用的M2型极化,从而减弱并下调其与T细胞的联系,最终出现严重的全身炎性反应[35]。多种干扰素(interferon,IFN)类细胞因子也被认为参与PM/DM-ILD的发病过程。IFN-γ诱导的趋化因子CXCL9、CXCL10和C反应蛋白(C-reactive protein,CRP)参与抗Jo-1抗体相关的肌炎并发ILD[36]。 IFN-γ 和 IL-10通过转铁蛋白受体或二价金属离子转运体刺激巨噬细胞使铁滞留在巨噬细胞内,从而导致巨噬细胞聚集于肺泡内[37]。IFN-α参与ILD的进程,且与抗MDA5抗体相关,血清IFN-α浓度在抗MDA5抗体阳性的ILD患者中增高[38]。另外,TNF-α和M2型巨噬细胞在肺部炎症和纤维化中起重要作用[39]。Gono等[40]发现,TNF-α是由M2型巨噬细胞和单核细胞产生,并参与PM/DM-ILD过程。TNF-α和IL-6、IL-8、IL-10、IL-18与血清铁蛋白升高密切相关,且在ILD-PM/DM中显著升高[41]。

组织蛋白酶 组织蛋白酶属于木瓜蛋白酶家族,位于细胞溶酶体内;参与体内各种与组蛋白水解有关的生命活动,如胚胎干细胞的定向分化、神经肽和甲状腺激素含量的调节、骨的重建和再吸收、毛发生长的控制及抗原提呈等[42]。通过柯萨奇病毒1诱导PM豚鼠模型,发现组织蛋白酶B参与PM的肌肉发病。组织蛋白酶B的蛋白表达在PM患者中显著升高,且与细胞凋亡、组织炎症程度相关;用组织蛋白酶B特异性抑制剂CA-074Me干预后,发现CA-074Me对PM肌纤维有保护作用[19]。在肺组织中,ECM的动态平衡依赖合理的蛋白水解作用的调节,组织蛋白酶可降解ECM,肺部纤维化和炎症与其异常活性有关,其中组织蛋白酶B通过激活前金属蛋白酶(pro-MMPs),促进ECM降解和炎性细胞迁移[43]。组织蛋白酶在慢性肺疾病(如矽肺、哮喘、肺泡纤维化等)中含量增加,导致基底膜和ECM的重构,使炎症加重[44]。组织蛋白酶K缺失将加重肺纤维化,然而组织蛋白酶K的增加将减少过度的ECM层积[45]。近期,我们发现组织蛋白酶B参与ILD发病,CA-074Me可通过减少TGF-β1、巨噬细胞和CD8+T淋巴细胞,减轻肺部炎症来细胞凋亡及纤维化[46]。更多关于组织蛋白酶B的机制有待被发现。

免疫遗传学研究STAT4基因是一个自身免疫病的危险基因,在日本人中首次发现STAT4与肌炎有关。Sugiura等[47]对日本460例IIM患者(187例DM,273例PM)和683例正常人的核型rs7574865多态性进行调查,发现等位基因rs7574865T与PM/DM密切相关。Gono等[48]调查发现,在抗MDA5抗体阳性的患者中HLA-DRB1*0101和DRB1*0405出现的频率分别是29%和71%,显著高于正常人的10%和25%,其中94%患者有DRB1*0101 或 DRB1*0405等位基因。HLA-DRB1*3和吸烟的相互作用被认为是形成抗Jo-1抗体的危险因素[49]。Miller等[50]通过全基因组关联研究,发现DM自身免疫病存在遗传倾向。主要组织相容性复合体(major histocompatibility compler,MHC)是DM相关的主要基因区域,同时DM也有与其他自身免疫病相似的与MHC无关的遗传特征,提示有其他危险基因位点的存在。

结语 综上所述,PM/DM-ILD发病机制与自身免疫(自身免疫抗体及相关蛋白、淋巴细胞、细胞因子、蛋白酶)异常和遗传-环境作用相关。PM与DM发病机制不同,其中DM和ADM并发急性ILD常见,死亡率极高,可能有独特的发病机制。MDA5的出现对非创伤性诊断DM-ILD的意义重大。而免疫机制方面,免疫细胞(特别是CD8+T细胞和巨噬细胞)通过分泌多种细胞因子(如TGF-β1、TNF-α等),调节ECM,参与PM/DM相关ILD的炎症、凋亡和纤维化过程。组织蛋白酶B激活的信号通路参与PM-ILD的发病,可能成为临床治疗潜在的靶点。目前仍缺乏防治ILD的有效措施,进一步研究其发病机制,以期为临床治疗寻找关键点。

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复旦大学医科类20位学者荣登Elsevier“2014年中国高被引学者榜单”

2015年2月2日,国际著名科技出版集团Elsevier发布了“2014年中国高被引学者(Most Cited Chinese Researchers)榜单”,登上榜单的中国学者共有1 651位。其中我校基础医学院闻玉梅院士,公共卫生临床中心Lowrie,Douglas B.(免疫和微生物学榜单);药学院蒋新国教授、胡金锋教授、方晓玲教授、陈道峰教授、裴元英教授(药理学、毒理学和药剂学榜单);基础医学院袁正宏教授,中山医院汤钊猷院士、樊嘉教授、葛雷教授、孙惠川教授,华山医院钦伦秀教授,肿瘤医院邵志敏教授,妇产科医院郭孙伟教授(医学榜单);基础医学院姜世勃教授,药学院钱忠明教授,中山医院夏朴教授(生化、遗传和分子生物榜单学);脑科学研究院赵志奇教授、黄志力教授(神经科学榜单)荣登榜单(上述排序不分先后)。

“2014年中国高被引学者榜单”的研究数据来自爱思唯尔旗下的Scopus数据库。Scopus是全球最大的同行评议学术论文索引摘要数据库,提供了海量的与科研活动有关的文献、作者和研究机构数据,使得对中国学者的世界影响力进行科学的分析和评价成为可能。“高被引学者”是指作为第一作者和通讯作者发表论文的被引用总次数在中国(大陆地区)范围内、本学科中处于最高水平的研究者,意味着这些学者专家在其研究领域具有世界级的影响力。“高被引学者”的数量也被一些专业评估体系作为一个大学科学研究水平排名的指标之一,其在一定程度上体现了大学所拥有的顶尖人才水平。

(复旦大学上海医学院)

The pathogenesis of interstitial lung disease (ILD) associated with polymyositis (PM) and dermatomyositis (DM)

ZHANG Li,WANG Qiang△

(DepartmentofDermatology,ZhongshanHospital,FudanUniversity,Shanghai200032,China)

Interstitial lung disease (ILD) is a common complication of polymyositis (PM)/ dermatomyositis (DM),with bad outcomes and significant mortality,which is the primary reason for hospital admission and death.Steroids remain the first-line therapy for ILD in patients with DM/PM.However,steroids are often not sufficient for the improvement of ILD.The pathogenesis of PM/DM-ILD is not completely understood.Therefore,it is necessary to develop novel and effective therapies for ILD.This review mainly presents recent advances of autoantibody,immunocyte,cytokine,cathepsin and genetics in pathogenesis of PM/DM-ILD.

polymyositis (PM); dermatomyositis (DM); interstitial lung disease (ILD);pathogenesis

R 593.26; R 714.43

B

10.3969/j.issn.1672-8467.2015.02.022

2014-10-20;编辑:段佳)

上海市自然科学基金(08ZR1402800)

△Corresponding author E-mail:wang.qiang@zs-hospital.sh.cn

*This work was supported by the Natural Science Foundation of Shanghai (08ZR1402800).