多發性肌炎(PM)/皮肌炎(DM)相關的肺間質病變發(ILD)病機制的研究進展

張 立(綜述) 王 強(審校)

(復旦大學附屬中山醫院皮膚科 上海 200032)

多發性肌炎(PM)/皮肌炎(DM)相關的肺間質病變發(ILD)病機制的研究進展

張 立(綜述) 王 強△(審校)

(復旦大學附屬中山醫院皮膚科 上海 200032)

肺間質病變(interstitial lung disease,ILD)是多發性肌炎(polymyositis,PM )/皮肌炎(dermatomyositis,DM)的常見并發癥,預后不良且死亡率高,是PM/DM患者住院和死亡的重要原因。PM/DM相關ILD發病機制目前仍不清楚;治療上仍以激素為主,尚缺乏有效的治療方法,近年來,對ILD的發病機制和治療已成為一個研究熱點。本文就參與發病的自身抗體、免疫細胞、細胞因子、組織蛋白酶、遺傳因素學等方面對PM/DM相關的ILD的發病機制研究作一簡要綜述。

多發性肌炎(PM); 皮肌炎(DM); 肺間質病變(ILD); 發病機制

特發性炎性肌病(idiopathic inflammatory myopathies,IIM)是一組以不同程度骨骼肌炎癥為特征的結締組織病,主要包括多發性肌炎(polymyositis,PM)、皮肌炎(dermatomyositis,DM)和包涵體性肌炎(inclusion body myositis,IBM)。在PM/DM中肺間質病變(interstitial lung disease,ILD)的發生率約19.9%～78%[1],ILD會導致更嚴重的肺纖維化和肺動脈高壓,甚至呼衰;也是PM/DM患者住院和死亡的重要原因,嚴重威脅患者的健康。一些患者常會發生不可預測且致命性的急性發作,至今尚無有效的防治措施。近年來,ILD的發病機制和治療已成為一個研究熱點。

PM/DM-ILD發病機制相關的血清標記物

MDA5(melanoma differentiation-associated protein 5)蛋白 無肌病性皮肌炎(amyopathic dermatomyositis,ADM)在亞洲多發,特點為有典型的DM皮損而無肌炎的客觀體征。臨床無肌病性皮肌炎(dinical ADM,CADM)常發展為急性進行性ILD(RP-ILD)[2]。Sato等[3]于2005年用蛋氨酸標記的免疫沉淀技術和K562細胞標記的免疫印跡技術,在CADM患者中發現了一種重要自身抗體(相對分子質量140 000),命名為抗CADM-140抗體。MDA5,又稱IFIHl(IFN induced with helicase C domain protein 1),是RIG-I樣受體家族中一員,能識別胞質內的雙鏈核糖核酸(dsRNA)并誘導炎性因子和細胞表面分子的產生,是針對抗CADM-140抗體的特異性抗原[4]。與“金標準”免疫沉淀法相比,其敏感性為85%,特異性為100%,對診斷 CADM或RP-ILD很有意義[5]?？筂DA5抗體陽性的DM患者易出現皮膚潰瘍、Gottron丘疹、肌無力、RP-ILD、縱隔氣腫等,提示DM預后不良,發展為致死性ILD的風險增加[6]。研究發現,干擾素α(IFN-α)和血清鐵蛋白(ferritin)在抗MDA5陽性的DM患者血清中濃度明顯增高[7]。Gono等[8]發現高濃度的血清鐵蛋白與急性ILD有關,并可作為抗MDA5抗體陽性的DM患者預后不良的指標。Muro等[9]指出,抗MDA5抗體在CADM合并ILD患者的恢復期消失,并提出聯合抗MDA5抗體和血清鐵蛋白、IL-18 評價DM的預后更科學。

根據日本一項1994年至2010年的流行病學調查,CADM和抗MDA5抗體陽性出現相關度有增加趨勢,且抗MDA5陽性的DM患者表型在日本的分布有地域差異,表明環境因素影響抗MDA5抗體的產生[10]。而對地中海DM患者調查發現,抗MDA5抗體陽性的ILD患者比抗合成酶抗體陽性的ILD患者生存期少70個月[11]。

KL-6(Krebs von den Lungen-6)蛋白 KL-6是1985年首次發現并命名的高分子量糖蛋白,屬于黏蛋白家族,主要表達于Ⅱ型肺泡上皮細胞(alveolar epithelial cell,AEC)和細支氣管上皮細胞,是一種對于ILD診斷有重要價值的血清學指標。研究表明,KL-6是包含sulfo-Gal/Gal的黏蛋白型O-聚糖[12],對肺成纖維細胞有促纖維化和抗凋亡作用[13]。Fathi等[14]發現,在PM-ILD患者中KL-6水平顯著升高,且KL-6的升高程度與FEV1、VC、TLC、FVC、MVV40及DLco升高相關,能反映ILD的嚴重程度。血清KL-6濃度可作為診斷PM/DM-ILD非創傷性的有效方法,也是評估臨床療效的重要血清學指標。血清KL-6對ILD診斷的敏感性是100%,對PM/DM-ILD的特異性是83%。血清KL-6可作為PM/DM-ILD預后不良的診斷依據之一[15]。

肺表面活性蛋白D(surfactant protein D,SP-D) 多數ILD是由肺內T淋巴細胞和自身抗原引起的炎性反應造成AEC的損傷而引起。當I型肺泡上皮細胞(AECI)凋亡時,導致大量Ⅱ型肺泡上皮細胞(AECII)增殖,從而產生大量細胞因子、生長因子和肺泡表面活性蛋白和黏蛋白。其中,KL-6、SP-D和SP-A成為診斷嚴重ILD(特別是特發性肺纖維化IPF)的血清學指標[16]。Ihn等[17]指出,血清SP-D濃度在PM/DM-ILD患者中顯著升高,檢測準確度為93%,且其升高程度伴隨著肺活量和肺彌散功能的下降,說明SP-D可作為評價PM/DM-ILD的特異性標志物。研究表明,同時檢測SP-D和KL-6可提高診斷PM/DM-ILD的靈敏度[15]。

Jo-1抗體 抗氨基酰tRNA合成酶抗體包括抗Jo-1抗體,抗PL-7抗體,抗PL-12抗體,抗EJ抗體,抗OJ抗體和抗KS抗體?？购铣擅妇C合征(antisynthetase syndrome,AS)以肌炎、雷諾現象、關節炎和技工手為典型癥狀,常并發嚴重的ILD。最常見的抗氨基酰tRNA合成酶抗體是抗Jo-1抗體,在20%的肌炎患者中出現,更易并發普通ILD[18]。

免疫細胞

T淋巴細胞 在PM/DM肌肉組織中出現大量炎性細胞。PM由CD8+T淋巴細胞介導,與肌纖維細胞表達的I型主要組織相容性免疫復合體刺激相關細胞免疫[19];DM是炎性細胞浸潤在肌肉組織血管周邊部位,主要由CD4+T淋巴細胞和B淋巴細胞介導[20]。同樣,T細胞也參與PM/DM-ILD的發病。研究發現激活的T細胞,特別是CD8+T淋巴細胞,在PM/DM-ILD中起重要作用。在PM/DM-ILD中出現外周血T細胞總數減少和CD4+T淋巴細胞比例降低[21]。Sauty等[22]發現PM/DM-ILD血清中抗Jo-1抗體與肺泡灌洗液(bronchoalveolar lavage fluid,BALF)中CD8+T淋巴細胞增多有關。Kurasawa等[23]檢測22例ILD患者BALF,發現對激素治療敏感的患者CD8+和CD25+T淋巴細胞顯著增加。近期,CX3CL1及其受體 CX3CR1參與肌肉和肺組織的炎癥浸潤,CX3CL1在絕大多數CD8+T淋巴細胞和巨噬細胞及少數CD4+T淋巴細胞[24]中有所表達。

B淋巴細胞 DM患者肌肉局部血管周圍可見B細胞浸潤;包涵體肌炎患者肌肉中出現漿細胞浸潤。B細胞活化因子(B-cell activating factor,BAFF)是腫瘤壞死因子(tumor necrosis factor,TNF)家族中的一員,對B細胞的成熟和存活十分重要。BAFF在自身抗體的產生過程和T細胞的激活和分化過程中起重要作用[25]。傳統的激素和細胞抑制劑對AS合并嚴重ILD治療無效,最近研究表明抗B細胞免疫抑制治療有一定效果[26]。

巨噬細胞 巨噬細胞主要分為M1和M2型,前者由脂多糖(LPS)誘導產生,并能產生大量的炎性細胞因子,如IL-1β、IL-12、TNF-α 和iNOS[27];后者由TH2分泌的細胞因子(如IL-4、IL-13)誘導產生,并能產生IL-10、ARG-1、FIZZ-1和CCL17[28]。MMP28(基質金屬蛋白酶28,又稱上皮水解素)是蛋白酶的家族成員之一,參與巨噬細胞引起的ILD。MMP28由巨噬細胞產生,并能促進巨噬細胞趨化至肺組織。MMP28能抑制M1型巨噬細胞,促使其向M2型巨噬細胞極化,進而發生肺纖維化[29]。Yamashita等[30]研究認為,大量CD68巨噬細胞參與肺泡損傷機制,并由CCL19和CCR7介導趨化,大量聚集在肺泡纖維化區域。CHI3L1(chitinase 3-like 1)具有促肺泡炎癥和細胞凋亡的作用,其通過促進M2型巨噬細胞、成纖維細胞增殖和細胞外基質(extracellular matrix,ECM)沉積而促進纖維化進程[31]。 巨噬細胞的集聚和活化與增高的TGF-β和IFN 共同促進肺纖維化[32]。

細胞因子 轉化生長因子-β(transforming growth factorβ,TGF-β)是一種具有調節細胞增殖、分化、遷移和存活的多功能細胞因子,其中TGF-β1是免疫細胞表達的主要類型。TGF-β1能促進蛋白酶抑制肽C對組織蛋白酶的抑制作用,使ECM的降解減少[33]。TGF-β1能促進成纖維細胞的活化,并增殖分化為表達α平滑肌肌動蛋白的成肌纖維細胞。成肌纖維細胞分泌大量的ECM,其累積和長時間作用被認為是導致纖維化進展的重要因素[34]。研究發現,TGF-β信號促進巨噬細胞向M2型極化。TβRII功能缺陷的小鼠由于缺乏TβRII信號,肺組織中巨噬細胞無法向具有抗炎作用的M2型極化,從而減弱并下調其與T細胞的聯系,最終出現嚴重的全身炎性反應[35]。多種干擾素(interferon,IFN)類細胞因子也被認為參與PM/DM-ILD的發病過程。IFN-γ誘導的趨化因子CXCL9、CXCL10和C反應蛋白(C-reactive protein,CRP)參與抗Jo-1抗體相關的肌炎并發ILD[36]。 IFN-γ 和 IL-10通過轉鐵蛋白受體或二價金屬離子轉運體刺激巨噬細胞使鐵滯留在巨噬細胞內,從而導致巨噬細胞聚集于肺泡內[37]。IFN-α參與ILD的進程,且與抗MDA5抗體相關,血清IFN-α濃度在抗MDA5抗體陽性的ILD患者中增高[38]。另外,TNF-α和M2型巨噬細胞在肺部炎癥和纖維化中起重要作用[39]。Gono等[40]發現,TNF-α是由M2型巨噬細胞和單核細胞產生,并參與PM/DM-ILD過程。TNF-α和IL-6、IL-8、IL-10、IL-18與血清鐵蛋白升高密切相關,且在ILD-PM/DM中顯著升高[41]。

組織蛋白酶 組織蛋白酶屬于木瓜蛋白酶家族,位于細胞溶酶體內;參與體內各種與組蛋白水解有關的生命活動,如胚胎干細胞的定向分化、神經肽和甲狀腺激素含量的調節、骨的重建和再吸收、毛發生長的控制及抗原提呈等[42]。通過柯薩奇病毒1誘導PM豚鼠模型,發現組織蛋白酶B參與PM的肌肉發病。組織蛋白酶B的蛋白表達在PM患者中顯著升高,且與細胞凋亡、組織炎癥程度相關;用組織蛋白酶B特異性抑制劑CA-074Me干預后,發現CA-074Me對PM肌纖維有保護作用[19]。在肺組織中,ECM的動態平衡依賴合理的蛋白水解作用的調節,組織蛋白酶可降解ECM,肺部纖維化和炎癥與其異?；钚杂嘘P,其中組織蛋白酶B通過激活前金屬蛋白酶(pro-MMPs),促進ECM降解和炎性細胞遷移[43]。組織蛋白酶在慢性肺疾病(如矽肺、哮喘、肺泡纖維化等)中含量增加,導致基底膜和ECM的重構,使炎癥加重[44]。組織蛋白酶K缺失將加重肺纖維化,然而組織蛋白酶K的增加將減少過度的ECM層積[45]。近期,我們發現組織蛋白酶B參與ILD發病,CA-074Me可通過減少TGF-β1、巨噬細胞和CD8+T淋巴細胞,減輕肺部炎癥來細胞凋亡及纖維化[46]。更多關于組織蛋白酶B的機制有待被發現。

免疫遺傳學研究STAT4基因是一個自身免疫病的危險基因,在日本人中首次發現STAT4與肌炎有關。Sugiura等[47]對日本460例IIM患者(187例DM,273例PM)和683例正常人的核型rs7574865多態性進行調查,發現等位基因rs7574865T與PM/DM密切相關。Gono等[48]調查發現,在抗MDA5抗體陽性的患者中HLA-DRB1*0101和DRB1*0405出現的頻率分別是29%和71%,顯著高于正常人的10%和25%,其中94%患者有DRB1*0101 或 DRB1*0405等位基因。HLA-DRB1*3和吸煙的相互作用被認為是形成抗Jo-1抗體的危險因素[49]。Miller等[50]通過全基因組關聯研究,發現DM自身免疫病存在遺傳傾向。主要組織相容性復合體(major histocompatibility compler,MHC)是DM相關的主要基因區域,同時DM也有與其他自身免疫病相似的與MHC無關的遺傳特征,提示有其他危險基因位點的存在。

結語 綜上所述,PM/DM-ILD發病機制與自身免疫(自身免疫抗體及相關蛋白、淋巴細胞、細胞因子、蛋白酶)異常和遺傳-環境作用相關。PM與DM發病機制不同,其中DM和ADM并發急性ILD常見,死亡率極高,可能有獨特的發病機制。MDA5的出現對非創傷性診斷DM-ILD的意義重大。而免疫機制方面,免疫細胞(特別是CD8+T細胞和巨噬細胞)通過分泌多種細胞因子(如TGF-β1、TNF-α等),調節ECM,參與PM/DM相關ILD的炎癥、凋亡和纖維化過程。組織蛋白酶B激活的信號通路參與PM-ILD的發病,可能成為臨床治療潛在的靶點。目前仍缺乏防治ILD的有效措施,進一步研究其發病機制,以期為臨床治療尋找關鍵點。

[1] Hallowell RW,Ascherman DP,Danoff SK.Pulmonary manifestations of polymyositis/dermatomyositis [J].SeminRespirCritCareMed,2014,35(2):239-248.

[2] Teruya A,Kawamura K,Ichikado K,etal.Successful polymyxin B hemoperfusion treatment associated with serial reduction of serum anti-CADM-140/MDA5 antibody levels in rapidly progressive interstitial lung disease with amyopathic dermatomyositis [J].Chest,2013,144(6):1934-1936.

[3] Sato S,Hirakata M,Kuwana M,etal.Autoantibodies to a 140-kd polypeptide,CADM-140,in Japanese patients with clinically amyopathic dermatomyositis [J].ArthritisRheum,2005,52(5):1571-1576.

[4] Nakashima R,Imura Y,Kobayashi S,etal.The RIG-I-like receptor IFIH1/MDA5 is a dermatomyositis-specific autoantigen identified by the anti-CADM-140 antibody [J].Rheumatology(Oxford),2010,49(3):433-440.

[5] Sato S,Hoshino K,Satoh T,etal.RNA helicase encoded by melanoma differentiation-associated gene 5 is a major autoantigen in patients with clinically amyopathic dermatomyositis:Association with rapidly progressive interstitial lung disease [J].ArthritisRheum,2009,60(7):2193-2200.

[6] Koga T,Fujikawa K,Horai Y,etal.The diagnostic utility of anti-melanoma differentiation-associated gene 5 antibody testing for predicting the prognosis of Japanese patients with DM [J].Rheumatology(Oxford),2012,51(7):1278-1284.

[7] Horai Y,Koga T,Fujikawa K,etal.Serum interferon-alpha is a useful biomarker in patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis [J].ModRheumatol,2015,25(1):85-89.

[8] Gono T,Sato S,Kawaguchi Y,etal.Anti-MDA5 antibody,ferritin and IL-18 are useful for the evaluation of response to treatment in interstitial lung disease with anti-MDA5 antibody-positive dermatomyositis [J].Rheumatology(Oxford),2012,51(9):1563-1570.

[9] Muro Y,Sugiura K,Akiyama M.Limitations of a single-point evaluation of anti-MDA5 antibody,ferritin,and IL-18 in predicting the prognosis of interstitial lung disease with anti-MDA5 antibody-positive dermatomyositis [J].ClinRheumatol,2013,32(3):395-398.

[10] Muro Y,Sugiura K,Hoshino K,etal.Epidemiologic study of clinically amyopathic dermatomyositis and anti-melanoma differentiation-associated gene 5 antibodies in central Japan [J].ArthritisResTher,2011,13(6):R214.

[11] Labrador-Horrillo M,Martinez MA,Selva-O′Callaghan A,etal.Anti-MDA5 antibodies in a large Mediterranean population of adults with dermatomyositis [J].JImmunolRes,2014,2014:290797.

[12] Seko A,Ohkura T,Ideo H,etal.Novel O-linked glycans containing 6′-sulfo-Gal/GalNAc of MUC1 secreted from human breast cancer YMB-S cells:possible carbohydrate epitopes of KL-6 (MUC1) monoclonal antibody [J].Glycobiology,2012,22(2):181-195.

[13] Ohshimo S,Ishikawa N,Horimasu Y,etal.Baseline KL-6 predicts increased risk for acute exacerbation of idiopathic pulmonary fibrosis [J].RespirMed,2014,108(7):1031-1039.

[14] Fathi M,Barbasso HS,Lundberg IE.KL-6:a serological biomarker for interstitial lung disease in patients with polymyositis and dermatomyositis [J].JInternMed,2012,271(6):589-597.

[15] Arai S,Kurasawa K,Maezawa R,etal.Marked increase in serum KL-6 and surfactant protein D levels during the first 4 weeks after treatment predicts poor prognosis in patients with active interstitial pneumonia associated with polymyositis/dermatomyositis[J].ModRheumatol,2013,23(5):872-883.

[16] Bonella F,Costabel U.Biomarkers in connective tissue disease-associated interstitial lung disease [J].SeminRespirCritCareMed,2014,35(2):181-200.

[17] Ihn H,Asano Y,Kubo M,etal.Clinical significance of serum surfactant protein D (SP-D) in patients with polymyositis/dermatomyositis:correlation with interstitial lung disease [J].Rheumatology(Oxford),2002,41(11):1268-1272.

[18] Yousem SA,Gibson K,Kaminski N,etal.The pulmonary histopathologic manifestations of the anti-Jo-1 tRNA synthetase syndrome [J].ModPathol,2010,23(6):874-880.

[19] Feng Y,Ni L,Wang Q.Administration of cathepsin B inhibitor CA-074Me reduces inflammation and apoptosis in polymyositis [J].JDermatolSci,2013,72(2):158-167.

[20] Reed AM,Ernste F.The inflammatory milieu in idiopathic inflammatory myositis[J].CurrRheumatolRep,2009,11(4):295-301.

[21] Wang DX,Lu X,Zu N,etal.Clinical significance of peripheral blood lymphocyte subsets in patients with polymyositis and dermatomyositis [J].ClinRheumatol,2012,31(12):1691-1697.

[22] Sauty A,Rochat T,Schoch OD,etal.Pulmonary fibrosis with predominant CD8 lymphocytic alveolitis and anti-Jo-1 antibodies [J].EurRespirJ,1997,10(12):2907-2912.

[23] Kurasawa K,Nawata Y,Takabayashi K,etal.Activation of pulmonary T cells in corticosteroid-resistant and-sensitive interstitial pneumonitis in dermatomyositis/polymyositis [J].ClinExpImmunol,2002,129(3):541-548.

[24] Suzuki F,Kubota T,Miyazaki Y,etal.Serum level of soluble CX3CL1/fractalkine is elevated in patients with polymyositis and dermatomyositis,which is correlated with disease activity [J].ArthritisResTher,2012,14(2):R48.

[25] Krystufkova O,Vallerskog T,Helmers SB,etal.Increased serum levels of B cell activating factor (BAFF) in subsets of patients with idiopathic inflammatory myopathies [J].AnnRheumDis,2009,68(6):836-843.

[26] Rios FR,Callejas RJ,Sanchez CD,etal.Rituximab in the treatment of dermatomyositis and other inflammatory myopathies.A report of 4 cases and review of the literature [J].ClinExpRheumatol,2009,27(6):1009-1016.

[27] Vogel DY,Glim JE,Stavenuiter AW,etal.Human macrophage polarization in vitro:maturation and activation methods compared [J].Immunobiology,2014,219(9):695-703.

[28] Makita N,Hizukuri Y,Yamashiro K,etal.IL-10 enhances the phenotype of M2 macrophages induced by IL-4 and confers the ability to increase eosinophil migration [J].IntImmunol,2015,27(3):131-141.

[29] Gharib SA,Johnston LK,Huizar I,etal.MMP28 promotes macrophage polarization toward M2 cells and augments pulmonary fibrosis [J].JLeukocBiol,2014,95(1):9-18.

[30] Yamashita M,Iwama N,Date F,etal.Macrophages participate in lymphangiogenesis in idiopathic diffuse alveolar damage through CCL19-CCR7 signal [J].HumPathol,2009,40(11):1553-1563.

[31] Zhou Y,Peng H,Sun H,etal.Chitinase 3-like 1 suppresses injury and promotes fibroproliferative responses in Mammalian lung fibrosis [J].SciTranslMed,2014,6(240):240R-276R.

[32] Christmann RB,Sampaio-Barros P,Stifano G,etal.Association of Interferon-and transforming growth factor beta-regulated genes and macrophage activation with systemic sclerosis-related progressive lung fibrosis [J].ArthritisRheumatol,2014,66(3):714-725.

[33] Kasabova M,Joulin-Giet A,Lecaille F,etal.Regulation of TGF-beta1-driven differentiation of human lung fibroblasts:emerging roles of cathepsin B and cystatin C [J].JBiolChem,2014,289(23):16239-16251.

[34] Hinz B,Phan SH,Thannickal VJ,etal.The myofibroblast:one function,multiple origins [J].AmJPathol,2007,170(6):1807-1816.

[35] Gong D,Shi W,Yi SJ,etal.TGF beta signaling plays a critical role in promoting alternative macrophage activation [J].BMCImmunol,2012,13:31.

[36] Richards TJ,Eggebeen A,Gibson K,etal.Characterization and peripheral blood biomarker assessment of anti-Jo-1 antibody-positive interstitial lung disease [J].ArthritisRheum,2009,60(7):2183-2192.

[37] Weiss G,Schett G.Anaemia in inflammatory rheumatic diseases [J].NatRevRheumatol,2013,9(4):205-215.

[38] Sun WC,Sun YC,Lin H,etal.Dysregulation of the type I interferon system in adult-onset clinically amyopathic dermatomyositis has a potential contribution to the development of interstitial lung disease[J].BrJDermatol,2012,167(6):1236-1244.

[39] Bargagli E,Prasse A,Olivieri C,etal.Macrophage-derived biomarkers of idiopathic pulmonary fibrosis [J].PulmMed,2011,2011:717130.

[40] Gono T,Kaneko H,Kawaguchi Y,etal.Cytokine profiles in polymyositis and dermatomyositis complicated by rapidly progressive or chronic interstitial lung disease [J].Rheumatology(Oxford),2014,53(12):2196-2203.

[41] Kawasumi H,Gono T,Kawaguchi Y,etal.IL-6,IL-8,and IL-10 are associated with hyperferritinemia in rapidly progressive interstitial lung disease with polymyositis/dermatomyositis [J].BiomedResInt,2014,2014:815245.

[42] Reiser J,Adair B,Reinheckel T.Specialized roles for cysteine cathepsins in health and disease [J].JClinInvest,2010,120(10):3421-3431.

[44] Quinn DJ,Weldon S,Taggart CC.Antiproteases as therapeutics to target inflammation in cystic fibrosis [J].OpenRespirMedJ,2010,4:20-31.

[45] Zhang D,Leung N,Weber E,etal.The effect of cathepsin K deficiency on airway development and TGF-β1 degradation [J].RespirRes,2011,12:72.

[46] Zhang L,Fu XH,Yu Y,etal.Treatment with CA-074Me,a Cathepsin B inhibitor,reduces lung interstitial inflammation and fibrosis in a rat model of polymyositis[J].LabInvest,2015,95(1):65-77.

[47] Sugiura T,Kawaguchi Y,Goto K,etal.Positive association between STAT4 polymorphisms and polymyositis/dermatomyositis in a Japanese population [J].AnnRheumDis,2012,71(10):1646-1650.

[48] Gono T,Kawaguchi Y,Kuwana M,etal.Brief report:Association of HLA-DRB1*0101/*0405 with susceptibility to anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis in the Japanese population [J].ArthritisRheum,2012,64(11):3736-3740.

[49] Chinoy H,Adimulam S,Marriage F,etal.Interaction of HLA-DRB1*03 and smoking for the development of anti-Jo-1 antibodies in adult idiopathic inflammatory myopathies:a European-wide case study [J].AnnRheumDis,2012,71(6):961-965.

[50] Miller FW,Cooper RG,Vencovsky J,etal.Genome-wide association study of dermatomyositis reveals genetic overlap with other autoimmune disorders [J].ArthritisRheum,2013,65(12):3239-3247.

復旦大學醫科類20位學者榮登Elsevier“2014年中國高被引學者榜單”

2015年2月2日,國際著名科技出版集團Elsevier發布了“2014年中國高被引學者(Most Cited Chinese Researchers)榜單”,登上榜單的中國學者共有1 651位。其中我?；A醫學院聞玉梅院士,公共衛生臨床中心Lowrie,Douglas B.(免疫和微生物學榜單);藥學院蔣新國教授、胡金鋒教授、方曉玲教授、陳道峰教授、裴元英教授(藥理學、毒理學和藥劑學榜單);基礎醫學院袁正宏教授,中山醫院湯釗猷院士、樊嘉教授、葛雷教授、孫惠川教授,華山醫院欽倫秀教授,腫瘤醫院邵志敏教授,婦產科醫院郭孫偉教授(醫學榜單);基礎醫學院姜世勃教授,藥學院錢忠明教授,中山醫院夏樸教授(生化、遺傳和分子生物榜單學);腦科學研究院趙志奇教授、黃志力教授(神經科學榜單)榮登榜單(上述排序不分先后)。

“2014年中國高被引學者榜單”的研究數據來自愛思唯爾旗下的Scopus數據庫。Scopus是全球最大的同行評議學術論文索引摘要數據庫,提供了海量的與科研活動有關的文獻、作者和研究機構數據,使得對中國學者的世界影響力進行科學的分析和評價成為可能?！案弑灰龑W者”是指作為第一作者和通訊作者發表論文的被引用總次數在中國(大陸地區)范圍內、本學科中處于最高水平的研究者,意味著這些學者專家在其研究領域具有世界級的影響力?！案弑灰龑W者”的數量也被一些專業評估體系作為一個大學科學研究水平排名的指標之一,其在一定程度上體現了大學所擁有的頂尖人才水平。

(復旦大學上海醫學院)

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;編輯:段佳)

上海市自然科學基金(08ZR1402800)

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

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