系統(tǒng)性硬化癥自身抗體研究進(jìn)展

系統(tǒng)性硬化癥本身抗體研究進(jìn)展系統(tǒng)性硬化癥（systemicsclerosis,SSc）是一種以皮膚及多臟器纖維化為突出體現(xiàn)的系統(tǒng)性本身免疫性疾病，現(xiàn)在認(rèn)為炎癥和本身免疫應(yīng)答，血管病變及纖維化是介導(dǎo)SSc發(fā)病的重要環(huán)節(jié)。免疫細(xì)胞活化后釋放大量促炎、促纖維化因子，合成本身抗體，參加組織損傷和器官功效障礙。針對(duì)細(xì)胞內(nèi)、外靶點(diǎn)的本身抗體可作為SSc血清標(biāo)志物。超出95％的SSc患者在初次診療時(shí)可檢測(cè)到本身抗體，并與疾病亞型，皮膚病變，內(nèi)臟受累及預(yù)后親密有關(guān)。超出90%的SSc患者外周血抗核抗體陽(yáng)性。而60%~80%的SSc患者標(biāo)志性抗體陽(yáng)性ADDINEN.CITE<EndNote><Cite><Author>Mecoli</Author><Year></Year><RecNum>9104</RecNum><DisplayText><styleface="superscript">[1]</style></DisplayText><record><rec-number>9104</rec-number><foreign-keys><keyapp="EN"db-id="fdaza95xw5xfr6ezfp8ps9efwd020ppv9sp2">9104</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Mecoli,C.A.</author><author>Casciola-Rosen,L.</author></authors></contributors><auth-address>DivisionofRheumatology,JohnsHopkinsUniversitySchoolofMedicine,Baltimore,Maryland,USA.</auth-address><titles><title>Anupdateonautoantibodiesinscleroderma</title><secondary-title>CurrOpinRheumatol</secondary-title><alt-title>Currentopinioninrheumatology</alt-title></titles><periodical><full-title>CurrOpinRheumatol</full-title><abbr-1>Currentopinioninrheumatology</abbr-1></periodical><alt-periodical><full-title>CurrOpinRheumatol</full-title><abbr-1>Currentopinioninrheumatology</abbr-1></alt-periodical><pages>548-553</pages><volume>30</volume><number>6</number><dates><year></year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1531-6963(Electronic) 1040-8711(Linking)</isbn><accession-num>30148799</accession-num><urls><related-urls><url></url></related-urls></urls><electronic-resource-num>10.1097/BOR.0550</electronic-resource-num></record></Cite></EndNote>[1]，涉及抗拓?fù)洚悩?gòu)酶Ⅰ抗體、抗著絲點(diǎn)抗體和抗RNA聚合酶抗體，三者對(duì)SSc診療含有較高特異性，因而納入了美國(guó)風(fēng)濕病學(xué)會(huì)（ACR）/歐洲抗風(fēng)濕病聯(lián)盟（EULAR）對(duì)SSc的分類原則之中ADDINEN.CITEADDINEN.CITE.DATA[2]，并且有助于識(shí)別早期或極早期SScADDINEN.CITEADDINEN.CITE.DATA[3,4]。盡管三種標(biāo)志性抗體已廣泛應(yīng)用于臨床，然而有關(guān)抗體功效和臨床意義的研究仍不停進(jìn)展。另外，研究發(fā)現(xiàn)一系列本身抗體含有功效性序列可參加SSc纖維化和血管病變，如抗血管緊張素II-1型受體和內(nèi)皮素1受體抗體、抗血小板源性生長(zhǎng)因子受體抗體、抗毒蕈堿-3受體抗體等，與SSc臨床特性與發(fā)病環(huán)節(jié)親密有關(guān)，也為致病機(jī)制提供新的見(jiàn)解，而闡明本身抗體介導(dǎo)發(fā)病有關(guān)通路也有助于尋找潛在治療靶點(diǎn)。本綜述將重點(diǎn)關(guān)注SSc有關(guān)本身抗體，特別是新近發(fā)現(xiàn)的功效性本身抗體，著重介紹其臨床應(yīng)用價(jià)值和潛在致病機(jī)制。1抗拓?fù)洚悩?gòu)酶Ⅰ（TopoisomeraseI/Scl-70）抗體抗Scl-70抗體最初在SSc血清中鑒定發(fā)現(xiàn)，因其可與70kDa核抗原反映而得名。后來(lái)人們認(rèn)識(shí)到全長(zhǎng)本身抗原是拓?fù)洚悩?gòu)酶I（TopoisomeraseI,topoI），而70kDa蛋白是天然全長(zhǎng)100kDa蛋白分解產(chǎn)物。即使抗Scl-70的術(shù)語(yǔ)仍在使用，但更精確的命名應(yīng)為抗topoI抗體?？箃opoI抗體在SSc中報(bào)道的陽(yáng)性率為9.4％~42％，最常見(jiàn)的是IgG亞型，IgA和IgM亞型亦可見(jiàn)。盡管抗topoI抗體對(duì)SSc高度特異，但研究報(bào)道也可見(jiàn)于SLEADDINEN.CITE<EndNote><Cite><Author>Gussin</Author><Year></Year><RecNum>8416</RecNum><DisplayText><styleface="superscript">[5]</style></DisplayText><record><rec-number>8416</rec-number><foreign-keys><keyapp="EN"db-id="fdaza95xw5xfr6ezfp8ps9efwd020ppv9sp2">8416</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Gussin,H.A.</author><author>Ignat,G.P.</author><author>Varga,J.</author><author>Teodorescu,M.</author></authors></contributors><auth-address>UniversityofIllinoisCollegeofMedicine,Chicago60612,USA.</auth-address><titles><title>Anti-topoisomeraseI(anti-Scl-70)antibodiesinpatientswithsystemiclupuserythematosus</title><secondary-title>ArthritisRheum</secondary-title><alt-title>Arthritisandrheumatism</alt-title></titles><periodical><full-title>ArthritisRheum</full-title><abbr-1>Arthritisandrheumatism</abbr-1></periodical><alt-periodical><full-title>ArthritisRheum</full-title><abbr-1>Arthritisandrheumatism</abbr-1></alt-periodical><pages>376-83</pages><volume>44</volume><number>2</number><keywords><keyword>Autoantibodies/blood</keyword><keyword>Blotting,Western</keyword><keyword>Enzyme-LinkedImmunosorbentAssay</keyword><keyword>Humans</keyword><keyword>ImmunoglobulinG/metabolism</keyword><keyword>ImmunosorbentTechniques</keyword><keyword>LongitudinalStudies</keyword><keyword>LupusErythematosus,Systemic/*blood</keyword><keyword>NuclearProteins/*immunology</keyword><keyword>ProteinBinding</keyword><keyword>ReproducibilityofResults</keyword><keyword>Scleroderma,Systemic/blood</keyword></keywords><dates><year></year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0004-3591(Print) 0004-3591(Linking)</isbn><accession-num>11229469</accession-num><urls><related-urls><url></url></related-urls></urls><electronic-resource-num>10.1002/1529-0131(02)44:2<376::AID-ANR56>3.0.CO;2-2</electronic-resource-num></record></Cite></EndNote>[5]，然而血清識(shí)別抗原表位有所不同?？箃opoII抗體并非SSc所特異，可見(jiàn)于其它免疫有關(guān)疾病，如局灶性硬皮病，特發(fā)性肺纖維化，SLE和幼年型類風(fēng)關(guān)等?？箃opoI抗體被認(rèn)為與彌漫性皮膚型（diffusecutaneousSSc,dcSSc）高度有關(guān)，但也可見(jiàn)于局限性皮膚型（localizedcutaneousSSc,lcSSc）患者?？箃opoI抗體強(qiáng)烈提示不良預(yù)后，病死率增高，與間質(zhì)性肺病高度有關(guān)。另有報(bào)道抗topoI抗體與骨骼肌和心肌受累，手指攣縮畸形，及蛋白尿有關(guān)ADDINEN.CITEADDINEN.CITE.DATA[6]。而抗topoI抗體與腫瘤間的關(guān)聯(lián)仍存在爭(zhēng)議?，F(xiàn)在研究認(rèn)為內(nèi)皮細(xì)胞破壞釋放拓?fù)洚悩?gòu)酶，或翻譯后修飾如乙?；皆龈逜DDINEN.CITEADDINEN.CITE.DATA[7,8]，最后造成抗原釋放，免疫耐受失衡，機(jī)體產(chǎn)生抗topoI抗體。研究支持抗topoI抗體可能是SSc的致病性抗體，而非單純的隨著抗體：1）使用topoI抗原聯(lián)合佐劑免疫小鼠可誘導(dǎo)抗topoI抗體產(chǎn)生，造成皮膚和肺組織的炎癥和纖維化病變ADDINEN.CITE<EndNote><Cite><Author>Yoshizaki</Author><Year></Year><RecNum>76</RecNum><DisplayText><styleface="superscript">[9]</style></DisplayText><record><rec-number>76</rec-number><foreign-keys><keyapp="EN"db-id="52fx9aa0xfpvr4edd5v5p9sk2ev502ataxe2"timestamp="">76</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Yoshizaki,Ayumi</author><author>Yanaba,Koichi</author><author>Ogawa,Asako</author><author>Asano,Yoshihide</author><author>Kadono,Takafumi</author><author>Sato,Shinichi</author></authors></contributors><auth-address>NagasakiUniversityGraduateSchoolofBiomedicalSciences,Nagasaki,Japan.M4-Citavi</auth-address><titles><title>ImmunizationwithDNAtopoisomeraseIandFreund'scompleteadjuvantinducesskinandlungfibrosisandautoimmunityviainterleukin-6signaling</title><secondary-title>Arthritisandrheumatism</secondary-title></titles><periodical><full-title>Arthritisandrheumatism</full-title></periodical><pages>3575-3585</pages><volume>63</volume><number>11</number><keywords><keyword>Animals</keyword><keyword>Autoimmunity/immunology</keyword><keyword>DNATopoisomerases,TypeI/immunology</keyword><keyword>Freund'sAdjuvant/immunology</keyword><keyword>Immunization</keyword><keyword>Interleukin-6/metabolism</keyword><keyword>Mice</keyword><keyword>PulmonaryFibrosis/etiology/immunology/pathology</keyword><keyword>Scleroderma,Systemic/etiology/immunology/pathology</keyword><keyword>Skin/immunology/pathology</keyword><keyword>Th1Cells/immunology/pathology</keyword><keyword>Th2Cells/immunology/pathology</keyword></keywords><dates><year></year></dates><urls><pdf-urls><url>C:\Users\CHEN\Documents\Citavi6\Projects\SystemicSclerosis\CitaviAttachments\ImmunizationwithTopo.pdf</url></pdf-urls></urls><electronic-resource-num>10.1002/art.30539</electronic-resource-num><language>eng</language></record></Cite></EndNote>[9]；2）抗topoI抗體可作用于SSc皮膚成纖維細(xì)胞，增進(jìn)膠原合成，以及單核細(xì)胞募集ADDINEN.CITE<EndNote><Cite><Author>Hénault</Author><Year></Year><RecNum>25</RecNum><DisplayText><styleface="superscript">[10]</style></DisplayText><record><rec-number>25</rec-number><foreign-keys><keyapp="EN"db-id="52fx9aa0xfpvr4edd5v5p9sk2ev502ataxe2"timestamp="">25</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Hénault,Jill</author><author>Robitaille,Geneviève</author><author>Senécal,Jean-Luc</author><author>Raymond,Yves</author></authors></contributors><auth-address>Notre-DameHospital,CentreHospitalierdel'UniversitédeMontréal,Montreal,Quebec,Canada.M4-Citavi</auth-address><titles><title>DNAtopoisomeraseIbindingtofibroblastsinducesmonocyteadhesionandactivationinthepresenceofanti-topoisomeraseIautoantibodiesfromsystemicsclerosispatients</title><secondary-title>Arthritisandrheumatism</secondary-title></titles><periodical><full-title>Arthritisandrheumatism</full-title></periodical><pages>963-973</pages><volume>54</volume><number>3</number><keywords><keyword>Apoptosis</keyword><keyword>Autoantibodies/immunology</keyword><keyword>CellAdhesion/immunology</keyword><keyword>Cells,Cultured</keyword><keyword>DNATopoisomerases,TypeI/immunology</keyword><keyword>Electrophoresis</keyword><keyword>Enzyme-LinkedImmunosorbentAssay</keyword><keyword>Fibroblasts/immunology</keyword><keyword>FlowCytometry</keyword><keyword>FluorescentAntibodyTechnique</keyword><keyword>Humans</keyword><keyword>Immunoblotting</keyword><keyword>Microscopy,Confocal</keyword><keyword>Monocytes/immunology</keyword><keyword>Scleroderma,Systemic/immunology</keyword></keywords><dates><year></year></dates><urls><pdf-urls><url>C:\Users\CHEN\Documents\Citavi6\Projects\SystemicSclerosis\CitaviAttachments\TopoFibroblasts2.pdf</url></pdf-urls></urls><electronic-resource-num>10.1002/art.21646</electronic-resource-num><language>eng</language></record></Cite></EndNote>[10]；3）topoI抗原抗體免疫復(fù)合物可刺激原代人皮膚成纖維細(xì)胞上調(diào)體現(xiàn)促炎、促纖維化和縮血管因子ADDINEN.CITEADDINEN.CITE.DATA[11]。因而抗topoI抗體在SSc發(fā)生中含有潛在的致病性，可能在SSc本身免疫應(yīng)答與纖維化間起“橋接”作用，然而具體機(jī)制有待進(jìn)一步研究。2抗著絲點(diǎn)（Centromereprotein,CENP）抗體抗CENP抗體在SSc中的檢出率為20％~40％，CENP-B是一類80kDa的著絲粒蛋白，是與幾乎全部抗CENP陽(yáng)性血清反映的重要抗原，而抗CENP-A抗體比抗CENP-B抗體對(duì)SSc更具特異性ADDINEN.CITEADDINEN.CITE.DATA[12]，兩種亞型含有相似的臨床特性ADDINEN.CITEADDINEN.CITE.DATA[13]。其它抗CENP亞型也被陸續(xù)發(fā)現(xiàn)，抗CENP-C抗體與干燥綜合征有關(guān)，而抗CENP-I抗體可能是本身免疫性肝病的血清標(biāo)志物?？笴ENP抗體與lcSSc親密有關(guān)，特別是CREST綜合征（鈣質(zhì)從容，雷諾現(xiàn)象，食管運(yùn)動(dòng)障礙，指硬化和毛細(xì)血管擴(kuò)張）。嚴(yán)重的間質(zhì)性肺病和腎危象少見(jiàn)ADDINEN.CITEADDINEN.CITE.DATA[13]。約20％的抗CENP陽(yáng)性患者合并肺動(dòng)脈高壓（pulmonaryarterialhypertension,PAH），約50％該類患者死亡歸因于PAHADDINEN.CITE<EndNote><Cite><Author>Akiyama</Author><Year></Year><RecNum>3054</RecNum><DisplayText><styleface="superscript">[14]</style></DisplayText><record><rec-number>3054</rec-number><foreign-keys><keyapp="EN"db-id="fdaza95xw5xfr6ezfp8ps9efwd020ppv9sp2">3054</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Akiyama,Y.</author><author>Tanaka,M.</author><author>Takeishi,M.</author><author>Adachi,D.</author><author>Mimori,A.</author><author>Suzuki,T.</author></authors></contributors><auth-address>DepartmentofRheumatology,SaitamaMedicalSchool.</auth-address><titles><title>Clinical,serologicalandgeneticstudyinpatientswithCRESTsyndrome</title><secondary-title>InternMed</secondary-title><alt-title>Internalmedicine</alt-title></titles><periodical><full-title>InternMed</full-title><abbr-1>Internalmedicine</abbr-1></periodical><alt-periodical><full-title>InternMed</full-title><abbr-1>Internalmedicine</abbr-1></alt-periodical><pages>451-6</pages><volume>39</volume><number>6</number><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Autoantibodies/blood</keyword><keyword>CRESTSyndrome/blood/*diagnosis/*genetics</keyword><keyword>Female</keyword><keyword>HLAAntigens/blood</keyword><keyword>Humans</keyword><keyword>Japan</keyword><keyword>Male</keyword><keyword>MiddleAged</keyword></keywords><dates><year></year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0918-2918(Print) 0918-2918(Linking)</isbn><accession-num>10852162</accession-num><urls><related-urls><url></url></related-urls></urls></record></Cite></EndNote>[14]?？笴ENP抗體陽(yáng)性的孤立性雷諾將來(lái)發(fā)展為SSc的風(fēng)險(xiǎn)明顯升高ADDINEN.CITEADDINEN.CITE.DATA[15]，然而合并嚴(yán)重指端潰瘍的發(fā)生率并未增加ADDINEN.CITEADDINEN.CITE.DATA[13]?？笴ENP抗體陽(yáng)性SSc患者較其它標(biāo)志性抗體陽(yáng)性患者總體預(yù)后相對(duì)較佳，死亡率較低ADDINEN.CITE<EndNote><Cite><Author>Hesselstrand</Author><Year></Year><RecNum>8415</RecNum><DisplayText><styleface="superscript">[16]</style></DisplayText><record><rec-number>8415</rec-number><foreign-keys><keyapp="EN"db-id="fdaza95xw5xfr6ezfp8ps9efwd020ppv9sp2">8415</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Hesselstrand,R.</author><author>Scheja,A.</author><author>Shen,G.Q.</author><author>Wiik,A.</author><author>Akesson,A.</author></authors></contributors><auth-address>DepartmentofRheumatology,LundUniversityHospital,Lund,Sweden.</auth-address><titles><title>Theassociationofantinuclearantibodieswithorganinvolvementandsurvivalinsystemicsclerosis</title><secondary-title>Rheumatology(Oxford)</secondary-title><alt-title>Rheumatology</alt-title></titles><periodical><full-title>Rheumatology(Oxford)</full-title><abbr-1>Rheumatology</abbr-1></periodical><alt-periodical><full-title>Rheumatology(Oxford)</full-title><abbr-1>Rheumatology</abbr-1></alt-periodical><pages>534-40</pages><volume>42</volume><number>4</number><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Antibodies,Antinuclear/*blood</keyword><keyword>Biomarkers/blood</keyword><keyword>Centromere/immunology</keyword><keyword>Female</keyword><keyword>FluorescentAntibodyTechnique,Indirect</keyword><keyword>Follow-UpStudies</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>MiddleAged</keyword><keyword>NucleolusOrganizerRegion/immunology</keyword><keyword>Prognosis</keyword><keyword>ProportionalHazardsModels</keyword><keyword>Scleroderma,Systemic/*immunology/pathology</keyword><keyword>SurvivalAnalysis</keyword></keywords><dates><year></year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1462-0324(Print) 1462-0324(Linking)</isbn><accession-num>12649400</accession-num><urls><related-urls><url></url></related-urls></urls></record></Cite></EndNote>[16]。3抗RNA聚合酶（RNApolymerase,RNAP）抗體針對(duì)RNAPI和RNAPIII的本身抗體經(jīng)常共存，且對(duì)SSc高度特異。SSc中的陽(yáng)性率約為20％。然而中國(guó)漢族SSc患者中陽(yáng)性率僅為1.3%，遠(yuǎn)低于美國(guó)高加索人群17.4%，推測(cè)與種族基因背景有關(guān)ADDINEN.CITEADDINEN.CITE.DATA[17]。針對(duì)RNAPII的抗體少見(jiàn)，且并不特異于SSc，可在SLE和重疊綜合征患者中檢出ADDINEN.CITE<EndNote><Cite><Author>Parker</Author><Year></Year><RecNum>2891</RecNum><DisplayText><styleface="superscript">[18]</style></DisplayText><record><rec-number>2891</rec-number><foreign-keys><keyapp="EN"db-id="fdaza95xw5xfr6ezfp8ps9efwd020ppv9sp2">2891</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Parker,J.C.</author><author>Burlingame,R.W.</author><author>Webb,T.T.</author><author>Bunn,C.C.</author></authors></contributors><auth-address>DepartmentofClinicalImmunology,RoyalFreeHospital,London,UK.</auth-address><titles><title>Anti-RNApolymeraseIIIantibodiesinpatientswithsystemicsclerosisdetectedbyindirectimmunofluorescenceandELISA</title><secondary-title>Rheumatology(Oxford)</secondary-title><alt-title>Rheumatology</alt-title></titles><periodical><full-title>Rheumatology(Oxford)</full-title><abbr-1>Rheumatology</abbr-1></periodical><alt-periodical><full-title>Rheumatology(Oxford)</full-title><abbr-1>Rheumatology</abbr-1></alt-periodical><pages>976-9</pages><volume>47</volume><number>7</number><keywords><keyword>Antibodies,Antinuclear/*blood</keyword><keyword>Enzyme-LinkedImmunosorbentAssay/methods</keyword><keyword>FluorescentAntibodyTechnique,Indirect/methods</keyword><keyword>Humans</keyword><keyword>RNAPolymeraseIII/*immunology</keyword><keyword>Scleroderma,Systemic/*immunology</keyword><keyword>SensitivityandSpecificity</keyword></keywords><dates><year></year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1462-0332(Electronic) 1462-0324(Linking)</isbn><accession-num>18499715</accession-num><urls><related-urls><url></url></related-urls></urls><custom2>2430219</custom2><electronic-resource-num>10.1093/rheumatology/ken201</electronic-resource-num></record></Cite></EndNote>[18]?？筊NAPIII抗體在傳統(tǒng)以Hep-2細(xì)胞為底物的間接免疫熒光中顯示為斑點(diǎn)核仁型，但缺少特異性，常與其它本身抗體同時(shí)檢出，因而采用

酶聯(lián)免疫吸附測(cè)定（Enzymelinkedimmunosorbentassay,ELISA）測(cè)定可能是優(yōu)選辦法ADDINEN.CITEADDINEN.CITE.DATA[19]?？筊NAPI和III抗體與彌漫皮膚型SSc有關(guān)，且罹患腎危象的風(fēng)險(xiǎn)更高。值得關(guān)注的是，基于EUSTAR隊(duì)列進(jìn)行的病例對(duì)照研究，成果顯示抗RNAPIII抗體除了與腎臟受累、彌漫皮膚亞型、胃竇血管擴(kuò)張，快速進(jìn)展的皮膚病變有關(guān)外，還與隨著的腫瘤發(fā)生（-6~+12月）親密有關(guān)（OR7.38,95%CI1.61-33.8）ADDINEN.CITEADDINEN.CITE.DATA[20]。而JohnsHopkins隊(duì)列數(shù)據(jù)也應(yīng)證了這一成果，抗RNAPIII抗體陽(yáng)性患者中3年腫瘤標(biāo)化發(fā)病比為2.84（95%CI1.89~4.10），而乳腺癌和肺癌分列抗RNAPIII抗體陽(yáng)性的dcSSc和lcSSc患者之首ADDINEN.CITE<EndNote><Cite><Author>Igusa</Author><Year></Year><RecNum>3050</RecNum><DisplayText><styleface="superscript">[21]</style></DisplayText><record><rec-number>3050</rec-number><foreign-keys><keyapp="EN"db-id="fdaza95xw5xfr6ezfp8ps9efwd020ppv9sp2">3050</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Igusa,T.</author><author>Hummers,L.K.</author><author>Visvanathan,K.</author><author>Richardson,C.</author><author>Wigley,F.M.</author><author>Casciola-Rosen,L.</author><author>Rosen,A.</author><author>Shah,A.A.</author></authors></contributors><auth-address>DepartmentsofCivilEngineeringandAppliedMathematicsandStatistics,JohnsHopkinsUniversity,Baltimore,Maryland,USA. DivisionofRheumatology,JohnsHopkinsUniversitySchoolofMedicine,Baltimore,Maryland,USA. DepartmentsofEpidemiologyandMedicalOncology,JohnsHopkinsBloombergSchoolofPublicHealthandJohnsHopkinsUniversitySchoolofMedicine,Baltimore,Maryland,USA.</auth-address><titles><title>Autoantibodiesandsclerodermaphenotypedefinesubgroupsathigh-riskandlow-riskforcancer</title><secondary-title>AnnRheumDis</secondary-title><alt-title>Annalsoftherheumaticdiseases</alt-title></titles><periodical><full-title>AnnRheumDis</full-title><abbr-1>Annalsoftherheumaticdiseases</abbr-1></periodical><alt-periodical><full-title>AnnRheumDis</full-title><abbr-1>Annalsoftherheumaticdiseases</abbr-1></alt-periodical><pages>1179-1186</pages><volume>77</volume><number>8</number><dates><year></year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1468-2060(Electronic) 0003-4967(Linking)</isbn><accession-num>29678941</accession-num><urls><related-urls><url></url></related-urls></urls><custom2>6272061</custom2><electronic-resource-num>10.1136/annrheumdis--212999</electronic-resource-num></record></Cite></EndNote>[21]。因而對(duì)于抗RNAPIII抗體陽(yáng)性的SSc患者而言，除需親密隨訪腎臟病變外，還應(yīng)加強(qiáng)腫瘤篩查。4抗血管緊張素II-1型受體（angiotensinIItype1receptor,AT1R）和內(nèi)皮素1受體（endothelin-1typeAreceptor,ETAR）抗體AT1R和ETAR廣泛體現(xiàn)于脈管系統(tǒng)及免疫細(xì)胞。針對(duì)AT1R和ETAR的抗體可激活對(duì)應(yīng)受體參加多個(gè)血管病變，兩者高度有關(guān)且可發(fā)生交叉反映。85%的SSc患者抗AT1R和ETAR的抗體陽(yáng)性ADDINEN.CITEADDINEN.CITE.DATA[22]，與指端潰瘍ADDINEN.CITEADDINEN.CITE.DATA[23]及PAHADDINEN.CITEADDINEN.CITE.DATA[24]親密有關(guān)，也可見(jiàn)于其它結(jié)締組織病合并的PAH，可作為提示預(yù)后的血清標(biāo)志物ADDINEN.CITEADDINEN.CITE.DATA[24]。體內(nèi)實(shí)驗(yàn)證明抗AT1R和ETAR抗體可作用于血管內(nèi)皮細(xì)胞造成中性粒細(xì)胞黏附及膠原合成ADDINEN.CITEADDINEN.CITE.DATA[25]，也可增進(jìn)內(nèi)皮細(xì)胞和免疫細(xì)胞分泌促炎癥因子ADDINEN.CITEADDINEN.CITE.DATA[26]。體內(nèi)實(shí)驗(yàn)中過(guò)繼回輸抗AT1R和ETAR抗體IgG至小鼠體內(nèi)，可出現(xiàn)氣道血管壁增厚和間質(zhì)細(xì)胞浸潤(rùn)ADDINEN.CITEADDINEN.CITE.DATA[24]，從而提示了抗AT1R和ETAR抗體在SSc血管病變中的致病性。5抗血小板源性生長(zhǎng)因子受體（Platelet-derivedgrowthfactorreceptor,PDGFR）抗體PDGF通過(guò)作用于成纖維細(xì)胞或平滑肌細(xì)胞受體PDGFR，誘導(dǎo)活性氧（reactiveoxygenspecies,ROS）產(chǎn)生，增進(jìn)膠原合成。有研究將來(lái)自SSc患者的生物工程皮膚移植至免疫缺點(diǎn)小鼠，同時(shí)輸注針對(duì)PDGFR的刺激性抗體，證明這一抗體可增進(jìn)并維系SSc皮膚纖維化病變ADDINEN.CITEADDINEN.CITE.DATA[27]。另外，抗PDGFR抗體可誘導(dǎo)人肺血管平滑肌細(xì)胞的增殖和遷移，可能參加SSc血管病變ADDINEN.CITE<EndNote><Cite><Author>Svegliati</Author><Year></Year><RecNum>72</RecNum><DisplayText><styleface="superscript">[28]</style></DisplayText><record><rec-number>72</rec-number><foreign-keys><keyapp="EN"db-id="fd99dtadpvd0rjef9w9pzvtkeszvp05awtfw"timestamp="">72</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Svegliati,S.</author><author>Amico,D.</author><author>Spadoni,T.</author><author>Fischetti,C.</author><author>Finke,D.</author><author>Moroncini,G.</author><author>Paolini,C.</author><author>Tonnini,C.</author><author>Grieco,A.</author><author>Rovinelli,M.</author><author>Funaro,A.</author><author>Gabrielli,A.</author></authors></contributors><auth-address>ClinicaMedica,DipartimentodiScienzeClinicheeMolecolari,UniversitaPolitecnicadelleMarche,Ancona,Italy. DipartimentodiScienzeMediche,UniversitadiTorino,Torino,Italy</auth-address><titles><title>AgonisticAnti-PDGFReceptorAutoantibodiesfromPatientswithSystemicSclerosisImpactHumanPulmonaryArterySmoothMuscleCellsFunctionInVitro</title><secondary-title>FrontImmunol</secondary-title><alt-title>Frontiersinimmunology</alt-title></titles><periodical><full-title>FrontImmunol</full-title></periodical><pages>75</pages><volume>8</volume><edition>/02/24</edition><keywords><keyword>*autoantibodies</keyword><keyword>*plateletderivedgrowthfactor</keyword><keyword>*syntheticphenotype</keyword><keyword>*systemicsclerosis</keyword><keyword>*vascularsmoothmusclecells</keyword></keywords><dates><year></year></dates><isbn>1664-3224(Print) 1664-3224</isbn><accession-num>28228756</accession-num><urls><related-urls><url></url></related-urls></urls><custom2>PMC5296309</custom2><electronic-resource-num>10.3389/fimmu..00075</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[28]。有研究報(bào)道SSc來(lái)源的抗PDGFR抗體發(fā)揮激活作用參加發(fā)病，即使健康對(duì)照、SLE和原發(fā)性雷諾患者外周血中均可檢出抗PDGFR抗體，然而并不能發(fā)揮類似效應(yīng)ADDINEN.CITEADDINEN.CITE.DATA[29]，推測(cè)可能是天然存在的抗體，其作用表位與致病性抗體有所不同。已有研究通過(guò)分辨刺激性和非刺激性抗PDGFR抗體結(jié)合的抗原表位，繪制功效性表位圖譜，從而推動(dòng)臨床應(yīng)用ADDINEN.CITEADDINEN.CITE.DATA[30]。6抗毒蕈堿-3受體（Muscarinic-3receptor,M3R）抗體涉及胃食管反流在內(nèi)的消化道病變是SSc患者常見(jiàn)且突出的臨床體現(xiàn)，既往認(rèn)為食管蠕動(dòng)障礙，平滑肌萎縮，膠原沉積和纖維化是引發(fā)胃食管反流的重要因素，而Goldblatt等發(fā)現(xiàn)來(lái)自SSc患者的IgG可特異性阻斷腸肌層中的毒蕈堿-3受體對(duì)膽堿的應(yīng)答，并與SSc消化道癥狀親密有關(guān)ADDINEN.CITEADDINEN.CITE.DATA[31]。進(jìn)一步發(fā)現(xiàn)來(lái)自SSc的本身抗體首先阻斷神經(jīng)節(jié)膽堿能神經(jīng)傳遞引發(fā)神經(jīng)病變，隨著疾病進(jìn)展，可變化平滑肌細(xì)胞膜上乙酰膽堿功效引發(fā)肌肉病變?？筂3R抗體重要作用于靶點(diǎn)為M3R的第二胞外段，靜脈用丙種球蛋白（Intravenousgammaglobulin,IVIG）可阻斷抗M3R抗體Fab段的特異性作用，涉及對(duì)神經(jīng)病變和肌肉病變的雙重調(diào)控ADDINEN.CITEADDINEN.CITE.DATA[32]?？筂3R抗體除了可見(jiàn)于SSc患者，還可見(jiàn)于干燥綜合征及重癥肌無(wú)力患者，但抗M3R抗體陽(yáng)性的SSc中，64%的患者有營(yíng)養(yǎng)吸取障礙和/或胃腸道假性梗阻ADDINEN.CITEADDINEN.CITE.DATA[33]。因而抗M3R抗體的發(fā)現(xiàn)有助于加深我們對(duì)SSc消化道病變的認(rèn)識(shí)，在臨床應(yīng)用中，不僅能夠提示消化道合并癥，并為IVIG等免疫治療提供理論根據(jù)。7抗干擾素誘導(dǎo)基因16（Interferon-induciblegene16，IFI16）抗體IFI16是HIN-200家族組員，構(gòu)成性體現(xiàn)于血管內(nèi)皮細(xì)胞和角質(zhì)形成細(xì)胞，過(guò)體現(xiàn)IFI16可造成血管內(nèi)皮凋亡和促炎癥因子釋放ADDINEN.CITEADDINEN.CITE.DATA[34]。研究發(fā)現(xiàn)SSc外周血中存在抗IFI-16抗體，其陽(yáng)性率在21%~25%ADDINEN.CITEADDINEN.CITE.DATA[35],ADDINEN.CITEADDINEN.CITE.DATA[36]，lcSSc中更高ADDINEN.CITEADDINEN.CITE.DATA[35]，且與肢端潰瘍有關(guān)ADDINEN.CITEADDINEN.CITE.DATA[37]，抗CENP和抗IFI-16抗體雙陽(yáng)性性患者的肢端血管事件風(fēng)險(xiǎn)增加?，F(xiàn)在研究推測(cè)抗IFI-16抗體作用于內(nèi)皮細(xì)胞特異性抗原，參加SSc血管病變ADDINEN.CITE<EndNote><Cite><Author>Mecoli</Author><Year></Year><RecNum>64</RecNum><DisplayText><styleface="superscript">[38]</style></DisplayText><record><rec-number>64</rec-number><foreign-keys><keyapp="EN"db-id="fd99dtadpvd0rjef9w9pzvtkeszvp05awtfw"timestamp="">64</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Mecoli,C.A.</author><author>Casciola-Rosen,L.</author></authors></contributors><auth-address>DivisionofRheumatology,JohnsHopkinsUniversitySchoolofMedicine,Baltimore,Maryland,USA.</auth-address><titles><title>Anupdateonautoantibodiesinscleroderma</title><secondary-title>CurrOpinRheumatol</secondary-title><alt-title>Currentopinioninrheumatology</alt-title></titles><periodical><full-title>CurrOpinRheumatol</full-title></periodical><edition>/08/28</edition><dates><year></year><pub-dates><date>Aug24</date></pub-dates></dates><isbn>1040-8711</isbn><accession-num>30148799</accession-num><urls></urls><electronic-resource-num>10.1097/bor.0550</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[38]。8抗RuvBL1和RuvBL2抗體RuvBL1和RuvBL2是ATP酶同源物，參加轉(zhuǎn)錄、DNA修復(fù)及染色質(zhì)構(gòu)造重塑等生理過(guò)程ADDINEN.CITEADDINEN.CITE.DATA[39]。近來(lái)在SSc中發(fā)現(xiàn)抗RuvBL1和RuvBL2抗體，其在日本和北美人群中陽(yáng)性率約為2％，與dcSSc和骨骼肌受累有關(guān)ADDINEN.CITEADDINEN.CITE.DATA[40]。9抗真核起始因子-2B（EukaryoticInitiationFactor-2B，eIF-2B）抗體eIF-2B是一種細(xì)胞質(zhì)多聚體蛋白，參加真核細(xì)胞蛋白質(zhì)合成，協(xié)助tRNA與核糖體結(jié)合ADDINEN.CITE<EndNote><Cite><Author>Pavitt</Author><Year></Year><RecNum>81</RecNum><DisplayText><styleface="superscript">[41]</style></DisplayText><record><rec-number>81</rec-number><foreign-keys><keyapp="EN"db-id="fd99dtadpvd0rjef9w9pzvtkeszvp05awtfw"timestamp="">81</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Pavitt,G.D.</author></authors></contributors><auth-address>FacultyofLifeSciences,TheMichaelSmithBuilding,TheUniversityofManchester,OxfordRoad,ManchesterM139PT,UK.</auth-address><titles><title>eIF2B,amediatorofgeneralandgene-specifictranslationalcontrol</title><secondary-title>BiochemSocTrans</secondary-title><alt-title>BiochemicalSocietytransactions</alt-title></titles><periodical><full-title>BiochemSocTrans</full-title><abbr-1>BiochemicalSocietytransactions</abbr-1></periodical><alt-periodical><full-title>BiochemSocTrans</full-title><abbr-1>BiochemicalSocietytransactions</abbr-1></alt-periodical><pages>1487-92</pages><volume>33</volume><number>Pt6</number><edition>/10/26</edition><keywords><keyword>Animals</keyword><keyword>EukaryoticInitiationFactor-2B/genetics/*metabolism</keyword><keyword>*GeneExpressionRegulation</keyword><keyword>GuanineNucleotideExchangeFactors/metabolism</keyword><keyword>HereditaryCentralNervousSystemDemyelinatingDiseases/genetics</keyword><keyword>Humans</keyword><keyword>Mutation</keyword><keyword>*ProteinBiosynthesis</keyword><keyword>ProteinSubunits/genetics/metabolism</keyword></keywords><dates><year></year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0300-5127(Print) 0300-5127</isbn><accession-num>16246152</accession-num><urls><related-urls><url></url></related-urls></urls><electronic-resource-num>10.1042/bst1487</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[41]。Betteridge等首先在ANA陰性的SSc患者血清中發(fā)現(xiàn)此抗體，報(bào)道的陽(yáng)性率為1％~7％，臨床上與dcSSc和間質(zhì)性肺病有關(guān)ADDINEN.CITEADDINEN.CITE.DATA[42,43]。有研究提出抗eIF2B抗體的形成可能與EB病毒分子模擬有關(guān)ADDINEN.CITEADDINEN.CITE.DATA[44]。小結(jié)：SSc典型的特異性抗體如抗拓?fù)洚悩?gòu)酶Ⅰ抗體、抗著絲點(diǎn)抗體和抗RNA聚合酶抗體即使已經(jīng)廣泛應(yīng)用于SSc的診療分型和預(yù)后判斷中，然而對(duì)于其臨床意義和致病機(jī)制仍不停在拓展和進(jìn)一步，因而在此溫故而知新。另外，某些功效性抗體靶向于SSc重要致病環(huán)節(jié)，日前也備受關(guān)注，抗AT1R和ETAR抗體可增進(jìn)血管內(nèi)皮細(xì)胞收縮，進(jìn)而造成內(nèi)皮細(xì)胞凋亡和促炎癥因子釋放參加血管病變，針對(duì)PDGFR抗體可變化氧化應(yīng)激平衡，增進(jìn)細(xì)胞外基質(zhì)合成，而針對(duì)M3R抗體在消化道病變中發(fā)揮重要作用。因此功效性本身抗體不僅可提示臨床，尚有助于揭示潛在發(fā)病機(jī)制，也為IVIG、B細(xì)胞靶向治療、干細(xì)胞移植等免疫調(diào)節(jié)和重塑方略提供理論根據(jù)。最后，新近發(fā)現(xiàn)的SSc本身抗體，如抗IFI-16抗體、抗Ruv1/2抗體和抗eIF2B抗體等，與SSc特定臨床表型有關(guān)，有望應(yīng)用于臨床，然而其潛在作用機(jī)制有待進(jìn)一步。參考文獻(xiàn)：ADDINEN.REFLIST1 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