喻曉雯 王 琴 馮 婧 白殊同 劉金坤 高洪燕 吳 斌

(重慶市中醫(yī)院中醫(yī)藥基礎(chǔ)研究室，重慶 400021)

原發(fā)性干燥綜合征(primary Sj?gren′s syndrome，pSS)是一種病因未明的慢性自身免疫性疾病，以淋巴細(xì)胞浸潤(rùn)和外分泌腺功能損傷為特征。pSS好發(fā)于女性，多于40～60歲發(fā)病，口干、眼干是常見的臨床表現(xiàn)。成人患病率為0.5%～1%，是風(fēng)濕病科第二大疾病[1,2]。由于非專科醫(yī)生對(duì)本病認(rèn)識(shí)不足，同時(shí)pSS的診斷常需完善唾液腺功能、眼科檢查、唇腺活檢等，在基層醫(yī)院往往無(wú)法完成診斷，有研究提示超過一半的pSS患者出現(xiàn)漏診或誤診，平均需要3.9年才能確診[3,4 ]?；谏鲜鲈颍陨砜贵w在pSS診斷中的作用就尤為突出。在pSS患者血清中可檢測(cè)出多種自身抗體，抗Ro/SSA和抗La/SSB抗體是pSS的標(biāo)志性抗體，但其特異性較低[5]。近年來(lái)，抗M3毒蕈堿乙酰膽堿受體(anti-M3 muscarinic acetylcholine receptor,抗M3R)抗體和抗α-胞襯蛋白抗體(anti-α-Fodrin antibody,AFA)逐漸運(yùn)用于臨床診斷，且特異性有所提高[6]。此外，其他自身抗體也引起研究者的重視，如抗著絲點(diǎn)抗體、抗環(huán)瓜氨酸抗體、抗線粒體抗體和抗平滑肌抗體等[7]，其檢出率和臨床意義具體見表1。

1 抗Ro/SSA 和抗La/SSB抗體

抗Ro/SSA和抗La/SSB抗體是pSS的標(biāo)志性抗體，已經(jīng)被列入診斷標(biāo)準(zhǔn)[5]?？筊o/SSA和抗La/SSB抗體在pSS的病程中比較穩(wěn)定，即使是生物制劑利妥昔單抗治療后亦很難改變[10]。研究發(fā)現(xiàn)抗La/SSB與抗Ro/SSA抗體與pSS疾病活動(dòng)度有一定的相關(guān)性，其中抗Ro/SSA抗體具有更高的相關(guān)性[11]?？筊o/SSA抗體包括抗Ro52和抗Ro60兩種自身抗體，抗Ro52抗體是pSS患者中最常被檢出的自身抗體[7]。研究還發(fā)現(xiàn)12%的抗Ro/SSA抗體陰性的pSS患者可檢測(cè)到抗Ro52抗體陽(yáng)性，提示抗Ro52抗體提高了pSS的檢出率[5]。在臨床上，檢測(cè)抗Ro/SSA和抗La/SSB抗體的常用方法為ELISA，其敏感性偏低且易出現(xiàn)假陽(yáng)性。Volchenkov等[12]發(fā)現(xiàn)液相熒光素酶免疫沉淀系統(tǒng)技術(shù)能提高抗Ro/SSA和抗La/SSB抗體的檢出率，抗La/SSB抗體可提高11%，抗Ro60抗體可提高4%，可見新的實(shí)驗(yàn)方法可以提高pSS的診斷率。

抗Ro/SSA和抗La/SSB對(duì)pSS疾病有預(yù)測(cè)作用，早在1982年，Isenberg等[2]發(fā)現(xiàn)15例關(guān)節(jié)炎伴抗La/SSB抗體陽(yáng)性的患者，其中有11例患者2年后發(fā)展為pSS。最近亦發(fā)現(xiàn)抗Ro/SSA和抗La/SSB抗體在確診pSS前20年就已經(jīng)存在[13]。此外，Tandander等[14]也發(fā)現(xiàn)ANAs在pSS患者中最早出現(xiàn)，其次是類風(fēng)濕因子(Rheumatoid factor,RF)、抗Ro60/SSA、抗Ro52/SSA和抗La/SSB，表明早期檢測(cè)對(duì)pSS的早期篩查意義重大。

抗Ro/SSA和抗La/SSB抗體參與了pSS的發(fā)病機(jī)制。研究發(fā)現(xiàn)抗Ro/SSA抗體陽(yáng)性的pSS患者的唾液流率明顯低于抗Ro/SSA抗體陰性的患者，提示抗Ro/SSA抗體可能介導(dǎo)唾液腺的機(jī)能障礙[4]。其機(jī)制可能是自身抗體沉積于唾液腺，促炎的細(xì)胞因子KC、IL-1α、MIG、MIP2和PDGF-β的上調(diào)協(xié)助自身抗體介導(dǎo)唾液腺的損傷，進(jìn)而誘發(fā)口干癥狀[15]。此外，抗Ro/SSA和抗La/SSB抗體還介導(dǎo)了pSS患者的腺外損傷。有報(bào)道pSS患者中抗Ro/SSA和抗La/SSB抗體與腺外癥狀(脾腫大，淋巴結(jié)病，脈管炎和雷諾現(xiàn)象)呈正相關(guān)[10]。高滴度的抗-Ro52抗體與唇腺活檢陽(yáng)性，腮腺腫脹、貧血、白細(xì)胞減少和RF顯著相關(guān)[5]。韓國(guó)的一項(xiàng)研究也發(fā)現(xiàn)抗-Ro52與肝臟和肌肉的受累高度相關(guān)，而抗-Ro60與肝臟的受累呈負(fù)相關(guān)[16]。可見抗Ro/SSA、抗La/SSB參與了pSS腺體及腺體外損傷的發(fā)病機(jī)理，將近年研究發(fā)現(xiàn)的一些參與了pSS的發(fā)病機(jī)制自身抗體總結(jié)于表2。

2 抗M3R抗體

抗M3R抗體是可以作為pSS診斷的另一個(gè)的血清學(xué)標(biāo)志物。M3R是一個(gè)膜結(jié)合蛋白，表達(dá)于外分泌腺，在腺體分泌中發(fā)揮著關(guān)鍵作用。血清中的抗M3R抗體檢出率較低，約為50%[19]。采用唾液樣本可提高抗M3R抗體的檢出率，且特異性可達(dá)到88.16%。研究還發(fā)現(xiàn)唾液抗M3R IgG抗體與年齡、病程和球蛋白水平相關(guān)[17]。國(guó)內(nèi)報(bào)道69%的pSS患者在唾液中能檢測(cè)到抗M3R抗體[18]。從方便臨床診斷角度看，唾液中抗M3R抗體檢測(cè)可能更貼近臨床。

越來(lái)越多的證據(jù)表明抗M3R抗體可能是引起唾液腺分泌功能喪失的重要因素，其可能的機(jī)制如下：首先pSS患者血清中純化的抗膽堿自身抗體以肌醇磷脂、半胱天冬酶-3和MMP-3依賴的方式介導(dǎo)了A253細(xì)胞系的凋亡，抗M3R抗體通過與磷脂酶C、鈣通信激活半胱天冬酶-3和MMP-3，從而誘導(dǎo)上皮細(xì)胞凋亡，進(jìn)而導(dǎo)致唾液腺的破壞性損傷[22]。其次，抗M3R抗體能抑制人類頜下腺、唾液腺細(xì)胞的分泌功能[23]。如Iwabuchi等[24]發(fā)現(xiàn)在小鼠唾液腺中M3R的活化引起唾液的產(chǎn)生，M3R對(duì)唾液分泌的副交感神經(jīng)有非常重要的調(diào)控作用[25]，因此抗M3R抗體可能直接通過阻斷神經(jīng)傳輸導(dǎo)致干燥癥狀的顯現(xiàn)。最后，抗M3R抗體介導(dǎo)的氧化壓力與唾液腺的損傷有關(guān)。在正常情況下，淚腺和唾液腺的眼睛和口腔表面存在ROS/抗氧化劑的平衡，一旦這種平衡被打破，眼睛和口腔會(huì)受到損傷[26]。ROS的水平和抗氧化物酶系統(tǒng)的不平衡在唾液腺的致病性中發(fā)揮著關(guān)鍵的作用[27]。抗M3R抗體刺激pSS唾液腺中超氧化物歧化酶(Superoxide dismutase,SOD)和過氧化氫酶(Catalase,CAT)的活性增加，并且上調(diào)NO和前列腺素E2的表達(dá)。因此，我們推斷SOD和CAT在pSS患者中活性的增加可能是機(jī)體對(duì)ROS增加的一個(gè)防御反應(yīng)，但這種防御反應(yīng)一旦過度就會(huì)引起唾液腺細(xì)胞和組織不可逆的損傷[28]。

表1pSS疾病相關(guān)自身抗體

Tab.1AssociatedautoantibodiesdetectedinpSS

Autoantibodiesagainst PrevalenceClinicalSignificanceReferenceCryoglobulins 9%-15%Highriskforlymphomagenesis[7]Centromere(ACA) 4%-17%Overlappingclinicalmanifestationswithsystemicsclerosis[7，8]Cycliccitrullinatedpeptides(anti?CCP) 3%-10%HighriskforprogressingtoRA [7，9]Mitochondria(AMA)1 7%-13%Correlatedwithliverdamage[7]Smoothmuscle(ASMA) 30%Unknown[7]

表2參與pSS發(fā)病機(jī)理的相關(guān)自身抗體

Tab.2AssociationofautoantibodieswithpSSpathogenesis

AutoantibodiesPrevalenceSpecificityClinicalSignificanceReferenceAnti?Ro/SSAantibody 33%-74%52 1%Associatedwithlongerdiseaseduration，extensivelymphocyticinfiltrationofMSG，severeexocrineglanddamage，parotidenlargement[5，7，10，14，16]Anti?La/SSBantibody 23%-52%49%Associatedwithhypergammaglobulinemia，cryoglobulinemia，glandulardamageandorganinvolvement[5，7，14，16]Anti?M3Rantibody44 19%-69%88 1%-95 1%Associatedwithsalivaryglanddamage，gastrointestinalandbloodsystemabnormalities[17-19]Anti?α?fodrinantibody(AFA)39 3%-41 9%82 8%-83 1%Correlatedwithlymphocytesinfiltrationofsalivaryglandandinvolvinginearlypathogenesis[20，21]

抗M3R抗體也介導(dǎo)了pSS患者的腺外系統(tǒng)的損傷。pSS患者普遍存在胃腸道的損傷，但具體原因未知。Park等[29]發(fā)現(xiàn)在pSS患者中，抗M3R抗體有介導(dǎo)胃腸道多重機(jī)能不良的潛在風(fēng)險(xiǎn)，包括食道蠕動(dòng)減弱和結(jié)腸動(dòng)力改變等，因此推測(cè)pSS患者胃腸道動(dòng)力的改變可能部分是由抗M3R抗體介導(dǎo)的功能障礙。另外在pSS患者中，抗M3R抗體還介導(dǎo)了神經(jīng)免疫的相互作用，這種相互作用可能與pSS復(fù)雜的病理生理相關(guān)。換言之自身抗體的產(chǎn)生直接靶向自發(fā)的神經(jīng)遞質(zhì)受體抗M3R抗體，從而抑制了唾液的分泌[30]。此外，最近發(fā)現(xiàn)pSS患者的抗M3R抗體可誘導(dǎo)存在于質(zhì)膜的M3R和MHCⅠ類分子的下調(diào)和隨后的NK細(xì)胞介導(dǎo)的細(xì)胞死亡，這可能是pSS患者易發(fā)生白細(xì)胞減少的原因[31]。上述研究表明抗M3R抗體介導(dǎo)了腺外系統(tǒng)損傷，其機(jī)理是復(fù)雜的。

3 抗α-胞襯蛋白抗體

AFA是pSS早期診斷的標(biāo)志物[32]。AFA在唾液腺炎和組織凋亡時(shí)形成，是一個(gè)器官特異性自身抗原，與自身免疫損傷和組織破壞存在相關(guān)[10]。早在1997年，在pSS小鼠模型中發(fā)現(xiàn)了AFA[32]。通常AFA的出現(xiàn)早于抗Ro/SSA或抗La/SSB抗體[10]。有研究者檢測(cè)了64例pSS患者和108例非pSS患者血清中的AFA IgA和IgG抗體，通過ROC分析以評(píng)估其對(duì)pSS診斷的準(zhǔn)確性，結(jié)果發(fā)現(xiàn)敏感性分別為59%和55%，特異性為75%和73%，證明了其在pSS中的診斷潛能[33]。由于不同研究對(duì)AFA抗體在pSS診斷中的準(zhǔn)確性相差較大，Hu等[20]選取23個(gè)研究，通過meta分析系統(tǒng)評(píng)價(jià)了AFA對(duì)pSS診斷的準(zhǔn)確性，結(jié)果發(fā)現(xiàn)AFA的敏感性和特異性分別為39.3%和83%，IgG亞型、IgA亞型的敏感性分別為38%和41.9%，特異性分別為82.8%和83.1%，因此認(rèn)為AFA在pSS診斷中具有可靠性。最近發(fā)現(xiàn)在抗SSA/SSB抗體陰性的pSS患者中，AFA與RF和/或ANA聯(lián)合可把診斷的敏感性從56.9%提高到70.7%，提示可作為pSS診斷的替代免疫學(xué)標(biāo)準(zhǔn)[21]。此外，AFA的濃度與唾液腺中淋巴細(xì)胞的浸潤(rùn)程度呈正相關(guān)，AFA可能參與了早期的致病過程，因?yàn)锳FA IgG抗體陽(yáng)性的pSS患者往往有更短的疾病病程[10]。

4 其他自身抗體

在pSS患者中，一些抗體的出現(xiàn)可能提示發(fā)生相關(guān)疾病的風(fēng)險(xiǎn)，如aβ2GP Ⅰ 和p-ANCA抗體可能預(yù)示pSS患者有發(fā)生神經(jīng)病變的可能[34]。ADAMTS13抗體陽(yáng)性提示可能有并發(fā)血液系統(tǒng)疾病的風(fēng)險(xiǎn)[35]。IFN-γ的過度表達(dá)與肺間質(zhì)病變有緊密的聯(lián)系[36]。PAX6的下調(diào)與眼睛損傷高度相關(guān)，可作為預(yù)測(cè)pSS早期眼睛并發(fā)癥的指標(biāo)之一[37]。而且一些自身抗體具有一定的預(yù)測(cè)作用，如抗NA-14抗體陽(yáng)性提示pSS病程短[38]?？筂DM2陽(yáng)性提示pSS病程長(zhǎng)，同時(shí)常伴有貧血、血小板減少和抗-SSB抗體陽(yáng)性，且與疾病活動(dòng)度和IgG的水平正相關(guān)[39]。

表3近年發(fā)現(xiàn)與pSS相關(guān)的自身抗體

Tab.3AutoantibodiesnewlyfoundinpSS

AutoantibodiesClinicalSignificanceReferenceaβ2GPⅠHintingtheriskoftheoccurrenceofneuropathy[34]p?ANCAHintingtheriskoftheoccurrenceofneuropathy[34]Anti?ADAMTS13antibodyOverlappingpSSwiththromboticthrombocytopenicpurpura[35]Anti?NA?14antibodyIndicatingshortdiseaseduration[38]Anti?IFN?γantibodyReducingthefrequencyofpulmonaryfibrosis[36]Anti?PAX6antibodyDetectingearlylossofocularphenotype[37]Anti?MDM2antibodyLongerdiseaseduration，severeDiseaseactivity[39]Anti?REGIαantibodyDiminishedsalivaryglandacinarcellproliferation[40，41]

Reg家族基因產(chǎn)物作為生長(zhǎng)因子，可促進(jìn)細(xì)胞增殖和再生，與各種炎癥疾病關(guān)系密切。研究發(fā)現(xiàn)REG Iα在pSS患者的唾液腺導(dǎo)管上皮細(xì)胞中過表達(dá)，并且在血清中可檢測(cè)到抗REG Iα自身抗體[40]。Fujimura等[41]發(fā)現(xiàn)抗REG Iα抗體陽(yáng)性的患者唾液分泌功能低下，其機(jī)理與IL-6誘導(dǎo)REG Iα破壞唾液腺管狀上皮細(xì)胞的再生有關(guān)。各種近年發(fā)現(xiàn)自身抗體的臨床意義，見表3。

5 自身抗體與疾病預(yù)后

自身抗體與風(fēng)濕病預(yù)后往往存在一定的聯(lián)系，如在系統(tǒng)性硬化癥，抗ACA陽(yáng)性的患者預(yù)后多良好，而抗topo I抗體與不良預(yù)后相關(guān)[42]。高滴度的RF(IgM和/或IgA)、抗CCP抗體和抗核周因子等多提示類風(fēng)濕性關(guān)節(jié)炎疾病活動(dòng)度高，難以控制[43,44]。目前自身抗體與pSS預(yù)后相關(guān)的研究明顯不足，以后應(yīng)加強(qiáng)這方面的研究。

6 結(jié)語(yǔ)

自身抗體及其在疾病pSS的預(yù)測(cè)、診斷和發(fā)病機(jī)制中都發(fā)揮著重要的作用。當(dāng)前用于實(shí)驗(yàn)室診斷的自身抗體-抗Ro/SSA、抗La/SSB、抗M3R和AFA普遍存在著特異性或者敏感性較低的缺陷，致使pSS患者易出現(xiàn)漏診或誤診。探索提高診斷準(zhǔn)確性的方法就迫在眉睫，是否可以考慮多種自身抗體的聯(lián)合應(yīng)用？如AFA與RF和/或ANA聯(lián)合敏感性從56.9%提高到70.7%。另外新技術(shù)也是提高傳統(tǒng)自身抗體敏感性的有效途徑。此外，研究發(fā)現(xiàn)許多自身抗體與pSS相關(guān)，尋找特異性和敏感性較高的新的自身抗體或者通過整合生物標(biāo)志物體系，或許對(duì)提高診斷的準(zhǔn)確性和深入闡述致病機(jī)理具有重要意義。

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