系統(tǒng)性硬化癥自身抗體研究進(jìn)展

1、系統(tǒng)性硬化癥自身抗體研究進(jìn)展系統(tǒng)性硬化癥(systemic sclerosis, SSc)是一種以皮膚及多臟器纖維化為突 出表現(xiàn)的系統(tǒng)性自身免疫性疾病，目前認(rèn)為炎癥和自身免疫應(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， 合成自身抗體，參與組織損傷和器官功能障礙。 針對(duì)細(xì)胞內(nèi)、外靶點(diǎn)的自身抗體 可作為SSc血清標(biāo)志物。超過(guò)95%的SSc患者在首次診斷時(shí)可檢測(cè)到自身抗體， 并與疾病亞型，皮膚病變，內(nèi)臟受累及預(yù)后密切相關(guān)。超過(guò) 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1,包括抗拓?fù)洚?構(gòu)酶I抗體、抗著絲點(diǎn)抗體

2、和抗 RNA聚合酶抗體，三者對(duì)SSc診斷具有較高 特異性，因而納入了 2013年美國(guó)風(fēng)濕病學(xué)會(huì)(ACR)/歐洲抗風(fēng)濕病聯(lián)盟(EULAR) 對(duì)SSc的分類標(biāo)準(zhǔn)之中2,并且有助于識(shí)別早期或極早期 ssC3, 4。盡管三種標(biāo)志 性抗體已廣泛應(yīng)用于臨床，然而關(guān)于抗體功能和臨床意義的研究仍不斷進(jìn)展。止匕外，研究發(fā)現(xiàn)一系列自身抗體具有功能性序列可參與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臨床特征與發(fā)病環(huán)節(jié)密切相關(guān)，也為 致病機(jī)制提供新的見解，而闡明自身抗體介導(dǎo)發(fā)病相關(guān)通路也有助于尋找潛在治 療靶點(diǎn)。本綜述將重

3、點(diǎn)關(guān)注SSc相關(guān)自身抗體，尤其是新近發(fā)現(xiàn)的功能性自身抗 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 (Topoisomerase I / 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 70 kDa核抗原反應(yīng)而 得名。后來(lái)人們認(rèn)識(shí)到全長(zhǎng)自身抗原是拓?fù)洚悩?gòu)酶I (Topoisomerase I , topo I,而70 kDa蛋白是天然全長(zhǎng)100 kDa蛋白分解產(chǎn)物。雖然抗Scl-70的術(shù)語(yǔ)仍在使 用，但更準(zhǔn)確的命名應(yīng)為抗topo I抗體?？箃opo I抗體在SSc中報(bào)道的陽(yáng)性率為 9.4%42%,最常見的是IgG亞型，IgA和IgM亞型亦可見。盡管抗t

4、opo I抗體 對(duì)SSc高度特異，但研究報(bào)道也可見于 SLE 5,然而血清識(shí)別抗原表位有所不 同?？箃opo II抗體并非SSc所特異，可見于其他免疫相關(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opo I抗體被認(rèn)為與彌漫性皮 膚型（diffuse cutaneous SSc, dcSSC高度相關(guān)，但也可見于局限性皮膚型（localized cutaneous SSc, IcSSc患者?？箃opo I抗體強(qiáng)烈提示不良預(yù)后，病死率增高，與 間質(zhì)性肺病高度相關(guān)。另有報(bào)道抗topo I抗體與骨骼肌和心肌受累，手指攣縮畸 形，及蛋白尿相關(guān)6。而抗topo I抗體與月中瘤間的關(guān)

5、聯(lián)仍存在爭(zhēng)議。目前研究認(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?, 8,最終導(dǎo)致抗原釋放，免疫耐受失衡，機(jī)體產(chǎn)生抗topo I抗體。研究支持抗topo I抗體可能是SSc的致病性抗體，而非單純的伴隨抗體：1）使用topo I 抗原聯(lián)合佐劑免疫小鼠可誘導(dǎo)抗topo I抗體產(chǎn)生，導(dǎo)致皮膚和肺組織的炎癥和纖 維化病變9; 2）抗topo I抗體可作用于SSc皮膚成纖維細(xì)胞，促進(jìn)膠原合成， 以及單核細(xì)胞募集10; 3） topo I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)表達(dá)促炎、促纖維化和縮血管因子11。因而抗topo I抗體在SSc發(fā)生中 具有潛在的致病性，可能在SS

6、c自身免疫應(yīng)答與纖維化間起 橋接”作用，然而具 體機(jī)制有待深入研究。2 抗著絲點(diǎn)（Centromere protein, 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，是與幾乎所有抗 CENP陽(yáng)性血清反應(yīng)的主要抗原，而抗 CENP-A抗 體比抗CENP-B抗體對(duì)SSc更具特異性12,兩種亞型具有相似的臨床特征13。 其他抗CENP亞型也被陸續(xù)發(fā)現(xiàn)，抗 CENP-C抗體與干燥綜合征相關(guān)，而抗 CENP-I抗體可能是自身免疫性肝病的血清標(biāo)志物?？笴ENP抗體與lcSSc密切相關(guān)，尤其是CREST綜合征（鈣質(zhì)沉著，雷諾 現(xiàn)象，食管運(yùn)動(dòng)障礙

7、，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13。約20%的抗 CENP陽(yáng)性患 者合 并肺 動(dòng)脈高壓（pulmonary arterial hypertension, PAH）,約50%該類患者死亡歸因于 PAH14?？笴ENP抗體陽(yáng)性的 孤立性雷諾未來(lái)發(fā)展為SSc的風(fēng)險(xiǎn)顯著升高15,然而合并嚴(yán)重指端潰瘍的發(fā)生 率并未增加13?？笴ENP抗體陽(yáng)性SSc患者較其他標(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1603 抗 RNA 聚合酶(RNA polymerase, RNAP)抗體針又t RNAP I和RNAP III的自身抗體經(jīng)常共存，且對(duì)SSc高度特異。SSc中 的陽(yáng)性率約為

8、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)與種族基因背景相關(guān)17。針又t RNAP II的抗體少見，且并 不特異于SSc,可在SLE和重疊綜合征患者中檢出18?？筊NAP III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， 但缺乏特異性，常與 其他自身抗體同時(shí)檢出，因而采用 酶聯(lián)免疫吸附測(cè)定(Enzyme linked immunosorbent assay, ELISA 測(cè)定可能是優(yōu)選方法19?？筊NAP I和III抗體與彌漫皮膚型SSc相關(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

9、，結(jié)果顯示抗 RNAP III 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)展的皮膚病變相關(guān) 外，還與伴隨的月中瘤發(fā)生(-6 +12月)密切相關(guān)(OR 7.38, 95% CI 1.61-33.8) 20。而Johns Hopkins隊(duì)列數(shù)據(jù)也應(yīng)證了這一結(jié)果， 抗RNAP III抗體陽(yáng)性患者中 3年月中瘤標(biāo)化發(fā)病比為2.84 (95% CI 1.894.10),而乳腺癌和肺癌分列抗 RNAP III抗體陽(yáng)性的dcSSc和lcSSc患者之首21。因而對(duì)于抗RNAP III抗體陽(yáng)性的SSc 患者而言，除需密切隨訪腎臟病變外，還應(yīng)加強(qiáng)月中瘤篩查。4抗血管緊張素II-1型受體(angiote

10、nsin II type 1 receptor, AT1R)和內(nèi)皮素1受 體(endothelin-1 type A receptor, ETAR 抗體AT1R和ETAR廣泛表達(dá)于脈管系統(tǒng)及免疫細(xì)胞。針對(duì) AT1R和ETAR的抗 體可激活相應(yīng)受體參與多種血管病變，兩者高度相關(guān)且可發(fā)生交叉反應(yīng)。85%的SSc患者抗AT1R和ETAR的抗體陽(yáng)性陽(yáng)，與指端潰瘍23及PAH24密切相關(guān)， 也可見于其他結(jié)締組織病合并的PAH,可作為提示預(yù)后的血清標(biāo)志物24。體內(nèi)實(shí)驗(yàn)證實(shí)抗AT1R和ETAR抗體可作用于血管內(nèi)皮細(xì)胞導(dǎo)致中性粒細(xì)胞黏附及膠 原合成25,也可促進(jìn)內(nèi)皮細(xì)胞和免疫細(xì)胞分泌促炎癥因子26o體內(nèi)實(shí)驗(yàn)中

11、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)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-derived growth factor receptor, 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(reactive oxygen species, ROS產(chǎn)生，促進(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陷小鼠，同時(shí)輸注針對(duì)PDGFR的刺激性抗體，證實(shí)這一抗體可促進(jìn)并維系SSc皮膚纖維化病變27。止匕外，抗PDGFR抗體可誘導(dǎo)人

12、 肺血管平滑肌細(xì)胞的增殖和遷移，可能參與SSc血管病變28。有研究報(bào)道SSc來(lái)源的抗PDGFR抗體發(fā)揮激活作用參與發(fā)病，雖然健康對(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)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)區(qū)分刺 激性和非刺激性抗PDGFR抗體結(jié)合的抗原表位，繪制功能性表位圖譜，從而推 動(dòng)臨床應(yīng)用30 o6 抗毒蕈堿-3 受體(Muscarinic-3 receptor, M3R)抗體包括胃食管反流在內(nèi)的消化道病變是 SSc患者常見且突出的臨床表現(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

13、起胃食管反流的重要原 因，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消化道癥狀密切相關(guān)31o進(jìn)一步發(fā)現(xiàn)來(lái)自SSc的 自身抗體首先阻斷神經(jīng)節(jié)膽堿能神經(jīng)傳遞引起神經(jīng)病變，隨著疾病進(jìn)展，可改變平滑肌細(xì)胞膜上乙酰膽堿功能引起肌肉病變。抗M3R抗體主要作用于靶點(diǎn)為M3R的第二胞外段，靜脈用丙種球蛋白(Intravenous gamma globulin, IVIG )可 阻斷抗M3R抗體Fab段的特異性作用，包括對(duì)神經(jīng)病變和肌肉病變的雙重調(diào)控 32?？筂3R抗體除了可見于SSc患者，還可見于干燥綜合征及重癥肌無(wú)力患者， 但抗M3R抗體

14、陽(yáng)性的SSc中，64%的患者有營(yíng)養(yǎng)吸收障礙和/或胃腸道假性梗阻 330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，不但可以提示消化道合并癥，并為 IVIG等免疫治療提供理論依據(jù)。7 抗干擾素誘導(dǎo)基因 16 (Interferon-inducible gene 16, IFI16)抗體IFI16是HIN-200家族成員，構(gòu)成性表達(dá)于血管內(nèi)皮細(xì)胞和角質(zhì)形成細(xì)胞， 過(guò)表達(dá)IFI16可導(dǎo)致血管內(nèi)皮凋亡和促炎癥因子釋放340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%35,36, IcSSc中更高35,且與肢端潰瘍相關(guān)37,抗CENP和抗IFI-

15、16抗體雙陽(yáng)性性患者的肢端血管事件風(fēng)險(xiǎn)增加。目前研究推測(cè)抗IFI-16抗體作用于內(nèi)皮細(xì)胞特異性抗原，參與 SSc血管病變38.8 抗 RuvBL1 和 RuvBL2 抗體RuvBL1和RuvBL2是ATP酶同源物，參與轉(zhuǎn)錄、DNA修復(fù)及染色質(zhì)結(jié)構(gòu) 重塑等生理過(guò)程39。最近在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和骨骼肌受累相關(guān)40o9 抗真核起始因子-2B (Eukaryotic Initiation Factor-2B , eIF-2B)抗體eIF-2B是一種細(xì)胞質(zhì)多聚體蛋白，參與真核細(xì)胞蛋白質(zhì)合成，幫助tRNA與 核糖體結(jié)合41。B

16、etteridge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)性肺病相關(guān)42, 43。有研究提出 抗eIF2B抗體的形成可能與EB病毒分子模擬相關(guān)44。小結(jié)：SSc經(jīng)典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聚合酶抗體雖然已經(jīng)廣泛應(yīng)用于 SSc的診斷分型和預(yù)后判斷中，然而對(duì)于其臨床意 義和致病機(jī)制仍不斷在拓展和深入，因而在此溫故而知新。此外，一些功能性抗體靶向于SSc重要致病環(huán)節(jié)，日前也備受關(guān)注，抗AT1R和ETAR抗體可促進(jìn)血 管內(nèi)皮細(xì)胞收縮，進(jìn)而導(dǎo)致內(nèi)皮細(xì)胞凋亡和促炎癥因子釋放參與血管病變，針對(duì)PDGFR抗體可改變氧化應(yīng)

17、激平衡，促進(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。因此功能性自身抗體不但可提示臨床， 還有助于揭示 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)和重塑策 略提供理論依據(jù)。最后，新近發(fā)現(xiàn)的SSc自身抗體，如抗IFI-16抗體、抗Ruv1/2 抗體和抗eIF2B抗體等，與SSc特定臨床表型相關(guān)，有望應(yīng)用于臨床，然而其潛 在作用機(jī)制有待深入。參考文獻(xiàn):MECOLI C A, CASCIOLA-ROSENL. An update on autoantibodies in scleroderma J. Current opinion in rheumatolo

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19、, WALKER U A, et al. Preliminary criteria for the very early diagnosis of systemic sclerosis: results of a Delphi Consensus Study from EULAR Scleroderma Trials and Research Group J. Annals of the rheumatic diseases, 2011,70(3): 476-81.4 LEROYE C, MEDSGERT A, JR. Criteria for the classification of ea

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