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        多發(fā)性大動(dòng)脈炎免疫發(fā)病機(jī)制

        2014-04-09 02:01:08張倩茹
        關(guān)鍵詞:活動(dòng)期活動(dòng)度主動(dòng)脈

        張倩茹,郭 娟,周 煒

        (北京大學(xué)第一醫(yī)院風(fēng)濕免疫科,北京 100034)

        ChinJAllergyClinImmunol,2014,8(3):254- 258

        大動(dòng)脈炎(Takayasu’s arteritis, TA)是主要累及主動(dòng)脈及其主要分支的慢性非特異性全層動(dòng)脈炎性反應(yīng)。近年研究表明,細(xì)胞免疫在TA發(fā)病機(jī)制中占據(jù)重要地位,TA動(dòng)脈壁標(biāo)本免疫組織化學(xué)研究可見較多CD4+T細(xì)胞、CD8+T細(xì)胞、巨噬細(xì)胞、自然殺傷細(xì)胞、γδT細(xì)胞及中性粒細(xì)胞浸潤[1]。本文就近幾年TA免疫發(fā)病機(jī)制研究進(jìn)展作一綜述。

        Toll樣受體

        Toll樣受體 (Toll-like receptor, TLR) 是參與非特異性免疫的一類重要蛋白質(zhì)分子,也是連接非特異性免疫和特異性免疫的橋梁。當(dāng)微生物突破機(jī)體的物理屏障如皮膚黏膜等時(shí),TLR可將其識(shí)別并激活機(jī)體產(chǎn)生免疫應(yīng)答。為進(jìn)一步研究血管炎血管受累情況,Pryshchep等[2]對(duì)TLR 1~TLR 9在顳動(dòng)脈、主動(dòng)脈、鎖骨下動(dòng)脈、頸動(dòng)脈、髂動(dòng)脈及腸系膜動(dòng)脈的表達(dá)進(jìn)行了相關(guān)研究,發(fā)現(xiàn)TLR 2和TLR 4廣泛存在于上述6個(gè)部位的血管中;進(jìn)一步應(yīng)用免疫組織化學(xué)法證實(shí),TLR2和TLR4主要表達(dá)在大血管的中膜和外膜交界處,而非內(nèi)膜和中膜上。在體外試驗(yàn)中,以脂多糖刺激動(dòng)脈壁,導(dǎo)致樹突狀細(xì)胞標(biāo)記物CD86、CD83明顯升高,免疫組化法示CD86+細(xì)胞主要表達(dá)在外膜中,提示TLR可能主要表達(dá)于樹突狀細(xì)胞上。Deng等[3]報(bào)道樹突狀細(xì)胞能夠識(shí)別細(xì)菌等病原體并調(diào)控炎性反應(yīng)類型。將人顳動(dòng)脈(通過尸檢或手術(shù)切除獲得)植入SCID小鼠制成顳動(dòng)脈-SCID小鼠模型,移植后第7天將脂多糖注入小鼠體內(nèi),免疫組化法發(fā)現(xiàn)大量T細(xì)胞被招募,浸潤至移植動(dòng)脈并被激活。而在體外試驗(yàn)中, 樹突細(xì)胞通過TLR4識(shí)別脂多糖被活化,CC類趨化因子配體20(CC chemokine ligand 20, CCL20)表達(dá)增加;表達(dá)CCL20受體即CC類趨化因子受體6(CC chemokine receptor 6, CCR6)陽性的T細(xì)胞生成增多,從而導(dǎo)致全層動(dòng)脈炎,這在顳動(dòng)脈-SCID小鼠模型中也得到了證實(shí)。因此,阻斷CCL20-CCR6可能為血管炎的治療提供新方法。

        細(xì)胞因子

        白介素(interleukin, IL)-6是由活化的單核細(xì)胞、巨噬細(xì)胞和T細(xì)胞合成的促炎細(xì)胞因子,其作用為B細(xì)胞和T細(xì)胞激活,成纖維細(xì)胞增生、急性時(shí)相蛋白合成[4]。正常T細(xì)胞表達(dá)分泌的活性調(diào)節(jié)蛋白(regulated upon activation, normal T cell expressed and secreted,RANTES)和IL-8是對(duì)外周血單個(gè)核細(xì)胞(peripheral blood mononuclear cell,PBMC)有趨化作用的趨化因子。研究顯示,TA患者IL-6[5]、RANTES[5]和IL-8[6]增加,并和疾病活動(dòng)度相關(guān)。IL-6和RANTES誘導(dǎo)基質(zhì)金屬蛋白酶(matrix metalloproteinase, MMP)合成,從而降解動(dòng)脈壁的彈性纖維和膠原纖維。與健康對(duì)照組相比,TA患者血清中MMP-2、MMP-3和MMP-9明顯升高,且MMP-3和MMP-9與疾病活動(dòng)度相關(guān)[7]。由此可見,TA患者IL-6和RANTES升高可誘導(dǎo)浸潤的PBMC和或平滑肌細(xì)胞合成分泌MMP增加,破壞動(dòng)脈壁結(jié)構(gòu)。有報(bào)道應(yīng)用 IL-6受體拮抗劑治療難治性TA可使患者病情明顯緩解[8-10],這也證實(shí)了IL-6參與TA發(fā)病。

        Park等[11]報(bào)道,IL-18在TA活動(dòng)期升高,經(jīng)治療緩解后水平下降且差異有統(tǒng)計(jì)學(xué)意義,提示IL-18與TA疾病活動(dòng)度相關(guān)。有研究顯示,用植物血凝集素+12-十四酸佛波酯-13-乙酸鹽刺激PBMC,與健康對(duì)照組相比,TA患者干擾素(interferon,IFN)-γ、IL-2、IL-3、IL- 4、TNF-α的mRNA表達(dá)增加,IL-10表達(dá)減低;以脂多糖刺激PBMC,與健康對(duì)照組相比,TA患者IL-12表達(dá)增加,表明IFN-γ、IL-2、IL-3、IL- 4、TNF-α、IL-12、IL-10在TA不同的病理過程中起關(guān)鍵作用[12]。IFN-γ、IL-2、IL-3和IL-12主要由T輔助細(xì)胞(T helper cell,Th)1分泌[13]。IL- 4由Th2細(xì)胞分泌,在IL-2和IL-12存在的前提下能增加Th1所分泌細(xì)胞因子如IFN-γ分泌,誘導(dǎo)發(fā)生細(xì)胞免疫[14]。因此,IFN-γ、IL-2、IL-3、IL- 4和IL-12升高,以及IL-10減低,可提示Th1型細(xì)胞因子在TA患者中廣泛存在。

        細(xì)胞免疫

        TA為全層動(dòng)脈炎,動(dòng)脈壁外膜中浸潤的炎性細(xì)胞多由滋養(yǎng)血管內(nèi)溢出,這一過程需要激活滋養(yǎng)血管內(nèi)皮細(xì)胞,以便淋巴細(xì)胞能夠穿出血管壁[15]。TA患者中血漿可溶性血管細(xì)胞黏附分子1(soluble vascular cell adhesion molecule-1,sVACM1)水平升高[16],誘導(dǎo)動(dòng)脈組織中細(xì)胞間黏附分子(intercellular adhesion molecule-1, ICAM1)及Ⅰ、Ⅱ型人類白細(xì)胞抗原(human leukocyte antigen,HLA)表達(dá)增加,有助于識(shí)別黏附浸潤的淋巴細(xì)胞[1]。內(nèi)皮素-1為內(nèi)皮縮血管肽類,參與內(nèi)皮功能失調(diào)和血管重塑的發(fā)生,研究示TA患者內(nèi)皮素-1表達(dá)增加[17]。最終血管內(nèi)皮生長因子(vascular endothelial growth factor,VEGF)表達(dá)增加,導(dǎo)致新生血管形成。總之,動(dòng)脈外膜新生血管形成和黏附分子表達(dá)上調(diào)造成了TA炎性細(xì)胞的聚集。

        既往研究表明,TA患者浸潤細(xì)胞中有15%的CD4+T細(xì)胞和15%的CD8+T細(xì)胞[1]。CD4+T細(xì)胞能夠通過釋放IFN-γ刺激和維持肉芽腫形成[18]。TA患者外周血中CD4+CD8+比例升高[19],HLA-DR+T細(xì)胞數(shù)目增加[20],蛋白激酶C活性增加,細(xì)胞內(nèi)Ca水平升高[21],表明其T細(xì)胞處于激活狀態(tài)。體外培養(yǎng)人臍帶血管內(nèi)皮細(xì)胞時(shí)發(fā)現(xiàn),淋巴細(xì)胞細(xì)胞毒性增加[22]、純化的人主動(dòng)脈抗原存在時(shí),淋巴細(xì)胞增殖明顯[19],表明外周血淋巴細(xì)胞易于被主動(dòng)脈抗原激活。

        體液免疫

        體液免疫在TA發(fā)病中是否發(fā)揮作用,目前研究仍存在爭議。TA患者尚無特異性自身抗體存在。Park等[23]研究發(fā)現(xiàn),IgM抗內(nèi)皮細(xì)胞抗體(anti-endothelial cell autoantibodies,AECAs)可能與TA疾病活動(dòng)度相關(guān)。Blank等[24]報(bào)道,AECAs是通過增加黏附分子表達(dá)、核因子-κB (nuclear factor-kappa B,NF-κB)激活及單核細(xì)胞的黏附刺激內(nèi)皮細(xì)胞導(dǎo)致TA發(fā)生。而Tripathy等[25]研究發(fā)現(xiàn),TA患者AECAs通過補(bǔ)體依賴的細(xì)胞毒作用損壞內(nèi)皮細(xì)胞,而非抗體依賴的細(xì)胞毒作用。Tripathy等[26]還發(fā)現(xiàn),36%TA患者抗膜聯(lián)蛋白V抗體陽性,而對(duì)照組陽性率僅為6%,該蛋白可誘導(dǎo)血管內(nèi)皮細(xì)胞凋亡,為TA病理生理過程提供了新依據(jù);在該研究中,抗內(nèi)皮細(xì)胞抗體見于54%抗膜聯(lián)蛋白V抗體陽性的患者中。而Tripathy等[27]的另一項(xiàng)研究提示,TA患者抗單核細(xì)胞抗體顯著增加,且與疾病活動(dòng)度相關(guān)。TA患者存在抗主動(dòng)脈抗體早有報(bào)道[28],Dhingra等[29]應(yīng)用酶聯(lián)免疫吸附試驗(yàn)揭示TA患者較健康對(duì)照者抗主動(dòng)脈抗體滴度顯著升高。有研究表明,活動(dòng)期TA患者抗內(nèi)皮細(xì)胞抗體和抗主動(dòng)脈抗體檢出率明顯高于其他膠原病[30]。Baltazares等[31]應(yīng)用相應(yīng)抗體檢測(cè)35例TA患者血清中動(dòng)脈壁主要蛋白成分(如彈性蛋白、膠原蛋白),結(jié)果與對(duì)照組無顯著性差異。綜上所述,目前尚未發(fā)現(xiàn)TA特異性自身抗原,找到TA特異性自身抗體-抗原反應(yīng)將有助認(rèn)識(shí)TA發(fā)病機(jī)制。

        Nishino等[32]檢測(cè)9例TA患者血清中B細(xì)胞刺激因子(B cell activating factor,BAFF)水平發(fā)現(xiàn),活動(dòng)期TA患者BAFF較健康對(duì)照組和非活動(dòng)期TA患者明顯升高,提示BAFF與疾病活動(dòng)度相關(guān)。抗CD20單克隆抗體rituximab 可用于治療難治性TA。Galarza等[33]的回顧性研究中包括2例TA患者,這2例TA患者應(yīng)用甲氨蝶呤和腫瘤壞死因子拮抗劑均無效,改為rituximab后,1例緩解,另1例則再次改為環(huán)磷酰胺聯(lián)合硫唑嘌呤治療,提示rituximab效果亦欠佳。應(yīng)用rituximab成功治療難治性TA也見于其他文獻(xiàn)報(bào)道[34-35]。Hoyer 等[36]通過流式細(xì)胞術(shù)分析了17例TA患者外周血B細(xì)胞亞群情況,對(duì)照組為9例活動(dòng)期系統(tǒng)性紅斑狼瘡患者和9名健康志愿者,結(jié)果發(fā)現(xiàn)與對(duì)照組相比,活動(dòng)期TA患者外周血CD19+CD20-CD27high細(xì)胞增多,這些細(xì)胞中80%表達(dá)HLA-DR,提示新生細(xì)胞增多;活動(dòng)期TA患者漿母細(xì)胞數(shù)目和比例都明顯高于健康對(duì)照者和非活動(dòng)期TA,考慮其與疾病活動(dòng)度相關(guān);該項(xiàng)研究中有3例活動(dòng)期難治性TA患者應(yīng)用rituximab治療后病情緩解。這一結(jié)果提示B細(xì)胞失衡在TA發(fā)病中也發(fā)揮了重要作用。TA發(fā)病機(jī)制復(fù)雜,細(xì)胞免疫起主導(dǎo)作用,越來越多的證據(jù)提示體液免疫也發(fā)揮重要作用[37]。確定新的T細(xì)胞亞群(如Th17)是否參與TA發(fā)病、尋找TA特異性自身抗體,可加深對(duì)TA發(fā)病機(jī)制的認(rèn)識(shí),對(duì)TA的診斷和治療有重要意義。

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        [36] Hoyer BF, Mumtaz IM, Loddenkemper K, et al. Takayasu arteritis is characterised by disturbances of B cell homeostasis and responds to B cell depletion therapy with rituximab[J].Ann Rheum Dis, 2012, 71:75-79.

        [37] Arnaud L, Haroche J, Mathian A, et al. Pathogenesis of Takayasu’s arteritis:a 2011 update[J].Autoimmun Rev, 2011, 11:61-67.

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