白癜風(fēng)發(fā)病機(jī)制及治療策略

高天文　劉玲

近10年來，白癜風(fēng)發(fā)病機(jī)制的研究越來越受到重視，全球范圍內(nèi)在皮膚科學(xué)界頂級(jí)雜志J Invest Dermatol及以上級(jí)別雜志刊載相關(guān)文章達(dá)70余篇，其中新英格蘭醫(yī)學(xué)雜志（N Engl J Med）6篇[1-6]、自然遺傳雜志（Nature Genet）3篇[7-9]，皮膚學(xué)界對(duì)白癜風(fēng)的認(rèn)識(shí)正發(fā)生著深刻的變化。

2001年，筆者在第四軍醫(yī)大學(xué)學(xué)報(bào)發(fā)表了一篇小文章--挑戰(zhàn)白癜風(fēng)治療[10]，限于當(dāng)年的認(rèn)識(shí)，挑戰(zhàn)著眼于三方面：一是中醫(yī)中藥及免疫治療，二是能大量擴(kuò)增及建庫貯存的異體黑素細(xì)胞治療，三是針對(duì)產(chǎn)生黑素細(xì)胞自身抗體的B細(xì)胞的帶毒表位肽治療。彈指一揮間，10年前的一些認(rèn)識(shí)很快已成為歷史。得益于紫外光設(shè)備技術(shù)的進(jìn)步及黑素細(xì)胞培養(yǎng)技術(shù)的進(jìn)步，白癜風(fēng)的治療效果也早已是今非昔比，然而，白癜風(fēng)的臨床治療研究仍然還有漫長(zhǎng)的路。從宏觀看，白癜風(fēng)治療的突破有賴于發(fā)病機(jī)制的充分闡明及基于發(fā)病機(jī)制而制定的治療策略。

1白癜風(fēng)發(fā)病機(jī)制研究概況

白癜風(fēng)發(fā)病機(jī)制涉及到遺傳、黑素細(xì)胞凋亡、神經(jīng)內(nèi)分泌、自身免疫、氧化應(yīng)激、細(xì)胞因子等許多方面，各種發(fā)病假說多達(dá)7、8個(gè)，彼此間有聯(lián)系也有矛盾， Le poole[11]曾提出匯聚學(xué)說（convergence theory），即：遺傳、應(yīng)激、有毒化合物的聚集、感染、自身免疫、突變、細(xì)胞內(nèi)環(huán)境的改變以及黑素細(xì)胞遷移和增殖能力的減弱等多因素、多基因累積共同導(dǎo)致了白癜風(fēng)的發(fā)生，不同的個(gè)體則可能存在不同病因的組合。

近年白癜風(fēng)發(fā)病機(jī)制研究最重要的進(jìn)展在于三個(gè)方面：細(xì)胞免疫、氧化應(yīng)激、基于分子生物學(xué)的遺傳研究。①CD8+ CTL所參與的免疫應(yīng)答在黑素細(xì)胞破壞中發(fā)揮重要的殺傷效應(yīng)：大量的研究發(fā)現(xiàn)進(jìn)展期白癜風(fēng)患者皮損處CD8+和CD4+ T細(xì)胞所占比例均升高，但以CD8+T細(xì)胞最為顯著；體外實(shí)驗(yàn)發(fā)現(xiàn)從皮損處分離的CD8+T淋巴細(xì)胞可以特異性殺傷黑素細(xì)胞，引起皮膚色素脫失[12-13]；②白癜風(fēng)患者黑素細(xì)胞氧化應(yīng)激平衡障礙：皮膚作為機(jī)體的屏障，承受著內(nèi)外環(huán)境中活性氧簇（reactive oxygen species, ROS）的攻擊；白癜風(fēng)患者皮膚局部過氧化氫酶水平下降[14]，表皮H2O2的濃度遠(yuǎn)高于正常水平，角質(zhì)形成細(xì)胞可將H2O2輸送給鄰近黑素細(xì)胞[15]，從而滅活多種抗氧化酶類，包括DMSR、CAT、GST、乙酰膽堿酯酶和MsrA，這些酶類在白癜風(fēng)患者皮損區(qū)活性均有明顯降低[16-19]，從而進(jìn)一步加劇了ROS的聚集。我們的研究發(fā)現(xiàn)，與自身免疫或氧化應(yīng)激相關(guān)的基因，如FAS/FASL、COX2、GST、CAT、iNOS及COMT等基因變異在白癜風(fēng)發(fā)生、發(fā)展中有重要作用[16,20-24]；③多個(gè)免疫及色素相關(guān)的基因與白癜風(fēng)密切相關(guān)：Spritz及張學(xué)軍兩個(gè)團(tuán)隊(duì)利用全基因組關(guān)聯(lián)分析技術(shù)（genome-wide association analysis, GWS）在國(guó)際最權(quán)威的學(xué)術(shù)期刊發(fā)表多篇文章[2,7-9]，這些發(fā)現(xiàn)為白癜風(fēng)發(fā)病的遺傳學(xué)說找到了充分的依據(jù)[2,7-9,20-24]。

2白癜風(fēng)治療策略

從目前的研究手段及認(rèn)知水平看，“改良土地”即在基因水平上進(jìn)行治療尚無法實(shí)現(xiàn)；“播種”即黑素細(xì)胞移植，目前已獲得了很大進(jìn)展，特別是許愛娥研究團(tuán)隊(duì)在此領(lǐng)域做出了杰出貢獻(xiàn)[25,26]；“播種”需在充分“除蟲”后方能實(shí)現(xiàn)，所以“除蟲”應(yīng)為當(dāng)前及今后的研究重點(diǎn)。近年白癜風(fēng)治療最大的進(jìn)展是NB-UVB及準(zhǔn)分子激光的應(yīng)用，這些技術(shù)主要通過抑制或破壞浸潤(rùn)于皮損的T細(xì)胞而達(dá)到目的。根據(jù)我們的白癜風(fēng)發(fā)病機(jī)制假說，氧化應(yīng)激為白癜風(fēng)發(fā)生的始動(dòng)因素，未來治療的著眼點(diǎn)應(yīng)在抗氧化劑的使用上，在目前的NB-UVB及準(zhǔn)分子激光治療進(jìn)展基礎(chǔ)上，如果有一種或幾種特異性較高的抗氧化劑能應(yīng)用于臨床，白癜風(fēng)的治療將獲得真正的突破。

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[收稿日期]2012-06-15

編輯/張惠娟