白癜風發病機制及治療策略

高天文　劉玲

近10年來，白癜風發病機制的研究越來越受到重視，全球范圍內在皮膚科學界頂級雜志J Invest Dermatol及以上級別雜志刊載相關文章達70余篇，其中新英格蘭醫學雜志（N Engl J Med）6篇[1-6]、自然遺傳雜志（Nature Genet）3篇[7-9]，皮膚學界對白癜風的認識正發生著深刻的變化。

2001年，筆者在第四軍醫大學學報發表了一篇小文章--挑戰白癜風治療[10]，限于當年的認識，挑戰著眼于三方面：一是中醫中藥及免疫治療，二是能大量擴增及建庫貯存的異體黑素細胞治療，三是針對產生黑素細胞自身抗體的B細胞的帶毒表位肽治療。彈指一揮間，10年前的一些認識很快已成為歷史。得益于紫外光設備技術的進步及黑素細胞培養技術的進步，白癜風的治療效果也早已是今非昔比，然而，白癜風的臨床治療研究仍然還有漫長的路。從宏觀看，白癜風治療的突破有賴于發病機制的充分闡明及基于發病機制而制定的治療策略。

1白癜風發病機制研究概況

白癜風發病機制涉及到遺傳、黑素細胞凋亡、神經內分泌、自身免疫、氧化應激、細胞因子等許多方面，各種發病假說多達7、8個，彼此間有聯系也有矛盾， Le poole[11]曾提出匯聚學說（convergence theory），即：遺傳、應激、有毒化合物的聚集、感染、自身免疫、突變、細胞內環境的改變以及黑素細胞遷移和增殖能力的減弱等多因素、多基因累積共同導致了白癜風的發生，不同的個體則可能存在不同病因的組合。

近年白癜風發病機制研究最重要的進展在于三個方面：細胞免疫、氧化應激、基于分子生物學的遺傳研究。①CD8+ CTL所參與的免疫應答在黑素細胞破壞中發揮重要的殺傷效應：大量的研究發現進展期白癜風患者皮損處CD8+和CD4+ T細胞所占比例均升高，但以CD8+T細胞最為顯著；體外實驗發現從皮損處分離的CD8+T淋巴細胞可以特異性殺傷黑素細胞，引起皮膚色素脫失[12-13]；②白癜風患者黑素細胞氧化應激平衡障礙：皮膚作為機體的屏障，承受著內外環境中活性氧簇（reactive oxygen species, ROS）的攻擊；白癜風患者皮膚局部過氧化氫酶水平下降[14]，表皮H2O2的濃度遠高于正常水平，角質形成細胞可將H2O2輸送給鄰近黑素細胞[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，這些酶類在白癜風患者皮損區活性均有明顯降低[16-19]，從而進一步加劇了ROS的聚集。我們的研究發現，與自身免疫或氧化應激相關的基因，如FAS/FASL、COX2、GST、CAT、iNOS及COMT等基因變異在白癜風發生、發展中有重要作用[16,20-24]；③多個免疫及色素相關的基因與白癜風密切相關：Spritz及張學軍兩個團隊利用全基因組關聯分析技術（genome-wide association analysis, GWS）在國際最權威的學術期刊發表多篇文章[2,7-9]，這些發現為白癜風發病的遺傳學說找到了充分的依據[2,7-9,20-24]。

2白癜風治療策略

從目前的研究手段及認知水平看，“改良土地”即在基因水平上進行治療尚無法實現；“播種”即黑素細胞移植，目前已獲得了很大進展，特別是許愛娥研究團隊在此領域做出了杰出貢獻[25,26]；“播種”需在充分“除蟲”后方能實現，所以“除蟲”應為當前及今后的研究重點。近年白癜風治療最大的進展是NB-UVB及準分子激光的應用，這些技術主要通過抑制或破壞浸潤于皮損的T細胞而達到目的。根據我們的白癜風發病機制假說，氧化應激為白癜風發生的始動因素，未來治療的著眼點應在抗氧化劑的使用上，在目前的NB-UVB及準分子激光治療進展基礎上，如果有一種或幾種特異性較高的抗氧化劑能應用于臨床，白癜風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