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1、自身免疫性肝炎發(fā)病機(jī)制研究進(jìn)展馬雄上海市消化疾病研究所上海交通大學(xué)醫(yī)學(xué)院附屬仁濟(jì)醫(yī)院AutoimmuneHepatitis（AIH）Autoantibodies自身免疫性肝炎的分型特征I型AIHII型AIH自身抗體ANA，SMA，肌動(dòng)蛋白的抗體LKM-1，ALC-1(antiactin)，抗SLA/LP，pANCA地理分布全世界全世界，北美罕見年齡任何年齡大多為兒童及青少年性別75%為女性95%為女性伴發(fā)免疫性疾病常見常見臨床嚴(yán)重程度多樣性一般較嚴(yán)重組織學(xué)特征多樣性多為進(jìn)展性治療失敗少見常見停藥后復(fù)發(fā)不定常見長期維持治
2、療不定幾乎100%需要5自身免疫性肝炎的發(fā)病機(jī)理?遺傳易感性?Treg/Th17細(xì)胞平衡?體液免疫和細(xì)胞免疫6PositiveandnegativecostimulationofT-cellactivationAutoantigenAssociationofHLADRB1allelswithAIHHLAallelePopulationAdults/ChildrenRiskratioDRB1*0301ArgentinaChildren3.0DRB1*0301NorthAmerica,UK3.39DRB1*0301Indi
3、aAdults3.79DRB1*0404MexicoMixed7.71DRB1*0405ArgentinaAdults10.4DRB1*0405Japan,ChinaAdults4.97DRB1*1301ArgentinaChildren16.3DRB1*1301IndiaAdults6.47DRB1*1302ArgentinaChildren0.1DRB1*14IndiaAdults3.25DRB1*1501NorthAmerica,UK0.52DRB1*0301/0301NorthAmerica,UK7.618DR
4、B1*0301/04NorthAmerica,UK5.099自身免疫性肝炎的發(fā)病機(jī)理?遺傳易感性?Treg/Th17細(xì)胞平衡?體液免疫和細(xì)胞免疫10NKAPCLivercellIL-17ClassIIPeptideClassIClassIIIL-1Co-stimuliCIL-12IFN-?Th0TcTNF-?YYTh1YIL-2YIL-4TGF-?IFN-?MPTregTh2IL-17IL-4IL-10BIL-13IL-6Th17Autoimmuneattack11tothelivercellsVerganiD,eta
5、l.SeminarsinLiverDisease2007RegulatoryTcellsandTcellimmuneresponseVieringJM.Hepatology2011,53:385-388MaX,etal.Heptology2007,46:1519-1529ExpansionandDeNovoGenerationofPotentiallyTherapeuticRegulatoryTCellsinPatientswithAIHFOXP3proteinexpressioninnewlygeneratedT-r
6、egs14LonghiMS，etal.Hepatology,2008,47Autoantigen-specificregulatoryTcells,apotentialtoolforimmune-tolerancereconstitutionintype-2AIHLonghiMS，etal.Hepatology,2011,53:536-547EvidenceofimpairedimmuneregulationinAIH-1?Impairedsuppressorcellfunctioncorrectedbyinvitro
7、exposuretosteroids?DefectinasubsetofT-cellscontrollingresponsestoaliver-specificmembraneautoantigen?NumericalandfunctionalimpairmentofCD4+CD25+Tregs?TregsdefectiveatregulatingCD4andCD8T-cellproliferationandIFN-?production?Tregsdefectiveatpromotingsecretionofregu
8、latorycytokinesbytheirtargets?TregsunabletorestrainmonocyteactivationandfunctionEvidenceofimpairedimmuneregulationinAIH-2?NumericalandfunctionalimpairmentofCD4+CD25+T
