类风湿性关节炎的基础研究及进展.ppt

类风湿关节炎-基础研究及进展,目录病因-基因因素-环境因素病机-RA滑膜炎-RA骨侵蚀基础研究引导治疗的发展,WHATCAUSESRA?,病因,基因在RA遗传易感性和疾病严重程度中的关键作用,遗传易感性显示基因在RA的致病作用中占50%60%的比重,Genetics,RA的基因,Genetics,ChibnikLB,etal.PLoSOne.2011;6(9):e24380;BaxM,etal.Immunogenetics.2011August;63(8):459466;RaychaudhuriB.CurrOpinRheumatol.2010March;22(2):109118.,Genetics,RA易感基因-HLA-DRB1位点,PopulationRA-associatedDRB1alleleCaucasian*0401(HLA-DR4)AshkenaziJewish*0101(HLA-DR1)AsianIndian*0101(HLA-DR1)Spanish*1001(HLA-DR10)Israeli*1001(HLA-DR10)YakimaIndian*1402(HLA-DR6)Japanese*0405(HLA-DR4)Chinese*0405(HLA-DR4),Genetics,RA共同表位(SharedEpitope),HLA-DRB1*Aminoacidposition70717273740101QRRAA0401QKRAA0404QRRAA0405QRRAA0408QRRAA1001RRRAA1402QRRAA0402DERAA0403QRRAE,Genetics,非II类MHC与RA关联,Genetics,RA遗传学到了转变的时候,RA易感基因的功能学研究相对匮乏，仅有3篇相关报道例如：BTLA为一种表达于免疫细胞表面的抑制性受体，BTLA缺陷鼠可发生多种自身免疫病。已发现BTLA基因多态型与RA易感性相关。而且，在体外研究显示，BTLA590C等位基因的出现使该基因丧失对JurkatT细胞由ConA或抗CD3单抗诱导的IL-2产生的抑制作用。（ClinDevImmunol.2011;2011:305656）,Genetics,Genetics,Geneticsofrheumatoidarthritis:timeforachange!,deVries,Ren,CurrentOpinioninRheumatology:May2011p227232,Iconcludethatifyouwanttofindmoregenesyoushouldhavealotofpatience,timeandmoney,stopwithconventialGWASandinvestinlarge-scalesequencingofselectedpatientsandcontrols.Ihaveabettersuggestion,however:usetheinformationthatisalreadyavailabletoperformfunctionalstudiesinordertounderstandthemechanismoftheknownassociations!,1、对前期发现的RA易感基因在不同人种中的验证工作仍在继续；2、不同RA亚群与易感基因的关系得到进一步的理解；3、发现新RA易感基因的势头减缓；4、对RA易感基因的功能学研究仍显匮乏，遗传学研究到了需要转变观念的时候。,Genetics,遗传学研究总体态势：,环境因素,Geograph,Smoking,Infections,Others,病因,环境因素致RA的风险,相比西部地区患者，居住在东北区域的患者其发生RA的风险高达45%。相比高纬度的患者，居住在低纬度的RA患者起病更早。,地理区域所致RA的相对风险,地理位置与RA风险的相关性,CostenbaderKH,etal.ArchInternMed.2008August11;168(15):16641670.Ramos-RemusC,etal.ClinRheumatol2007;26:17251728.,Geograph,吸烟与不吸烟者发生血清阳性RA的相对危险度差异,吸烟-RA已知环境因素中高危险因素,KrishnanE,etal.ArthritisResTher.2003;5(3):R158R162;BakaZ,etal.ArthritisResearch54:38-46,SE和吸烟史共同作用于aCCP+RA患者的风险,Smoking,吸烟-anti-CCPs发生的高危因素,Smoking,吸烟在RA发病机制中的复杂作用,Smoking,感染因素-RA,Infections,A、B,免疫组化显示滑膜细胞中肽聚糖(红色).C,双染显示细菌肽聚糖聚积在滑液的巨噬细胞(箭头所示).,RA中聚积的细菌肽聚糖,SchrijverIA,etal:ArthritisRheum2000,43:2160,.),Infections,目录病因-基因因素-环境因素病机-RA滑膜炎-RA骨侵蚀基础研究引导治疗的发展,病机-滑膜炎,自身免疫性-RA,细胞因子网络-RA,BonehomeostasisinhealthyandRAjoints,YongwonChoi.etal.NatRevRheumatol.2009;5(10):543548.,骨侵蚀的机理,Damageandlackofrepairinrheumatoidarthritis.,Lories,R.Nat.Rev.Rheumatol.2011;7:700707.,破骨细胞在关节炎骨侵蚀起核心作用,来自炎性滑膜的破骨细胞正侵蚀软骨下骨盐,aGeorgSchettCellsofthesynoviuminrheumatoidarthritis-Osteoclasts,ArthritisResearch299(5):903-9.,艾得辛在BMP存在的条件下使Osx表达水平（RT-PCR）提高三倍。,CIA大鼠的骨保护作用-MRI,Refer：FangDu,liang-jingLv,etal.T-614,anovelimmunomodulator,attenuatesinflammationandarticulardamageincollageninducedarthritis.ArthritisResearchb:CIAratstreatedwithvehicle;c:CIAratstreatedwithMTX;d:CIAratstreatedwithnimesulidee/f:CIAratstreatedwithT614;g:CIAratstreatedwithT-614andMTX,softtissueswelling(yellowarrow)andlocalizationofbonemarrowedema(yellowtriangle),MRI检测结果：艾得辛能够几乎完全抑制CIA的炎症和骨髓内水肿。,影像学评估X线和CT,T-614offeredsignificantprotectionagainstjointdamage,NaiveVehicleMTXnimesulideT614(5)T614(20)MTX+T614(10),X线平片和CT检测结果显示：艾得辛还能够显著抑制骨吸收和关节破坏。,目录病因-基因因素-环境因素病机-RA滑膜炎-RA骨侵蚀基础研究引导治疗的发展,基础研究引导RA的靶向治疗,Tcell,APCs,Bcellormacrophage,Synoviocytes,Pannus,Articularcartilage,Chondrocytes,HLA,-DR,Productionofcollagenaseandotherneutralproteases,Abs,Immunecomplexes,Articularcartilage,Productionofcollagenaseandotherneutralproteases,Tcell,APCs,Macrophage,cytokines,Osteoclast,Complements,TNF-IL-1IL-6,RA治疗方法的递进,靶向治疗使RA的治疗目标更高,靶向治疗的种类,TNF-a在RA病理中的作用,促进滑膜细胞增殖诱导趋化因子分泌募集白细胞上调血管粘附分子表达白细胞渗出抑制细胞调亡促进血管生长细胞因子分泌新生血管增加前炎性细胞因子等炎性介质产生刺激基质金属蛋白酶(MMPs)表达促进破骨细胞分化、成熟,TNF,炎性细胞浸润、聚集,滑膜增生,血管翳形成,滑液渗出,软骨降解,骨侵蚀,Choy,E.H.S.etal.NEnglJMed2001;344:907-916；MMJHerenius,1RMThurlingsetal.AnnRheumDis.2011June1;70(6):11601162.,TNF拮抗剂,TNFBA+MTX治疗52周对RA放射学的影响,BreedveldFC,etal.ArthritisRheum.2006.54:26-37.StClairEW,etal.ArthritsRheum.2004;50:3432-43.EmeryP,etal.Lancet.2008;372:375-82.KlareskogL,etal.Lancet2004;363:67581.,TSS自基线变化均值,均为随机双盲安慰剂对照入组条件:MTX-nave,PREMIER:阿达木;ASPIRE:英夫利昔;COMET和TEMPO:依那西普,TNFBA显著抑制RA放射学进展,AnnRheumDis2010;69:88-96.,IL-6受体治疗靶向(Actemra-tocilizuma),Anti-IL-6,BL的进展,CD19Expression,CD40Expression,CD20Expression,CD22Expression,Pro-Bcell,ImmatureBcell,MatureBcell,MemoryBcell,IgM,IgM,IgD,BBlast,Ig,GCBcell,Plasmacell,Ig,CD27+CD38+/+IgD-,CD27-,CD38+IgD-,CD27+CD38-IgD-,Plasmablast,IgM,IgD,MemoryBcell,CD27+CD38-,Anti-BcellinRA,抗CD20单抗在TNF拮抗剂治疗RA患者中的疗效:疗程6月,18,5,1,51,27,12,0,10,20,30,40,50,60,ACR20,ACR50,ACR70,%Patients,Placebo(N=201),Rituximab(N=298),p0.0001,p0.0001,p0.0001,CohenS,etal.ArthritisandRheumatism2006:54(9):2793-2806,Anti-Tcell,CTLA4lg,CTLA4lg(Abatacept)EffectivelyBlocksCD28DependentCostimulatorySignals,抑制T细胞激活,Anti-Tcell,在RA患者中通过阻断共刺激途径抑制T细胞活化,1.Kremeretal.AnnalsofInternalMedicine:2006;144:865-876,ACR20,ACR50,ACR70,Placebo+MTX,Abatacept+MTX,ACRResponse,抑制细胞信号传导通路,原理抑制酪氨酸激酶CIA有效性成功RA治疗的病例报道p38MAPK抑制剂PamapimodSCIO-469phaseIIRCT:缺乏有效性,抑制B细胞和细胞因子,KeiichiTanaka,Iguratimod(T-614):anoveldisease-modifyinganti-rheumaticdrug.RheumatologyReports2009;volume1:e4,生物制剂治疗,抑止细胞因子或细胞因子受体的TNFa拮抗