免疫炎性疾病新认识及中西医结合临床对策

免疫炎性疾病新认识及中西医结合临床对策,南方医科大学珠江医院风湿免疫科于清宏2014年9月13日沈阳,5/31/2020,5/31/2020,5/31/2020,非可控性炎症免疫炎性疾病病的共同通道,Acellular,immuneandmetabolicresponsetoinjuryandinfection,Definitionofinflammation,炎症定义,Inflammationisatwo-edgedsword,servesasaprotectiveresponse,butisoftenamajorcauseoftissuedamageininfectious,immunologic,andvasculardiseases,aswellasaftertrauma.,红肿热痛功能障碍,促炎/抗炎细胞因子平衡,炎症是一个程序化过程,炎症细胞表型转变,Heredity,Nonresolvinginflammationandautoimmunediseases,先天禀赋,外感内伤,证候,部分自身免疫性疾病,免疫介导的炎性疾病,Chronicdiseaseswithprominentinflammation,oftencausedbyfailureoftoleranceorregulationRA,IBD,MS,psoriasis,manyothersAffect2-5%ofpeople,incidenceincreasingMayresultfromimmuneresponsesagainstselfantigens(autoimmunity)ormicrobialantigens(Crohnsdisease?)MaybecausedbyTcellsandantibodiesMaybesystemicororgan-specific,自身免疫病理过程,Susceptibilitygenes,Environmentaltrigger(e.g.infections,tissueinjury),Failureofself-tolerance,Activationofself-reactivelymphocytes,Immuneresponsesagainstselftissues,Persistenceoffunctionalself-reactivelymphocytes,ActivationEffectorTcells,Normal:reactionsagainstpathogensInflammatorydisease,e.g.reactionsagainstself,ToleranceRegulatoryTcells,NoresponsetoselfControlledresponsetopathogens,淋巴细胞活化及控制的平衡,阳,阴,自身免疫的遗传背景,HumanautoimmunediseasesarecomplexpolygenictraitsIdentifiedbygenome-wideassociationmappingSinglegenemutationsareusefulforpathwayanalysisSomepolymorphismsareassociatedwithmultiplediseasesMaycontrolgeneralmechanismsoftoleranceandimmuneregulationOthergeneticassociationsaredisease-specificMayinfluenceend-organdamage,NOD2:polymorphismassociatedwith25%ofCrohnsdiseaseMicrobialsensorPTPN22:commonestautoimmunity-associatedgene;polymorphisminRA,SLE,othersPhosphataseCD25(IL-2R):associatedwithMS,others;genome-wideassociationmappingRoleinTregs,自身免疫遗传背景:最近发现,感染与自身免疫,InfectionstriggerautoimmunereactionsClinicalprodromes,animalmodelsAutoimmunitydevelopsafterinfectioniseradicated(i.e.theautoimmunediseaseisprecipitatedbyinfectionbutisnotdirectlycausedbytheinfection)Someautoimmunediseasesarepreventedbyinfections(type1diabetes,multiplesclerosis,others?-increasingincidenceindevelopedcountries):mechanismunknownThe“hygienehypothesis”,主要免疫反应类型决定疾病自然病程Th1response:inflammation,autoantibodyproduction;autoimmunediseasesTh2response:IgE+eosinophil-mediatedinflammation;allergicreactionsTh17response:acute(andchronic?)inflammation;increasinglyrecognizedinimmune-mediateddiseases,Th1cells(IFN-g),Th2cells(IL-4,IL-5),Th17cells(IL-17),NaveCD4Tcell,CD4细胞亚群:产生及功能,RegulatoryTcells,IFN-,IL-12:T-bet,Stat4,IL-4:GATA3,Stat6,TGF-+IL-6:RORt,Stat3,TGF-IL-2:Foxp3,Stat5,Hostdefense:manymicrobesSystemicandorgan-specificautoimmunediseases,Hostdefense:helminthsAllergicdiseases,Hostdefense:fungi,bacteriaOrgan-specificautoimmunediseases,Afteramicrobialinfection,activa-tedmicrobe-speci-ficTH1(mTH1)cellsmigratetotheinfectedorgan.A.Molecularmimicry.B.Epitopespre-ading.C.Bystanderactivation.D.Crypticantigen.,部分隐蔽抗原,器官特异性自身免疫病理,Currenttherapiestargetlatestagesofthereaction(lymphocyteactivation,inflammation).Ultimategoalshouldbetotackletheunderlyingcauseandrestorecontroloftheabnormallydirectedresponse,免疫炎性疾病代表疾病,类风湿关节炎?,脊柱关节炎?,血管炎?,类风湿关节炎免疫炎症机制研究状况,HLA表型与等位基因变异检测,类风湿关节炎相关HLA-DR4结合表位,RA相关共享表位氨基酸序列,多基因疾病,脊柱关节炎免疫炎症机制研究现状,强直性脊柱炎的易感基因,NatureGenetics2013;45(7):730-8,IBD/subclinicalileitisHLA-B27,excessIL-23,ExcessIL-23Rsensitivity(SNPs),TheIL-23R+spondyloarthropogeniccell,CuaandSherlock,NatMed.2011Sep7;17(9):1055-6.,SherlockJP,etal.NatMed.2012;18:106976,ERAP1associatedwithHLA-B27+veAS,NatureGenetics2011;43:761-767,PicturecourtesyofDr.EricReits,ERAP1/ERAP2processantigenicpeptideepitopesbeforeloadingontoHLA-B27,Nucleus,ImmunoreceptorRecognitionofAberrantB27,ArthritogenicPeptidesandAutoreactiveTCells,B27Misfolding,ERStress,andUPRActivation,NodefiningmechanismbywhichHLA-B27causesAS,AlteredAPCFunction,ERAP2SNPN392Kaffectsbothenzymeactivityandspecificity,Thekcatoftheenzymechangesby25-fold,Effectsontrimmingratearesubstrate-specific!,Vanhilleetal.MolecularGenetics1(2):98107,Evnouchidouetal.JImmunol2012;189(5):2383,ERAP1SNPsatpositions528and730affectbothenzymeactivityandantigenpresentation,kcat/KM,Ki,MHCIlevels,Evnouchidouetal.JImmunol2011,Lengthselectioncanbealteredbypolymorphicvariation,Garciaetal.MCP,2012,Evnouchidouetal.JImmunol2012;189(5):2383,SNPsare“scattered”allovertheproteinstructure,AS易感基因的贡献值,肠道菌微生态与免疫炎性疾病,AS,CD,HC,Bacteroides,Acintobacteria,Firmicutes,Fusobacteria,Proteobacteria,ASgutmicrobiomeisdifferenttoCDandHC,Bacterialcontrol,机械压力的骨赘形成的作用,AnnRheumDis2013,遗传和环境因素共同导致疾病的发生,NatureMed2012;18:1018,IL23介导的T细胞参与了AS的致病,强直性脊柱炎的致病机理假说,IL-17IL-1IL-6TNF-,Nature2014,ConnectionofbiologicalRAriskgenestodrugtargets,Scheretal.eLife2013;2:e01202.DOI:10.7554/eLife.01202,Prevotellacopricorrelateswithenhancedsusceptibilitytoarthritis,血管炎发病机制研究现状,免疫学新进展-,免疫系统,创新点选择-,免疫学新进展-应答类型,肠道上皮细胞的正常屏障作用,MicrobialrecognitionpromotesIEChealthandfunction,NatureReviewImmunology,2013,13:75-87,新的免疫细胞-ILC（innateLymphoidcells),模式识别受体（patternrecognitionreceptors,PRRs):TLRs,NLR,nudeotideoligmerizationdomain（NOD）-likereceptors,NLRs,CARD:CaspaseactivationandrecruitmentdomainASC:Apoptosis-associatedspeck-likeproteincontainingCARD,5/31/2020,NOD-likereceptors,NLRs,NLRP3,植物药抗炎机制研究举例,调节免疫功能紊乱,WeiWetal,IntImmunophar,2002,2005,2009梁君山，魏伟，等.中国药理学通报，1989,5:354-357王兴旺，魏伟，等.中国药理学通报，1990,6:363-366周玲玲，魏伟，等.中国药理学通报，2002,18:175-177,白芍总苷机理研究,TGP是否能够作用与DC及相应后果？,DC分化发育和成熟,MDP：Lin-CX3CR1+CD11b-CD115+cKit+CD135+CDP：Lin-CD115+Flt3+CD117lo,Flt3：FMS样酪氨酸激酶3，(Flt3L，配体),imDC,mDC,TGP,白芍总苷（totalglucosidesofpaeonia，TGP）,OVA免疫,明确现象-TGP抑制免疫应答,抑制T细胞活化增殖,抑制机体对于新入侵抗原的免疫应答,探讨关键表型-TGP抑制DC成熟,被动转移实验：mDC恢复小鼠对于OVA反应,证实TGP抑制DC成熟而导致免疫应答降低,探讨机理-TGP抑制TLR-MyD88/NF-kB活化,与疾病治疗-RA-CIA模型,CII+CFACII+IFA,细胞亚群、细胞因子、信号转导,n=10/组3次重复16分评分,DBA1,明确现象-TGP延缓和减轻CIA发病与炎症,提前使用TGP，延缓并减轻CIA发病,机理-TGP抑制DC成熟降低CII免疫应答,明确表型-TGP降低Th1/Th17细胞亚群和功能,临床验证-TGP降低RA患者Th1/Th17,TNFa产生细胞减少,PSA?TGP?,TGP作用后PSA样小鼠体内M1细胞活性降低,TGP抑制M1，上调M2（体外）,TheNovelRoleofTotalGlucosidesofPaeonyinRegulatingTypeIandIIMacrophagesActivitiesinvivoandinvitro,ExperimentalDermatology,2014,inrevision,TGP干扰TLR4与LPS结合，阻断信号转导IntImmunophar,2012,12:275-82,TLR4和TGP,TLR4-MD2-LPSComplex(Nature2009),TLR4-LPS结合部位,TLR4和TGP,免疫炎性疾病治疗现状,糖皮质激素作用机制,糖皮质激素受体（GCR）有核细胞都有GCR直接或间接影响基因转录10-100个基因具有GC反应元素（GCresponseelement送，GCE）直接抑制NF-kB,抑制细胞因子产生间接抑制NF-kB、I-kB影响转录后过程mRNA翻译、蛋白质合成、蛋白质分泌,抑制促炎因子IL-1、IL-6、IL-13、GM-CSF、TNF-a减少炎症部位白细胞聚集通过抑制促炎症因子、NF-kB抑制黏附分子E-selectin、VCAM-1、ICAM-1抑制烷酸产物如白三烯（leukotriene）降低血管渗透性,皮质类固醇抗炎作用相当剂量盐皮激效应药理T1/2血浆T1/2hmin氢化可的松120281290可的松0.825281230强的松3.551123660强的松龙4511236200甲强龙5401236180曲安西龙5402448300地塞米松300.7503654100300倍他米松250.8003654100300氯地米松400.500,全身性应用皮质类固醇的当量比较,糖皮质激素全身应用副作用,内分泌系统抑制肾上腺抑制生长、儿童性成熟延迟体重增加、柯兴貌糖尿病代谢紊乱低血钾症、高血糖、高血脂骨骼肌肉系统骨质疏松、椎骨压缩性骨折骨无菌性坏死（髋、肩、膝）肌病（急性或慢性）皮肤皮肤变薄紫纹痤疮多毛,眼白内障青光眼免疫系统IgG降低丧失延迟性过敏反应感染增加心血管系统高血压动脉粥样硬化血液系统淋巴细胞减少嗜酸细胞减少中性粒细胞增加精神/神经情绪反常精神分裂,免疫抑制剂类型,CalcineurininhibitorsCyclosporineTacrolimusPurinesynthesisinhibitorsAzathioprineMycophenolatemofetilNonspecificprednisone,TargetofRapamycininhibitorSirolimusPolyclonalantibodies(bindseveralCDs)ThymoglobulinAtgamMonoclonalAntibodiesBlocksIL-2receptorDaclizumabBasilixmabOKT3(anti-CD3),IL-2R,G0,G0,G1,S,G2/M,G1/0,T-cell,STEROIDCTLA-4-FcFUSIONPROTEINU.V.,CYCLOSPORINFK506STEROID,RAPAMYCIN,AZATHIOPRINE(6MP)METHOTREXATEMIZORBINEMYCOPHENOLICBREQUINAR,CYCLOSPHOSPHAMIDEX-RAYS,Activationbyantigen,IL-2response,DNAsynthase,Mitosis,ANTI:TCRCD3CD4/8CD45RBLFA-1ICAM1,ANTI-IL-2RTOXINS,IL-2R,Cytokinesynthesis,Therapeuticmonoclonals,Drugsandothertreatments,部分免疫抑制剂转环节,ReduceinflammationTNF-alphablockers(RA,Crohnsdis.,psoriasis)e.g.,Enbrel,Remicade,HumiraIL-1receptorantagonist(RA)AbsagainstIL6RandIL-15RStatins,showntolowerCRP(RA,MS)Rituxin=monoclonalAb=anti-CD20EliminatesBcellsinnon-Hodgkinslymphoma(maybealsoRA,andotherAb-mediatedautoimmunediseases),免疫炎性疾病生物制剂治疗,其他可能的治疗通道,Tcellvaccines(againstactivatedAg-specificTcells)Interferewithantigenpresentation(anti-MHC)MonoclonalantibodiesagainstavarietyoftargetantigensOralinductionoftolerance(MS)Sofar,effortshavebeenmoresuccessfulinmicethanhumans,其他可能的治疗通道,中西医结合抗炎机制研究思路,炎症的消退是多个协同作用的结果；多机制通道可以恢复细胞环境；内源性抗炎因子产生的机制有待深入研究；调节炎症产生的环境是新的治疗选择。,中药抗炎药物应用的思路,如何调节炎症产生的环境？氧