免疫炎性疾病新認(rèn)識及中西醫(yī)結(jié)合臨床對策于清宏9沈陽

免疫炎性疾病新認(rèn)識及中西醫(yī)結(jié)合臨床對策南方醫(yī)科大學(xué)珠江醫(yī)院風(fēng)濕免疫科

于清宏

2014年9月13日沈陽本文檔共98頁；當(dāng)前第1頁；編輯于星期二\9點52分本文檔共98頁；當(dāng)前第2頁；編輯于星期二\9點52分本文檔共98頁；當(dāng)前第3頁；編輯于星期二\9點52分本文檔共98頁；當(dāng)前第4頁；編輯于星期二\9點52分非可控性炎癥——免疫炎性疾病病的共同通道本文檔共98頁；當(dāng)前第5頁；編輯于星期二\9點52分

‘Acellular,immuneandmetabolicresponsetoinjuryandinfection’Definitionofinflammation炎癥定義Inflammationisatwo-edgedswordservesasaprotectiveresponse,butisoftenamajorcauseoftissuedamageininfectious,immunologic,andvasculardiseases,aswellasaftertrauma.

本文檔共98頁；當(dāng)前第6頁；編輯于星期二\9點52分紅腫熱痛功能障礙促炎/抗炎細胞因子平衡炎癥是一個程序化過程炎癥細胞表型轉(zhuǎn)變本文檔共98頁；當(dāng)前第7頁；編輯于星期二\9點52分本文檔共98頁；當(dāng)前第8頁；編輯于星期二\9點52分Heredity,Nonresolvinginflammationandautoimmunediseases先天稟賦外感內(nèi)傷證候本文檔共98頁；當(dāng)前第9頁；編輯于星期二\9點52分部分自身免疫性疾病本文檔共98頁；當(dāng)前第10頁；編輯于星期二\9點52分免疫介導(dǎo)的炎性疾病Chronicdiseaseswithprominentinflammation,oftencausedbyfailureoftoleranceorregulationRA,IBD,MS,psoriasis,manyothersAffect2-5%ofpeople,incidenceincreasingMayresultfromimmuneresponsesagainstselfantigens(autoimmunity)ormicrobialantigens(Crohn’sdisease?)MaybecausedbyTcellsandantibodiesMaybesystemicororgan-specific本文檔共98頁；當(dāng)前第11頁；編輯于星期二\9點52分自身免疫病理過程SusceptibilitygenesEnvironmentaltrigger(e.g.infections,tissueinjury)Failureofself-toleranceActivationofself-reactivelymphocytesImmuneresponsesagainstselftissuesPersistenceoffunctionalself-reactivelymphocytes本文檔共98頁；當(dāng)前第12頁；編輯于星期二\9點52分ActivationEffectorTcellsNormal:reactionsagainstpathogensInflammatorydisease,e.g.reactionsagainstselfToleranceRegulatoryTcellsNoresponsetoselfControlledresponsetopathogens淋巴細胞活化及控制的平衡陽陰本文檔共98頁；當(dāng)前第13頁；編輯于星期二\9點52分自身免疫的遺傳背景HumanautoimmunediseasesarecomplexpolygenictraitsIdentifiedbygenome-wideassociationmappingSinglegenemutationsareusefulforpathwayanalysisSomepolymorphismsareassociatedwithmultiplediseasesMaycontrolgeneralmechanismsoftoleranceandimmuneregulationOthergeneticassociationsaredisease-specificMayinfluenceend-organdamage本文檔共98頁；當(dāng)前第14頁；編輯于星期二\9點52分NOD2:polymorphismassociatedwith~25%ofCrohn’sdiseaseMicrobialsensorPTPN22:commonestautoimmunity-associatedgene;polymorphisminRA,SLE,othersPhosphataseCD25(IL-2R):associatedwithMS,others;genome-wideassociationmappingRoleinTregs自身免疫遺傳背景:最近發(fā)現(xiàn)本文檔共98頁；當(dāng)前第15頁；編輯于星期二\9點52分感染與自身免疫InfectionstriggerautoimmunereactionsClinicalprodromes,animalmodelsAutoimmunitydevelopsafterinfectioniseradicated(i.e.theautoimmunediseaseisprecipitatedbyinfectionbutisnotdirectlycausedbytheinfection)Someautoimmunediseasesarepreventedbyinfections(type1diabetes,multiplesclerosis,others?--increasingincidenceindevelopedcountries):mechanismunknownThe“hygienehypothesis”本文檔共98頁；當(dāng)前第16頁；編輯于星期二\9點52分主要免疫反應(yīng)類型決定疾病自然病程Th1response:inflammation,autoantibodyproduction;autoimmunediseasesTh2response:IgE+eosinophil-mediatedinflammation;allergicreactionsTh17response:acute(andchronic?)inflammation;increasinglyrecognizedinimmune-mediateddiseases本文檔共98頁；當(dāng)前第17頁；編輯于星期二\9點52分Th1cells(IFN-g)Th2cells(IL-4,IL-5)Th17cells(IL-17)Na?veCD4TcellCD4細胞亞群:產(chǎn)生及功能RegulatoryTcellsIFN-,IL-12:T-bet,Stat4IL-4:GATA3,Stat6TGF-+IL-6:

RORt,Stat3TGF-IL-2:Foxp3,Stat5Hostdefense:manymicrobesSystemicandorgan-specificautoimmunediseasesHostdefense:helminthsAllergicdiseasesHostdefense:fungi,bacteriaOrgan-specificautoimmunediseases本文檔共98頁；當(dāng)前第18頁；編輯于星期二\9點52分Afteramicrobialinfection,activa-tedmicrobe-speci-ficTH1(mTH1)cellsmigratetotheinfectedorgan.

A.Molecularmimicry.

B.Epitopespre-ading.

C.Bystanderactivation.

D.Crypticantigen.本文檔共98頁；當(dāng)前第19頁；編輯于星期二\9點52分部分隱蔽抗原本文檔共98頁；當(dāng)前第20頁；編輯于星期二\9點52分器官特異性自身免疫病理Currenttherapiestargetlatestagesofthereaction(lymphocyteactivation,inflammation).Ultimategoalshouldbetotackletheunderlyingcauseandrestorecontroloftheabnormallydirectedresponse本文檔共98頁；當(dāng)前第21頁；編輯于星期二\9點52分免疫炎性疾病代表疾病類風(fēng)濕關(guān)節(jié)炎?脊柱關(guān)節(jié)炎?血管炎?本文檔共98頁；當(dāng)前第22頁；編輯于星期二\9點52分類風(fēng)濕關(guān)節(jié)炎免疫炎癥機制研究狀況本文檔共98頁；當(dāng)前第23頁；編輯于星期二\9點52分HLA表型與等位基因變異檢測本文檔共98頁；當(dāng)前第24頁；編輯于星期二\9點52分類風(fēng)濕關(guān)節(jié)炎相關(guān)HLA-DR4結(jié)合表位本文檔共98頁；當(dāng)前第25頁；編輯于星期二\9點52分本文檔共98頁；當(dāng)前第26頁；編輯于星期二\9點52分RA相關(guān)共享表位氨基酸序列本文檔共98頁；當(dāng)前第27頁；編輯于星期二\9點52分

CaraccidentCancerRAHPNASHemophilia

多基因疾病本文檔共98頁；當(dāng)前第28頁；編輯于星期二\9點52分脊柱關(guān)節(jié)炎免疫炎癥機制研究現(xiàn)狀本文檔共98頁；當(dāng)前第29頁；編輯于星期二\9點52分

強直性脊柱炎的易感基因NatureGenetics2013;45(7):730-8

本文檔共98頁；當(dāng)前第30頁；編輯于星期二\9點52分IBD/subclinicalileitisHLA-B27excessIL-23ExcessIL-23Rsensitivity(SNPs)TheIL-23R+spondyloarthropogeniccellCuaandSherlock,NatMed.2011Sep7;17(9):1055-6.SherlockJP,etal.NatMed.2012;18:1069–76本文檔共98頁；當(dāng)前第31頁；編輯于星期二\9點52分ERAP1associatedwithHLA-B27+veASNatureGenetics2011;43:761-767本文檔共98頁；當(dāng)前第32頁；編輯于星期二\9點52分PicturecourtesyofDr.EricReitsERAP1/ERAP2processantigenicpeptideepitopesbeforeloadingontoHLA-B27本文檔共98頁；當(dāng)前第33頁；編輯于星期二\9點52分NucleusNK/MoDCImmunoreceptorRecognitionofAberrantB27CD8+ArthritogenicPeptidesandAutoreactiveTCellsERBiPUPRB27Misfolding,ERStress,andUPRActivationNodefiningmechanismbywhichHLA-B27causesASAlteredAPCFunctionCD4+本文檔共98頁；當(dāng)前第34頁；編輯于星期二\9點52分ERAP2SNPN392KaffectsbothenzymeactivityandspecificityThekcatoftheenzymechangesby>25-foldEffectsontrimmingratearesubstrate-specific!Vanhilleetal.MolecularGenetics&GenomicMedicine2013;1(2):98–107Evnouchidouetal.JImmunol2012;189(5):2383本文檔共98頁；當(dāng)前第35頁；編輯于星期二\9點52分ERAP1SNPsatpositions528and730affectbothenzymeactivityandantigenpresentationkcat/KMKiMHCIlevelsEvnouchidouetal.JImmunol2011本文檔共98頁；當(dāng)前第36頁；編輯于星期二\9點52分Lengthselectioncanbealteredbypolymorphicvariation Garciaetal.MCP,2012本文檔共98頁；當(dāng)前第37頁；編輯于星期二\9點52分AffectsactivityAffectsSpecificityEvnouchidouetal.JImmunol2012;189(5):2383本文檔共98頁；當(dāng)前第38頁；編輯于星期二\9點52分SNPsare“scattered”allovertheproteinstructure本文檔共98頁；當(dāng)前第39頁；編輯于星期二\9點52分AS易感基因的貢獻值本文檔共98頁；當(dāng)前第40頁；編輯于星期二\9點52分腸道菌微生態(tài)與免疫炎性疾病ASCDHCBacteroidesAcintobacteriaFirmicutesFusobacteriaProteobacteria本文檔共98頁；當(dāng)前第41頁；編輯于星期二\9點52分ASgutmicrobiomeisdifferenttoCDandHCASCDHCBacterialcontrol本文檔共98頁；當(dāng)前第42頁；編輯于星期二\9點52分機械壓力的骨贅形成的作用AnnRheumDis2013本文檔共98頁；當(dāng)前第43頁；編輯于星期二\9點52分遺傳和環(huán)境因素共同導(dǎo)致疾病的發(fā)生本文檔共98頁；當(dāng)前第44頁；編輯于星期二\9點52分NatureMed2012;18:1018IL23介導(dǎo)的T細胞參與了AS的致病本文檔共98頁；當(dāng)前第45頁；編輯于星期二\9點52分？？？？？強直性脊柱炎的致病機理假說IL-17IL-1IL-6TNF-α本文檔共98頁；當(dāng)前第46頁；編輯于星期二\9點52分Nature2014ConnectionofbiologicalRAriskgenestodrugtargets

本文檔共98頁；當(dāng)前第47頁；編輯于星期二\9點52分Scheretal.eLife2013;2:e01202.DOI:10.7554/eLife.01202Prevotellacopricorrelateswithenhancedsusceptibilitytoarthritis本文檔共98頁；當(dāng)前第48頁；編輯于星期二\9點52分血管炎發(fā)病機制研究現(xiàn)狀本文檔共98頁；當(dāng)前第49頁；編輯于星期二\9點52分免疫學(xué)新進展-免疫系統(tǒng)本文檔共98頁；當(dāng)前第50頁；編輯于星期二\9點52分4-96hours96HourslaterPostInfectionInnateAdaptiveTargetCell+Na?veTTh-1Th-2Th-17TregTGF-βTGF-βIL-6/23IL-4IFN-γIL-12CD28TCRBCellAntiboddyIFN-γIL-12MacrophageNKcellDCEpithelialcellCellimmunityHumoral

immunityInflammationImmunosuppressionIFN-γTNF-αIL-4,5.13IL-17,6TNF-αTGF-βEosinophilBasophilMastCellNeutrophilγδTcellNKTcellCD8+Tcell創(chuàng)新點選擇-免疫學(xué)新進展-應(yīng)答類型本文檔共98頁；當(dāng)前第51頁；編輯于星期二\9點52分腸道上皮細胞的正常屏障作用本文檔共98頁；當(dāng)前第52頁；編輯于星期二\9點52分MicrobialrecognitionpromotesIEChealthandfunction本文檔共98頁；當(dāng)前第53頁；編輯于星期二\9點52分NatureReviewImmunology,2013,13:75-87新的免疫細胞-ILC（innate

Lymphoid

cells)本文檔共98頁；當(dāng)前第54頁；編輯于星期二\9點52分模式識別受體（patternrecognitionreceptors,PRRs):TLRs,NLR本文檔共98頁；當(dāng)前第55頁；編輯于星期二\9點52分nudeotideoligmerizationdomain（NOD）-likereceptors,NLRsCARD:CaspaseactivationandrecruitmentdomainASC:Apoptosis-associatedspeck-likeproteincontainingCARD本文檔共98頁；當(dāng)前第56頁；編輯于星期二\9點52分NOD-likereceptors,NLRs6/25/2023本文檔共98頁；當(dāng)前第57頁；編輯于星期二\9點52分NLRP3本文檔共98頁；當(dāng)前第58頁；編輯于星期二\9點52分植物藥抗炎機制研究舉例本文檔共98頁；當(dāng)前第59頁；編輯于星期二\9點52分調(diào)節(jié)免疫功能紊亂

TGPTcellTh/Ts細胞比值

Bcell巨噬細胞TNF-αIL-1

LTB4

活性氧類

免疫調(diào)節(jié)肝損傷小鼠

免疫性關(guān)節(jié)炎大鼠

系統(tǒng)性紅斑狼瘡小鼠

WeiWetal,IntImmunophar,2002,2005,2009梁君山，魏偉，等.中國藥理學(xué)通報，1989,5:354-357王興旺，魏偉，等.中國藥理學(xué)通報，1990,6:363-366周玲玲，魏偉，等.中國藥理學(xué)通報，2002,18::175-177白芍總苷機理研究本文檔共98頁；當(dāng)前第60頁；編輯于星期二\9點52分TGP？TGP是否能夠作用與DC及相應(yīng)后果？本文檔共98頁；當(dāng)前第61頁；編輯于星期二\9點52分DC分化發(fā)育和成熟MDP：Lin-CX3CR1+CD11b-CD115+cKit+CD135+CDP：Lin-CD115+Flt3+CD117loFlt3：FMS樣酪氨酸激酶3，(Flt3L，配體)本文檔共98頁；當(dāng)前第62頁；編輯于星期二\9點52分imDCmDCTGP本文檔共98頁；當(dāng)前第63頁；編輯于星期二\9點52分白芍總苷（totalglucosidesofpaeonia，TGP）OVA免疫本文檔共98頁；當(dāng)前第64頁；編輯于星期二\9點52分明確現(xiàn)象---TGP抑制免疫應(yīng)答抑制T細胞活化增殖抑制機體對于新入侵抗原的免疫應(yīng)答本文檔共98頁；當(dāng)前第65頁；編輯于星期二\9點52分探討關(guān)鍵表型--TGP抑制DC成熟本文檔共98頁；當(dāng)前第66頁；編輯于星期二\9點52分被動轉(zhuǎn)移實驗：mDC恢復(fù)小鼠對于OVA反應(yīng)證實TGP抑制DC成熟而導(dǎo)致免疫應(yīng)答降低本文檔共98頁；當(dāng)前第67頁；編輯于星期二\9點52分探討機理--TGP抑制TLR-MyD88/NF-kB活化**MyD88本文檔共98頁；當(dāng)前第68頁；編輯于星期二\9點52分與疾病治療-RA-CIA模型CII+CFACII+IFA細胞亞群、細胞因子、信號轉(zhuǎn)導(dǎo)n=10/組3次重復(fù)16分評分DBA1本文檔共98頁；當(dāng)前第69頁；編輯于星期二\9點52分明確現(xiàn)象-TGP延緩和減輕CIA發(fā)病與炎癥提前使用TGP，延緩并減輕CIA發(fā)病本文檔共98頁；當(dāng)前第70頁；編輯于星期二\9點52分機理-TGP抑制DC成熟降低CII免疫應(yīng)答本文檔共98頁；當(dāng)前第71頁；編輯于星期二\9點52分明確表型-TGP降低Th1/Th17細胞亞群和功能本文檔共98頁；當(dāng)前第72頁；編輯于星期二\9點52分臨床驗證-TGP降低RA患者Th1/Th17

TNFa產(chǎn)生細胞減少本文檔共98頁；當(dāng)前第73頁；編輯于星期二\9點52分PSA?TGP?本文檔共98頁；當(dāng)前第74頁；編輯于星期二\9點52分TGP作用后PSA樣小鼠體內(nèi)M1細胞活性降低本文檔共98頁；當(dāng)前第75頁；編輯于星期二\9點52分本文檔共98頁；當(dāng)前第76頁；編輯于星期二\9點52分TGP–抑制M1，上調(diào)M2（體外）本文檔共98頁；當(dāng)前第77頁；編輯于星期二\9點52分TheNovelRoleofTotalGlucosidesofPaeonyinRegulatingTypeIandIIMacrophagesActivitiesinvivoandinvitro,ExperimentalDermatology,2014,inrevision

本文檔共98頁；當(dāng)前第78頁；編輯于星期二\9點52分TGP干擾TLR4與LPS結(jié)合，阻斷信號轉(zhuǎn)導(dǎo)IntImmunophar,2012,12:275-82

TLR4和TGPTLR4-MD2-LPSComplex(Nature2009)本文檔共98頁；當(dāng)前第79頁；編輯于星期二\9點52分TLR4-LPS結(jié)合部位TLR4和TGP本文檔共98頁；當(dāng)前第80頁；編輯于星期二\9點52分免疫炎性疾病治療現(xiàn)狀本文檔共98頁；當(dāng)前第81頁；編輯于星期二\9點52分糖皮質(zhì)激素作用機制糖皮質(zhì)激素受體（GCR）有核細胞都有GCR直接或間接影響基因轉(zhuǎn)錄10-100個基因具有GC反應(yīng)元素（GCresponseelement送，GCE）直接抑制NF-kB,抑制細胞因子產(chǎn)生間接抑制NF-kB、I-kB影響轉(zhuǎn)錄后過程mRNA翻譯、蛋白質(zhì)合成、蛋白質(zhì)分泌抑制促炎因子IL-1、IL-6、IL-13、GM-CSF、TNF-a減少炎癥部位白細胞聚集通過抑制促炎癥因子、NF-kB抑制黏附分子E-selectin、VCAM-1、ICAM-1抑制烷酸產(chǎn)物如白三烯（leukotriene）降低血管滲透性本文檔共98頁；當(dāng)前第82頁；編輯于星期二\9點52分皮質(zhì)類固醇抗炎作用相當(dāng)劑量鹽皮激效應(yīng)藥理T1/2

血漿T1/2

hmin氫化可的松1202＋8～1290可的松0.8252＋8～1230強的松3.551＋12～3660強的松龍451＋12～36200甲強龍54012～36180曲安西龍54024～48300地塞米松300.75036～54100～300倍他米松250.80036～54100～300氯地米松400.500

全身性應(yīng)用皮質(zhì)類固醇的當(dāng)量比較

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