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日沈陽目前一頁\總數(shù)九十八頁\編于二點目前二頁\總數(shù)九十八頁\編于二點目前三頁\總數(shù)九十八頁\編于二點目前四頁\總數(shù)九十八頁\編于二點非可控性炎癥——免疫炎性疾病病的共同通道目前五頁\總數(shù)九十八頁\編于二點

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

目前六頁\總數(shù)九十八頁\編于二點紅腫熱痛功能障礙促炎/抗炎細(xì)胞因子平衡炎癥是一個程序化過程炎癥細(xì)胞表型轉(zhuǎn)變目前七頁\總數(shù)九十八頁\編于二點目前八頁\總數(shù)九十八頁\編于二點Heredity,Nonresolvinginflammationandautoimmunediseases先天稟賦外感內(nèi)傷證候目前九頁\總數(shù)九十八頁\編于二點部分自身免疫性疾病目前十頁\總數(shù)九十八頁\編于二點免疫介導(dǎo)的炎性疾病Chronicdiseaseswithprominentinflammation,oftencausedbyfailureoftoleranceorregulationRA,IBD,MS,psoriasis,manyothersAffect2-5%ofpeople,incidenceincreasingMayresultfromimmuneresponsesagainstselfantigens(autoimmunity)ormicrobialantigens(Crohn’sdisease?)MaybecausedbyTcellsandantibodiesMaybesystemicororgan-specific目前十一頁\總數(shù)九十八頁\編于二點自身免疫病理過程SusceptibilitygenesEnvironmentaltrigger(e.g.infections,tissueinjury)Failureofself-toleranceActivationofself-reactivelymphocytesImmuneresponsesagainstselftissuesPersistenceoffunctionalself-reactivelymphocytes目前十二頁\總數(shù)九十八頁\編于二點ActivationEffectorTcellsNormal:reactionsagainstpathogensInflammatorydisease,e.g.reactionsagainstselfToleranceRegulatoryTcellsNoresponsetoselfControlledresponsetopathogens淋巴細(xì)胞活化及控制的平衡陽陰目前十三頁\總數(shù)九十八頁\編于二點自身免疫的遺傳背景HumanautoimmunediseasesarecomplexpolygenictraitsIdentifiedbygenome-wideassociationmappingSinglegenemutationsareusefulforpathwayanalysisSomepolymorphismsareassociatedwithmultiplediseasesMaycontrolgeneralmechanismsoftoleranceandimmuneregulationOthergeneticassociationsaredisease-specificMayinfluenceend-organdamage目前十四頁\總數(shù)九十八頁\編于二點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)目前十五頁\總數(shù)九十八頁\編于二點感染與自身免疫InfectionstriggerautoimmunereactionsClinicalprodromes,animalmodelsAutoimmunitydevelopsafterinfectioniseradicated(i.e.theautoimmunediseaseisprecipitatedbyinfectionbutisnotdirectlycausedbytheinfection)Someautoimmunediseasesarepreventedbyinfections(type1diabetes,multiplesclerosis,others?--increasingincidenceindevelopedcountries):mechanismunknownThe“hygienehypothesis”目前十六頁\總數(shù)九十八頁\編于二點主要免疫反應(yīng)類型決定疾病自然病程Th1response:inflammation,autoantibodyproduction;autoimmunediseasesTh2response:IgE+eosinophil-mediatedinflammation;allergicreactionsTh17response:acute(andchronic?)inflammation;increasinglyrecognizedinimmune-mediateddiseases目前十七頁\總數(shù)九十八頁\編于二點Th1cells(IFN-g)Th2cells(IL-4,IL-5)Th17cells(IL-17)Na?veCD4TcellCD4細(xì)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目前十八頁\總數(shù)九十八頁\編于二點Afteramicrobialinfection,activa-tedmicrobe-speci-ficTH1(mTH1)cellsmigratetotheinfectedorgan.

A.Molecularmimicry.

B.Epitopespre-ading.

C.Bystanderactivation.

D.Crypticantigen.目前十九頁\總數(shù)九十八頁\編于二點部分隱蔽抗原目前二十頁\總數(shù)九十八頁\編于二點器官特異性自身免疫病理Currenttherapiestargetlatestagesofthereaction(lymphocyteactivation,inflammation).Ultimategoalshouldbetotackletheunderlyingcauseandrestorecontroloftheabnormallydirectedresponse目前二十一頁\總數(shù)九十八頁\編于二點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?目前二十二頁\總數(shù)九十八頁\編于二點類風(fēng)濕關(guān)節(jié)炎免疫炎癥機(jī)制研究狀況目前二十三頁\總數(shù)九十八頁\編于二點HLA表型與等位基因變異檢測目前二十四頁\總數(shù)九十八頁\編于二點類風(fēng)濕關(guān)節(jié)炎相關(guān)HLA-DR4結(jié)合表位目前二十五頁\總數(shù)九十八頁\編于二點目前二十六頁\總數(shù)九十八頁\編于二點RA相關(guān)共享表位氨基酸序列目前二十七頁\總數(shù)九十八頁\編于二點

CaraccidentCancerRAHPNASHemophilia

多基因疾病目前二十八頁\總數(shù)九十八頁\編于二點脊柱關(guān)節(jié)炎免疫炎癥機(jī)制研究現(xiàn)狀目前二十九頁\總數(shù)九十八頁\編于二點

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

目前三十頁\總數(shù)九十八頁\編于二點IBD/subclinicalileitisHLA-B27excessIL-23ExcessIL-23Rsensitivity(SNPs)TheIL-23R+spondyloarthropogeniccellCuaandSherlock,NatMed.2011Sep7;17(9):1055-6.SherlockJP,etal.NatMed.2012;18:1069–76目前三十一頁\總數(shù)九十八頁\編于二點ERAP1associatedwithHLA-B27+veASNatureGenetics2011;43:761-767目前三十二頁\總數(shù)九十八頁\編于二點PicturecourtesyofDr.EricReitsERAP1/ERAP2processantigenicpeptideepitopesbeforeloadingontoHLA-B27目前三十三頁\總數(shù)九十八頁\編于二點NucleusNK/MoDCImmunoreceptorRecognitionofAberrantB27CD8+ArthritogenicPeptidesandAutoreactiveTCellsERBiPUPRB27Misfolding,ERStress,andUPRActivationNodefiningmechanismbywhichHLA-B27causesASAlteredAPCFunctionCD4+目前三十四頁\總數(shù)九十八頁\編于二點ERAP2SNPN392KaffectsbothenzymeactivityandspecificityThekcatoftheenzymechangesby>25-foldEffectsontrimmingratearesubstrate-specific!Vanhilleetal.MolecularGenetics&GenomicMedicine2013;1(2):98–107Evnouchidouetal.JImmunol2012;189(5):2383目前三十五頁\總數(shù)九十八頁\編于二點ERAP1SNPsatpositions528and730affectbothenzymeactivityandantigenpresentationkcat/KMKiMHCIlevelsEvnouchidouetal.JImmunol2011目前三十六頁\總數(shù)九十八頁\編于二點Lengthselectioncanbealteredbypolymorphicvariation Garciaetal.MCP,2012目前三十七頁\總數(shù)九十八頁\編于二點AffectsactivityAffectsSpecificityEvnouchidouetal.JImmunol2012;189(5):2383目前三十八頁\總數(shù)九十八頁\編于二點SNPsare“scattered”allovertheproteinstructure目前三十九頁\總數(shù)九十八頁\編于二點AS易感基因的貢獻(xiàn)值目前四十頁\總數(shù)九十八頁\編于二點腸道菌微生態(tài)與免疫炎性疾病ASCDHCBacteroidesAcintobacteriaFirmicutesFusobacteriaProteobacteria目前四十一頁\總數(shù)九十八頁\編于二點ASgutmicrobiomeisdifferenttoCDandHCASCDHCBacterialcontrol目前四十二頁\總數(shù)九十八頁\編于二點機(jī)械壓力的骨贅形成的作用AnnRheumDis2013目前四十三頁\總數(shù)九十八頁\編于二點遺傳和環(huán)境因素共同導(dǎo)致疾病的發(fā)生目前四十四頁\總數(shù)九十八頁\編于二點NatureMed2012;18:1018IL23介導(dǎo)的T細(xì)胞參與了AS的致病目前四十五頁\總數(shù)九十八頁\編于二點？？？？？強(qiáng)直性脊柱炎的致病機(jī)理假說IL-17IL-1IL-6TNF-α目前四十六頁\總數(shù)九十八頁\編于二點Nature2014ConnectionofbiologicalRAriskgenestodrugtargets

目前四十七頁\總數(shù)九十八頁\編于二點Scheretal.eLife2013;2:e01202.DOI:10.7554/eLife.01202Prevotellacopricorrelateswithenhancedsusceptibilitytoarthritis目前四十八頁\總數(shù)九十八頁\編于二點血管炎發(fā)病機(jī)制研究現(xiàn)狀目前四十九頁\總數(shù)九十八頁\編于二點免疫學(xué)新進(jìn)展-免疫系統(tǒng)目前五十頁\總數(shù)九十八頁\編于二點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(jìn)展-應(yīng)答類型目前五十一頁\總數(shù)九十八頁\編于二點腸道上皮細(xì)胞的正常屏障作用目前五十二頁\總數(shù)九十八頁\編于二點MicrobialrecognitionpromotesIEChealthandfunction目前五十三頁\總數(shù)九十八頁\編于二點NatureReviewImmunology,2013,13:75-87新的免疫細(xì)胞-ILC（innate

Lymphoid

cells)目前五十四頁\總數(shù)九十八頁\編于二點模式識別受體（patternrecognitionreceptors,PRRs):TLRs,NLR目前五十五頁\總數(shù)九十八頁\編于二點nudeotideoligmerizationdomain（NOD）-likereceptors,NLRsCARD:CaspaseactivationandrecruitmentdomainASC:Apoptosis-associatedspeck-likeproteincontainingCARD目前五十六頁\總數(shù)九十八頁\編于二點NOD-likereceptors,NLRs4/28/2023目前五十七頁\總數(shù)九十八頁\編于二點NLRP3目前五十八頁\總數(shù)九十八頁\編于二點植物藥抗炎機(jī)制研究舉例目前五十九頁\總數(shù)九十八頁\編于二點調(diào)節(jié)免疫功能紊亂

TGPTcellTh/Ts細(xì)胞比值

Bcell巨噬細(xì)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(jī)理研究目前六十頁\總數(shù)九十八頁\編于二點TGP？TGP是否能夠作用與DC及相應(yīng)后果？目前六十一頁\總數(shù)九十八頁\編于二點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)目前六十二頁\總數(shù)九十八頁\編于二點imDCmDCTGP目前六十三頁\總數(shù)九十八頁\編于二點白芍總苷（totalglucosidesofpaeonia，TGP）OVA免疫目前六十四頁\總數(shù)九十八頁\編于二點明確現(xiàn)象---TGP抑制免疫應(yīng)答抑制T細(xì)胞活化增殖抑制機(jī)體對于新入侵抗原的免疫應(yīng)答目前六十五頁\總數(shù)九十八頁\編于二點探討關(guān)鍵表型--TGP抑制DC成熟目前六十六頁\總數(shù)九十八頁\編于二點被動轉(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)答降低目前六十七頁\總數(shù)九十八頁\編于二點探討機(jī)理--TGP抑制TLR-MyD88/NF-kB活化**MyD88目前六十八頁\總數(shù)九十八頁\編于二點與疾病治療-RA-CIA模型CII+CFACII+IFA細(xì)胞亞群、細(xì)胞因子、信號轉(zhuǎn)導(dǎo)n=10/組3次重復(fù)16分評分DBA1目前六十九頁\總數(shù)九十八頁\編于二點明確現(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)病目前七十頁\總數(shù)九十八頁\編于二點機(jī)理-TGP抑制DC成熟降低CII免疫應(yīng)答目前七十一頁\總數(shù)九十八頁\編于二點明確表型-TGP降低Th1/Th17細(xì)胞亞群和功能目前七十二頁\總數(shù)九十八頁\編于二點臨床驗證-TGP降低RA患者Th1/Th17

TNFa產(chǎn)生細(xì)胞減少目前七十三頁\總數(shù)九十八頁\編于二點PSA?TGP?目前七十四頁\總數(shù)九十八頁\編于二點TGP作用后PSA樣小鼠體內(nèi)M1細(xì)胞活性降低目前七十五頁\總數(shù)九十八頁\編于二點目前七十六頁\總數(shù)九十八頁\編于二點TGP–抑制M1，上調(diào)M2（體外）目前七十七頁\總數(shù)九十八頁\編于二點TheNovelRoleofTotalGlucosidesofPaeonyinRegulatingTypeIandIIMacrophagesActivitiesinvivoandinvitro,ExperimentalDermatology,2014,inrevision

目前七十八頁\總數(shù)九十八頁\編于二點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)目前七十九頁\總數(shù)九十八頁\編于二點TLR4-LPS結(jié)合部位TLR4和TGP目前八十頁\總數(shù)九十八頁\編于二點免疫炎性疾病治療現(xiàn)狀目前八十一頁\總數(shù)九十八頁\編于二點糖皮質(zhì)激素作用機(jī)制糖皮質(zhì)激素受體（GCR）有核細(xì)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(xì)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(xì)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）降低血管滲透性目前八十二頁\總數(shù)九十八頁\編于二點皮質(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(qiáng)的松3.551＋12～3660強(qiáng)的松龍451＋12～36200甲強(qiáng)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

目前八十三頁\總數(shù)九十八頁\編于二點糖皮質(zhì)激素全身應(yīng)用副作用內(nèi)分泌系統(tǒng)抑制腎上腺抑制生長、兒童性成熟延遲體重增加、柯興貌糖尿病代謝紊亂低血鉀癥、高血糖、高血脂骨骼肌肉系統(tǒng)骨質(zhì)疏松、椎骨壓縮性骨折骨無菌性壞死（髖、肩、膝）肌?。毙曰蚵裕┢つw皮膚變薄紫紋痤瘡多毛眼白內(nèi)障青光眼免疫系統(tǒng)IgG降低喪失延遲性過敏反應(yīng)感染增加心血管系統(tǒng)高血壓動脈粥樣硬化血液系統(tǒng)淋巴細(xì)胞減少嗜酸細(xì)胞減少中性粒細(xì)胞增加精神/神經(jīng)情緒反常精神分裂目前八十四頁\總數(shù)九十八頁\編于二點免疫抑制劑類型CalcineurininhibitorsCyclosporineTacrolimusPurinesynthesisinhibitorsAzathioprineMycophenolatemofetilNonspecificprednisoneTargetofRapamycininhibitorSirolimusPolyclonalantibodies(bindseveralCD’s)ThymoglobulinAtgamMonoclonalAntibodiesBlocksIL-2receptorDaclizumabBasilixmabOKT3(anti-CD3)目前八十五頁\總數(shù)九十八頁\編于二點IL-2RG0G0G1SG2/MG1/0T-cellSTEROIDCTLA-4-FcγFUSIONPROTEINU.V.CYCLOSPORINFK506STEROIDRAPAMYCINAZATHIOPRINE(6MP)METHOTREXATEMIZORBINEMYCOPHENOLICBREQUINARCYCLOSPHOSPHAMIDEX-RAYSActivationbyantigenIL-2responseDNAsynthaseMitosisANTI:TCRCD3CD4/8CD45RBLFA-1ICAM1ANTI-IL-2R±TOXINSIL-2RCytokinesynthesisTherapeuticmonoclonalsDrugsandothertreatments部分免疫抑制劑轉(zhuǎn)環(huán)節(jié)目前八十六頁\總數(shù)九十八頁\編于二點ReduceinflammationTNF-alphablockers(RA,Crohn’sdis.,psoriasis) e.g.,Enbrel,Remicade,HumiraIL-1receptorantagonist(RA)Ab’sagainstIL6RandIL-15RStatins,showntolowerCRP(RA,MS)Rituxin=monoclonalAb=anti-CD20 EliminatesBcellsinnon-Hodgkins lymphoma(maybealsoRA,andother Ab-mediatedautoimmunediseases)

免疫炎性疾病生物制劑治療目前八十七頁\總數(shù)九十八頁\編于二點其他可能的治療通道目前八十八頁\總數(shù)九十八頁\編于二點Tcellvaccines (againstactivatedAg-specificTcells)Interferewithantigenpresentation(anti-MHC)Monoclonalantibodiesagainsta varietyoftarg