免疫缺陷性疾病.ppt

HIV的致病机制,ImmunodeiciencyDiseases,ChapterVIIII,一、概念：,免疫缺陷病（disorders）：免疫系统中任何一个环节或其组分因先天发育不全或后天各种因素所致损害，使免疫活性细胞的发生、分化、增殖和代谢异常而引起的免疫功能不全综合征。,常见的原发性免疫缺陷性疾病,B,1、原发性B细胞缺陷病：,某种原因使B细胞发育停滞先天性B细胞缺乏或分化成熟障碍。,B细胞发育过程,VHDHJH,VLJL,IgM,不成熟B细胞,DHJH,B220,B祖细胞,IgD,IgM,成熟B细胞,替代轻链,前B细胞,M,D,M,M,不成熟B细胞,ImmatureBcells,M,前B细胞（胞浆出现IgM重链）,Pre-Bcells,祖B细胞,Pro-Bcells,M,D,G,M,D,A,成熟B细胞,MatureBcells,Igm,Vpre-B,l5,Ig-a/Ig-b,Lyn，Fyn，Blk，Btk，Syk,信号转导,Pre-BCR,前B细胞首先开始表达Igm链，在k或者l轻链基因发生重排并表达之前，Igm链与替代轻链l5和Vpre-B以及Iga/b共同组成Pre-BCR表达于细胞的表面。Iga/b执行信号转导功能。,B细胞发育障碍或者缺乏T细胞帮助均可导致体液免疫应答缺陷。临床表现为反复的胞外寄生菌感染。,原发性B细胞免疫缺损,IgA浆细胞,淋巴干细胞,XLA,btk基因突变,前B细胞,sIgM,XHLM,CD40L基因缺陷,成熟细胞,IgG/IgA/IgM/IgD/IgE,B记忆细胞,IgA,选择性IgA缺陷,？,A,G,M,B,B,B,浆细胞,CVID,(1)性联无免疫球蛋白血症（XLA）Bruton病,a1a2bg,白蛋白,球蛋白,（a）（b）（c）,X-linkedagammaglobulinemia,XLA,btk基因突变,淋巴干细胞,前B细胞,sIgM,Brutonstyrosinkinase,BtkBruton酪氨酸激酶,染色体水平：X染色体长臂q21.3-22多基因缺陷转录水平：B细胞Ig重链重排正常，但Ig的轻链基因重排和表达有缺陷细胞水平：B细胞不能发育成熟表现：外周血或淋巴组织中B细胞很少或缺如，淋巴结很小，无生发中心，无浆细胞，扁桃体缺如，血清中多种Ig水平很低或测不出，但T细胞数目和功能基本正常。症状：反复化脓性感染,性联低丙球蛋白血症,Brutonagammaglobulinemia.Thispatientpresentedwithrecurrentotitis(耳炎)andareasofcellulitis（蜂窝织炎）inthediaperarea.PseudomonasaeruginosaandStaphylococcusaureuswereisolatedfromtheskinlesions.Autoimmunehemolyticanemiaandautoimmuneneutropenia（中性粒细胞减少症）wereconfirmedbythepresenceofautoantibodies.Thepatienthasamutationonexon15,A504T,whichchangedanasparagine（天冬氨酸）residuetoavaline（缬氨酸）residue.,Picture2.Brutonagammaglobulinemia(ie,X-linkedagammaglobulinemiaXLA)inbrothers.XLAwasdiagnosedintheless-robustyoungerbrotherwhenhepresentedwithneutropeniaandtyphlitis.Theolderbrother,withahistoryof7episodesofpneumonia,wasthenevaluatedandgiventhediagnosisofXLA.InbothbrothersCD19-Bcellswerelessthan1%;thisfindingisconsistentwithXLA.,(2)性联高IgM血症（XLHM）,性联遗传病：X染色体上CD40L基因突变IgG、IgA和IgE重链类别转换有障碍表现：IgG和IgA血清浓度极低，反复细菌胞外感染。,IgM,J链,X-linkedhyperimmunoglobulinMsyndrome,前B细胞,sIgM,XHLM,CD40L基因缺陷,成熟细胞,IgG/IgA/IgM/IgD/IgE,XLHM患者淋巴小结的特点,正常生发中心,XLHM淋巴小结,B细胞活化受阻,记忆性B细胞,B细胞大量凋亡,IgM,未活化B细胞,IgM,IgM,T细胞不表达CD40L,T细胞表达CD40L,辅助性T细胞帮助B2细胞活化,1,2,CD40/CD40L,B细胞,Th细胞,TD抗原,CD4,Th,B7,MHC-IITCR,CD4,ICAMLFA-1,APC,Th,Th,B,CD40LCD40,分泌细胞因子,Th,Th细胞活化、增殖,B细胞扩增,浆细胞,BCR,抗原,TD抗原诱导体液免疫应答的过程,Bm,CD28,IgClass(Isotype)Switching,Plasmacells,IgM,IgEorIgG2,IgAorIgG2b,IgG2orIgG3,ActivatedBcell(centroblast),ProliferatingBcell(centrocytes),ProliferationcytokinesIL-2,IL-4,IL-5,DifferentioncytokinesIL-2,IL-4,IL-5,IFN-,TGF-,IL-2IL-4IL-5,IL-2IL-4IL-5,IL-4,IFN-,TGF-,CD40L,BMThymiccell,CD40Lknockout(mimickinghumanX-linkedhyperIgM),Retroviralvector,CD40L,Lowexpression,CVID:commonvariableimmunodeficiency普通变化型免疫缺陷病,为IgA,IgG缺陷,(3)选择性IgA缺陷或IgA和IgG缺陷,A,G,M,B,B,B,浆细胞,CVID,J链,分泌链,IgAdimer,Endoscopicimagingoftheduodenumshowsmultipleprominentnodules35mminsize,consistentwithnodularlymphoidhyperplasia,常染色体显/隐性遗传病或胚胎期风疹病毒感染/药物造成的畸变。细胞水平：表达IgA的B细胞不能分化成分泌IgA抗体的浆C。表现：仅IgA缺陷而IgM和IgG水平正常。症状：IgA低呼、消、泌尿生殖粘膜感染。,选择性IgA缺陷,2、原发性T细胞缺陷症,Thissyndromewasdescribedinthe1960s.Itisageneticconditionandsothereareoftenseveralpeopleinthefamilyaffected.Theunderlyingproblemisamissingportionofthe22ndchromosome.,胚胎三、四咽囊发育障碍先天胸腺发育不良，伴随甲状旁腺、主动脉弓、唇、耳发育不良细胞水平：T细胞不能成熟（随年龄增长T细胞能在胸腺外成熟）表现：血中Tcell缺乏，细胞免疫缺陷症状：易患病毒、真菌感染，移植物抗宿主反应，自身免疫病，恶性肿瘤,(1)先天性胸腺发育不全（DiGeorge综合症）,FuneralHeldFor2-Year-OldHeart-ConditionVictim,SkeletalpreparationsfromwildtypeandTbx1mutantembryos.Themutantembryoontherighthasabnormalitiesinthepharyngeal(咽的)arch-derivedskeletalstructuresinthehead.ThismutantprovidesamousemodelofthehumanDiGeorgesyndrome,ThisisametaphasecellthathasbeenhybridizedwiththeprobeforDiGeorgewhichiscausedbyamicrodeletiononchromosome22.Theprobeisadual-colormixtureoftwoseperateprobesforchromosome22.Thegreensignalisaninternalcontrolandislocatedat22q13.Itallowsforquickidentificationofboth#22chromosomes.TheredsignalislocatedattheDiGeorgeregionat22q11.2.Sinceboth22shavetheredsignalinthiscellthereisnotamicrodeletionwithintheDiGeorgeregionandthispatientwouldnothaveDiGeorgesyndrome.,PatientwithDiGeorgesyndromeDepletedthymus-sependentarea(TDA)smallprimaryfolicles(PF),Normalsubject:ThepopulatedT-cellareathewell-developedsecondaryfoliclewithitsmantleofsmalllymphocytes(M)Germinalcenter(GC),无胸腺的裸鼠是T细胞选择性缺陷的天然动物模型,Athymic,ornude,mouse(nu/nu:onchromosome11),Thisdefectleadstoabsenceofthethymusoravestigialthymusandcell-mediatedimmunodificiency.Cannoteasilysurvive,mortality:100%within25weeks;50%within2weeksafterbirth.,AthymicnudemicearekeptbehindabarrierwithHEPAfilteredair;autoclavedfee,bedding,waterandcages.Aresearchassistantusesasepticprocedurestoprotectthesemicefromorganismsintheenvironment,TumorsformedbyRat1cellsexpressingmyr-p110.Nudemicewereinjectedontheleftflankwith1X106Rat-1Acellsexpressingmyr-p110andontherightflankwithanequalnumberofcontrolRat-1Acells.Thispicturewastaken10dayspostinoculation.,Practicalexperimentaluses:Hybridomasorsolidtumorsfromanyoriginmaybegrownin,(2)TCR信号转导障碍,激酶链的信号整合,转录因子被活化,早期基因,IL-2基因,IL-2Ra基因,T细胞活化的信号转导,fyn,PLC,Ca+,ZAP-70,CD4,TCR,LCK,PI-3k,HLA表达障碍,IL-2生成障碍,CD3链缺陷,TCR-CD3表达水平降低CD3链缺失,T细胞活化缺陷,3、原发性T、B细胞联合免疫缺陷病,Achildwithseverecombinedimmunodeficiencyshowingskinlesionsduetoinfectionwithvacciniagangrenosumresultingfromsmallpoximmunization.Lesionswerewidespreadoverthewholebody.,严重联合免疫缺陷病染色体水平：2号染色体上腺苷脱氨酶（ADA）基因缺陷或突变14号染色体上嘌呤核苷磷酸化酶（PNP）基因缺陷或突变性联隐性遗传：X染色体IL2受体链基因突变TAP基因突变MHCI表达低II类反式活化子、RFX5和RFXAP基因突变MHCII转录障碍表现：T、B细胞分化发育成熟障碍症状：对各种类型感染均易感,5%,5%,50%,20%,20%,常染色体隐性SCID,X-联SCID,ADA缺陷,PNP缺陷,其他原因（TCR及IL-2免疫缺陷,MHC表达缺陷）,严重联合免疫缺陷病(severecombined-immunodeficiencydisease,SCID),性联重症联合免疫缺陷病(X-linkedSCID,XSCID),Mutationsinthec(commonchain)chainofthereceptorsforinterleukinsIL-2,-4,-7,-9and-15*Signaltransduction,*lymphocytedifferentiation,proliferationandmaturation,IL-2RIL-4RIL-7RIL-9RIL-15R,-链参与组成的细胞因子受体,共用的链,II嘌呤核苷磷酸化酶（PNP）和腺苷脱氨酶(ADA)缺陷,Mutationofthepurinenucleotidephosphorylaseandadenosinedeaminase,3、吞噬细胞缺陷：,慢性肉芽肿病(chronicgranulomatousdisease,CGD)染色体水平：性联隐性遗传：X染色体p21编码细胞色素b19kD链常染色体隐性遗传：辅酶（NADPH）氧化酶中47kD和67kD缺陷,正常吞噬细胞,消化无能吞噬细胞,细胞色素b558,细菌,黄素蛋白,吞噬体,细菌,吞噬体,中性粒细胞,NADPHH+,NADPHH+,e-+O2,O2-,H+,H2O2,慢性肉芽肿病（CGD）,慢性肉芽肿,Granulomainaleprosypatient,(2)白细胞粘附障碍(leukocyteadhesiondeficiency,LAD),整合素(integrin),CD18gene,encode,LFA-1Mac-1/CR3gp150,95/CR4,This3-year-oldgirlhadleukocyteadhesiondeficiencytypeI(LADI)withcompleteabsenceofCD18expression.Thetypicalgingivostomatitis(龈口炎),whichwasculture-negativeforanypathogen,This10-month-oldpatientwithsevereleukocyteadhesiondeficiencytypeI(LADI)developedacervicaladenitis（颈淋巴结炎）causedbyKlebsiellapneumoniae.Followingincisionanddrainage,woundhealingtook4months.,pq,CGD,WAS,SCID,XLA,XLP,XLHM,4、治疗策略,骨髓移植、胸腺移植或干细胞移植（无相同HLA配型）注射抗体注射抗生素免疫调节：如：IFN-改善慢性肉芽肿病人嗜中性粒细胞的功能,感谢上帝给了我一双好用的手！,二、继发性免疫缺陷性疾病,继发性免疫缺陷病是指非先天性继发于某些疾病或使用某些药物后产生的免疫缺陷病。,病因：感染营养不良或营养过度恶性肿瘤：何杰金氏病T细胞免疫受损慢性淋巴细胞白血病体液免疫减弱。其它：消化系统疾病、代谢性和内分泌性疾病放/化疗、免疫抑制剂,获得性免疫缺陷综合征（acquiredimmunedeficiencysyndrome，AIDS）艾滋病主要靶子是免疫系统,HIVIncubationPeriod(Adults),NotInfected-Infected-Infectious-AIDS-Death,-3-10years-,-1yr-,一、流行情况,世界范围1981年5月第一例，年底共152人1983年13500人1999年50，000，000人估计2000年300000001亿人至1999年底死亡人数16，000，000人我国1985年第一例1999年15088人估计实际40万2000年50万2010年将达1000万,Subsaharan撒哈拉沙漠,Inthefiveminutesthatittakesyoutoreadthisorwalkinthehallwaybetweenclasses,25peoplearoundtheworldwilldieofAIDS,thediseasethatdestroysthebodysimmunesystem.HIV,thevirusthatcausesAIDS,hasinfected42millionmen,womenandchildrenworldwide,5millioninthelastyearalone.,AIDSCasesbyAgeandSex,Reported1981-1998,UnitedStates,EstimatednumberofAIDSrelateddeathsworldwide1980-2000WHO,MothertochildtransmissionofHIV1979-1999bybreast-feedingorothercauseWHO,二、病原：,HIVdsRNA两条相同的单股正链RNA主要靶子免疫细胞,HIVbuddingfromhumanlymphtissue(TEMx133,335),三、HIV的致病机制,TAT:Trans-ActivatorofTranscriptionREV:RegulatorofVirionproteinexpressionNEF:NegativeRegulatoryFactorVIF:VirionInfectivityFactorVPU:ViralProteinUVPR:ViralProteinR,病毒gene,ThenecessityforCD4antigenexpressionforentryofHIVintoahumancell.HeLacellsdonothaveCD4antigenandarenotinfected.HeLacellstransfectedwithCD4geneareinfected,NEFeffectsonCD4,NEFeffectsonCD4,NEFinducescytokinesthatattractTcellstoaninfectedmacrophage,趋化因子受体,CXCR:CXC类趋化因子受体,CCR:CC类趋化因子受体,CC类趋化因子,CXC类趋化因子,CXC,CC,H2N,COOH,COOH,H2N,(基质细胞衍生因子),(趋化因子炎性蛋白因子),Chemokinereceptorsareinvolved,inassociationwithCD4antigen,ininfectionbyHIV(left).Thechemokinecanblockattachmentofthevirustoitsreceptors(middle).MutationsinthechemokinereceptorcanleadtoresistencetoHIVinfection(right),趋化因子受体拮抗剂抗HIV-1治疗,表达趋化因子受体的细胞,A.Buddingcausescelllysis,SomepossiblemechanismforthelossofT4cellsafterHIVinfection,BSyncytiaformation,Multinucleatedcell(syncytium)intouchpreparationfromcutsurfaceofenlargedlymphnodefrompatientwithHIV-1infection.Cellfusionproducingalargemultinucleatedcellisaviralcytopathiceffectcharacteristic,butnotdiagnostic,ofinfectionbyHIV-1.,C.InfectedcellsaredestroyedbycytotoxicTcells,Virustiter,CD4cellnumberandanti-gp120titerduringthecourseofHIVinfection,Virustiter,CD4andCD8cellnumberduringthecourseofHIVinfection,AbundanceofHIVinlymphoidtissueinsituhybridizationoflymphnodesectionsfromarepresentativeHIV-infectedpatientinearlystagedisease.AHIVRNAisindicatedbythesilvergrainswhichappearaswhitedots.Anintensehybridizationsignalispredominantlyrestrictedtotheareaofthegerminalcenters.BHighermagnificationofaprotease-digestedsectionshowingtheintensedistributionofsilvergrainsinthelightzoneofagerminalcenter.,LesionsonthestomachofapatientwithKaposissarcoma,Figure-KaposisSarcoma,Kaposissarcoma(skin).,SkinshowingAIDS-associatedKaposissarcoma,ScanningelectronmicrographofHIV-1buddingfromculturedlymphocyte.Multipleroundbumpsoncellsurfacerepresentsitesofassemblyandbuddingofvirions,FacialsarcoidosisinAIDS,Hairyleukoplakiaoftongue,Oralthrush.,Orofacialgranulomatosiswithcobblestonemucosa,Candidaandherpessimplex,Severeangularcheilitis,CryptococcosisoflunginpatientwithAIDS.Methenaminesilverstain.HistopathologyoflungshowsnumerousextracellularyeastsofCryptococcusneoformanswithinanalveolarspace.,CystsofPneumocystiscariniiinAIDS.Methenaminesilverstain.Histopathologyoflungshowscharacteristiccystswithcupformsanddot-likecystwallthickenings.,HAART:highlyactiveantiretroviraldrugtherapy,FactorsaffectingHIVprogression.,TherapeuticstrategiesforcontrollingAIDS,TOWARDSANANTI-HIVVACCINE,Goalsforananti-HIVvaccineprovidesterilizingimmunity(actagainstfreevirusandHIV-infectedcells)2.depressinitialratesofHIVreplication(longtermnon-progression),Subunits(e.g.gp120)presentedinasolubleformorexpressedfromarecombinantvector(vacciniaorvaccinestrainofpoliohavebeenused),THESTATEOFPROTECTIVEANTI-HIVVACCINES,Subunitvaccines,DNAencodinggp120,Recombinantplasmid,Vacciniapromoter,Vaccinia,polio,Tissue-culturecells,RecombinantvacciniaVectorvaccine,express,Subunitvacci