免疫缺陷性疾病课件

HIV的致病机制9免疫缺陷性疾病ImmunodeiciencyDiseasesChapterVIIII9免疫缺陷性疾病一、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。9免疫缺陷性疾病9免疫缺陷性疾病9免疫缺陷性疾病常见的原发性免疫缺陷性疾病TB9免疫缺陷性疾病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。9免疫缺陷性疾病B细胞发育过程VHDHJHVLJLIgM

不成熟B细胞DHJHB220B祖细胞IgDIgM

成熟B细胞替代轻链前B细胞9免疫缺陷性疾病MDMM不成熟B细胞ImmatureBcellsM

前B细胞（胞浆出现IgM重链）Pre-Bcells

祖B细胞Pro-BcellsMDGMDA

成熟B细胞MatureBcells9免疫缺陷性疾病IgmVpre-Bl5Ig-a/Ig-bLyn，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。9免疫缺陷性疾病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。9免疫缺陷性疾病原发性B细胞免疫缺损IgA浆细胞淋巴干细胞XLAbtk基因突变前B细胞sIgMTTTTTXHLMCD40L基因缺陷成熟细胞IgG/IgA/IgM/IgD/IgEB记忆细胞IgA

选择性IgA缺陷？AGMBBB浆细胞CVID9免疫缺陷性疾病(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,9免疫缺陷性疾病XLAbtk基因突变淋巴干细胞前B细胞sIgMBruton’styrosinkinase,BtkBruton酪氨酸激酶9免疫缺陷性疾病9免疫缺陷性疾病染色体水平：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9免疫缺陷性疾病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.9免疫缺陷性疾病Picture2.Brutonagammaglobulinemia(ie,X-linkedagammaglobulinemia[XLA])inbrothers.XLAwasdiagnosedintheless-robustyoungerbrotherwhenhepresentedwithneutropeniaandtyphlitis.Theolderbrother,withahistoryof7episodesofpneumonia,wasthenevaluatedandgiventhediagnosisofXLA.InbothbrothersCD19-Bcellswerelessthan1%;thisfindingisconsistentwithXLA.9免疫缺陷性疾病(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。IgMJ链X-linkedhyperimmunoglobulinMsyndrome9免疫缺陷性疾病前B细胞sIgMTTTTTXHLMCD40L基因缺陷成熟细胞IgG/IgA/IgM/IgD/IgE9免疫缺陷性疾病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IgMIgMT细胞不表达CD40LT细胞表达CD40L9免疫缺陷性疾病辅助性T细胞帮助B2细胞活化12CD40/CD40LB细胞Th细胞TD抗原CD49免疫缺陷性疾病ThB7MHC-IITCRCD4ICAMLFA-1APCThThBCD40LCD40分泌细胞因子ThBBBTh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BmCD289免疫缺陷性疾病IgClass(Isotype)SwitchingPlasmacellsIgMIgEorIgG2IgAorIgG2bIgG2orIgG3IgM/IgDActivatedBcell(centroblast)ProliferatingBcell(centrocytes)ProliferationcytokinesIL-2,IL-4,IL-5DifferentioncytokinesIL-2,IL-4,IL-5,IFN-

,TGF-

IL-2IL-4IL-5IL-2IL-4IL-5IL-4IFN-

TGF-

9免疫缺陷性疾病CD40LBMThymiccellCD40Lknockout(mimickinghumanX-linkedhyperIgM)RetroviralvectorCD40LLowexpression9免疫缺陷性疾病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AGMBBB浆细胞CVIDJ链分泌链IgAdimer9免疫缺陷性疾病Endoscopicimagingoftheduodenumshowsmultipleprominentnodules3–5mminsize,consistentwithnodularlymphoidhyperplasia9免疫缺陷性疾病常染色体显/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9免疫缺陷性疾病2、原发性T细胞缺陷症Thissyndromewasdescribedinthe1960s.Itisageneticconditionandsothereareoftenseveralpeopleinthefamilyaffected.Theunderlyingproblemisamissingportionofthe22ndchromosome.9免疫缺陷性疾病

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）9免疫缺陷性疾病FuneralHeldFor2-Year-OldHeart-ConditionVictim9免疫缺陷性疾病

SkeletalpreparationsfromwildtypeandTbx1mutantembryos.Themutantembryoontherighthasabnormalitiesinthepharyngeal(咽的)arch-derivedskeletalstructuresinthehead.ThismutantprovidesamousemodelofthehumanDiGeorgesyndrome9免疫缺陷性疾病

BacktoFISHInformationprintMetaphaseFISHExamples

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ThisisanexampleofametaphasecellthathasbeenhybridizedwiththeprobeforDiGeorge/Velo-Cardio-Facial/CATCH22/Shprintzensyndromewhichiscausedbyamicrodeletiononchromosome22.Theprobeinthisparticularcaseisadual-colormixtureoftwoseperateprobesforchromosome22.Thegreensignalisaninternalcontrolandislocatedat22q13.Itallowsforquickidentificationofboth#22chromosomes.TheredsignalislocatedattheDiGeorgeregionat22q11.2.Sinceboth22'shavetheredsignalinthiscellthereisnotamicrodeletionwithintheDiGeorgeregionandthispatientwouldnothaveDiGeorgesyndrome.

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Thismetaphasehasbeenhybridizedwitha"painting"probeforchromosome4whichcausestheentirechromosometofluoresce.Onechromosome4fromthispatientwasabnormalbutitwasdifficulttodeterminefromroutineCytogeneticsifithadasmallterminaldeletionat4qorwastheresultofamorecomplexrearrangement.Sinceboth4'sarefluorescentalongtheirentirelengthandnofluorescentmaterialispresentonanyotherchromosome,thissuggeststhattheabnormalityisasmallterminaldeletion.Themetaphasebelowisfromthesamepatientandfurtherconfirmsthisdiagnosis.

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Thismetaphasefromthesamepatientasthecellabovehasbeenhybridizedwithaprobefortheterminalpartofchromosome4q.Sincethereisonlyonegreensignalthisconfirmsthatonechromosome4ismissingmaterialfromtheterminalendof4q.ThiscaseisagoodexampleofhowroutineCytogeneticsandFISHcanbeusedtogethertoaccuratelydiagnosesubtlechromosomeabnormalities.

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ThisisanexampleofametaphasecellthathasbeenhybridizedwiththeprobeforSteroidSulfataseDeficiencywhichiscausedbyamicrodeletionontheXchromosome.TheprobeinthisparticularcaseisamixtureoftwoseperateprobesfortheXchromosome,bothredincolor.The"Xcen"probesignalisaninternalcontrolandislocatedattheXcentromere.ItallowsforquickidentificationoftheXchromosome(s).The"Xp22.3"probesignalislocatedattheSteroidSulfataseregionatXp22.3.SincetherearetwoXchromosomesandonlyonehastheSteroidSulfatasegenesignal,thisindividualisafemalecarrierforSteroidSulfataseDeficiency.

ThisisametaphasecellthathasbeenhybridizedwiththeprobeforDiGeorgewhichiscausedbyamicrodeletiononchromosome22.Theprobeisadual-colormixtureoftwoseperateprobesforchromosome22.Thegreensignalisaninternalcontrolandislocatedat22q13.Itallowsforquickidentificationofboth#22chromosomes.TheredsignalislocatedattheDiGeorgeregionat22q11.2.Sinceboth22'shavetheredsignalinthiscellthereisnotamicrodeletionwithintheDiGeorgeregionandthispatientwouldnothaveDiGeorgesyndrome.9免疫缺陷性疾病PatientwithDiGeorgesyndromeDepletedthymus-sependentarea(TDA)smallprimaryfolicles(PF)Normalsubject:ThepopulatedT-cellareathewell-developedsecondaryfoliclewithitsmantleofsmalllymphocytes(M)Germinalcenter(GC))9免疫缺陷性疾病无胸腺的裸鼠是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.9免疫缺陷性疾病AthymicnudemicearekeptbehindabarrierwithHEPAfilteredair;autoclavedfee,bedding,waterandcages.Aresearchassistantusesasepticprocedurestoprotectthesemicefromorganismsintheenvironment9免疫缺陷性疾病TumorsformedbyRat1cellsexpressingmyr-p110.Nudemicewereinjectedontheleftflankwith1X106Rat-1Acellsexpressingmyr-p110andontherightflankwithanequalnumberofcontrolRat-1Acells.Thispicturewastaken10dayspostinoculation.Practicalexperimentaluses:Hybridomasorsolidtumorsfromanyoriginmaybegrownin9免疫缺陷性疾病(2)TCR信号转导障碍9免疫缺陷性疾病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fynPLCCa++ZAP-70CD4TCRLCKPI-3kHLA表达障碍IL-2生成障碍9免疫缺陷性疾病ITAM:Immunoreceptortyrosine-basedactivationmotifsCD3

链缺陷,TCR-CD3表达水平降低CD3

链缺失,T细胞活化缺陷9免疫缺陷性疾病3、原发性T、B细胞联合免疫缺陷病Achildwithseverecombinedimmunodeficiencyshowingskinlesionsduetoinfectionwithvacciniagangrenosumresultingfromsmallpoximmunization.Lesionswerewidespreadoverthewholebody.9免疫缺陷性疾病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9免疫缺陷性疾病5%5%50%20%20%常染色体隐性SCIDX-联SCIDADA缺陷PNP缺陷其他原因（TCR及IL-2免疫缺陷,MHC表达缺陷）9免疫缺陷性疾病严重联合免疫缺陷病(severecombined-immunodeficiencydisease,SCID)9免疫缺陷性疾病性联重症联合免疫缺陷病(X-linkedSCID,XSCID)Mutationsinthe

c(common

chain)chainofthereceptorsforinterleukinsIL-2,-4,-7,-9and-15**Signaltransduction,**lymphocytedifferentiation,proliferationandmaturation9免疫缺陷性疾病9免疫缺陷性疾病IL-2RIL-4RIL-7RIL-9RIL-15R

-链参与组成的细胞因子受体共用的

链9免疫缺陷性疾病9免疫缺陷性疾病ADA与PNP基因突变造成免疫缺陷的途径GMPAMPIMP肌苷腺苷鸟苷ADA6-氧嘌呤PNP鸟嘌呤PNP黄嘌呤尿酸腺苷脱氧腺苷鸟苷脱氧鸟苷dAMPdADPdATPdGMPdGDPdGTP抑制核苷酸还原酶T、B细胞增殖障碍II嘌呤核苷磷酸化酶（PNP）和腺苷脱氨酶(ADA)缺陷Mutationofthepurinenucleotidephosphorylaseandadenosinedeaminase9免疫缺陷性疾病OKT3抗体,IL-2ADAADAADAmonocyteTcell9免疫缺陷性疾病9免疫缺陷性疾病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Ⅱ（NADPH）氧化酶中47kD和67kD缺陷9免疫缺陷性疾病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-

+O2O2-H+H2O2慢性肉芽肿病（CGD）9免疫缺陷性疾病Th1细胞多核巨大细胞巨噬细胞内皮样细胞细菌纤维母细胞慢性肉芽肿9免疫缺陷性疾病9免疫缺陷性疾病Granulomainaleprosypatient9免疫缺陷性疾病(2)白细胞粘附障碍(leukocyteadhesiondeficiency,LAD)中性粒细胞的渗出过程

ABC毛细血管内皮细胞侵入细菌附壁粘着游出ECEC9免疫缺陷性疾病

整合素(integrin)CD18geneencodeLFA-1Mac-1/CR3gp150,95/CR49免疫缺陷性疾病9免疫缺陷性疾病This3-year-oldgirlhadleukocyteadhesiondeficiencytypeI(LADI)withcompleteabsenceofCD18expression.Thetypicalgingivostomatitis(龈口炎),whichwasculture-negativeforanypathogen9免疫缺陷性疾病This10-month-oldpatientwithsevereleukocyteadhesiondeficiencytypeI(LADI)developedacervicaladenitis（颈淋巴结炎）causedbyKlebsiellapneumoniae.Followingincisionanddrainage,woundhealingtook4months.9免疫缺陷性疾病pqCGDWASSCIDXLAXLPXLHM9免疫缺陷性疾病9免疫缺陷性疾病9免疫缺陷性疾病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9免疫缺陷性疾病9免疫缺陷性疾病感谢上帝给了我一双好用的手！9免疫缺陷性疾病二、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。9免疫缺陷性疾病病因：①感染②营养不良或营养过度③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。④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9免疫缺陷性疾病获得性免疫缺陷综合征（acquiredimmunedeficiencysyndrome，AIDS）——艾滋病

主要靶子是免疫系统

9免疫缺陷性疾病HIVIncubationPeriod(Adults)Not

Infected-Infected---Infectious---AIDS----Death--3-10years---1yr-9免疫缺陷性疾病9免疫缺陷性疾病一、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30000000—1亿人至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1000万9免疫缺陷性疾病9免疫缺陷性疾病Subsaharan撒哈拉沙漠Inthefiveminutesthatittakesyoutoreadthisorwalkinthehallwaybetweenclasses,25peoplearoundtheworldwilldieofAIDS,thediseasethatdestroysthebody'simmunesystem.HIV,thevirusthatcausesAIDS,hasinfected42millionmen,womenandchildrenworldwide,5millioninthelastyearalone.9免疫缺陷性疾病AIDSCasesbyAgeandSex,Reported1981-1998,UnitedStates

9免疫缺陷性疾病EstimatednumberofAIDSrelateddeathsworldwide1980-2000

WHO9免疫缺陷性疾病MothertochildtransmissionofHIV1979-1999bybreast-feedingorothercause

WHO

9免疫缺陷性疾病9免疫缺陷性疾病9免疫缺陷性疾病9免疫缺陷性疾病二、病原：HIVdsRNA两条相同的单股正链RNA主要靶子免疫细胞

9免疫缺陷性疾病HIVbuddingfromhumanlymphtissue(TEMx133,335)9免疫缺陷性疾病9免疫缺陷性疾病9免疫缺陷性疾病三、HIV的致病机制TAT:Trans-ActivatorofTranscriptionREV:RegulatorofVirionproteinexpressionNEF:NegativeRegulatoryFactorVIF:VirionInfectivityFactorVPU:ViralProteinUVPR:ViralProteinR病毒gene9免疫缺陷性疾病ThenecessityforCD4antigenexpressionforentryofHIVintoahumancell.HeLacellsdonothaveCD4antigenandarenotinfected.HeLacellstransfectedwithCD4geneareinfected

9免疫缺陷性疾病NEFeffectsonCD49免疫缺陷性疾病NEFeffectsonCD49免疫缺陷性疾病9免疫缺陷性疾病NEFinducescytokinesthatattractTcellstoaninfectedmacrophage9免疫缺陷性疾病趋化因子受体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CXCCCH2NCOOHCOOHH2N(基质细胞衍生因子)(趋化因子炎性蛋白因子)9免疫缺陷性疾病9免疫缺陷性疾病Chemokinereceptorsareinvolved,inassociationwithCD4antigen,ininfectionbyHIV(left).Thechemokinecanblockattachmentofthevirustoitsreceptors(middle).MutationsinthechemokinereceptorcanleadtoresistencetoHIVinfection(right)

9免疫缺陷性疾病趋化因子受体拮抗剂抗HIV-1治疗9免疫缺陷性疾病Th表达趋化因子受体的细胞9免疫缺陷性疾病A.BuddingcausescelllysisSomepossiblemechanismforthelossofT4cellsafterHIVinfection9免疫缺陷性疾病BSyncytiaformation9免疫缺陷性疾病Multinucleatedcell(syncytium)intouchpreparationfromcutsurfaceofenlargedlymphnodefrompatientwithHIV-1infection.Cellfusionproducingalargemultinucleatedcellisaviralcytopathiceffectcharacteristic,butnotdiagnostic,ofinfectionbyHIV-1.9免疫缺陷性疾病C.InfectedcellsaredestroyedbycytotoxicTcells9免疫缺陷性疾病Virustiter,CD4cellnumberandanti-gp120titerduringthecourseofHIVinfection

9免疫缺陷性疾病Virustiter,CD4

andCD8cellnumber

duringthecourseofHIVinfection

9免疫缺陷性疾病AbundanceofHIVinlymphoidtissueinsituhybridizationoflymphnodesectionsfromarepresentativeHIV-infectedpatientinearlystagedisease.AHIVRNAisindicatedbythesilvergrainswhichappearaswhitedots.Anintensehybridizationsignalispredominantlyrestrictedtotheareaofthegerminalcenters.BHighermagnificationofaprotease-digestedsectionshowingtheintensedistributionofsilvergrainsinthelightzoneofagerminalcenter.9免疫缺陷性疾病LesionsonthestomachofapatientwithKaposi'ssarcoma

Figure-Kaposi'sSarcomaKaposi'ssarcoma(skin).SkinshowingAIDS-associatedKaposi'ssarcoma

9免疫缺陷性疾病ScanningelectronmicrographofHIV-1buddingfromculturedlymphocyte.Multipleroundbumpsoncellsurfacerepresentsitesofassemblyandbuddingofvirions9免疫缺陷性疾病9免疫缺陷性疾病FacialsarcoidosisinAIDS

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