醫(yī)學(xué)精品課件：14 Immunodeficiency

IMMUNODEFICIENCYXiaodongZhao,MD,Ph.DProfessorofPediatricsChildren’sHospitalofChongqingMedicalUniversity

ReviewofbasicImmunologyPhysiologicalfeaturesofimmunefunctioninchildhoodDefinitionofimmunodeficiencydiseaseClassificationofPIDsCommonclinicalpresentationsScreeninglaboratorytestsPrinciplesofPIDmanagementSecondaryimmunodeficiency

OUTLINERecognizeselfRejectnon-selfImmunefunction

--Anti-infection

Clearinfectiousagents

--Immunehomeostasis

Clearaged,damagedanddeadcells,maintainingstability

--Immunesurveillance

Identifyandremovemutatedcellsandpreventtumor

ClassicalImmunologyModernImmunologyThreeIntegralpartsofimmunologyImmunefunctionsByeffecterfunction

Cellularimmunity: hostedbycells

Humoralimmunity: carryoutbyfluid-borne moleculesByantigenspecificity

Innateimmunity: Non-antigen-specific,suchas skinandmucosalbarriers, interferons,NKcells, phagocytes,etc.

Adaptiveimmunity: Antigen-specific,mediated onlybylymphocytes

ImmuneorgansImmunecellsImmunemolecules

Cytokines:secretedbyimmunecellsMembraneboundmolecules--Adherencemolecules--Receptors--OthersurfacemarkersSolublemolecules:antibody,complement

ImmunesystemSLSCProBCFUM?PMNPletRBCPreBPTTBCD8+PlasmaCD4+TH1TH2IgMBPlasmaIgAIgAIgMBPlasmaIgGIgGBPlasmaIgEIgETHYRUMEpi.

Cytokines（IL-1~18，INF，IFN，IGFβ-1）

Membranemarkers（CD28-B7，CD40-CD40L，MHCI,Ⅱ，cytokinereceptors）

Adhesionmolecules（ICAM-1，LFA-1，SELECTIN,andsoon）

ComplementsBMCD3+CD19/20PluripotentstemcellsPOSITIVESELECTIONSelfMHCrestricted:(1)Rescueofdouble-positivethymocytesfromprogrammedcelldeath,and(2)determinetheexpressionofCD4orCD8coreceptoronmatureTcells.

bindtoMHCclassI CD8TcellBindtoselfMHC alive bindtoMHCclassII CD4TcellDonotbindselfMHC Apoptosis

NEGATIVESELECTIONSelftolerant:Thymocytesrecognizingselfpeptide:selfMHCcomplexestoowellareinducedtoundergoapoptosis.BindtoselfMHC-selfantigen ApoptosisDonotbindtoselfMHC-selfantigen AliveThymiccorticalepithelialcellsBonemarrowderiveddendriticcellsandmacrophages1stphase:Antigenpresenting2ndphase:proliferationoflymphocytes3rdphase:Effecterfunction4thphase:ApoptosisofactivatedlymphocytesImmuneresponseAgM?TH1CTLNKADCCBPMNIL-4，5，6，7，8，9，10，11，13，14，16，17AbImmunecomplexActivatecomplementEndothelialsOsteoblasts

Osteoclasts

Fibroblasts

Mastcells

Eosinophils

TH2Ag

CKs&mediatorsInflammationTH0IL-12,IL-18IL-1IL-10IL-4IL-2IFNIL-1，IL-6，TNFTr1TH3IL-10MHCIICD4TCR

CD3AntigenpresentingAPCTcellAgPI3-KinasePLCr1VavSH2SH2

JNKBcellBcellTcellIgAIgMIgGIgETCD40L

TCRCD28Ag

IL-6IL-5IL-4BCD40MHCB7ReceptorsTandBcellinteractionAgM?TH1CTLNKADCCBPMNIL-4，5，6，7，8，9，10，11，13，14，16，17AbImmunecomplexActivatecomplementEndothelialsOsteoblasts

Osteoclasts

Fibroblasts

Mastcells

Eosinophils

TH2Ag

CKs&mediatorsInflammationTH0IL-12,IL-18IL-1IL-10IL-4IL-2IFNIL-1，IL-6，TNFTr1TH3IL-10ImmuneresponseisalwaysaccompaniedbyinflammationEnsureanappropriateimmuneresponsetocleartheantigen,Preventexcessiveinflammatoryresponse

Summary

ReviewofbasicImmunologyPhysiologicalfeaturesofimmunefunctioninchildhoodDefinitionofimmunodeficiencydiseaseClassificationofPIDCommonclinicalpresentationsScreeninglaboratorytestsPrinciplesofPIDmanagementSecondaryimmunodeficiency

OUTLINE

﹡

Phagocytosis

--macrophages,dentriticcells(APC)↓

--neutraphil↓

﹡Tlymphocyte:

--CD40L↓,CD28expression↓

--TH1/TH2↓

﹡Blymphocyte:

--maternalIgGcrossplacenta

--IgG2latedevelopment(after2yo)

﹡complements

1412108642g/L1.80.6123456789101112mosMaternalIgG

TotalIgG

BabyIgG

DevelopmentofIgG

g/L1412108642

1.8-0.64812ms2481012yrsIgGIgMIgAImmunoglobulindevelopmentininfantsandchildrensummaryNearlyallbranchesofimmunefunctionarematurelydevelopedatbirthTransientdysfunctionorimmunocomprimiseconditionismainlyduetoinsufficientexposuretoantigens

ReviewofbasicImmunologyPhysiologicalfeaturesofimmunefunctioninchildhoodDefinitionofimmunodeficiencydiseaseClassificationofPIDCommonclinicalpresentationsScreeninglaboratorytestsPrinciplesofPIDmanagementSecondaryimmunodeficiency

OUTLINEAdiversegroupofillnessesthat,asaresultofoneormoreabnormalitiesoftheimmunesystem,increasedsusceptibilitytoinfection.

Definitionofimmunodeficiency

--Genemutationassociated:

primaryimmunodeficiency,PID)

--Environment-associated:

Secondaryimmunodeficiency，SID

orimmunocompromise

--HIVinfection:

Acquiredimmunodeficiencysyndrome，AIDSThreetypesofimmunodeficiencyMilestonesofPIDSyllaba&Henner：1926年描述毛細(xì)血管擴(kuò)張、共濟(jì)失調(diào)（ataxia-telangiectasia）Thorpe&Handley：1929年描述皮膚粘膜念珠菌?。╩ucocutaneouscandidiasis）Wiskott：1937年描述濕疹、血小板減少伴免疫缺陷綜合征（Wiskott-Aldrichsyndrome）Glanzmann&Riniker：1950年描述細(xì)胞免疫缺陷Bruton：報(bào)道了1952年首例先天性無(wú)丙種球蛋白血癥，從此免疫缺陷病這一名詞才被廣泛應(yīng)用和受到重視Hitzig：1958年則發(fā)現(xiàn)抗體缺陷和細(xì)胞免疫缺陷在一個(gè)病人同時(shí)存在，稱(chēng)為瑞士型無(wú)丙種球蛋白血癥2011年P(guān)ID分類(lèi)：200種PID，由160余種基因突變所致；主要表現(xiàn)為感染、自身免疫和易患腫瘤患病率：重癥1/2000活產(chǎn)嬰，我國(guó)存活患兒5-10萬(wàn)，不足5%確診診治困難、預(yù)后極差：確診常需基因診斷，根治常需要免疫重建；如不正規(guī)治療，多數(shù)于幼年夭折或生活質(zhì)量極其低下多數(shù)患兒至死未能確診，導(dǎo)致家族中患兒再次出生（139個(gè)家族史陽(yáng)性PID家系僅2.2%確定了先證者）我國(guó)目前尚無(wú)防治規(guī)范：病人的要求、社會(huì)的需要

原發(fā)性免疫缺陷病(PrymaryImmunodeficiencyDiseases,PIDs)LuigiD,etal.JACI2009BoyleJM,etal.JClinEndocrinolMetab.2002Total

GDP:

10.88

trilliondollarsGDPpercapita:

8000

dollarsOpportunitiesRare

diseases

including

PIDs：more

and

more

attention

fromthe

government

and

society亞太免疫缺陷學(xué)會(huì)（APSID）成立2016.4香港

Nomenclature

--bynameorplace

--byunderlyinggeneticdefectsor

immunologicalmechanisms

Brutondisease(Bruton,1952)→Xlinkedagammaglobulinemia，XLA

Swisstypeagammaglobulinemia(Hitzigetal,1958)→SeverecombinedID

ReviewofbasicImmunologyPhysiologicalfeaturesofimmunefunctioninchildhoodDefinitionofimmunodeficiencydiseaseClassificationofPIDCommonclinicalpresentationsScreeninglaboratorytestsPrinciplesofPIDmanagementSecondaryimmunodeficiency

OUTLINENewestclassificationofPIDJacksonHole,Wyo:8categories（JAllergyClinImmunol2007）CombinedT-cellandB-celldeficienciesPredominantlyantibodydeficienciesOtherwelldefinedimmunodeficiencysyndromes

DiseasesofimmunedysregulatonCongenitaldefectsofphagocytenumber,function,orbothDefectsininnateimmunityAutoinflammatorydisordersComplementdeficiencies

DifferentfeaturesofinfectionsinPIDJCAI2009X-linkedagammaglobulinemia(XLA)Bruton’sdiseaseDuetobtkgenemutation,causingblockadeofPre-BtomatureBcellPredominantlyantibodydeficiencyMaleRecurrentbacterialinfectionsofrespiratorytractorothertissueIncreasedsusceptibilitytoenterovirusesProfounddecreaseofallIgsAbsenceor<2%ofBcellsintheblood

XLAcase，19yearsold

Brain,throatwall,prevertebralabscess

SLSCProBCFUM?PMNPletRBCPreBPTTBCD8+PlasmaCD4+TH1TH2IgMBPlasmaIgAIgAIgMBPlasmaIgGIgGBPlasmaIgEIgETHYRUMEpi.Cytokines（IL-1~18，INF，IFN，IGFβ-1）Membranemarkers（CD28-B7，CD40-CD40L，MHCI,Ⅱ，cytokinereceptors）Adhesionmolecules（ICAM-1，LFA-1，SELECTIN,andsoon）ComplementsBMCD3+HyperIgMsymdromeCombinedimmunodeficiencyX-linkedorautosomalrecessiveRecurrentbacterial,fungal,protozoaninfectionsAutoimmune:autoimmunehemolyticanemia,hepatosplenomegaly,neutrapeniaNormalnumberofperipheralBcellsDecreasedIgG,IgA;normalorincreasedIgMNeedstemcelltransplantation(SCT)toreconstitutetheimmunefunctionIgAIgMIgGIgETCD40L

TCRCD28Ag

IL-6IL-5IL-4BCD40MHCB7Receptors

Severecombinedimmunodeficiency(SCID)CombinedimmunodeficiencyX-linkedorautosomalrecessiveOnsetinearlymonthsoflifeLife-threateninginfectionofalmostallkindsofpathogens,disseminatedinfectionofvaccinesuchasBCGChronicdiarrhea,failuretothriveNeedSCTasearlyaspossible

γcγ

γ

IL-2R

γcβIL-2,IL-4,IL-7,IL-9,IL-15

Jak-3TcellX-linkedseverecombinedimmunodeficiency（IL-2receptorcommonγchaindefect）WiskottAldrichsyndromeWelldefinedimmunodeficiencysyndromeX-linkedTriad:thrombocytopenia,eczema,increasedsusceptibilitytoinfectionMildcasesmaypresentsolelythrombocytopenia,so-calledX-linkedthrombocytopeniaTypicalcasesneedSCTtosavelifeWAS例5，男，10月，家族史陽(yáng)性，2004年4月5日入院WASpexpressiononPBMC

Normal

carrier

patient

mildcase

partialexpressionWASpatients@CQ13319195/122/84/82/115/163/211/4XLT

patientWAS

patientYearsTotal152WAS/XLTcasesdiagnosedinthepast12yearsSummaryofWASpgenemutation原發(fā)性免疫缺陷病的相對(duì)發(fā)病率T細(xì)胞/B細(xì)胞聯(lián)合缺陷

補(bǔ)體缺陷吞噬細(xì)胞缺陷T細(xì)胞缺陷

2%50%20%10%

18%抗體缺陷DistributionofPIDcasesinCMU

ReviewofbasicImmunologyPhysiologicalfeaturesofimmunefunctioninchildhoodDefinitionofimmunodeficiencydiseaseClassificationofPIDCommonclinicalpresentationsScreeninglaboratorytestsPrinciplesofPIDmanagementSecondaryimmunodeficiency

OUTLINE

--反復(fù)感染

-反復(fù)性呼吸道感染

-嚴(yán)重細(xì)菌性感染(肺炎,敗血癥,腦膜炎,骨髓炎和其它

-感染難以控制

-嚴(yán)重病毒性感染

-機(jī)會(huì)感染(卡氏肺囊蟲(chóng),隱孢子菌，支原體）

--自身免疫性疾病:關(guān)節(jié)痛,關(guān)節(jié)炎,狼瘡等

--淋巴系統(tǒng)腫瘤

--其它:

家族史,生長(zhǎng)發(fā)育遲緩,肝脾淋巴結(jié)腫大或扁桃體/淋巴結(jié)

缺如

ReviewofbasicImmunologyPhysiologicalfeaturesofimmunefunctioninchildhoodDefinitionofimmunodeficiencydiseaseClassificationofPIDCommonclinicalpresentationsScreeninglaboratorytestsPrinciplesofPIDmanagementSecondaryimmunodeficiency

OUTLINE實(shí)驗(yàn)室過(guò)篩檢查(1)

■B細(xì)胞缺陷

-血清IgG,IgM,IgA水平-ASO，血型抗體

-疫苗抗體反應(yīng)-IgG亞類(lèi)

-外周血B細(xì)胞計(jì)數(shù)(CD19orCD20)

-X-線了解增殖體影

■T細(xì)胞缺陷

-外周血白細(xì)胞計(jì)數(shù)和形態(tài)學(xué)觀察

-遲發(fā)皮膚過(guò)敏反應(yīng)(毛霉菌,腮腺炎病毒,念珠菌,破傷風(fēng)類(lèi)毒素)

-外周血T細(xì)胞亞群(CD3,CD4,CD8)

-抗原或絲裂原增殖反應(yīng)實(shí)驗(yàn)室過(guò)篩檢查(2)

■吞噬細(xì)胞缺陷

-

外周血白細(xì)胞計(jì)數(shù)和形態(tài)學(xué)觀察

-NBT染料試驗(yàn)

-血清IgE水平

-趨化功能

-

吞噬和殺菌功能

■補(bǔ)體缺陷

-CH50活性

-C3、C4水平和其它補(bǔ)體成分測(cè)定

無(wú)刺激

患兒

正常

對(duì)照

四唑氮藍(lán)試驗(yàn)（NBT）PMA刺激慢性肉芽腫病(CYBB)備解素缺陷（PFC）濕疹血小板減少綜合征(WASP)嚴(yán)重聯(lián)合免疫缺陷?。↖L-2RG）X-連鎖無(wú)丙種球蛋白血癥（btk）X-連鎖淋巴增生性疾病.(XLP）X-連鎖高IgM血癥（CD40L）22.322.221.12111.411.311.211.2121321

22232425262728pq基因診斷AssaysestablishedtodefinePIDsSyndromeDNA-basedassaysProtein-basedassaysCIDIL2RG,RAG1/2,CD40L,TCRspectratypingCD40LAbdeficiencyBTK,μchain,Igα/β,λ5,CD40,AID,Ung,Nemo,Taci,WHIMBtk,CD40WelldefinedWASP,ATWASPPhagocytedeficiencyCYBB,NCF1NBT,DHRImmunedysregulationFOXP3,SAP,FAS,FASL,Caspase8and10FoxP3,FAS,FASL,SAP,Perforin,DNTInnatedefectMyD88,IRAK-4Autoinflammatorydiseasebkd（HID）、TRAPS、CARD15（NOD2）

ReviewofbasicImmunologyPhysiologicalfeaturesofimmunefunctioninchildhoodDefinitionofimmunodeficiencydiseaseClassificationofPIDCommonclinicalpresentationsScreeninglaboratorytestsPrinciplesofPIDmanagementSecondaryimmunodeficiency

OUTLINE

■

一般處理

＊預(yù)防和治療感染＊心理學(xué)支持

＊鼓勵(lì)正常的學(xué)習(xí)和生活＊可接種滅活疫苗

＊防止移植物抗宿主反應(yīng)＊脾切除為禁忌癥

■

替代治療

＊靜脈丙種球蛋白滴注(0.2~0.4g/kg/m)

＊特異性免疫血清

(VZIG,RIG,TIG,HBIG,RSV-IG)

＊血漿(20ml/kg)

＊中性粒細(xì)胞輸注（僅用于嚴(yán)重感染者）

＊其它(酶，IFN-γ,IL-2,胸腺素,轉(zhuǎn)移因子

)

■

免疫重建

＊胎兒胸腺移植及胸腺上皮移植/胎兒肝臟移植

＊骨髓移植

--HLA-同型移植

--HLA-半合子移植

--無(wú)關(guān)配型移植

＊臍血干細(xì)胞移植

＊外周血干細(xì)胞移植

＊基因治療(ADA缺陷,LAD-1,CGD)造血干細(xì)胞移植干細(xì)胞移植原發(fā)性免疫缺陷病免疫重建造血干細(xì)胞移植是根治療某些原發(fā)性免疫缺陷病的最佳方案，全球已有近萬(wàn)例病兒接受該治療，成功率40-80%，我國(guó)上海和重慶已成功進(jìn)行3例造血干細(xì)胞移植治療。2歲6個(gè)月Wiskott-Aldrichsyndrome(WAS)患兒在重慶醫(yī)科大學(xué)兒童醫(yī)院經(jīng)同胞（姐）供體同型骨髓移植后無(wú)病健康存活。圖為患者母親、患者和供髓的姐姐在一起。WAS免疫重建效果Pre-SCTPost-SCT成功植入完全的造血重建和免疫重建PID

patients

treated

with

transplantationChallenges1362554818YearsDiseaseNumberAliveDeadWAS41356CGD413SCID211X-HigM33XLA22Gene

therapyChallengesFuture

of

PIDGene

therapyCGD

X-SCID,

CGD,

ADA-SCID,

WASX-SCID,

CGD,

ADA-SCID,

WASGene

therapy

planwithCRISPR-cas9strategyandAAV-6initiatesthisyear

Clinical

trialforXSCID

isexpectedtobeopenasearlyas2018

ChallengesFuture

of

PIDWASgenemutationselectivelyinfluenceTCRrepertoiredevelopmentorexpansioninmemoryCD4

Tcells.ThismayreflectrelativelylessefficiencyofTcellmemoryestablishmentascomparedtonormalindividuals.SkewedTCRdiversityinmemorypopulationsofTcellsinWASPIDresearch

Wuetal.JAllergClinImmunol,2015WASpplaysancriticalroleinTfh

developmentandfunctionWASpdeficiencyleadstoimpairedTfhdevelopmentandfunctioninpatients,knock-outmice,chimericmiceandCD4transferedmice,whichisTcellintrinsic.AcceptedbyBLOODPIDresearch

Humansamples,DOCK8KOmouseDOCK8komicewerep