心血管免疫學(xué)生課件

LiningZhang,M.D,Ph.DDepartmentofImmunologyShandongUniversitySchoolofMedicine

心血管免疫LiningZha心血管系統(tǒng)心血管系統(tǒng)心血管系統(tǒng)異常與疾?、賱?dòng)脈粥樣硬化：常累及主動(dòng)脈、冠狀動(dòng)脈、腦動(dòng)脈、腎動(dòng)脈、周圍動(dòng)脈等。冠狀動(dòng)脈粥樣硬化引起心肌血供障礙時(shí)，稱冠狀動(dòng)脈粥樣硬化性心臟病（冠心?。┗蛉毖孕呐K病。腦血管動(dòng)脈粥樣硬化引起腦中風(fēng)（缺血或出血）②原發(fā)性高血壓：顯著而持久的動(dòng)脈血壓增高可影響心臟，導(dǎo)致高血壓性心臟?。ǜ咝牟?。③風(fēng)濕性心臟病（風(fēng)心?。杭毙云谝鹦膬?nèi)膜、心肌和心包炎癥，稱為風(fēng)濕性心臟炎；慢性期主要形成瓣膜狹窄和（或）關(guān)閉不全，稱為風(fēng)濕性心瓣膜病。④肺源性心臟病（肺心?。簽榉?、肺血管或胸腔疾病引起肺循環(huán)阻力增高而導(dǎo)致的心臟病。⑤感染性心臟?。簽椴《尽⒓?xì)菌、真菌、立克次體、寄生蟲等感染侵犯心臟而導(dǎo)致的心臟病。⑥內(nèi)分泌病性心臟?。喝缂谞钕俟δ芸哼M(jìn)性、甲狀腺功能減退性心臟病等。⑦血液病性心臟?。喝缲氀孕呐K病等。⑧營養(yǎng)代謝性心臟?。喝缇S生素B↓1缺乏性心臟病等。⑨心臟神經(jīng)癥：為自主（植物）神經(jīng)功能失調(diào)引起的心血管功能紊亂心血管系統(tǒng)異常與疾病①動(dòng)脈粥樣硬化：常累及主動(dòng)脈、冠狀動(dòng)脈、心血管系統(tǒng)疾病的危害心腦血管疾病是一種嚴(yán)重威脅人類，特別是50歲以上中老年人健康的常見病，即使應(yīng)用目前最先進(jìn)、完善的治療手段，仍可有50%以上的腦血管意外幸存者生活不能完全自理!全世界每年死于心腦血管疾病的人數(shù)高達(dá)1500萬人，居各種死因首位心血管系統(tǒng)疾病的危害心腦血管疾病是一種嚴(yán)重威脅人類，特別是5心腦血管疾病具有“發(fā)病率高、致殘率高、死亡率高、復(fù)發(fā)率高并發(fā)癥多”即“四高一多”的特點(diǎn).國心腦血管疾病患者已經(jīng)超過2.7億人！我國每年死于心腦血管疾病近300萬人，占我國每年總死亡病因的51%。幸存下來的患者75%不同程度喪失勞動(dòng)能力，40%重殘！我國腦中風(fēng)病人出院后第一年的復(fù)發(fā)率是30%，第五年的復(fù)發(fā)率高達(dá)59%，而二級預(yù)防做得較好的美國僅為10%。心血管系統(tǒng)疾病的危害心腦血管疾病具有“發(fā)病率高、致殘率高、死亡率高、復(fù)發(fā)率高并發(fā)動(dòng)脈粥樣硬化是心腦血管疾病的常見病理基礎(chǔ)

AtherosclerosisispathologicalbasisofCardiovasculardiseasesCoronaryarterydisease(CAD)

UnstableanginaMyocardialInfarctionCardiovasculardiseases

Cerebrovasculardisease

Themostcommonforms

AtherosclerosisBraininfarction

16.7milliondeaths動(dòng)脈粥樣硬化是心腦血管疾病的常見病理基礎(chǔ)

Atheroscl動(dòng)脈粥樣硬化是大中血管慢性進(jìn)展性病變Aslowlyprogressingchronicdisorderoflargeandmedium-sizedarteriesWhenitcausesthrombosis,itbecomesclinicallymanifest---acutecoronarysyndrome：unstableangina

pectorisandacutemyocardialinfarction急性冠脈綜合征動(dòng)脈粥樣硬化是大中血管慢性進(jìn)展性病變血管的結(jié)構(gòu)內(nèi)膜：內(nèi)皮、內(nèi)皮下層

內(nèi)彈力膜中膜：平滑肌、外彈力膜外膜：血管的結(jié)構(gòu)內(nèi)膜：內(nèi)皮、內(nèi)皮下層動(dòng)脈粥樣硬化是脂質(zhì)代謝異常誘發(fā)的大中血管壁的慢性炎癥

Atherosclerosisisanchronicinflammatorydiseaseofarterialwallanaccumulationoflipidsinfiltrationofimmunocytes,macrophages,Tcellsandmastcellsvascularsmoothmusclecellscollagen.

動(dòng)脈粥樣硬化是脂質(zhì)代謝異常誘發(fā)的大中血管壁的慢性炎癥

Ath固有免疫和適應(yīng)性免疫均參入動(dòng)脈粥樣硬化的的發(fā)生IRABcell:innateresponseactivatorBcell固有免疫和適應(yīng)性免疫均參入動(dòng)脈粥樣硬化的的發(fā)生IRABc一、巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用單核細(xì)胞在內(nèi)膜中轉(zhuǎn)化成巨噬細(xì)胞，斑塊中的巨噬細(xì)胞主要是M1巨噬細(xì)胞通過清道夫受體（SR-A）、TLR4、CD36或CD36依賴的TLR2/6異源二聚體的識別氧化性LDL（oxLDL），攝入脂蛋白轉(zhuǎn)變成泡沫細(xì)胞（foam

cell）巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用抑制斑塊形成斑塊的不穩(wěn)定性：吞噬脂質(zhì)和轉(zhuǎn)運(yùn)脂質(zhì)清理凋亡的細(xì)胞（efferocytosis）促進(jìn)斑塊或促進(jìn)斑塊的不穩(wěn)定性：

分泌多種細(xì)胞因子：IL-1beta，IL-6，TNF、IL-12趨化因子：MCP-1，,IL-8,andMIP-3??遞呈抗原，啟動(dòng)適應(yīng)性T細(xì)胞免疫（Th1、Th17）凋亡或死亡一、巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用單核細(xì)胞在內(nèi)膜中轉(zhuǎn)化成巨噬單核細(xì)胞向巨噬細(xì)胞的分化單核細(xì)胞向巨噬細(xì)胞的分化一、巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用單核細(xì)胞在內(nèi)膜中轉(zhuǎn)化成巨噬細(xì)胞，斑塊中的巨噬細(xì)胞主要是M1巨噬細(xì)胞轉(zhuǎn)化成泡沫細(xì)胞（foam

cell）巨噬細(xì)胞吞噬LDL巨噬細(xì)胞通過清道夫受體（SR-A）、TLR4、CD36或CD36依賴的TLR4/6異源二聚體的識別氧化性LDL（oxLDL巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用抑制斑塊形成斑塊的不穩(wěn)定性：吞噬脂質(zhì)和轉(zhuǎn)運(yùn)脂質(zhì)清理凋亡的細(xì)胞（efferocytosis）促進(jìn)斑塊或促進(jìn)斑塊的不穩(wěn)定性：

分泌多種細(xì)胞因子：IL-1beta，IL-6，TNF、IL-12趨化因子：MCP-1，,IL-8,andMIP-3??遞呈抗原，啟動(dòng)適應(yīng)性T細(xì)胞免疫（Th1、Th17）凋亡或死亡一、巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用單核細(xì)胞在內(nèi)膜中轉(zhuǎn)化成巨噬ModifiedLDL

uptakeLDLuptakeLipideffluxKathrynJ.Moore,FrederickJ.SheedyandEdwardA.FisherNATUREREVIEWSIMMUNOLOGY,

2013Lipoprotein

uptake

and

efflux

in

macrophagefoamcellformationPART3ModifiedLDLuptakeLDLLipidKat一、巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用單核細(xì)胞在內(nèi)膜中轉(zhuǎn)化成巨噬細(xì)胞，斑塊中的巨噬細(xì)胞主要是M1巨噬細(xì)胞轉(zhuǎn)化成泡沫細(xì)胞（foam

cell）巨噬細(xì)胞吞噬LDL巨噬細(xì)胞通過清道夫受體（SR-A）、TLR4、CD36或CD36依賴的TLR4/6異源二聚體的識別氧化性LDL（oxLDL巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用抑制斑塊形成斑塊的不穩(wěn)定性：吞噬脂質(zhì)和轉(zhuǎn)運(yùn)脂質(zhì)清理凋亡的細(xì)胞（efferocytosis）促進(jìn)斑塊或促進(jìn)斑塊的不穩(wěn)定性：

分泌多種細(xì)胞因子：IL-1beta，IL-6，TNF、IL-12趨化因子：MCP-1，,IL-8,andMIP-3??遞呈抗原，啟動(dòng)適應(yīng)性T細(xì)胞免疫（Th1、Th17）凋亡—二次死亡一、巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用單核細(xì)胞在內(nèi)膜中轉(zhuǎn)化成巨噬ModifiedLDL

uptakeLDLuptakeLipideffluxKathrynJ.Moore,FrederickJ.SheedyandEdwardA.FisherNATUREREVIEWSIMMUNOLOGY,

2013Lipoprotein

uptake

and

efflux

in

macrophagefoamcellformationPART3ModifiedLDLuptakeLDLLipidKat

ThemacrophageapoptosisplaysacriticalroleinEarlylesionandadvancedlesionThemacrophageapoptosisplay一、巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用單核細(xì)胞在內(nèi)膜中轉(zhuǎn)化成巨噬細(xì)胞，斑塊中的巨噬細(xì)胞主要是M1巨噬細(xì)胞轉(zhuǎn)化成泡沫細(xì)胞（foam

cell）巨噬細(xì)胞吞噬LDL巨噬細(xì)胞通過清道夫受體（SR-A）、TLR4、CD36或CD36依賴的TLR4/6異源二聚體的識別氧化性LDL（oxLDL巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用抑制斑塊形成斑塊的不穩(wěn)定性：吞噬脂質(zhì)和轉(zhuǎn)運(yùn)脂質(zhì)清理凋亡的細(xì)胞（efferocytosis）促進(jìn)斑塊或促進(jìn)斑塊的不穩(wěn)定性：

分泌多種細(xì)胞因子：IL-1beta，IL-6，TNF、IL-12趨化因子：MCP-1，,IL-8,andMIP-3??遞呈抗原，啟動(dòng)適應(yīng)性T細(xì)胞免疫（Th1、Th17）凋亡—二次死亡一、巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用單核細(xì)胞在內(nèi)膜中轉(zhuǎn)化成巨噬CD36,ascavengerreceptorimplicatedinatherosclerosis.ParkYM，ExpMolMed.2014Jun6;46:e99CD36,ascavengerreceptorimp巨噬細(xì)胞分泌多種細(xì)胞因子和趨化因子巨噬細(xì)胞分泌多種細(xì)胞因子和趨化因子炎癥小體與動(dòng)脈粥樣硬化炎癥小體與動(dòng)脈粥樣硬化一、巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用單核細(xì)胞在內(nèi)膜中轉(zhuǎn)化成巨噬細(xì)胞，斑塊中的巨噬細(xì)胞主要是M1巨噬細(xì)胞轉(zhuǎn)化成泡沫細(xì)胞（foam

cell）巨噬細(xì)胞吞噬LDL巨噬細(xì)胞通過清道夫受體（SR-A）、TLR4、CD36或CD36依賴的TLR4/6異源二聚體的識別氧化性LDL（oxLDL巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用抑制斑塊形成斑塊的不穩(wěn)定性：吞噬脂質(zhì)和轉(zhuǎn)運(yùn)脂質(zhì)清理凋亡的細(xì)胞（efferocytosis）促進(jìn)斑塊或促進(jìn)斑塊的不穩(wěn)定性：

分泌多種細(xì)胞因子：IL-1beta，IL-6，TNF、IL-12趨化因子：MCP-1，,IL-8,andMIP-3??遞呈抗原，啟動(dòng)適應(yīng)性T細(xì)胞免疫（Th1、Th17）凋亡—二次死亡一、巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用單核細(xì)胞在內(nèi)膜中轉(zhuǎn)化成巨噬巨噬細(xì)胞遞呈抗原，啟動(dòng)適應(yīng)性T細(xì)胞免疫CytokinesoxLDL巨噬細(xì)胞遞呈抗原，啟動(dòng)適應(yīng)性T細(xì)胞免疫Cyto一、巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用單核細(xì)胞在內(nèi)膜中轉(zhuǎn)化成巨噬細(xì)胞，斑塊中的巨噬細(xì)胞主要是M1巨噬細(xì)胞轉(zhuǎn)化成泡沫細(xì)胞（foam

cell）巨噬細(xì)胞吞噬LDL巨噬細(xì)胞通過清道夫受體（SR-A）、TLR4、CD36或CD36依賴的TLR4/6異源二聚體的識別氧化性LDL（oxLDL巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用抑制斑塊形成斑塊的不穩(wěn)定性：吞噬脂質(zhì)和轉(zhuǎn)運(yùn)脂質(zhì)清理凋亡的細(xì)胞（efferocytosis）促進(jìn)斑塊或促進(jìn)斑塊的不穩(wěn)定性：

分泌多種細(xì)胞因子：IL-1beta，IL-6，TNF、IL-12趨化因子：MCP-1，,IL-8,andMIP-3??遞呈抗原，啟動(dòng)適應(yīng)性T細(xì)胞免疫（Th1、Th17）凋亡—二次死亡一、巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用單核細(xì)胞在內(nèi)膜中轉(zhuǎn)化成巨噬

ThemacrophageapoptosisplaysacriticalroleinEarlylesionandadvancedlesionThemacrophageapoptosisplay二、DC與動(dòng)脈粥樣硬化二、DC與動(dòng)脈粥樣硬化Complement

system

三、體和動(dòng)脈粥樣硬化ComplementsystemComplement

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Complementsysteminhealthan

1.Lytic2.Sub-lyticComplement

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補(bǔ)體的活化和調(diào)節(jié)蛋白的調(diào)節(jié)作用1.Classical

pathway2.

MBL

pathway3.

Alternative

pathway1.LyticComplementactivationCrryisregardedasafunctionalhomologofhuman

MCP

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DAFinthemouse,and

appearstobefunctionallythemostimportantregulatorofcomplementactivationinmouse.

H.Molina.

Cell.Mol.LifeSci.2002CrryCrryC3b/C4bC3

convertaseCrry:

membraneinhibitor

ofC3convertaseCrry抑制C3轉(zhuǎn)化酶CrryisregardedasafunctionIschemia/reperfusioninjuryAtkinsonC,

et

al.

JClinInvest.2005

Circulation.2013HeS,

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et

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H,

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JImmunol.2007Murine

lupusAtkinsonC,

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JImmunol.2008ColitisSchepp-BerglindJ,et

al.

JImmunol.2012

Therapeutic

effect

ofsolubleCrryin

disease

modelTagMembrane

CrrySoluble

CrryIschemia/reperfusioninjuryAtkCD59

restricts

membrane

attack

complex(MAC)

formation

CD59CD59restrictsmembraneattackDysregulation

of

Complement

System

involving

in

human

disease

DysregulationofComplementSyComplementsystemandatherosclerosis補(bǔ)體和動(dòng)脈粥樣硬化ComplementsystemandatheroscAtherosclerosisHyperlipidemiaHyperglycemiaCD59Wuetal.CircRes.

2009?(1)(2)

Soluble

complementinhibitorCrryQuestion:

Role

of

Complement

regulator

inatherosclerosis

?

Therapeuticeffect

on

atherosclerosis

?AtherosclerosisHyperlipidemiaHPart

1:

Role

of

CD59

in

diabetes-induced

atherosclerosisPart

2:

Effect

of

solubleCrryin

treatment

of

atherosclerosis

Part

3:

Mechanismofacceleratedatherosclerosis

developmentinducedbycomplement

activationOBJECTIVEPart1:RoleofCD59indiabetSTZ

treatment

in

2

weeks

to

induce

diabetesPBS

treatment

in

2

weeks

as

non-diabetes

control

Normal

diet

for

16

weeksMeasure

blood

glucose

every

weekAtherosclerosis

plaqueMAC

depositionImmune

cell

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CD59與糖尿病相關(guān)動(dòng)脈粥樣硬化mCd59ab-/-

mice

x

Apoe-/-

micemCd59ab-/-/Apoe-/-

miceApoe-/-

miceSTZtreatmentin2weekstoinABEstablishmentofSTZinduceddiabeticatherosclerosismice

model糖尿病相關(guān)動(dòng)脈粥樣硬化模型建立

STZ-mCd59ab-/-Apoe-/-STZ-mCd59ab+/+/Apoe-/-

PBS-mCd59ab-/-Apoe-/-PBS-mCd59ab+/+/Apoe-/-ABEstablishmentofSTZinduced2.CD59Deficiencypromoteddiabeticatherosclerosis

development-12.CD59DeficiencypromoteddiH&E

stainingOil-red

O

staining2.CD59Deficiencypromoteddiabeticatherosclerosis

development-2

H&EstainingOil-redOstainingmCd59ab-/-/Apoe-/-

Apoe-/-

mCd59ab-/-/Apoe-/-

Apoe-/-mCd59ab-/-/Apoe-/-

Apoe-/-

mCd59ab-/-/Apoe-/-

Apoe-/-STZ-DiabeticPBS-Non-DiabeticSTZ-DiabeticPBS-Non-Diabeticnsns3.

CD59Deficiencyhave

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lipid

profilensnsmCd59ab-/-/Apoe-/-ApomCd59ab-/-/Apoe-/-C9deposition4xmCd59ab+/+/Apoe-/-Macrophagedeposition4xmCd59ab-/-/Apoe-/-mCd59ab+/+/Apoe-/-4.Increased

MAC

deposition

and

macrophage

infiltration

in

aortic

root

of

mCd59-/-/Apoe-/-

micemCd59ab-/-/Apoe-/-C9depositiCONCLUSIONComplement

activationClassicalMBLAlternativeC3

convertaseC5

convertaseMACCR2-CrryCD59AtherosclerosisDiabeticAtherosclerosismacrophagefoamcell

formationandinduceinflammatorycytokineandgrowthfactor

expressionCONCLUSIONComplementactivatio適應(yīng)性免疫參入動(dòng)脈粥樣硬化的的發(fā)生IRABcell:innateresponseactivatorBcell適應(yīng)性免疫參入動(dòng)脈粥樣硬化的的發(fā)生IRABcell:i四、體液免疫與動(dòng)脈粥樣硬化B1細(xì)胞抑制動(dòng)脈粥樣硬化的形成B2和IRAB細(xì)胞促進(jìn)動(dòng)脈粥樣硬化的形成IRABcell:innateresponseactivatorBcellIgM中和oxLDL四、體液免疫與動(dòng)脈粥樣硬化B1細(xì)胞抑制動(dòng)脈粥樣硬化的形成B2心血管免疫學(xué)生課件適應(yīng)性免疫均參入動(dòng)脈粥樣硬化的的發(fā)生IRABcell:innateresponseactivatorBcell適應(yīng)性免疫均參入動(dòng)脈粥樣硬化的的發(fā)生IRABcell:T細(xì)胞與動(dòng)脈粥樣硬化T細(xì)胞與動(dòng)脈粥樣硬化不同T細(xì)胞與動(dòng)脈粥樣硬化不同T細(xì)胞與動(dòng)脈粥樣硬化Atherosclerosis＋－?－Th17ThedifferentCD4+subsetshavevariousrolesinAtherosclerosis?Atherosclerosis＋－?－Th17TheTheroleofTh17anditsmajoreffectormoleculeIL-17inthedevelopmentofatheroscleroticplaqueThemechanismbywhichIL-17isinvolvedinatherosclerosis

Th17andIL-17

inatherosclerosisTheroleofTh17anditsmajoAACS

NCBCCD4IL-17SA﹡﹡﹡﹡﹡﹡

﹡﹡1.ThecirculatingTh17cellsandIL-17significantlyincreaseinpatientswithACScomparedwithnormalcontrolandstableangina

NC：NormalcontrolSA：stableanginapectorisACS：Acutecoronarysyndrome-----unstableanginaacutemyocardialinfarction

Th17IL-17Th17andIL-17maybeinvolvedinatherosclerosis.AACSNCBCCD4IL-17SA﹡﹡﹡﹡﹡﹡﹡﹡2.EstablishmentoftwoatheroscleroticmicemodelsHighfatdietto16weeksor24weeks

ApoE-/-mice8weeksRapidcarotidmodel

StandardmodelHighfatdietFor6weeksor14weeks

Aorticroot

carotidApoE-/-mice8weeks2.Establishmentoftwoathero3.ThedynamicchangeofTh17subsetinspleenduringthedevelopmentofatherosclerosis(1)0.5%C57ApoE-/-C57ApoE-/-8weeksIL-17IFN-gC57ApoE-/-3.ThedynamicchangeofTh173.ThedynamicchangeofTh17subsetinspleenduringthedevelopmentofatherosclerosis(2)CarotidC57ApoE-/-C57ApoE-/-16weeks24weeks3.0%IL-17IFN-gIL-17IFN-g4.4%Advancedplaque

3.ThedynamicchangeofTh174.ThepercentageofTh17inspleenhasapositivecorrelationtosizeofplaque8weeks16weeks24weeksCD4+IL-17+(%)Plaquearea(m2)Th174.ThepercentageofTh17ins5.ExpressionofIL-17anditstranscriptionalfactorROR-tinarterialwallsduringformationofplaqueEstablishedplaqueadvancedplaque

ROR-tIL-17b-actinNoplaqueIL-175.ExpressionofIL-17anditmacrophageCD4+Tcells5.IL-17isexpressedinbothCD4+TcellsandMacrophageTh17andIL-17areinvolvedintheatherosclerosismacrophageCD4+Tcells5.IL-17Neutrolizinganti-IL-17antibodyorexogenousIL-17wasinjectedintoApoE-/-micetoconfirmcausativerole

Highfatdiet+Neutrolizing

anti-IL-17antibodyorExogenousIL-17for5weeks

ApoE-/-mice

Rapidcarotidmodel

Standardmodel

Highfatdiet+NeutrolizingAnti-IL-17antibodytreatmentfor5weeksplaqueinaorticroot

plaqueincarotidApoE-/-miceNeutrolizinganti-IL-17antibo6.BlockageofendogenousIL-17markedlysuppressesthe

developmentofplaqueincarotidModel1CarotidN=10/groupGao,etal,J.Immuno,2010Anti-IL-17IsotypeLesionsarea(um2)Anti-IL-17IsotypeHELesionsarea(um2)Anti-IL-17IsotypeUltrosoundimaging

6.BlockageofendogenousIL-17.BlockageofIL-17markedlysuppressesthe

developmentofplaqueinstandardmodel

Aorticroot

N=5/groupGao,etal,J.Immuno,2010Anti-IL-17IsotypeOROLesionsarea(um2)Anti-IL-17IsotypeModel27.BlockageofIL-17markedlysOROSMCMacrophageControlIL-17

Gao,etal,J..Immuno2010

8.TreatmentofExogenousIL-17

acceleratesplaque

formation

inApoE-/-miceOROSMCMacrophageControlIL-17GIL-17promotesthedevelopmentofatherosclerosisBlockadeofendogenousIL-17byneutrolizingantibodyattenuatesformationofplaque

ConclusionIL-17promotesthedevelopmentI.TheroleofTh17andIL-17inthedevelopmentofatheroscleroticplaqueII.ThemechanismsbywhichIL-17acceleratesatherosclerosis

Th17andIL-17

inatherosclerosisI.TheroleofTh17andIL-17

ThemacrophageapoptosisplaysacriticalroleinEarlylesionandadvancedlesionHypothesis:IL-17promotesatherosclerosisvia

inducingmacrophageapoptosisThemacrophageapoptosisplay

1.TheimpactofIL-17onmacrophageapoptosiswasdetectedbyHocheststaining

IL-17Culturedmacrophage1.TheimpactofIL-17on2.TheIL-17-inducedapoptosisisinconcentration–dependentmanner

byFlowCytometryIL-170ng/ml25ng/ml50ng/ml100ng/mlPIAnnexinVAnnexinV+PI+(%)02550100ng/ml****2.TheIL-17-inducedapoptControl10ng/ml50ng/ml0246Caspase-9(Foldchange)control10ng/ml50ng/ml0.80.91.01.11.21.3Bcl-2(Foldchange)Caspase3-actin-actinABEDCFCaspase9-actin-actinBcl-2-actinBaxCaspase8﹡﹡﹡﹡﹡﹡﹡﹡

3.IL-17mainlyactivatesmitochondrialapoptoticpathwayZhuFetalClinImmuno2011IL-17ng/mlControl10ng/ml50ng/ml0246Caspa固有免疫和適應(yīng)性免疫均參入動(dòng)脈粥樣硬化的的發(fā)生IRABcell:innateresponseactivatorBcell固有免疫和適應(yīng)性免疫均參入動(dòng)脈粥樣硬化的的發(fā)生IRABcThankYou!ThankYou!

LiningZhang,M.D,Ph.DDepartmentofImmunologyShandongUniversitySchoolofMedicine

心血管免疫LiningZha心血管系統(tǒng)心血管系統(tǒng)心血管系統(tǒng)異常與疾病①動(dòng)脈粥樣硬化：常累及主動(dòng)脈、冠狀動(dòng)脈、腦動(dòng)脈、腎動(dòng)脈、周圍動(dòng)脈等。冠狀動(dòng)脈粥樣硬化引起心肌血供障礙時(shí)，稱冠狀動(dòng)脈粥樣硬化性心臟病（冠心?。┗蛉毖孕呐K病。腦血管動(dòng)脈粥樣硬化引起腦中風(fēng)（缺血或出血）②原發(fā)性高血壓：顯著而持久的動(dòng)脈血壓增高可影響心臟，導(dǎo)致高血壓性心臟?。ǜ咝牟?。③風(fēng)濕性心臟?。L(fēng)心?。杭毙云谝鹦膬?nèi)膜、心肌和心包炎癥，稱為風(fēng)濕性心臟炎；慢性期主要形成瓣膜狹窄和（或）關(guān)閉不全，稱為風(fēng)濕性心瓣膜病。④肺源性心臟?。ǚ涡牟。簽榉?、肺血管或胸腔疾病引起肺循環(huán)阻力增高而導(dǎo)致的心臟病。⑤感染性心臟?。簽椴《?、細(xì)菌、真菌、立克次體、寄生蟲等感染侵犯心臟而導(dǎo)致的心臟病。⑥內(nèi)分泌病性心臟?。喝缂谞钕俟δ芸哼M(jìn)性、甲狀腺功能減退性心臟病等。⑦血液病性心臟?。喝缲氀孕呐K病等。⑧營養(yǎng)代謝性心臟?。喝缇S生素B↓1缺乏性心臟病等。⑨心臟神經(jīng)癥：為自主（植物）神經(jīng)功能失調(diào)引起的心血管功能紊亂心血管系統(tǒng)異常與疾病①動(dòng)脈粥樣硬化：常累及主動(dòng)脈、冠狀動(dòng)脈、心血管系統(tǒng)疾病的危害心腦血管疾病是一種嚴(yán)重威脅人類，特別是50歲以上中老年人健康的常見病，即使應(yīng)用目前最先進(jìn)、完善的治療手段，仍可有50%以上的腦血管意外幸存者生活不能完全自理!全世界每年死于心腦血管疾病的人數(shù)高達(dá)1500萬人，居各種死因首位心血管系統(tǒng)疾病的危害心腦血管疾病是一種嚴(yán)重威脅人類，特別是5心腦血管疾病具有“發(fā)病率高、致殘率高、死亡率高、復(fù)發(fā)率高并發(fā)癥多”即“四高一多”的特點(diǎn).國心腦血管疾病患者已經(jīng)超過2.7億人！我國每年死于心腦血管疾病近300萬人，占我國每年總死亡病因的51%。幸存下來的患者75%不同程度喪失勞動(dòng)能力，40%重殘！我國腦中風(fēng)病人出院后第一年的復(fù)發(fā)率是30%，第五年的復(fù)發(fā)率高達(dá)59%，而二級預(yù)防做得較好的美國僅為10%。心血管系統(tǒng)疾病的危害心腦血管疾病具有“發(fā)病率高、致殘率高、死亡率高、復(fù)發(fā)率高并發(fā)動(dòng)脈粥樣硬化是心腦血管疾病的常見病理基礎(chǔ)

AtherosclerosisispathologicalbasisofCardiovasculardiseasesCoronaryarterydisease(CAD)

UnstableanginaMyocardialInfarctionCardiovasculardiseases

Cerebrovasculardisease

Themostcommonforms

AtherosclerosisBraininfarction

16.7milliondeaths動(dòng)脈粥樣硬化是心腦血管疾病的常見病理基礎(chǔ)

Atheroscl動(dòng)脈粥樣硬化是大中血管慢性進(jìn)展性病變Aslowlyprogressingchronicdisorderoflargeandmedium-sizedarteriesWhenitcausesthrombosis,itbecomesclinicallymanifest---acutecoronarysyndrome：unstableangina

pectorisandacutemyocardialinfarction急性冠脈綜合征動(dòng)脈粥樣硬化是大中血管慢性進(jìn)展性病變血管的結(jié)構(gòu)內(nèi)膜：內(nèi)皮、內(nèi)皮下層

內(nèi)彈力膜中膜：平滑肌、外彈力膜外膜：血管的結(jié)構(gòu)內(nèi)膜：內(nèi)皮、內(nèi)皮下層動(dòng)脈粥樣硬化是脂質(zhì)代謝異常誘發(fā)的大中血管壁的慢性炎癥

Atherosclerosisisanchronicinflammatorydiseaseofarterialwallanaccumulationoflipidsinfiltrationofimmunocytes,macrophages,Tcellsandmastcellsvascularsmoothmusclecellscollagen.

動(dòng)脈粥樣硬化是脂質(zhì)代謝異常誘發(fā)的大中血管壁的慢性炎癥

Ath固有免疫和適應(yīng)性免疫均參入動(dòng)脈粥樣硬化的的發(fā)生IRABcell:innateresponseactivatorBcell固有免疫和適應(yīng)性免疫均參入動(dòng)脈粥樣硬化的的發(fā)生IRABc一、巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用單核細(xì)胞在內(nèi)膜中轉(zhuǎn)化成巨噬細(xì)胞，斑塊中的巨噬細(xì)胞主要是M1巨噬細(xì)胞通過清道夫受體（SR-A）、TLR4、CD36或CD36依賴的TLR2/6異源二聚體的識別氧化性LDL（oxLDL），攝入脂蛋白轉(zhuǎn)變成泡沫細(xì)胞（foam

cell）巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用抑制斑塊形成斑塊的不穩(wěn)定性：吞噬脂質(zhì)和轉(zhuǎn)運(yùn)脂質(zhì)清理凋亡的細(xì)胞（efferocytosis）促進(jìn)斑塊或促進(jìn)斑塊的不穩(wěn)定性：

分泌多種細(xì)胞因子：IL-1beta，IL-6，TNF、IL-12趨化因子：MCP-1，,IL-8,andMIP-3??遞呈抗原，啟動(dòng)適應(yīng)性T細(xì)胞免疫（Th1、Th17）凋亡或死亡一、巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用單核細(xì)胞在內(nèi)膜中轉(zhuǎn)化成巨噬單核細(xì)胞向巨噬細(xì)胞的分化單核細(xì)胞向巨噬細(xì)胞的分化一、巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用單核細(xì)胞在內(nèi)膜中轉(zhuǎn)化成巨噬細(xì)胞，斑塊中的巨噬細(xì)胞主要是M1巨噬細(xì)胞轉(zhuǎn)化成泡沫細(xì)胞（foam

cell）巨噬細(xì)胞吞噬LDL巨噬細(xì)胞通過清道夫受體（SR-A）、TLR4、CD36或CD36依賴的TLR4/6異源二聚體的識別氧化性LDL（oxLDL巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用抑制斑塊形成斑塊的不穩(wěn)定性：吞噬脂質(zhì)和轉(zhuǎn)運(yùn)脂質(zhì)清理凋亡的細(xì)胞（efferocytosis）促進(jìn)斑塊或促進(jìn)斑塊的不穩(wěn)定性：

分泌多種細(xì)胞因子：IL-1beta，IL-6，TNF、IL-12趨化因子：MCP-1，,IL-8,andMIP-3??遞呈抗原，啟動(dòng)適應(yīng)性T細(xì)胞免疫（Th1、Th17）凋亡或死亡一、巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用單核細(xì)胞在內(nèi)膜中轉(zhuǎn)化成巨噬ModifiedLDL

uptakeLDLuptakeLipideffluxKathrynJ.Moore,FrederickJ.SheedyandEdwardA.FisherNATUREREVIEWSIMMUNOLOGY,

2013Lipoprotein

uptake

and

efflux

in

macrophagefoamcellformationPART3ModifiedLDLuptakeLDLLipidKat一、巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用單核細(xì)胞在內(nèi)膜中轉(zhuǎn)化成巨噬細(xì)胞，斑塊中的巨噬細(xì)胞主要是M1巨噬細(xì)胞轉(zhuǎn)化成泡沫細(xì)胞（foam

cell）巨噬細(xì)胞吞噬LDL巨噬細(xì)胞通過清道夫受體（SR-A）、TLR4、CD36或CD36依賴的TLR4/6異源二聚體的識別氧化性LDL（oxLDL巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用抑制斑塊形成斑塊的不穩(wěn)定性：吞噬脂質(zhì)和轉(zhuǎn)運(yùn)脂質(zhì)清理凋亡的細(xì)胞（efferocytosis）促進(jìn)斑塊或促進(jìn)斑塊的不穩(wěn)定性：

分泌多種細(xì)胞因子：IL-1beta，IL-6，TNF、IL-12趨化因子：MCP-1，,IL-8,andMIP-3??遞呈抗原，啟動(dòng)適應(yīng)性T細(xì)胞免疫（Th1、Th17）凋亡—二次死亡一、巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用單核細(xì)胞在內(nèi)膜中轉(zhuǎn)化成巨噬ModifiedLDL

uptakeLDLuptakeLipideffluxKathrynJ.Moore,FrederickJ.SheedyandEdwardA.FisherNATUREREVIEWSIMMUNOLOGY,

2013Lipoprotein

uptake

and

efflux

in

macrophagefoamcellformationPART3ModifiedLDLuptakeLDLLipidKat

ThemacrophageapoptosisplaysacriticalroleinEarlylesionandadvancedlesionThemacrophageapoptosisplay一、巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用單核細(xì)胞在內(nèi)膜中轉(zhuǎn)化成巨噬細(xì)胞，斑塊中的巨噬細(xì)胞主要是M1巨噬細(xì)胞轉(zhuǎn)化成泡沫細(xì)胞（foam

cell）巨噬細(xì)胞吞噬LDL巨噬細(xì)胞通過清道夫受體（SR-A）、TLR4、CD36或CD36依賴的TLR4/6異源二聚體的識別氧化性LDL（oxLDL巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用抑制斑塊形成斑塊的不穩(wěn)定性：吞噬脂質(zhì)和轉(zhuǎn)運(yùn)脂質(zhì)清理凋亡的細(xì)胞（efferocytosis）促進(jìn)斑塊或促進(jìn)斑塊的不穩(wěn)定性：

分泌多種細(xì)胞因子：IL-1beta，IL-6，TNF、IL-12趨化因子：MCP-1，,IL-8,andMIP-3??遞呈抗原，啟動(dòng)適應(yīng)性T細(xì)胞免疫（Th1、Th17）凋亡—二次死亡一、巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用單核細(xì)胞在內(nèi)膜中轉(zhuǎn)化成巨噬CD36,ascavengerreceptorimplicatedinatherosclerosis.ParkYM，ExpMolMed.2014Jun6;46:e99CD36,ascavengerreceptorimp巨噬細(xì)胞分泌多種細(xì)胞因子和趨化因子巨噬細(xì)胞分泌多種細(xì)胞因子和趨化因子炎癥小體與動(dòng)脈粥樣硬化炎癥小體與動(dòng)脈粥樣硬化一、巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用單核細(xì)胞在內(nèi)膜中轉(zhuǎn)化成巨噬細(xì)胞，斑塊中的巨噬細(xì)胞主要是M1巨噬細(xì)胞轉(zhuǎn)化成泡沫細(xì)胞（foam

cell）巨噬細(xì)胞吞噬LDL巨噬細(xì)胞通過清道夫受體（SR-A）、TLR4、CD36或CD36依賴的TLR4/6異源二聚體的識別氧化性LDL（oxLDL巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用抑制斑塊形成斑塊的不穩(wěn)定性：吞噬脂質(zhì)和轉(zhuǎn)運(yùn)脂質(zhì)清理凋亡的細(xì)胞（efferocytosis）促進(jìn)斑塊或促進(jìn)斑塊的不穩(wěn)定性：

分泌多種細(xì)胞因子：IL-1beta，IL-6，TNF、IL-12趨化因子：MCP-1，,IL-8,andMIP-3??遞呈抗原，啟動(dòng)適應(yīng)性T細(xì)胞免疫（Th1、Th17）凋亡—二次死亡一、巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用單核細(xì)胞在內(nèi)膜中轉(zhuǎn)化成巨噬巨噬細(xì)胞遞呈抗原，啟動(dòng)適應(yīng)性T細(xì)胞免疫CytokinesoxLDL巨噬細(xì)胞遞呈抗原，啟動(dòng)適應(yīng)性T細(xì)胞免疫Cyto一、巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用單核細(xì)胞在內(nèi)膜中轉(zhuǎn)化成巨噬細(xì)胞，斑塊中的巨噬細(xì)胞主要是M1巨噬細(xì)胞轉(zhuǎn)化成泡沫細(xì)胞（foam

cell）巨噬細(xì)胞吞噬LDL巨噬細(xì)胞通過清道夫受體（SR-A）、TLR4、CD36或CD36依賴的TLR4/6異源二聚體的識別氧化性LDL（oxLDL巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用抑制斑塊形成斑塊的不穩(wěn)定性：吞噬脂質(zhì)和轉(zhuǎn)運(yùn)脂質(zhì)清理凋亡的細(xì)胞（efferocytosis）促進(jìn)斑塊或促進(jìn)斑塊的不穩(wěn)定性：

分泌多種細(xì)胞因子：IL-1beta，IL-6，TNF、IL-12趨化因子：MCP-1，,IL-8,andMIP-3??遞呈抗原，啟動(dòng)適應(yīng)性T細(xì)胞免疫（Th1、Th17）凋亡—二次死亡一、巨噬細(xì)胞在動(dòng)脈粥樣硬化中的作用單核細(xì)胞在內(nèi)膜中轉(zhuǎn)化成巨噬

ThemacrophageapoptosisplaysacriticalroleinEarlylesionandadvancedlesionThemacrophageapoptosisplay二、DC與動(dòng)脈粥樣硬化二、DC與動(dòng)脈粥樣硬化Complement

system

三、體和動(dòng)脈粥樣硬化ComplementsystemComplement

system

in

health

and

disease

Complementsysteminhealthan

1.Lytic2.Sub-lyticComplement

activation

cascade

補(bǔ)體的活化和調(diào)節(jié)蛋白的調(diào)節(jié)作用1.Classical

pathway2.

MBL

pathway3.

Alternative

pathway1.LyticComplementactivationCrryisregardedasafunctionalhomologofhuman

MCP

and

DAFinthemouse,and

appearstobefunctionallythemostimportantregulatorofcomplementactivationinmouse.

H.Molina.

Cell.Mol.LifeSci.2002CrryCrryC3b/C4bC3

convertaseCrry:

membraneinhibitor

ofC3convertaseCrry抑制C3轉(zhuǎn)化酶CrryisregardedasafunctionIschemia/reperfusioninjuryAtkinsonC,

et

al.

JClinInvest.2005

Circulation.2013HeS,

et

al.

JClinInvest.2009

SpinalcordinjuryQiaoF,

et

al.

AmJPathol.2006Collagen-inducedarthritisSong

H,

et

al.

JImmunol.2007Murine

lupusAtkinsonC,

et

al.

JImmunol.2008ColitisSchepp-BerglindJ,et

al.

JImmunol.2012

Therapeutic

effect

ofsolubleCrryin

disease

modelTagMembrane

CrrySoluble

CrryIschemia/reperfusioninjuryAtkCD59

restricts

membrane

attack

complex(MAC)

formation

CD59CD59restrictsmembraneattackDysregulation

of

Complement

System

involving

in

human

disease

DysregulationofComplementSyComplementsystemandatherosclerosis補(bǔ)體和動(dòng)脈粥樣硬化ComplementsystemandatheroscAtherosclerosisHyperlipidemiaHyperglycemiaCD59Wuetal.CircRes.

2009?(1)(2)

Soluble

complementinhibitorCrryQuestion:

Role

of

Complement

regulator

inatherosclerosis

?

Therapeuticeffect

on

atherosclerosis

?AtherosclerosisHyperlipidemiaHPart

1:

Role

of

CD59

in

diabetes-induced

atherosclerosisPart

2:

Effect

of

solubleCrryin

treatment

of

atherosclerosis

Part

3:

Mechanismofacceleratedatherosclerosis

developmentinducedbycomplement

activationOBJECTIVEPart1:RoleofCD59indiabetSTZ

treatment

in

2

weeks

to

induce

diabetesPBS

treatment

in

2

weeks

as

non-diabetes

control

Normal

diet

for

16

weeksMeasure

blood

glucose

every

weekAtherosclerosis

plaqueMAC

depositionImmune

cell

infiltration

CD59與糖尿病相關(guān)動(dòng)脈粥樣硬化mCd59ab-/-

mice

x

Apoe-/-

micemCd59ab-/-/Apoe-/-

miceApoe-/-

miceSTZtreatmentin2weekstoinABEstablishmentofSTZinduceddiabeticatherosclerosismice

model糖尿病相關(guān)動(dòng)脈粥樣硬化模型建立

STZ-mCd59ab-/-Apoe-/-STZ-mCd59ab+/+/Apoe-/-

PBS-mCd59ab-/-Apoe-/-PBS-mCd59ab+/+/Apoe-/-ABEstablishmentofSTZinduced2.CD59Deficiencypromoteddiabeticatherosclerosis

development-12.CD59DeficiencypromoteddiH&E

stainingOil-red

O

staining2.CD59Deficiencypromoteddiabeticatherosclerosis

development-2

H&EstainingOil-redOstainingmCd59ab-/-/Apoe-/-

Apoe-/-

mCd59ab-/-/Apoe-/-

Apoe-/-mCd59ab-/-/Apoe-/-

Apoe-/-

mCd59ab-/-/Apoe-/-

Apoe-/-STZ-DiabeticPBS-Non-DiabeticSTZ-DiabeticPBS-Non-Diabeticnsns3.

CD59Deficiencyhave

no

effect

on

lipid

profilensnsmCd59ab-/-/Apoe-/-ApomCd59ab-/-/Apoe-/-C9deposition4xmCd59ab+/+/Apoe-/-Macrophagedeposition4xmCd59ab-/-/Apoe-/-mCd59ab+/+/Apoe-/-4.Increased

MAC

deposition

and

macrophage

infiltration

in

aortic

root

of

mCd59-/-/Apoe-/-

micemCd59ab-/-/Apoe-/-C9depositiCONCLUSIONComplement

activationClassicalMBLAlternativeC3

convertaseC5

convertaseMACCR2-CrryCD59AtherosclerosisDiabeticAtherosclerosismacrophagefoamcell

formationandinduceinflammatorycytokineandgrowthfactor

expressionCONCLUSIONComplementactivatio適應(yīng)性免疫參入動(dòng)脈粥樣硬化的的發(fā)生IRABcell:innateresponseactivatorBcell適應(yīng)性免疫參入動(dòng)脈粥樣硬化的的發(fā)生IRABcell:i四、體液免疫與動(dòng)脈粥樣硬化B1細(xì)胞抑制動(dòng)脈粥樣硬化的形成B2和IRAB細(xì)胞促進(jìn)動(dòng)脈粥樣硬化的形成IRABcell:innateresponseactivatorBcellIgM中和oxLDL四、體液免疫與動(dòng)脈粥樣硬化B1細(xì)胞抑制動(dòng)脈粥樣硬化的形成B2心血管免疫學(xué)生課件適應(yīng)性免疫均參入動(dòng)脈粥樣硬化的的發(fā)生IRABcell:innateresponseactivatorBcell適應(yīng)性免疫均參入動(dòng)脈粥樣硬化的的發(fā)生IRABcell:T細(xì)胞與動(dòng)脈粥樣硬化T細(xì)胞與動(dòng)脈粥樣硬化不同T細(xì)胞與動(dòng)脈粥樣硬化不同T細(xì)胞與動(dòng)脈粥樣硬化Atherosclerosis＋－?－Th17ThedifferentCD4+subsetshavevariousrolesinAtherosclerosis?Atherosclerosis＋－?－Th17TheTheroleofTh17anditsmajoreffectormoleculeIL-17inthedevelopmentofatheroscleroticplaqueThemechanismbywhichIL-17isinvolvedinatherosclerosis

Th17andIL-17

inatherosclerosisTheroleofTh17anditsmajoAACS

NCBCCD4IL-17SA﹡﹡﹡﹡﹡﹡

﹡﹡1.Th