博士生课程2(2)-固有免疫模式识别

The

most

ancient

defense>Physical&chemical

barriers

and

cellular

line>Recognitionby

theinnateimmunesystem

sets

thestage

foraneffectiveadaptiveimmuneresponse.机体在种系发生和进化过程中逐渐形成的一种

天然免疫防御功能，

构

成机体抵御病原生物入曼

的

第

一

道

防

线

.复

习

Innate

Immunity皮

肤

黏

膜

屏

障

：

物理、化学、微生物血

-

脑

屏

障、

血

-

胸

腺

屏

障血

-

胎

屏

障、

气

-

血

屏

障单核-巨噬细胞、中性粒细胞、树突

状细胞、YδT细

胞

、

NK

细胞

、

NKT

细胞、

B1

细胞、肥大细胞、嗜碱性粒细胞和嗜酸性粒细胞等。抗菌肽、溶菌酶、急性

期

蛋

白

、

补

体

、

细胞因子和黏附分子、——、

固

有

免

疫

系

统

的

组

成屏

障细

胞分

子SkinGastrointestinaltractRespiratorytractUrogenitaltractEyesMechanicalEpithelial

cells

joined

by

tight

junctionsFlow

of

fluid,perspiration,sloughing

oflof

skinFlow

of

fluid,

mucus,foodand

salivaFlow

of

fluidand

mucus,e.g.,by

ciliaAir

flowFlow

of

fluid,urine,mucus,spermFlow

of

fluid,

tearsChemicalSebum(fatty

acids,lactic

acid,

lysozyme)Acidity,enzymes

(proteases)Lysozyme

in

nasal

secretionsAcidity

invaginal

secretionsSpermine

andzinc

in

semenLysozymein

tearsAntimicrobial

peptides(defensins)MicrobiologicalNormal

flora

of

the

skinNormal

floraof

thegastrointestinaltractNormal

floraof

therespiratorytractNormal

floraof

theurogenitaltractNormal

flora

of

theeyes1、

固有

免

疫

屏障Physical,chemicalandmicrobiologicalbarriersofourbodyFigure

1.6The

ImmuneSystem.3ed.(OGarland

Science

2009)Normal

Flora

competing

with

Invading

Pathogens.Antibiotic

treatments

disrupt

the

natural

ecology

of

the

colonC

fo

ileand

producesdcliofhifgainlosC.difficile王号三∵

*NThe

colonis

colo-Antibioticskillmany

ofthesec

alasrineeactmm

lbetween

injuredepithelial

cellssndtlagucentoiolsk

blophirNThismaycauseinflammationand

bleedinghyooaoonm三二二一nized

by

largenumbers

of

com-mensal

bacteriatoxins

that

causemucosal

injuryGut

lumen2

、

固

有

免

疫

细

胞Recognition

of

an

infection

once

it

gets

pastthe

epithelialbarrier

>

Phagocyte

macrophage

NeutrophilMonocyte->NK>

ILLs>DC

MCaso

0

CγδT细胞B1

细

胞(

固

有

样

淋

巴

细

胞)

NKT细胞nilLysosomeMicrobeingestedPhagolysosomeFIGURE2-8

Phagocytosisandintracellulardestructionofmicrobes.Microbes

may

be

ingested

bydifferent

membrane

receptors

ofphagocytes;somedrectlybindmicrobes,andothersbind

opsonized

microbes.(Note

that

the

Mac-1

integrin

binds

microbes

opsonizedwithcomplementproteins,notshown)Themicrobesareintermalized

into

phagosomes,whichfusewith

lysosomes

to

torm

phagolysosomes,eie

he

microbesare

killed

by

reactiveoxygenand

nitrogen

intermediatesand

proteolyticenzymes.NO,nitnicoxide;ROS,reacive

oxygenstecerspwhMicrobesbind

tophagocyte

receptorsMac-1integrinMannose,

Scavengerreceptor

receptorKilling

ofphagocytosedmicrobes

byROS

and

NOiNOSArgininemKici

nbgeso

yenzymes

inphagolysosomesrolli

i

gii

g

e

mteedFusionmhathwPPhagocytemembrane

zipsuparound

microbeLysosome

withenzymesofin

phagosomePhagocyte

oxidasephagosomewith

lysosomeActivationphagocytelysosomalofPolarizationofTumor-associatedmacrophages(TAM)Down-regulationofM1andadaptive

immunityInflammatory'cell

Tissuecell

Fibroblast

VesselTissuerepairandangiogenesisD

d

思8哥8Q6TumorpromotiontiasueamageGM-CSFM-CSFLPS/IFNyMonocyteM1Defense

against

bacteriaBacteria

TumorsuppressionTNF-aIL-12IL-23CXCL10M-CSFIL-4,IL-13,IL-10corticosteroidsIL-10CCL17CCL22Immuno-stimulationIL-1raIL-1RdecoyTumor

cellCCL18M2IL-1ROIsiteM1M2巨

噬

细

胞

的

功

能分泌酶溶

菌

酶弹性纤维蛋白酶抗原呈递作用2细胞因子IL-1IL-6IL-12

TNF-aEK&csF其它因子素烯腺白前吞噬并杀伤病原微生物杀伤肿瘤细胞免疫调节作乍用酸性水解酶赖氨酸酶酯酶胶原蛋白酶补体成分维蛋白合蛋白凝血因子Leukocyterecruitmenttositesofinfection:amulti-stepnavigationRolling

adhesion

TightbindingDiapedesisMigration1.Selectins2.Chemokines3.IntegrinsCD31chemokine

(CXCL8)IL-8Figure8-19part2of3The

Immune

System,2/e(O

Garland

Science

2005)LFA-1ICAM-IreceptorCXCL8GCellularAdhesionMolecules(CAMs):1.Mucin-like

CAMs2.Selectins3.Integrins4.Ig-superfamilyCAMsICAMInitiationofextravasationNeutrophilChemokineor

oarttractantMucinE-selectinpmrececheInteractionbetween

Neutrophilsand

EndotheliumSelectin-mucin

interactionsmediate

rollingFigure3-7bChemokines/chemoattractants

inducechangein

integrinsChemokineorother³chemoattractantSSIntegrinsadherefirmlyto

ICAMsKubyIMMUNOLOGY,Sxth

Edition●2007

W.H.Freeman

and

CompanyIntegrin③②KilleractivatoryreceptorKiller

inhibitory

receptor

FunctionKIR:

KIR2DS,KIR3DSKLR:CD94/NKG2CNKG2D一

P0AI)

|TLC2ABind

class

I

HLA

moleculesBind

non-class

I

HLAmoleculesReceptorsassociatedwithkilleractivation

and

killerinhibitionon

NK

cells未

活

化

N

K

细

胞活

化

N

K

细

胞活

化

N

K

细

胞异常细胞KIRMHC

1类分子KAR抗

原(

多糖类)改变的

MHC

I

类分子正

常

组

织

细

胞异常细胞K

A

R(

杀

伤

细

胞

活

化

受

体

)

与自

身

细

胞上多糖类抗原结合产生活化信号，同

时KIR(

杀

伤

细

胞

抑

制

受

体

)

与

M

H

CI

类

分

子

结

合

，

产

生

抑

制

信

号且占主导地位，NK细胞不能被激活，自身组织细胞不被破坏。某

些

异

常

细

胞

表

面

M

H

C

I

类

分

子发生改变，KIR不能与之结合

产生抑制信号，结果KAR的作用占主导地位，从而使NK细胞活化产生杀伤效应

。某

些

异

常

细

胞

表

面

M

H

C

I

类

分子减少或缺失，亦影响KIR与之结合

，

而不能产生抑制信号

，

从而表现为NK细胞活化，产生

杀伤效应。N

K

细

胞

K

I

R

和

K

A

R

的

作

用tmmunology>NK

γδT细胞

>

ILLs

(

固

有

样

淋

巴

细

胞

)

NKT细胞B1

细胞胞Monocyte-macrophage

Neutrophil2

、

固有

免

疫

细>

Phagocyte>MC>Basop

1>Eosinophil>DC

抗原的处理与提呈过敏性疾

病oType-2

immunity:responsible

for

protective

immune

responsestohelminthparasitesandtheunderlyingcauseof

thepathogenesisof

allergic

asthma.o

Type-2

cytokines:interleukin

IL-4,IL-5

and

IL-13.oNuocytes

expand

invivo

inresponseto

the

type-2-inducingcytokines

IL-25

and

IL-33,andrepresentthepredominant

earlysource

of

IL-13during

helminth

infection.o

In

the

combined

absence

ofIL-25

and

IL-33

signalling,nuocytes

failto

expand,resulting

in

a

severe

defectinworm

expulsionthatisrescuedbytheadoptivetransferof

invitroculturedwild-type,but

not

IL-13-deficient,nuocytes.Nuocytesrepresentanewinnateeffectorleukocytethatmediatestype-2

immunity.Naiirn

2ntoMar

3抗菌肽

antimicrobialpeptides溶菌酶

lysozyme急性期蛋白(acutephaseproteins,APP)脂多糖结合蛋白(LBP)血清淀粉样蛋白(SAP)甘露糖结合蛋白(MBP)C

反

应

蛋

白

等

(CRP)补体

补体系统细胞因子和黏附分子

细胞因子和免疫相关细胞表面分子指体表分泌液以及血浆和其它体液中能够识别或攻击病原体

的

可

溶

性

分

子

。3、

固

有

性

免

疫

分

子病原相关分子模式(Pathogen-associated

molecular

patterns,PAMPs)

伤tt

分,D

P

)(damage-associated

molecular模式识别受体

(Pattern

Recognition

Receptors)ns关er相pa损二

、

固

有

免

疫

识

别·病原相关分子模式(Pathogen-associatedmolecularpatterns,PAMP):是病原微生物(尤其是原核生物)表面存在一些人体所没有的，但可为许多相关微生物所共享、结构恒定、进化保守的分子结构。PAMP的特

征1.通常为病原微生物所特有，乃天然免疫系统区分“自己”与“非己(微生

物)”的分子基础。脂多糖：多数革兰阴性菌细胞壁成分；磷壁酸：多数革兰阳性菌胞壁成分；肽聚糖：革兰阳性/阴性菌、真菌胞壁成分；甘露糖：微生物细胞壁上糖蛋白和糖脂成分2.为微生物生存和致病性所必需PAMP突变或缺失→微生物死亡或微生物对外界环境适应性

3.宿主泛特异性识别的分子基础PAMP是由一群或一类特定的微生物所共有的恒定结构(如LPS)。宿主由种系编码的有限数量PRR

→可察觉任何微生物感染的存在PatternLipopolysaccharide(LPS)Lipoteichoic

acidBacterial

lipopeptidesPeptidoglycanYeastand

gram+bacteriaBacterial

DNA(CpG)FlagellinTerminal

mannose/fucoseViral

DNA(CpG)SSRNAdsRNAPathogen-Associated

Molecular

Patterns(PAMP)porinlipopolysaccharideoutermembranelipoproteinpeptidoglycanplasmamembraneGram-negativebacteriateichoicacidpeptidoglycanlipoteichoic

acidplasmamembraneGram-positivebacteriaInnate

immune

recognition

of

bacterial

cell

wallcomponentsSterile

inflammatorysignalPutative

sensor

Associated

pathology

Refs*EndogenousHMGB1TLR2.TLR4.TLR9,RAGE

and

CD24Cellular

injuryand

necrosis

26,93,98,106HSPsTLR2.TLR4,.CD91,CD24.CD14andCD40

Cellular

injuryandnecrosis11.25.106,122S100

proteinsRAGE

Cellular

injuryandnecrosis

19SAP130CLEC4E

Cellular

injury

and

necrosis72RNATLR3

Celhular

irjuryand

necrosis39.123DNATLR9

and

AlMZ

Cellular

injury

and

necrosis40,48-50UricacidandMSU

crystalsNLRP3

Gout

13.55ATPNLRP3Cellular

injuryandnecrosis20.60HyaluronanTLR2.TLR4and

CD44

Cellular

injuryandnecrosis

31,32.103BiglycanTLR2

and

TLR4

Cellular

injury

and

necrosis14.33VersicanTLR2

Cellular

injury

and

necrosis34Heparan

sulphateTLR4

Cellular

injury

and

necrosis124Formylpeptidesimitochondrial)FPR1

Cellular

injuryand

necrosis

125DNA

(mitochondrial)TLR9

Cellular

injury

and

necrosis125CPPD

crystakNLRP3

Pseudogout

55β-amyloidNLRP3.CD36and

RAGE

Alzheimer'sdisease56,94.105Cholesterol

crystalsNLRP3

and

CD36

Atherosclerosis

59.10L-1aIL-1R

Cellular

injuryandnecrosis

15.22.41L-33ExogenousSilicaST2

Cellular

injuryandnecrosis16.86NLRP3

Silicosisandpulmonaryinterstitial

fibrosis44,57.58AsbestosNLRP3

Asbestosis

and

pulmonary

57interstitial

fibrosis损

伤

相

关

分

子

模

式(damage-associated

molecular

patterns,DAMPs)机体自身细胞所释

放的内源性分子，即

内源

性

危险信号

，

来源于受损或坏死

组织和某些激活

的免疫细胞。主要有

M

lsacb

pi

elrnm6m

P2R.C1L

4mE.yCi

teyp

ldeectr

nce4

t:

P

i.:c

lMci

mB

yrhoipghtomsp

tl

t

igh

t

;oD

M

:

a

g.

-eaasts

ioa

dprotein;ILimrerteukinMSU.momosodium

urate;IL-1R,IL-1receptor;NLRP3.NOD.LRR-and

pyin

domain-containing3:RACE.receptor

for

advancedglycationendproducts;5AP130,spliceosomeassociatedprotein

130;TiR.Toll-likereceptor.*Referencesmaynotbeallindusive.HMGB1蛋白等。、

热

体

克PAMP

vsDAMPconservedmicrobialmotifsVSnon-microbialsignalsNF-kBactivationInflammation·Pathogen

elimination·Collateral

tissue

damage·Adaptive

immunityInflammation·Limitation

oftissue

damage·?tissue

reconstruction·?adaptive

immunityBacterialmoleculeSiglec-GSterileNF-KBEndogenous(tissuedamage)Exogenous(pathogen)Host.

molecule

(HMGB1)and

gene

expressioninflammationHost

cellNudeusCD24TLR以模式识别受体(Pattern

Recognition

Receptors,PRRs)固有免

疫

细

胞

表

面

、

内

体、

溶

酶

体、

细

胞

质中、

可

识

别一种或多

种PAMPs或DAMPs的识别

分

子

。甘露聚糖凝集素(

MBL)C

反

应

蛋

白(CRP)血清淀粉样蛋白(SAP)脂多糖结合蛋白

(

LBP)甘

露

糖

受

体

(MR

)清

道

夫

受

体

(SR

)

c

F(

R))甲酰甲硫氨酰肽受体(fMLPR)cCR细胞膜

TLR1、

2、4、

5、

6、

10、

11、

12、

13内体、溶酶体

TLR3、7、8、9细胞质

NLRs、

RLRs、ALRs可溶性：体液和血液细胞吞噬型：细胞膜信号转导型PRREXTRACELLULAR/SECRETEDPRRs

/Pin(MBP))nAProtpterginoenrdtipiodLPS-bindiSerum

amC-reactiveMannoseooooAcute

phase

response

(APR)

:the

serum

changes(during

the

acuteSitesofinjury

or

infectionsignals(proinflammatory

cytokines:TNF-a,IL-1,&IL-6↓stimulating

produced

by

phagocytes)Liver:synthesisofAPRproteinsIncrease

inthelevelofC-reactiveprotein

&Mannose-bindingAPR

proteins:

their

concentrations

rose

or

fell

phase)lectin/MBL

&Serum

amyloid

protein/SAP

&fibrinogen)Acutephase

proteinsfibrinogen

C-r

tbi

tpe

oi

el

f

,pahci

h

lineopsoninandasacomplement

activatoras

anochonsacesindssuinrrceavncoeaMannose-binding

lectinbindstocar

r

e

no

p

ti

r

ds

ces,aaasurfanialnencsobaonasasatgdtihcoabSAP

made

in

acute

phase

liverresponseInvolved

inClottingTwoSecretedPRRs:CRP,MBPBacteriainducemacrophagestoproduceIL-6

sai

t

fo

ho

sy

e

r

inndsuceeiottopsetacpate-pacutn

heosscehnthisy,wlivermannose-bindingFigure2.38The

ImmuneSystem,3ed.(OGarlandScience2009)complementactivatorC-reactiveproteinlectinIL-6

Mannose-binding

lectinRecognizing

mannose-containing

molecular

patterns

foundonmicrobesbut

not

onvertebrate

cellsUdirectingcomplementattagkMBLcarbohydrateMannose

binding

lectinFicolins“pattern

recognitionreceptors”;in

this

casepattern

of

terminalsugarsoncell

surfacesLung

surfactants

A,DoMannose

binding

protein(MBP)Afterbindingto

pathogensurfacethis·PartofC-type

lectinsuperfamily·Associateswithandactivatesserine·proteases:MASP-1and

MASP-2complexactivates

lectin

pathway

ofcomplementsystem,C2and

C4ActivatedMASP-2alsocleavesC2to

C2aand

C2bC2C2bC2aC4bMB-LECTINMASP

=MBL-associatedserineproteaseMBLmannoseActivatedMASP-2cleavesC4toC4aand

C4b.SomeC4bbinds

covalentlytothemicrobialsurfaceC4

C4aC4bFigure2.40The

ImmuneSystem,3ed.(O

GarlandScience2009)pathogensurfaceC4b2abindsC3

and

cleavesittoC3aand

C3b.C3b

bindscovalentlytothemicrobialsurfaceC3aC2aC4bC3blC2abindstosurface

C4bconvertase,C4b2aC3C2aC4bformingtheclassicalC3MB-LECTINANOTHERVERSIONPOINTS

OUTTOTALITY

OF

CLEAVEDC3

FUNCTIONSLectinbindstoan

invading

cell.Boundlectinsplits

C2

and

C4.i

e

16.9).ungaFeoinalmeoecC3(C4tendaaivaactC2Opsonization

C3bC3a

InflammationMicrobeLectinCarbohydratemannosecontainingC2

C4C2a

C4bCytolysisC4aC2bC32C-reactiveprotein(CRP)andserum(belongstoafamilyofpentamericprotein

called

pentraxins)bindingtopolysaccharide&phophorylcholine

(=ligands)onthecomplementsystem

→

lysis,opsonizationU

promotingphagocytosis&pathogenclearanceBind

to

phor

ryylcl

i

e(pPi

her,oPteriaSAbanneotC)rondholoiphamicroorganisms,damaged

host

cell

membraneso

l

p

c

at

ic

acids,capsular

carbohydrates,anddesichoriehncisnyuolfoipoPCo

RequiresCa++●

Function

directly

as

opsonins(enhancer

of

phagocytosis)

a

ey

nleg

ssical

complementcascade1q

ofclantCmetopivlyd

actidirectnnaiayonthwnctipaFucellwallofbacteria&fungiina

calcium-dependent

reaction↓activatingFigure2.43The

ImmuneSystem,3ed.(oGarlandScience2009)C4bthenbinds

C2,whichiscleaved

byC1s,to

C2aandC2b,formingtheC4b2bcomplexC2ciaOnemolecule

ofC4b2bcancleave

upto

1000moleculesofC3toC3b.ManyC3bmoleculesbindto

themicrobialsurfaceC4b2b

isanactive

C3convertasecleavingC3toC3aandC3b,which

bindstothemicrobialsurface

ortotheconvertase

itselfActivatedC1scleavesC4toC4a

and

C4b,whichbinds

to

themicrobialsurfaceC4C1SC4b2b3bC3bFigure

2-22Immunobiology,6/e.(◎

GarlandScience2005)C4b2bC4b2bC4bC3bC3aC4aC3C3Lipidtransfermoleculebindsto

monomeric

LPSLBP

+bactericidal

permeability

increasing

proteini

.a

4,R4D1LCTorte

latethenSntorriapeectcaLPSS

onyPinits

LffdanhbhigPI)a(Bandto

high-affinity

LPS

receptornamedCD14LPS-bindingprotein(LBP)and,on

macrophage,neutrophils,DCsBacteriu

m<14Mdoe

t

insFR

AF∈A1E

<H

1J下

N<1x<EBExtracellularfactor(LPS)carried

by

LBPto

CD14where

itbindstoTLR4

andthen

MD2

bindsNIKBNF

PrcmalsMlamHavingbound

LPS:LBP,CD14interactswith

Toll-like

receptor4(TLR-4)resultingin

activation

of

NFkB

in

the

nucleusSimplifiedTheLPS:LBP

complex

binds

to

CD14

onthe

surface

of

phagocytesuro

m

puuy

nuug

poune

oy

an

Pprotein,LPS-binding

protein

(LBP)VersionLPS4CD14'LBPTLR4▲模式识别受体(Pattern

Recognition

Receptors,PRRs)固有免

疫

细

胞

表

面

、

内

体、

溶

酶

体、

细

胞

质中、

可

识

别一种或多

种PAMPs或DAMPs的识别

分

子

。甘露聚糖凝集素(

MBL)C

反

应

蛋

白(CRP)血清淀粉样蛋白(SAP)脂多糖结合蛋白

(

LBP)甘

露

糖

受

体

(MR

)清

道

夫

受

体

(SR

)

c

F(

R))甲酰甲硫氨酰肽受体(fMLPR)cCR细胞膜

TLR1、

2、4、

5、

6、

10、

11、

12、

13内体、溶酶体

TLR3、7、8、9细胞质

NLRs、

RLRs、ALRs可溶性：体液和血液细胞吞噬型：细胞膜信号转导型PRRMANNOSE

RECEPTORThe

mannose

receptor(MR)isa

175

kDatype

I

membraneMycobacteriumtuborculosis,HIV

sa

rinitry

productscretoCPSseeSryiniaLPetomoaexcreuonis

epnummuriccuspneiscollaroericehputebsiTSKcansocya

alneanmoleculeexpressed

inthe

mouseby

mosttissuemacrophagesand

lymphaticand

hepatic

endothelia.

rrgt

(1

-L+cells))R1CRsALan(SdteandsapnhdasteioronpdirnoiLLSCLTMCTclear

/cpyr

tationesentosis:eoanEnMicrobialligandsCR:cysteine-rich

domainsesdlaeeoxidas-derivu

HlinydrerphlomoproogsoFNIl:fibronectin

type

ll

domainCTLD:C-type

lectin-like

domain

::

lma

i

r

iel

domainanmmsepsonyrEndogenousligandsSO₄

(3)-Gal-SO(314)-GaINAcMannose,

Fucose,

GIcNAcDengue

virusCR

FNIICollagensCTLDCR

domain

FNII

domain

CTLDMRNeutral

binding

pocket

Collagen

I,II,III,IV>>>VTrpl17

essential

for

binding

to

sulphatedgalactose

and

N-acetyl-galactosaminen=8CTLD4

and

-5

contain

residues

required

for

Ca²*-dependent

sugar

bindingCTLD-4-7

display

the

same

binding

activity

as

the

whole

receptorn=8CTLD-2

essential

for

Ca²*-dependent

binding

to

immobilised

N-acetylglucosaminemannose

and

fucoseNo

physiological

ligand

characterisedn=8None

predicted

to

have

lectin

activity

CTLD-5

mediates

ligand

bindingn=10None

predicted

to

have

lectin

activity

No

physiological

ligand

characterisedEndo

180

No

lectin

activityPLA2R

No

lectin

activityCollagen(V>I=IV)inhibits

bindingof

Endo

180

to

uPAR

and

pro-uPA,

therefore

the

FNII

domain

could

be

involved

in

the

formation

of

thetrimolecular

complexCollagenDEC205

No

lectin

activity

Collagen(predicted)TABLE1.

Characteristics

and

binding

properties

of

the

members

of

the

MRfamily

of

receptorsScavengerreceptors

l

oSp

i

ii

e

s

eselsucelissiatrcaGsenecellstdotigepaInADdzpoteichoic

acPRRs

recognlinanrotPc

modified

low-density

lipoproteins●Sixclasses

CO中c

Bz

Orodx

a甲酰甲硫氨酰肽受体(fMLPR

)fMLP

PathwayGincasEtin

CnBrntnanhTtrtaStaphylococcal

Protein

A

Inhibits

Phagocytosis

by

Blocking

FcS.aureus

isfree

to

begin

infecting

cellsFc

receptorsCopyrightThe

MeGran-HllCompanies,ine.ParmissionrequlredforreproductionordisplayPhagocytosis

ofS.epidermidisbegins(a)Staphylococcus.

aureusantibodyFc

portion

oflgG

is

notavailableforreceptorStaphylococcus

epidermidisFcreceptorsFcportionlgG

antibodyCellSurfaceFc

portionPhagocytePhagocyteProtein

AEpitopes(b)lgG果蝇

的Toll受体胞浆

的功能域与IL-1受体很相像(Toll/IL-1

receptor(TIR)

domain),

显然具有重要的免疫功

能

。Toll突变后果蝇很

容易受

霉菌

感

染。

Cell

86:973-83.In

1996,Hoffmann'sgroup→Tollfunctionsasa

PRR

in

DrosophilaTol-like

recepto

(TLR)Julie

A.Hoffmann,Ph.D.

Strasbourg,FranceToll-Like

Receptors(TLRs)Totalof

13TLRs

have

been

identified

in

mammalsHuman

(TLRs

1-10)Mouse

(TLRs

1-9,11-13)In

general

TLRs

recognize

constituents

of

microbial

cell

walls

orpathogen-specific

nucleic

acids

that

are

essential

to

the

integrity

,function

or

replication

of

microbes

/viruses

that

cannot

readily

bemodified.dsRNAFlagellinPGLPZymGPI圭王工2

3

4

5

6

7

8

910ψGram-negativebacteriumLBPLBP-LPS

lipoprotein

tiagellinCD36celcytosolTLR4-MD-2

TLR2+TLR6TLR5lysingvirion

CpGDNAviral

RNATLR7dsRNATLR9TLR3Toll-LikeReceptors(TLRs)IMQ

RSQ848phagolysosomeorendosomeexteriorCpGLPSCD14The

evolution

vertebratereceptorsofToll-likeTLR22Pg

72R4mouseTLR4

·lecular

ve

rate

of

TLR4

tebreerttheMo1TLR1188

nTLR7nTLR11TLR23毫您鼻fugu

ha2SbtiR2—ash

TR2-oeeTtRiXeneout

TRL3human

taiT

Thiman

TtRbsix

majorTLR1

TLRs,each

includesTherecladesareofrecognizingclass

ofpatterns.a

general

molecularTLR166STLR2ab6xmoeTLoposumhamun

DRPg

TiR.BZ=一TIRZ—TLR21

TLR13TLR370TLR58

3Toll-like(TLRs).XenogunRiaTLR14Ae

Ifevautiewtt意

名TLR3opowsumchicken

nH4-TLRSTreceptorsLR6&LR10)TLR4

59chickenTLR2TLR12TLR9TLR7TLR8TA4——ny57Toll-LikeReceptors(TLRs):BasicArchitecture一

Leucine

Rich

Repeats

(LRR);BINDINGToll/interleukin

1receptor(TlR)domain;SIGNALINGLeader

PeptideTMCYTStructuralorganizationofhumanTLRs.灵灵

灵

式

式去

元习

灵LnRTRRLRKLERLRRLRR

CRRCnRLRRLRRRRLRRLRR

LRRLRRLRRLRRLRRLRRLRRLRRNTLRRRRLRRLRRLRRLRRRLRRLRRLRRLRRLRLRR

RF

Rc1LRRRRaRRRRRLRR

款RRRFRRFRFRLRR

R

RRRFRRRNLeucine

rich

repeatTransmembranedomainSignal

peptideURRNTLRRLRRLRRLRRLRR

LRRRRRR_RRR型RRL

RRLRRC1LRRLRRLRR(LRRCTRIRL

LRR

RRRRC1RRRRTIR

domainLeucine

rich

repeat

C-terminal

domainER

LRRLRRRRCRRRRRRRRLCRRLRRCRRRRRRLRRF

LRR么馨LL

RLRRRRRRLRIRRRRLRRLRRLRR

L[RRRR

C1RTRR

LRRhTLRsLRRLRRLRRRhTLR5hTLR3hTLR1hTLR4hTLR10hTLR7hTLR9hTLR8hTLR6hTLR2LR器一一接ENDOTOXIN-Structuralcomponentoftheouterleafletoftheouter

membraneofGramnegative

bacteria-ContainstheO-antigenicpolysaccharidedeterminant.-Presenceofpolysaccharide

andlipid

components.-Also

termed

Lipopolysaccharide(LPS).-Thelipidcomponentor

LipidA(glycophosp