2024年5月12日发(作者：华为mate30pro上市)

InternationalJournalofRheumaticDiseases2009;12:293–298

REVIEWARTICLE

Fccreceptorbiologyandsystemiclupuserythematosus

VojislavJOVANOVIC,XileiDAI,YanTingLIM,andPaulA.M

AC

ARY

DepartmentofMicrobiology,LifeSciencesInstituteImmunologyProgram,TheYongLooLinSchoolofMedicine,National

UniversityofSingapore,SingaporeCity,Singapore

Abstract

Themaintenanceofimmunehomeostasisandtheregulationofpro-inflammatoryresponsesthatunderlie

autoimmunepathologyrequireacoordinatedinterplaybetweencytokines,cellularreceptorsanddownstream

ilyoffragmentcrystallizablereceptorsforimmunoglobulinG(IgG)(FccR)repre-

sentsagoodexampleofhowcontrollingthesimultaneoustriggeringofactivatoryand/orinhibitoryreceptors

layacrucialroleinlinkingtheantibody-mediatedrecognition

ofpathogens,review,wedetail

howdysfunctioninFccRpathwaysislinkedtothedevelopmentoftheautoimmunedisease,systemiclupus

erythematosus.

Keywords:autoimmunedisease,biomarker,fragmentcrystallizablereceptor(FcR),signaling,systemiclupus

erythematosus(SLE).

FRAGMENTCRYSTALLIZABLERECEPTORS

INHUMANS

Fragmentcrystallizablereceptors(FcRs)arereceptors

onimmunecellsthatbindtotheFcregionofimmu-

indtothemostcommontypeof

immunoglobulin(IgG)andareexpressedonthesur-

faceofmanydifferentimmunecelltypesincluding

monocytes,macrophages,dendriticcells(DC),natural

killercellsandneutrophils.

1–4

Inbroadterms,FccRs

canbeseparatedintohighorlowaffinityreceptors

basedontheiraffinityforIgGorintoactivatoryor

inhibitoryreceptorsbasedontheirsignalingactivity

andassociatedfunctions.

5

Inhumans,threemajor

classesofIgG-receptorhavebeendescribed;FccRI

(CD64),FccRII(CD32),andFccRIII(CD16).These

classescanbefurthersub-dividedintodiscreteiso-

formssuchasFccRIIA,FccRIIB,FccRIIC,FccRIIIAand

FccRIIIBthatexhibitsignificantdifferencesintheir

affinityforindividualIgGsub-classesandtissuedistri-

Correspondence:,ImmunologyProgram,

NationalUniversityofSingapore,3rdFloor,CentreforLife

Sciences,28MedicalDrive,SingaporeCity,Singapore

:micpam@

,isa72kDtype-Imembraneglycopro-

teinthatisahighaffinityreceptorcapableofbinding

tomonomericIgGandisconstitutivelyexpressedon

sa

memberofthemulti-chainimmunerecognitionrecep-

torfamily,comprisinghetero-oligomericcomplexesof

aligand-bindingachain,andacommonc-chainthat

isfoundinassociationwithseveralotherimmune

riggersitsprincipleintracellular

signaltransductioncascadesthroughthecommon

c-chainthatencodesanimmune-receptortyrosine-

basedactivationmotif(ITAM).FccRIIIAisalow-affin-

ityreceptorexpressedonnaturalkiller(NK)cellsand

macrophagesthatalsoutilizesthecommonc-chainto

triggersignaltransduction.

6–8

Themostbroadlydistributedactivatoryreceptorin

humansisFccRIIAwhichisexpressedonmonocytes,

macrophages,neutrophilsandplatelets.

9

Thisisalow-

affinityreceptorthatpreferentiallybindstocomplexes

ofIgG,andalongwithFccRIIC(foundinNKcells)

expressesaninherentITAMinitscytoplasmictail,thus

FccRIIAdoesnotneedtooligomerisewithac-chain

inordertosignal.

10,11

FccRIIIBisaGPI-linkedreceptorexpressedprinci-

pallyonneutrophilsandsomeeosinophilswithno

ª

AsiaPacificLeagueofAssociationsforRheumatology

vicetal.

identifiedtransmembranedomain.

5

SinceFccRIIIB

doesnotcontainacytoplasmictail,itisthoughtto

signalthroughassociationwithothersurfaceproteins

suchasFccRIIaandthetype3complementreceptor

(CR3).

12,13

ACTIVATORY

FUNCTION

FCcRSIGNALLINGAND

Fccreceptorsignalingistriggereduponaggregationor

cross-linkingofthesurfacereceptors.

14

Underphysio-

logicalconditions,thisoccurswhenmultiplesurface

Fccreceptorsareengagedbymultivalentantigensor

IgGcontainingimmunecomplexes(ICs).Forlow-affin-

ityreceptorssuchasFccRIIandFccRIII,multipleIgG

moleculeslinkedtoICscanbindsimultaneouslyto

rast,thehigh-affinity

receptorFccRI,isnormallyoccupiedbymonomericIgG

presentathighconcentrationsinserum,andisthus

activatedwhenmultipleFccRIbound-IgGmolecules

bindthesamemultivalentantigensimultaneously.

5

Uponreceptoraggregation,downstreamsignalingis

initiatedbyeithertheITAMmotifsontheactivatory

receptors,ortheimmune-tyrosineinhibitorymotifs

(ITIMs)activatory

receptors,regardlessofwhethertheITAMmotifsare

intrinsictothereceptorsorwhethertheyarepresent

onthecytoplasmictailsoftheassociatedc-chain,the

processofreceptoraggregationcausestheITAMsto

recruitSrc-familykinases,whichphosphorylatethe

ITAMs.

6

TheSrc-familymemberthatisrecruitedeach

timeisunclear,asmultipleSrc-familykinasesappear

y

bedependentonthecelltypeinvolved,theexactFcc

receptorthatisactivated,andtheformoftargetanti-

genthatisprovidingthestimulus.

15–18

However,the

currentconsensusisthatinvivo,LynistheSrc-family

kinasemostlikelytobeinvolvedintheearlyphos-

phorylationoftyrosineresiduesonITAMmotifs.

19,20

UponphosphorylationofITAMsonactivatoryFcc

receptors,Syk-familykinasesarerecruited,suchasSyk

itself.

21,22

Sykinturnphosphorylatesandactivates

downstreamsignalingmediatorssuchasphospho-

inositide-3-kinase(PI3K),whichresultsinphospho-

lipase-inducedcalciumsignaling(PLD1orPLCc1)and

theactivationofcalcium-dependentandcalcium-

independentisoformsofproteinkinaseC(PKC)depen-

o

phosphorylatessonofsevenless(SOS),theguanine

nucleotideexchangefactor(GEF)thatactivatesmitogen

activatedprotein(MAP)kinasesignaling.

5,23

294

INHIBITORY

FUNCTION

FCcRSIGNALINGAND

Inhumansandmice,theprincipalinhibitoryFcrecep-

Bisexpressedonmonocytes,

macrophages,dendriticcells,neutrophilsandB-lym-

ofaregulatedimmuneresponseto

complexesformedbetweenpathogensandIgGwe

needsimultaneoustriggeringofbothactivatoryand

cRIIBisco-ligatedwith

theBcellreceptor(BCR),itinhibitsBcellprolifera-

tionandactivation.

24

FccRIIBmayalsoregulatethe

activityofdendriticcells(DC)

25

whereexpressionand

aggregationcontrolsimmunecomplex-inducedmatu-

ration.

1

FccRIIBactivityhasbeenlinkedtoanimbal-

ancebetweentoleranceandautoimmunitywith

dysfunctioninthisreceptorassociatedwithchronic

inflammatorydemyelinatingpolyneuropathy(CIDP)

26

andjointdamageinrheumatoidarthritis.

27

Thebest

correlationbetweenimpairedFccRIIBfunctionand

autoimmunepathogenesisisseeninsystemiclupus

erythematosus(SLE).

FccRIIBtransmitsitssignalthroughanimmunore-

ceptortyrosine-basedinhibitorymotif(ITIM).

28,29

AggregationoftheinhibitoryreceptorFccRIIbwith

anotherITAM-bearingreceptorsuchastheBCRcauses

phosphorylationofitsintrinsicITIMmotifsbyLyn.

29

Thisresultsintherecruitmentoftheinositolphospha-

taseSHIPtotheITIMmotifsonFccRIIb,whereit

proceedstoconvertthesignalingmediatorphospho-

tidylinositol3,4,5triphosphate(PIP

3

)intoPI(3,4)P

2

.

30

SincetherecruitmentofBruton’styrosinekinase(Btk)

andPLCcaredependentonPIP3,thedecreasein

PIP3duetoSRC-homology-2-domaincontainingino-

sitol-5-phosphatase(SHIP)activitywillpreventBtk

andPLCcactivation,aswellasinhibitcalciumsignal-

way,FccRIIbactstoinhibittheactivity

ofITAM-bearingreceptorssuchastheBCRandother

activatoryFcreceptors.

THE

IMMUNE

ROLE

DYSFUNCTION

OFFCcRECEPTORS

ANDSLE

IN

Inhumanpatientsaswellasinexperimentalanimal

models,FccRshavebeenimplicatedinimmunedys-

functionandthedevelopmentofautoimmunity.

FccRIIBexpressiononBcellshasbeenshowntoregu-

latetheaccumulationofautoreactiveplasmacells

31

andmalfunctioningFcyRsresultinimpairedphago-

cytosisofapoptoticcellsbymonocyte-derivedmacro-

phages.

32

FccRIIImediatesneutrophilrecruitment

InternationalJournalofRheumaticDiseases2009;12:293–298