the adaptive immune system in diseases of the...ing genetic, autoimmune, infectious, or...
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The adaptive immune system in diseases of thecentral nervous system
David C. Wraith, Lindsay B. Nicholson
J Clin Invest. 2012;122(4):1172-1179. https://doi.org/10.1172/JCI58648.
Tissues of the CNS, such as the brain, optic nerves, and spinal cord, may be affected by arange of insults including genetic, autoimmune, infectious, or neurodegenerative diseasesand cancer. The immune system is involved in the pathogenesis of many of these, either bycausing tissue damage or alternatively by responding to disease and contributing to repair.It is clearly vital that cells of the immune system patrol the CNS and protect againstinfection. However, in contrast to other tissues, damage caused by immune pathology in theCNS can be irreparable. The nervous and immune systems have, therefore, coevolved topermit effective immune surveillance while limiting immune pathology. Here we willconsider aspects of adaptive immunity in the CNS and the retina, both in the context ofprotection from infection as well as cancer and autoimmunity, while focusing on immuneresponses that compromise health and lead to significant morbidity.
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Review series
1172 TheJournalofClinicalInvestigationâ â â http://www.jci.orgâ â â Volumeâ122â â â Numberâ4â â â Aprilâ2012
The adaptive immune system in diseases of the central nervous system
David C. Wraith1 and Lindsay B. Nicholson1,2
1School of Clinical Sciences and 2School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
TissuesoftheCNS,suchasthebrain,opticnerves,andspinalcord,maybeaffectedbyarangeofinsultsinclud-inggenetic,autoimmune,infectious,orneurodegenerativediseasesandcancer.Theimmunesystemisinvolvedinthepathogenesisofmanyofthese,eitherbycausingtissuedamageoralternativelybyrespondingtodiseaseandcontributingtorepair.ItisclearlyvitalthatcellsoftheimmunesystempatroltheCNSandprotectagainstinfec-tion.However,incontrasttoothertissues,damagecausedbyimmunepathologyintheCNScanbeirreparable.Thenervousandimmunesystemshave,therefore,coevolvedtopermiteffectiveimmunesurveillancewhilelimit-ingimmunepathology.HerewewillconsideraspectsofadaptiveimmunityintheCNSandtheretina,bothinthecontextofprotectionfrominfectionaswellascancerandautoimmunity,whilefocusingonimmuneresponsesthatcompromisehealthandleadtosignificantmorbidity.
Immune privilegeAârangeâofâmechanismsâexistâtoâlimitâimmuneâresponsesâinâtheâCNS;âindeed,âtheâCNSâisâconsideredâtoâbeâanâimmune-privilegedâsite.âAsâearlyâasâ1921,âitâwasâshownâthatâratâsarcomaâcellsâgrowâwellâinâmouseâbrainâparenchymaâbutânotâwhenâtransplantedâunderâtheâskinâorâintoâmuscleâ(1).âForâdecadesâthereafter,âitâwasâassumedâthatâtheâCNSâandâretinaâenjoyâimmuneâprivilegeâbecauseâtheyâareâhiddenâbehindâtheâblood-brainâbarrierâ(BBB),âbloodâcerebrospinalâfluidâbarrierâ(BCSFB),âorâtheâblood-retinalâbarrierâ(BRB)â(Figureâ1).âHowever,âtheâviewâthatâtheâCNSâisâcompletelyâignoredâbyâtheâimmuneâsystemâhasâturnedâoutâtoâbeâoverlyâsimplistic.âThisâisâinâpartâbecauseâimmuneâprivilegeâisârelativeâratherâthanâabsolute;âtheâimmuneâresponseâtoânontumorâforeignâtissueâinâtheâCNSâisâdelayedâratherâthanâpreventedâ(2).âThisâdelayâisârelatedâtoâseveralâfactorsâââtheâCNSâlacksâconven-tionalâlymphoidâdrainageâ(3)âandâCNS-derivedâantigenâmayâbeâtrans-portedâtoâcervicalâlymphânodesâinâtheâfluidâphaseâ(4)âorâassociatedâwithâDCsâfollowingâtissueâtraumaâ(5).âTheâparenchymaâofâtheânormalâbrainâandâspinalâcordâhasâaâlimitedâcapacityâforâantigenâprocessingâandâpresentation,âsinceâitâcontainsâfewâprofessionalâAPCsâandâneu-ronsâonlyâexpressâMHCâunderâexceptionalâconditionsâ(6).âTheâeffer-entâarmâofâtheâimmuneâresponseâisâalsoâhindered,âsinceâlymphocytesâhaveâtoâbeâactivatedâbeforeâtheyâcanâcrossâtheâBBBâorâBRBâ(7,â8),âandâevenâthenâthisâtransmigrationâprocessâisâchallenging.âOnceâinâCNSâtissue,âtheâenvironmentâremainsâinherentlyâhostileâtoâactivatedâlym-phocytesâexpressingâFAS,âligationâofâwhichâbyâFASâligandâ(FASL),âexpressedâonâallâcellsâinâtheâCNS,âresultsâinâdeathâbyâapoptosisâ(9,â10).âMicroglia,âtheâinnateâimmuneâcellsâofâtheâCNS,âfurtherârespondâtoâinflammationâbyâupregulationâofâimmunoregulatoryâmoleculesâincludingâB7-H1â(11)âandâIDOâ(12),âwhileâneuronsâprotectâthem-selvesâbyâsecretingâTGF-βâuponâcontactâwithâactivatedâlymphocytesâ(13).âFASâandâTGF-βâhaveâalsoâbeenâimplicatedâinâtheâsuppressionâofâimmuneâresponsesâinâtheâeyeâ(refs.â14,â15,âandâFigureâ2).
Immune surveillanceTheânatureâandâoriginâofâAPCsâinâtheâCNSâisâonlyânowâbecom-ingâclear.âResidentâbrainâmicroglialâcellsâareâderivedâfromâprimi-
tiveâmyeloidâprogenitorsâthatâdifferentiateâinâtheâyolkâsacâ(16),âalthoughâboneâmarrowâderivedâcellsâmayâreconstituteâtheâCNSâfollowingâtraumaâ(17).âGreterâandâcolleaguesâhaveâshownâthatâimmuneâresponsesâinâtheâCNSâdependâonâCD11c+âcellsâfoundâinâtheâjuxtavascularâparenchyma,âwithâcellâprocessesâextendingâintoâtheâgliaâlimitansâ(18).âImportantly,âtheseâcellsâmayâbeâbloodâbornâorâalternativelyâderiveâfromâanâintraparenchymal,âmicroglialâpre-cursorâstimulatedâwithâGM-CSFâ(19).âCellsâsharingâtheâpropertiesâofâconventionalâDCsâhaveârecentlyâbeenâfoundâinâtheâmeningesâandâchoroidâplexusâofâhealthyâmouseâbrainâ(20).âTheseâcellsâareâderivedâfromâboneâmarrowâpre-DCâprogenitorsâandâshareâmor-phologicalâcharacteristics,âgeneâexpressionâpatterns,âandâtheâabil-ityâtoâpresentâantigenâwithâsplenicâDCsâ(20).âApartâfromâtheseâpopulationsâofâDCs,âtheâCNSâparenchymaâisârelativelyâdevoidâofâAPCs.âThisâallâchanges,âhowever,âinâtheâinflamedâCNSâorâretinaâwhenâmyeloidâ(CD11b+)âDCsâfloodâ intoâtheâsite,âamplifyâtheâimmuneâresponse,âandâpromoteâepitopeâspreadingâ(21â23).
Theânon-inflamedâbrainâandâretinaâareâprotectedâbyâvascularâendotheliumâatâtheâBBBâandâBRB,âwhileâepithelialâcellsâofâtheâcho-roidâplexusâformâtheâBCSFBâ(Figureâ3).âFurthermore,âastrocyticâendâfeetâandâtheâparenchymalâbasementâmembraneâformâaâfurtherâbarrier,âtheâgliaâlimitans.âNevertheless,âCSFâfromâindividualsâwithânoâinflammatoryâneurologicalâdiseaseâcontainsâaboutâ150,000ââTâlymphocytesâ(24).âTheseâcellsâcirculateâthroughâtheâCSFâforâapproximatelyâsixâhoursâbeforeâreturningâtoâtheâcirculationâ(24)âââaâlowârateâofâcellâtrafficâwhenâcomparedâwithâperipheralâlymphocyteârecirculationâ(25).âTheâTâcellsâinâhumanâCSFâareâmainlyâeffectorâmemoryâ(CD45RAâ,âCD27+,âL-selectinhi),âandâtheâmajorityâareâCD4âpositiveâ(26).âThisâphenotypeâpermitsâtraffickingâthroughâextra-lymphoidâtissueâasâwellâasâsubsequentâreturnâtoâtheâlymphaticâsys-temâviaâhigh-endothelialâvenules.âActivatedâlymphocytesâmakeâfor-malâcontactâwithâtheâBBBâviaâÎą4-integrinâandâendothelialâVCAM-1â(27)âandâcrossâtheâbarrierâbyâdiapedesis.âThisâisâaâdifficultâprocess,âespeciallyâinâtheânon-inflamedâCNS,âalthoughâentryâtoâtheâlepto-meningealâcompartmentâcanâoccurâmoreâreadilyâinâaâP-selectinâdependentâmannerâ(28).âEvenâthen,âentryâtoâtheâCNSâparenchymaâisâdependentâonâfurtherâencounterâwithâcognateâantigen.âIfâantigenâisâseen,âthenâtheâimmuneâcellsâmountâanâinflammatoryâresponse,âdrawâotherâimmuneâcellsâintoâtheâspecificâsite,âandâthenâcollectivelyâbreechâtheâgliaâlimitansâtoâinfiltrateâtheâparenchyma.
Conflictofinterest:âDavidâC.âWraithâhasâaâfinancialâinterestâinâApitope,âwhichâisâdevelopingâantigen-specificâtherapiesâforâautoimmuneâdiseases.
Citationforthisarticle:âJ Clin Invest.â2012;122(4):1172â1179.âdoi:10.1172/JCI58648.
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LymphocyteâmigrationâintoâandâwithinâtheâCNSâisâregulatedâbyâchemokinesâandâtheirâreceptors.âWithoutâconcomitantâinflam-mation,âCD4+âmigrationâoutsideâofâbloodâvesselsâisâconstrainedâtoâpathwaysâthatârunâalongâtheirâaxesâ(29)âandâisâdifferentâfromâtheârandomâmotilityâofâCD8+âcellsâ(29â31).âThisâconfinementâisâregulatedâbyâtheâinteractionâofâtheâchemoattractantâCXCL12âwithâtheâreceptorâCXCR4,âexpressedâonâtheâsurfaceâofâlymphocytes.âTheâmigrationâofâleukocytesâintoâtheâCNSâmayâbeâmodulatedâbyâsequestrationâofâCXCL12âbyâotherâreceptorsâ(32),âorâbyâtheâphysicalâredistributionâofâCXCL12âthatâoccursâinâMSâandâtheâdiseaseâmodelâEAEâ(30,â31).âInâaddition,âblockadeâofâCXCR4âallowsâCD4âTâcellsâtoâescapeâfromâtheirâperivascularâcontainmentâandâpenetrateâdeep-erâintoâbrainâparenchymaâ(29,â30).âCollectivelyâtheseâmechanismsâensureâthatâimmunosurveillanceâwithinâtheânormalâCNSâoccursâatâaâslowerâpaceâthanâinâtheâperipheryâandâisâbiasedâtoârecentlyâacti-vatedâCD4+âcellsâwithâaâphenotypeâthatâallowsâthemâtoâtrafficâbackâtoâsecondaryâlymphoidâtissueâonceâtheyâleaveâtheânervousâsystem.âHowever,âimmunosurveillanceâofâtheâCNSâisâaâcriticalâmechanism,âasâillustratedârecentlyâbyâtheâobservationâofâcomplicationsâassoci-atedâwithâantibodyâtherapiesâforâMSâthatâblockâthisâprocess.âTreat-mentâwithânatalizumab,âanâantiâÎą4-integrin,âincreasesâtheâriskâofâprogressiveâmultifocalâleukoencephalopathyâ(PML)âcausedâbyâtheâJohnâCunninghamâ(JC)âVirusâ(33).âThisâisâvirtuallyâneverâseenâinâimmune-competentâindividualsâ(34),âattestingâtoâtheâeffectivenessâofâtheâimmuneâsurveillanceâofâCNSâtissue.
CNS disease associated with infectionInfectionsâofâtheâCNSâfrequentlyâcauseâdevastatingâdiseaseâwithâlong-termâneurologicalâsequelae.âItâisâalsoâappreciatedâthatâtheâtissueâdamageâcausedâbyâsuchâfulminantâinflammatoryâresponsesâ
inâtheâbrainâmayâhaveâmoreâsevereâconsequencesâthanâtheâinfec-tionâitself.âHowever,âlife-threateningâinflammationâisânotâtheâonlyâmanifestationâofâimmuneâresponsesâwithinâtheâCNS,âandâcertainâviralâinfectionsâofâtheâCNSâandâmeningesâcanâproduceâtransientâsymptomsâthatâresolveâcompletely.âStudyingâadap-tiveâimmuneâresponsesâwithinâimmunoprivilegedâsitesâthatâcanâresolveâwithoutâclinicalâsequelaeâ isâchallenging,âespeciallyâ inâhumans.âInâtheâretina,âsuchâeventsâmanifestâasâmultipleâevanes-centâwhiteâdotâsyndrome,âputativeâimmuneâgranulomasâoftenâofâunknownâcauseâthatâhaveâaâspectrumâofâclinicalâoutcomesâfromâresolutionâtoâchronicâdiseaseâ(35).âOtherâexamplesâofâclinicallyâsilentâpathologyâincludeâasepticâmeningitis,âmostâcommonlyâcausedâbyâenteroviruses,âinâwhichâtheâinfectionâisâclearedâfromâtheâtissue,âandâinfectionâfollowedâbyâlatencyâasâcausedâbyâher-pesâviruses.âInâthisâlatterâcase,âimmunosuppressionâcanâpromoteâreactivationâofâtheâvirusâââforâexample,â inâpatientsâreceivingâtreatmentâwithâantibodiesâthatâdepleteâperipheralâlymphocytesâ(36),âwhichâcanâleadâtoâacuteâretinalâpathologyâ(37).âTheâpreciseâoriginâofâtheâreactivationâisâdifficultâtoâdetermine,âbutâinâanimalâmodels,âlatentâvirusâcanâbeâdetectedâinâtheâtrigeminalâganglionâandâhypothalamusâ(38).âTogetherâthisâevidenceâdemonstratesâthatâtheâCNSâcanâsupportâeffectiveâadaptiveâimmuneâresponsesâwhileâpreservingânormalâfunction.
Infectiousâagentsâmayâcauseâneurologicalâdiseaseâbyâaâdirectâlyticâeffect,âexemplifiedâbyâVenezuelanâequineâencephalitisâvirusâinâchildrenâandâWestâNileâvirusâinâolderâadultsâ(39).âAlternative-ly,âdamageâcanâbeâcausedâbyâtheâimmuneâresponseâtoâtheâvirus-infectedâcells;âexamplesâofâvirusesâcausingâimmunopathologyâinâtheâCNSâincludeâEasternâequineâencephalitisâvirusâinâhumansâandâSindbisâvirusâinâmiceâ(40).âHumanâT-lymphotrophicâvirusâtypeâ1â
Figure 1Physical barriers protecting the brain. The brain is the most highly protected organ in the body. It is protected from physical insult by the skull and associated tissues. The BBB provides protection from pathogens in the blood and from the cells and antibodies of the immune system. The BBB is more effective than other vascular-tissue barri-ers because the endothelial cells form tight junctions of high electrical resistance that limit transcellular movement of molecules. The glia limitans, formed from parenchymal basement membrane and astrocytic foot processes, forms a further barrier between blood and neuronal tissue.
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1174 TheJournalofClinicalInvestigationâ â â http://www.jci.orgâ â â Volumeâ122â â â Numberâ4â â â Aprilâ2012
(HTLV-1)âinfectionâmayâresultâinâHTLV-associatedâmyelopathyâ(HAM),âalsoâknownâasâtropicalâspasticâparaparesisâ(TSP),âbutâthisâmustâoccurâbyâaâdifferent,âindirectâmechanism.âHTLV-1âinfectsâbothâCD4âandâCD8âlymphocytesâandâcausesâTâcellâleukemia/lymphomaâamongâCD4âcellsâ(41).âInterestingly,âhowever,âthereâisâlittleâorânoâHTLV-1âinfectionâofâCNSâcellsâinâHAM/TSPâ(42),âandâriskâofâdevelopingâHAM/TSPâcorrelatesâmostâstronglyâwithâtheâproportionâofâperipheralâbloodâmononuclearâcellsâcarryingâintegratedâHTLV-1âprovirus.âInâcontrast,âaâstrongâCD8âantivi-ralâresponseâreducesâproviralâloadâandâhenceâreducesâtheâriskâofâHAM/TSPâ(43).âAâpoorâCD8âresponseâtoâtheâvirusâresultsâinâaâhighânumberâofâinfectedâandâactivatedâCD4âTâcells,âandâaâhighâpercentageâofâtheseâcellsâisâableâtoâenterâtheâCNS,âwhereâtheyâformâanâimmuneâbattlegroundâbetweenâtheâinfectedâcellsâandâHTLV-1âspecificâlymphocytes.âTheâlatterâsecreteâinflammatoryâcytokinesâandâmetalloproteinases,âandâtheseâcauseâtissueâdamageâinâaâbystanderâfashion.
Aâ furtherâ mechanismâ ofâ neuronalâ diseaseâ associatedâ withâinfectionâisârevealedâthroughâstudiesâofâSydenhamâchorea.âThisâdisorderâmayâoccurâmonthsâafterâgroupâAâstreptococcalâinfec-tionâandâisâassociatedâwithâantibodiesâagainstâbasalâgangliaâ(44).âMonoclonalâantibodiesâfromâpatientsâwithâSydenhamâchoreaâwereâshownâtoâreactâwithâ intracellularâtubulin,âextracellularâlysogangliosideâGM1,âandâtheâGlcNAcâepitopeâofâstreptococcalâgroupâAâcarbohydrate,âconsistentâwithâaâmechanismâofâmolecu-larâmimicryâ(45).âAntibodiesâfromâSydenhamâchoreaâpatientsâreactâstronglyâwithâcytoplasmicâantigensâinâhumanâcaudateâandâsubthalamicânucleiâasâwellâasâcerebralâcortexâneuronsâ(44).âTheseâantibodiesâareâspecificâtoâpatientsâwithâsymptomsâofâchoreaâandâareânotâseenâinârheumaticâheartâdisease,âandâtheirâlevelsâcorre-lateâwithâseverityâandâdurationâofâchoreicâsymptoms.âWhetherâorânotâanti-tubulinâorâanti-lysogangliosideâantibodiesâcauseâtheâpathologyâremainsâunclear.âSomeâantibodiesâagainstâlysogangli-osideâhave,âhowever,âbeenâshownâtoâactivateâcalcium/calmodu-lin-dependentâproteinâkinaseâIIâinâhumanâneuronalâcellsâ(46).âOneâquestionâthatâarisesâisâhowâsuchâcross-reactiveâantibodiesâ
crossâtheâBBBâorâBCSFBâinâtheâfirstâplace.âEvidenceâfromâaâstudyâofâsystemicâlupusâerythematosusâ(SLE)âhasâshownâthatâanti-dsDNAâantibodiesâcanâcross-reactâwithâNMDAâreceptorâonâtheâcellâsurfaceâandâinduceâapoptosisâofâneuronsâinâtheâhippocam-pusâandâlateralâamygdalaâ(47).âImportantly,âinâthisâstudyâHuertaâandâcolleaguesâshowedâthatâtheâBBBâhadâfirstâtoâbeâdisruptedâforâtheseâantibodiesâtoâcauseâpathology.âTheâphenomenaâofâmolecu-larâmimicryâandâtheâinductionâofâcross-reactiveâantibodiesâareâprobablyâmoreâcommonâthanâweâappreciate.âTheâintegrityâofâtheâBBBâandâBCSFBâmeans,âhowever,âthatâthisârarelyâmanifestsâasâaâclinicalâfeatureâofâeitherâtheâinfectionâorâautoimmuneâcondition.âInâsummary,âinfectiousâagentsâmayâcauseâneurologicalâdiseaseâthroughâaâdirectâ lyticâeffect,âbyâ inducingâimmunopathologyâdirectedâagainstâCNSâtissue,âbyâinductionâofâimmuneârespons-esâthatâdamageâCNSâtissueâinâaâbystanderâfashion,âorâthroughâinductionâofâmolecularâmimicry.
Theâcontrolâofâvirusâinfectionâandâsurvivalâofâtheâhost,âespe-ciallyâinâresponseâtoâvirusesâadaptedâtoâevadeâtheâimmuneâsys-tem,âmayârequireâtheâproductionâofâantibodiesâwithinâtheâCNSâand/orâtheâgenerationâofâprotectiveâbutânon-lyticâeffectorâfunc-tions.âForâexample,âcoronavirusâinfectionâofâmiceâresultsâinâacuteâencephalomyelitisâfollowedâbyâpersistentâinfectionâ(48).âSerumâantibodyâlevelsâcorrelateâwithâlevelsâofâtissueâantibody-secret-ingâcellsâinâtheâperipheryâandâdeclineâfollowingâviralâclearance.âHowever,âantibody-secretingâcellsâpersistâinâtheâCNSâconsistentâwithâintrathecalâantibodyâsynthesis.âTheâCNSâisâthereforeâableâtoâsupportâantibody-secretingâcellsâevenâafterâresolutionâofâvirusâinfection.âEvidenceâforâlong-termâpersistenceâofâCD103+âpatho-gen-specificâmemoryâCD8+âcellsâinâtheâCNSâcomesâfromâelegantâworkâusingâvesicularâstomatitisâvirusâ(49).âFurthermore,âhumanâtissueâstudiesâhaveâidentifiedâCD8+âcellsâassociatedâwithâtrigemi-nalâgangliaâinfectedâwithâherpesâsimplexâvirusâ(50).âAlthoughâgranzymeâBâwasâexpressedâbyâtheseâcells,âtheyâappearedâtoâbeânon-cytolytic.âSimilarâfindingsâhaveâbeenâdescribedâinâanimalâmodelsâofâherpesvirusâinfection,âinâwhichâbothâgranzyme-âandâcytokine-dependentâ effectorâ mechanismsâ areâ importantâ forâ
Figure 2Immunological barriers protecting the brain. Cells of the CNS, including (A) astrocytes, (B) neurons, and (C) microglial cells express FASL. Activated T cells upregulate FAS and are, therefore, susceptible to apoptosis in the CNS. (B) Neurons respond to contact with T cells by secret-ing TGF-β, which in turn promotes the generation of regulatory T cells. (C) Resident microglial cells express B7-H1, a costimulatory molecule that promotes secretion of the anti-inflammatory cytokine IL-10, and indoleamine 2,3-dioxygenase (IDO), which converts tryptophan (TRP) to kynurenic acid (KYN). Metabolites of tryptophan induce FAS-independent apoptosis in neighboring cells.
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maintainingâ theâ latentâ stateâ ofâ theâ virusâ (51).â Inâ thisâ latterâmodel,âitâwasâpossibleâtoâdemonstrateâlyticâgranule-dependentâdegradationâofâviralâproteinâwithoutâconcomitantâneuronalâcellâdeath.âTakenâtogether,âtheseâstudiesâsuggestâthatâtheâimmuneâsystemâcanâcontrolâCNSâinfectionsâusingâmechanismsâthatâlimitâtissueâdamage.
Paraneoplastic diseases of the CNSInâadditionâtoâtheâmovementâdisordersâassociatedâwithâinfec-tionâbyâgroupâAâstreptococcusâorâautoimmunityâ(e.g.,âSLE),âanâimportantâsubsetâofâparaneoplasticâneurologicalâdiseasesâ(PNDs)âisâlinkedâtoâcancerâ(52).âTheseâconditionsâareâoftenâassociatedâwithâlymphocyteâpleocytosisâinâtheâCSFâandâappearanceâofâoli-goclonalâbandsâ(multipleâbandsâofâimmunoglobulinâdetectedâbyâelectrophoresis,âevidenceâofâBâcellâclonalâexpansion)âand,âmoreâspecifically,âanti-neuronalâantibodies.âTumorsâinvolvedâinâPNDâmayâexpressâneuroendocrineâproteinsâ(e.g.,âsmall-cellâlungâcancerâ[SCLC]âandâneuroblastoma),âaffectâorgansâinvolvedâinâimmuneâregulationâ(thymoma),âorâcontainâmatureâorâimmatureâneuronalâtissueâ(teratomas)â(Tableâ1).
Inâsomeâcases,âtheâpathogenicâroleâofâparaneoplasticâantibodiesâisâclear.âForâexample,âantibodiesâdirectedâtoâtheâNR1âsubunitâofâtheâNMDAâreceptorâcauseâitsâinternalizationâandâtheâassociatedâreductionâinâreceptorâsignalingâ(53).âFurthermore,âstiffâpersonâsyndromeâisâunequivocallyâlinkedâtoâantibodiesâthatâinterfereâwithâ
theâGABA-receptorâpathwayâ(GAD65,âamphiphysin,âGABARAP);âasâyet,âhowever,âwhichâofâtheseâantibodiesâresultsâinâpathologyâisâlessâclearâ(52).âTheâsameâisâtrueâforâantibodiesâassociatedâwithâotherâmovementâdisorders,âespeciallyâthoseâspecificâforâcytoplas-micâantigens,âinâwhichâtheâpathogenicâlinkâremainsâobscure.âInâmanyâcases,âparaneoplasticâmovementâdisordersâareâsuccessful-lyâtreatedâbyâremovalâofâtheâtumorâwithâorâwithoutâadditionalâimmuneâsuppression.
Autoimmune diseases of the CNSAutoimmuneâdiseasesâareâcharacterizedâbyâstrongâassociationâwithâgenes,âusuallyâclassâII,âinâtheâMHCâ(54);âweakâassociationâwithâaârangeâofâotherâgenesâencodingâproteinsâknownâtoâregulateâimmuneâresponsesâ(55);âlymphocyteâinfiltrationâofâtheâaffectedâtissueâ (56);â raisedâ levelsâ ofâ class-switchedâ autoantibodiesâ inâserumâorâtheâaffectedâtissueâ(57);âhigherâfrequencyâofâactivatedâorâmemoryâlymphocytesâ(CD45RO+âTâcellsâinâhumans)âspecificâforâself-antigensâ(58);âandâtheâsuppressionâofâdiseaseâprogressionâthroughâtreatmentâwithâstrongâimmune-suppressiveâdrugsâ(59).âAutoimmuneâdiseasesâthatâaffectâtheâCNSâincludeâMSâandâneu-romyelitisâopticaâ(NMO).
Untilârecently,âNMO,âorâDevicâsâdisease,âwasâconsideredâtoâbeâaâformâofâMS,âsinceâtheâimmuneâsystemâtargetsâmyelinâinâbothâdis-easesâ(60).âPathogenicâlesionsâinâMSâareâfoundâinâbothâbrainâandâspinalâcord,âwhereasâtheâautoimmuneâattackâinâNMOâspecificallyâaffectsâtheâspinalâcordâandâopticânerve;âhence,âtheâsymptomsâofâNMOâareâlossâofâvisionâandâspinalâcordâfunction.âDefiniteâdiagno-sisâofâNMOâisâbasedâonâevidenceâofâopticâneuritis,âacuteâmyelitis,âandâatâleastâ2âofâtheâfollowingâadditionalâcriteria:â(a)âcontiguousâspinalâcordâMRIâlesionsâoverâ3âvertebralâsegments,â(b)âbrainâMRIânotâmeetingâcriteriaâforâMS,âandâ(c)âpresenceâofâantibodiesâagainstâaquaporin-4,âaâhighlyâspecificâmarkerâofâNMOâ(61).âTheseâantibod-iesâareâdetectableâinâatâleastâ80%âofâpatientsâwithâNMOâandâhaveâbeenâshownâtoâcauseârelevantâpathologyâwhenâeitherâtransferredâdirectlyâintoâtheâCNSâofâmiceâ(62)âorâinjectedâintoâanimalsâwithâEAEâthatâhaveâaâdisruptedâBBBâ(63),âallowingâfreeâpassageâofâIgGâantibodiesâintoâtheâbrain.âThereâisâalsoâevidenceâforâincreasedâT-cellâimmunityâagainstâaquaporin-4âinâNMOâ(64).âImportantly,âMSâisâmoreâcommonâinâpopulationsâofâmixedâEuropeanâdescent,âwhereasâNMOâisârelativelyâmoreâfrequentâinâindividualsânotâofâmixedâEuro-peanâdescent,âimplyingâaâstrongâgeneticâcontributionâtoâsuscepti-bility.âInâMSâthereâisâaâclearâassociationâwithâtheâHLA-DRB1*1501âalleleâinâpopulationsâofâEuropeanâorigin,âwhileâHLA-DRB1*0301âandâDRB1*0405âareâmoreâcommonâinâSardiniaâ(65);âtheseâallelesâofâtheâMHCâclassâIIâHLA-DRâlocusâconstituteâtheâstrongestâgeneticâassociationâwithâMSâ(66).âSimilarly,âNMOâisâassociatedâwithâHLAâclassâII,âandâitâappears,âfromâtheâfewâsmallâstudiesâconducted,âthatâtheâassociatedâalleleâdependsâonâethnicity.âThatâis,âNMOâhasâbeenâassociatedâwithâHLA-DP*0501âinâJapanâ(67),âwhereasâpatientsâinâFranceâ(68)âandâBrazilâ(69)âexpressingâtheâanti-aquaporinâantibodyâareâlikelyâtoâbeâHLA-DRB1*03.âTherefore,âNMOâisâanâautoimmuneâdiseaseâofâtheâCNSâthatâsharesâsomeâofâtheâfeaturesâwithâMSâbutâisâdistinctâbothâgeneticallyâandâinâimmunopathology.
Narcolepsyâfulfilsâsome,âbutânotâall,âofâtheâfeaturesâofâanâautoim-muneâdisease.âThisâdisablingâCNSâdisorderâcausesâdaytimeâsleepi-nessâandâsleepâattacksâthatâdevelopâbecauseâofâaâdeficiencyâofâhypo-cretin-producingâneuronsâinâtheâhypothalamusâ(70).âTheâmajorityâofâpatientsâwithânarcolepsyâcarryâtheâHLAâDQB1*0602âalleleâ(71).âRecentâstudiesâhaveâalsoârevealedâdisease-associatedâpoly-morphismsâinâgenesâencodingâtheâTCRâÎą-chainâ(72),âTNF-Îąâ(73)ââ
Figure 3Comparison of the BBB and BCSFB. Brain barriers are made up of the endothelial BBB and the epithelial BCSFB. (A) The BBB has two protective layers, the endothelium with tight junctions and the glia limi-tans, made up of parenchymal basement membrane and astrocyte foot processes. (B) In contrast to the CNS parenchyma, microvessels in the choroid plexus are fenestrated, allowing free diffusion between the blood and CSF. The BCSFB is made up of the choroid epithelial cells with their unique tight junctions.
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andâtheâTNFâreceptorâIIâ(74).âDespiteâsuchâtantalizingâimmu-nogeneticâevidence,âthereâisâinsufficientâdefinitiveâproofâthatânarcolepsyâisâanâautoimmuneâcondition.âOligoclonalâbandsâareânotâseenâinâtheâCSFâ(75),ânorâareâthereâsignsâofâinflammationâinâtheâhypothalamusâinâpostmortemâstudiesâ(76,â77).âAsâdiscussedâabove,âneurologicalâdisturbanceâcanâresultâfromâvariousâmech-anisms,ârangingâfromâdirectâimmuneâattack,âbystanderâactiva-tion,âorâmolecularâmimicry.âItâremainsâpossibleâthatâaâsubtle,âlocalâbystanderâactivationâmechanism,âdistinctâfromâtheâtypeâofâpathologyâseenâinâMSâandâNMO,âcouldâaccountâforâtheâspe-cificâdepletionâofâhypothalamicâneuronsâproducingâhypocretinâpeptides,âbutâthisâawaitsâfurtherâinvestigation.
Theâavailableâtherapiesâforâmanyâautoimmuneâdiseasesâareânotâcurativeâandâareâoftenâassociatedâwithâunacceptableâsideâeffects.âOverâtheâpastâ20âyears,âadvancesâ inâourâunderstandingâofâtheâimmuneâpathologyâofâautoimmuneâdiseasesâhaveâledâtoânewâtreat-mentsâthatâofferâsignificantâadvantagesâoverâpreviousâtherapies.âThisâisâwellâillustratedâinâtheâcaseâofâMS,âforâwhichâvariousâtreat-mentâapproachesâhaveârecentlyâenteredâclinicalâtrialsâorâhaveâbeenâaddedâtoâtheâarmamentariumâofâtheâneurologistâ(Figureâ4).âInter-feron-βâwasâintroducedâinâtheâ1980s,âinâtheâbeliefâthatâMSâwasâcausedâbyâanâunknownâvirus,âandâwasâshownâtoâsuppressâinflam-
mationâinâsomeâbutânotâallâpatients.âRecently,âAxtellâandâcolleaguesâprovidedâinsightâintoâwhyâtheâeffectsâofâinterferon-βâmayâvaryâ(78).âInâtheâmouseâEAEâmodel,âinterferon-βâwasâshownâtoâsuppressâdis-easeâcausedâbyâmyelin-specificâTh1âcellsâbutâtoâexacerbateâTh17-associatedâdisease.âInterestingly,âpatientsâwhoâdoânotârespondâtoâtreatmentâwithâinterferon-βâhaveâconstitutivelyâhighâlevelsâofââIL-17Fâ(78).âExtrapolatingâtheseâfindingsâtoâtheâgeneralâpopula-tionâofâpatientsâwithâMS,âoneâcouldâspeculateâthatâtheâefficacyâofâinterferon-βâinâaâgivenâindividualâmightâdependâonâtheâbalanceâofâTh1âandâTh17âcellsâcausingâpathology.âRelativeâcytokineâproduc-tionâbyâperipheralâbloodâcellsâinâresponseâtoâmyelinâantigensâcouldâbeâusedâtoâstratifyâpatientsâandâtherebyâimproveâtheâeffectiveâtreat-mentâofâMSâwithâinterferon-β.
ThereâisânowânoâdoubtâthatâMSâisâanâautoimmuneâdiseaseâassoci-atedâwithâtheâadaptiveâimmuneâresponseâtoâmyelinâantigens.âMostâstrikingly,âpatientsâwithârelapsingâMSâhaveâshownâanâimpressiveâreductionâinâdisabilityâatâ6âmonthsâafterâtreatmentâwithâtheâCD52-targetingâmonoclonalâantibodyâalemtuzumabâ(Campathâ1H)â(79).âThisâantibodyâhasâaâprofoundâandâlong-lastingâeffectâonâtheâCD4âlymphocyteâcount,âandâthisâaloneâimplicatesâCD4âTâcellsâasâkeyâinâcontrollingâtheâpathogenesisâofâMS.âTreatmentâwithârituximab,âanâantibodyâtargetingâtheâCD20âmoleculeâonâBâcellsâandâleadingâtoââ
Table 1Examples of paraneoplastic movement disorders
Disease Relatedtumor Antibodytarget ReferenceChorea SCLC and thymoma CRMP-5 94NMDA receptor encephalitis Teratoma (in women) NMDAR (NR1) 95Brainstem encephalitis Testis (in men under 50 years of age), MA2 96 solid tumor (in men over 50), lymphoma (in women)Cerebellar degeneration Breast, ovary Yo 97 Hodgkinâs lymphoma TR 98 SCLC VGCC 99Stiff person syndrome SCLC, breast GAD65, amphiphysin, GABARAP 100, 101Opsoclonus-myoclonus Neuroblastoma (in children); Not known 102 SCLC, breast, ovarian (in adults)
Figure 4Current and future therapies for MS. The holy grail for treatment of autoimmune disease is to design a drug that will selectively tar-get the cells causing the disease, avoid nonspecific immune sup-pression, and have minimal adverse effects. Increasingly specific approaches target the adaptive immune response to antigens in the CNS. Examples of these include antilymphocyte drugs (alemtu-zumab), antiâT cell drugs (daclizumab), drugs targeting lymphocyte migration (natalizumab and fingolimod), APL (GA), and the target antigen (myelin peptides or DNA vaccine).
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Bâcellâdepletion,âhasâalsoâbeenâshownâtoâlowerâtheâburdenâofâbrainâlesionsâinâMSâandâsignificantlyâreduceârelapsesâ(80).âThisâmayâsuggestâaâpreviouslyâunderappreciatedâroleâforâautoantibodiesâinâimmuneâpathology,âorâalternativelyâanâimportantâroleâforâBâcellsâinâtheâpresentationâofâantigenâtoâpathogenicâCD4âTâcells.âWorkâinâtheâEAEâmodelâpreviouslyârevealedâtheâroleâofâVLA-4âasâtheâinte-grinâinvolvedâinâlymphocyteâtrafficâintoâtheâCNS;âtheâantiâVLA-4âantibodyâHP2/1âpreventedâonsetâofâEAEâinâtheâLewisâratâmodelâ(27).âNatalizumab,âtheâhumanâequivalentâofâHP2/1,âhasâbeenâhighlyâeffectiveâinâreducingâinflammatoryâlesionsâinâMS.âClinicalâtrialsâhave,âhowever,ârevealedâanâincreasedâsusceptibilityâtoâPMLâinâpatientsâtreatedâwithânatalizumabâ(81).âPMLâisâcausedâbyâtheâreac-tivationâofâtheâJCâVirusâpolyomavirusâinâtheâCNSâofâimmune-com-promisedâindividualsâ(82).âSimilarâviralâcomplicationsâmayâalsoâariseâuponâtreatmentâwithâfingolimodâ(Gilenya),âaâsphingosine-1âphosphateâ(S1P)âreceptorâmodulator.âS1Pâsignalingâisârequiredâforâlymphocytesâtoâegressâfromâlymphânodes.âHence,âtreatmentâwithâfingolimodâpreventsâlymphocytesâleavingâtheâlymphânodesâandâenteringâtheâCNS.âInâaârecentâtrial,âfingolimodâsignificantlyâloweredârelapseârateâinârelapsing-remittingâMSâ(83).âHowever,âtwoâfatalâviralâinfections,âdisseminatedâvaricellaâandâherpesâsimplexâencephalitis,âoccurredâamongâ369âpatientsâtreatedâatâtheâhigherâdoseâofâtheâdrugâ(83).âClearly,âfurtherâanalysisâofâdoseâandâdura-tionâofâtreatmentâwillâbeârequiredâtoâassessâtheâlong-termâsafetyâofâdrugsâthatâmodulateâlymphocyteâmigration.
Anâantigen-specificââtolerogenicââapproachâspecificallyâtargetingâtheâTCRsâofâpathogenicâcellsâisâconsideredâtheâholyâgrailâforâimmu-notherapyâ(84).âAlteredâpeptideâligandsâ(APLs)âareâvariantsâofââTâcellâepitopesâdesignedâtoâalterâtheâresponseâofâTâcellsâbyâinducingâapoptosis,âanergy,âorâmodulationâofâcytokineâsecretionâ(85).âTheâprototypicâAPLâforâtreatmentâofâautoimmuneâdiseaseâisâcopoly-merâ1,âalsoâknownâasâcopaxoneâorâglatiramerâacetateâ(GA)â(86).âGAâisâthoughtâtoâworkâbyâmodulatingâmyelinâbasicâproteinâspecificâ(MBP-specific)âTâcellsâtowardâaâTh2/anti-inflammatoryâphenotypeâ(87)âor,âalternatively,âbyâupregulatingâIL-10âsecretionâbyâCD8âcellsâ(88).âAPLâmoreâspecificallyâtargetingâtheâTCRsâofâmyelin-specificâcellsâhaveâbeenâdesignedâandâtestedâinâclinicalâtrials.âHighâdosesâofâAPL,âbasedâonâMBPâpeptideâ83â99,âcausedâallergicâcomplica-tionsâwhenâinjectedâsubcutaneouslyâ(89)âandâmayâhaveâledâtoâdis-
easeâexacerbationâinâsomeâpatientsâ(90).âItâwasâpreviouslyâshownâthatâanâantagonistâforâoneâTCRâmayâfunctionâasâanâagonistâforâtheânextâ(91);âthisâimpugnsâtheâadvantageâofâusingâAPLâoverâtheânativeâsequence.âSinceâtheâearlyâstudiesâwithâAPL,âantigen-specificâthera-piesâbasedâonâpeptidesâandâDNAâvaccinesâhaveâbeenâdeveloped.âHigh-doseâtreatmentâwithâMBPâpeptideâ82â98âledâtoâaâreductionâinâanti-MBPâantibodiesâandâdelayedâdiseaseâprogressionâinâtheâHLA-DR2/DR4âsubgroupâofâpatientsâ(92).âAâDNAâvaccineâencod-ingâMBP,âwithâCpGâmotifsâreplacedâbyâGpG,âwasârecentlyâtestedâinâMSâpatientsâ(93).âTreatmentâwithâaâ0.5-mgâdoseâofâDNAâresult-edâinâtheâreductionâofânewâlesionsâinâtheâCNS,âcoincidingâwithâaâdecreaseâinâtheâTh1âresponseâtoâmyelinâantigens.âWhetherâantigen-specificâtherapyâwillâbeâsufficientlyâpowerfulâtoâreduceâprogressionâofâdiseaseâcannotâbeâdeterminedâwithoutâfurtherâtesting.âOneâcanâenvisionâaâsituationâinâwhichâdiseaseâisâtreatedâbyâshort-termâdos-ageâwithâaâstrong,ânonspecificâimmuneâsuppressant,âwithâdiseaseâsuppressionâbeingâmaintainedâinâtheâlongâtermâwithâaâsafer,âanti-gen-specificâapproach.
ConclusionInâsummary,âtheâCNSâhasâco-evolvedâaâcloseârelationshipâwithâtheâimmuneâsystemâthatâallowsâaâsophisticatedâandânuancedâmanifes-tationâofâtheânormalâinflammatoryâprocessâ(Figureâ5).âAnâongoingâimmuneâresponseâwithinâtheâimmune-privilegedâtissueâmodifiesâitsâimmunosurveillance,âandâthisâisâcharacterizedâbyâchangesâinâtheâimmuneâcellâcontentâofâtheâtargetâorgan.âSuchâchangesâcanâbeâsuccessfulâinâcontrollingâlocalâpathologyâwhileâpreservingâfunc-tionâbutâmayâalterâtheâriskâofâCNSâsequelaeâfollowingâperipheralâimmuneâactivation.
AcknowledgmentsD.C.âWraithâacknowledgesâfinancialâsupportâfromâtheâWellcomeâTrustâ&âMSâSocietyâUK.âL.B.âNicholsonâacknowledgesâsupportâfromâtheâNationalâEyeâResearchâCentreâ&âMSâSocietyâUK.
Addressâ correspondenceâ to:â Davidâ C.â Wraith,â Departmentâ ofâPathologyâandâMicrobiology,âUniversityâofâBristol,âUniversityâWalk,âBristolâBS8â1TD,âUnitedâKingdom.âPhone:â44.117.928.7883;âFax:â44.117.928.7896;âE-mail:â[email protected].
Figure 5Adaptive immune responses in the CNS. Immune responses in the CNS may be helpful or harmful. Constant immune surveillance is required to control infections in the CNS, to control transient infec-tions, or to maintain latent infections. Depletion of immune cells may lead to virus reactivation, while cross-reacting antibodies, which arise as a result of infection, autoimmune disease, or cancer, may cause movement disorders. Chronic inflammation arises when the adap-tive immune response fails to eradicate an infection or alternatively responds to a CNS antigen, leading to autoimmune disease.
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