Table Of ContentHANDBOOK OF CLINICAL
NEUROLOGY
Series Editors
MICHAEL J. AMINOFF, FRANC¸OIS BOLLER, AND DICK F. SWAAB
VOLUME 122
EDINBURGH LONDON NEW YORK OXFORD PHILADELPHIA
ST LOUIS SYDNEY TORONTO 2014
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Availabletitles
Vol.79,Thehumanhypothalamus:basicandclinicalaspects,PartI,D.F.SwaabISBN9780444513571
Vol.80,Thehumanhypothalamus:basicandclinicalaspects,PartII,D.F.SwaabISBN9780444514905
Vol.81,Pain,F.CerveroandT.S.Jensen,eds.ISBN9780444519016
Vol.82,Motorneuronedisordersandrelateddiseases,A.A.EisenandP.J.Shaw,eds.ISBN9780444518941
Vol.83,Parkinson’sdiseaseandrelateddisorders,PartI,W.C.KollerandE.Melamed,eds.ISBN9780444519009
Vol.84,Parkinson’sdiseaseandrelateddisorders,PartII,W.C.KollerandE.Melamed,eds.ISBN9780444528933
Vol.85,HIV/AIDSandthenervoussystem,P.PortegiesandJ.Berger,eds.ISBN9780444520104
Vol.86,Myopathies,F.L.MastagliaandD.HiltonJones,eds.ISBN9780444518996
Vol.87,Malformationsofthenervoussystem,H.B.SarnatandP.Curatolo,eds.ISBN9780444518965
Vol.88,Neuropsychologyandbehaviouralneurology,G.GoldenbergandB.C.Miller,eds.ISBN9780444518972
Vol.89,Dementias,C.DuyckaertsandI.Litvan,eds.ISBN9780444518989
Vol.90,Disordersofconsciousness,G.B.YoungandE.F.M.Wijdicks,eds.ISBN9780444518958
Vol.91,Neuromuscularjunctiondisorders,A.G.Engel,ed.ISBN9780444520081
Vol.92,Stroke–PartI:Basicandepidemiologicalaspects,M.Fisher,ed.ISBN9780444520036
Vol.93,Stroke–PartII:Clinicalmanifestationsandpathogenesis,M.Fisher,ed.ISBN9780444520043
Vol.94,Stroke–PartIII:Investigationsandmanagement,M.Fisher,ed.ISBN9780444520050
Vol.95,HistoryofNeurology,S.Finger,F.BollerandK.L.Tyler,eds.ISBN9780444520081
Vol.96,Bacterialinfectionsofthecentralnervoussystem,K.L.RoosandA.R.Tunkel,eds.ISBN9780444520159
Vol.97,Headache,G.NappiandM.A.Moskowitz,eds.ISBN9780444521392
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Vol.99,SleepdisordersPartII,P.MontagnaandS.Chokroverty,eds.ISBN9780444520074
Vol.100,Hyperkineticmovementdisorders,W.J.WeinerandE.Tolosa,eds.ISBN9780444520142
Vol.101,Musculardystrophies,A.AmatoandR.C.Griggs,eds.ISBN9780080450315
Vol.102,Neuro-ophthalmology,C.KennardandR.J.Leigh,eds.ISBN9780444529039
Vol.103,Ataxicdisorders,S.H.SubramonyandA.Durr,eds.ISBN9780444518927
Vol.104,Neuro-oncologyPartI,W.GrisoldandR.Sofietti,eds.ISBN9780444521385
Vol.105,Neuro-oncologyPartII,W.GrisoldandR.Sofietti,eds.ISBN9780444535023
Vol.106,Neurobiologyofpsychiatricdisorders,T.SchlaepferandC.B.Nemeroff,eds.ISBN9780444520029
Vol.107,EpilepsyPartI,H.StefanandW.H.Theodore,eds.ISBN9780444528988
Vol.108,EpilepsyPartII,H.StefanandW.H.Theodore,eds.ISBN9780444528995
Vol.109,Spinalcordinjury,J.VerhaagenandJ.W.McDonaldIII,eds.ISBN9780444521378
Vol.110,Neurologicalrehabilitation,M.BarnesandD.C.Good,eds.ISBN9780444529015
Vol.111,PediatricneurologyPartI,O.Dulac,M.LassondeandH.B.Sarnat,eds.ISBN9780444528919
Vol.112,PediatricneurologyPartII,O.Dulac,M.LassondeandH.B.Sarnat,eds.ISBN9780444529107
Vol.113,PediatricneurologyPartIII,O.Dulac,M.LassondeandH.B.Sarnat,eds.ISBN9780444595652
Vol.114,Neuroparasitologyandtropicalneurology,H.H.Garcia,H.B.TanowitzandO.H.DelBrutto,
eds.ISBN9780444534903
Vol.115,Peripheralnervedisorders,G.SaidandC.Krarup,eds.ISBN9780444529022
Vol.116,Brainstimulation,A.M.LozanoandM.Hallett,eds.ISBN9780444534972
Vol.117,Autonomicnervoussystem,R.M.BuijsandD.F.Swaab,eds.ISBN9780444534910
Vol.118,Ethicalandlegalissuesinneurology,J.L.BernatandH.R.Beresford,eds.ISBN9780444535016
Vol.119,NeurologicaspectsofsystemicdiseasePartI,J.BillerandJ.M.Ferro,eds.ISBN9780702040863
Vol.120,NeurologicaspectsofsystemicdiseasePartII,J.BillerandJ.M.Ferro,eds.ISBN9780702040870
Vol.121,NeurologicaspectsofsystemicdiseasePartIII,J.BillerandJ.M.Ferro,eds.ISBN9780702040887
Foreword
TheHandbookofClinicalNeurology,foundedbyPierreVinkenandGeorgeBruynin1968,isaprestigious,multi-
volumereferenceworkcoveringalldisordersofclinicalneurology.Rapidprogressinneurologynecessitatesregular
updates.Sowhenthefirstserieswasconcludedin1982,itwasfollowedbyasecondone,editedagainbyVinkenand
Bruyn.Wetookoveraseditorsofthecurrentthirdseries,withvolume79appearinginlate2003andsincethenmore
than40volumeshaveappeared.
Multiplesclerosis(MS)wasfirstdistinguishedclinicallyfromParkinson’sdiseasein1868byJean-MartinCharcot
(1825–1893),andnamedbyhimlascl(cid:2)roseenplaques.Pathologicdescriptionsoftheconditionprecededitsclinical
description.ForinstancetheSwisspathologistGeorgEduardRindfleisch(1836–1908)had5yearsearlierdescribedthe
inflammation-associatedlesionsdistributedaroundbloodvesselsandproposedavascularetiology.Eversincesuch
observations some 150 years ago, MS has been the focus of attention from clinical neurologists. MS and related
inflammatorydemyelinatingdisorderswerecoveredinvolumes9and47ofthefirstandsecondseriesoftheHand-
book. Novel imaging procedures since then have changed the field dramatically. A new volume on this topic also
becamenecessarybecauseoftheextremelyrapidadvancesthathaveoccurredinmolecularbiology,neuropathology,
genetics,immunology,neurophysiology,andCSFanalyses,bythedevelopmentofexperimentalmodelsofthedisease
andanemphasisonevidence-basedtreatments,andbythebetterinsightsindifferentialdiagnosis,etiologicfactors,
clinicaloutcomemeasures,andprognosisthatfollowedtheseotheradvances.
Dr.DouglasGoodin,directoroftheMultipleSclerosisCenterattheUniversityofCaliforniaMedicalCenterinSan
Francisco,isaneurologistandinternationallyrenownedexpertonthisdisease.Hehasassembledatrulyinternational
groupofauthorswithacknowledgedexpertiseandproducedwiththemanauthoritative,comprehensive,andupto
datevolumeonMS.ItsavailabilityelectronicallyonElsevier’sScienceDirectsiteaswellasinprintformatshould
ensureitsreadyaccessibilityandfacilitatesearchesforspecificinformation.
WearegratefultoDr.Goodinandtoallthecontributorsfortheireffortsincreatingsuchaninvaluableresource.
Asserieseditorswereadandcommentedeachofthechapterswithgreatinterest.Wearethereforeconfidentthatboth,
cliniciansandresearchersinmanydifferentdisciplineswillfindmuchinthesevolumestoappealtothem.
AsalwaysitisapleasuretothankElsevier,ourpublishers–andinparticularTomStone,MichaelParkinson,and
KristiAnderson–fortheirunfailingandexpertassistanceinthedevelopmentandproductionofthisvolume.
MichaelJ.Aminoff
Franc¸oisBoller
DickF.Swaab
Preface
Multiplesclerosis(MS)seemstobeamodernillnessthatafflictsonlyhumans.Thus,therearenoknownspontaneous
conditionsinanimalsthatreliablymimicthehumancondition.Also,priortothe14thcentury,therearenoreportsof
conditionsthatbearanyresemblancetomodern-daycasesofMS.Indeed,someauthorsidentify,astheindexcase,
thatofLidwinatheVirginfromSchiedam(Holland)who,atage15years,in1395,fellwhileice-skatingandfractureda
rib.Subsequenttothisfall,Lidwinadevelopedaprogressiveneurologiccondition,whichincludedaparalysisinher
legsandrightarm,blindnessinoneeye,andseverepain.Lidwina’shistoryisoftentakenforanexampleofapro-
gressiveformofMS.Nevertheless,herrepeatedvisionsofGod,theecstasiesthatsheexperienced,andthereligious
fervorthatsurroundeddescriptionsofherillnessmakethediagnosisofMSlessconvincing.Amorereliableindexcase
isthatofAugustusd’Este(1794–1848),thegrandsonofKingGeorgeIII(England)who,beginningin1822,documen-
tedthecourseofhisillnessinadiaryand,almostcertainly,hadtheconditionthatwerefertotodayasrelapsing/remit-
tingMS.
Duringthe19thcentury,ourunderstandingofthediseaseMSaccumulatedonlyslowly.Thefirstdescriptionsofthe
pathologyofMSbyRichardCarswell(1838)andJeanCruvelhier(1841)laggedbehindthisindexcasebyapproximately
twodecadesandthefirstclinicaldescriptionoftheillnessbyJean-MartinCharcot(1868)onlyappeared2to3decades
thereafter(Charcotnamedthecondition:lascl(cid:2)roseenplaques).However,beginninginthe20thcentury,thepaceof
advancesinourunderstandingincreaseddramatically.Theanimalmodel,experimentalautoimmuneencephalomy-
elitis(EAE),wasintroducedinthe1930s;ascaletomeasuredisabilityinMSpatientswasfirstintroducedin1955;the
characteristicoligoclonalIgGbandsweredescribedinthespinalfluidofMSpatientsinthe1960s;variousclinical
neurophysiologictechniques(evokedpotentials)wereintroducedfordiagnosticpurposesinthe1970s;thefirstran-
domized,multicenter,controlledclinicaltrialofatherapyinMSwaspublishedin1970;thefirstMS-susceptibilitygene
(DRB1)wasunequivocallyidentifiedontheshortarmofchromosome6inthe1970s;magneticresonanceimaging
(MRI),whichrevolutionizedourabilitytovisualize(invivo)thepathologyofMS,wasintroducedtomedicineinthe
1980s;andthemoderneraofdiseasemodifyingtherapyforMSwaslaunchedwiththeapprovalofinterferonbeta-1b
therapyin1993.
Nevertheless,despitetheconsiderableprogressmadeduringthe20thcentury,the21stcentury(nowlittlemorethan
adecadeold)hasseenanexponentialexpansioninourknowledgeaboutthepathophysiology,epidemiology,immu-
nology, genetics, molecular mechanisms, neurophysiology, and treatment of MS. We have steadily improved the
designandconductofourclinicaltrialsandourstatisticalmethodssuchthateightdifferent,proven-effective,ther-
apeuticagentsforMSarenowcommerciallyavailableandseveralmoreareinthelatestagesofdrug-development.
UsingbothmodernMRIandmodernspinalfluidanalysis,wenowhavetheabilitytodiagnoseMSinitsveryearliest
(evenpre-clinical)stagesandcanbegintothinkaboutthepossibilityoftherapies,usedattheverybeginningofthe
illness,thatmightarrestthefurthercourseofdisabilityprogression.
Wehavetentativelyidentifiedtwoimportantenvironmentalfactors(vitaminDdeficiencyandEpstein-Barrviral
infections)thatcontributetodiseasedevelopmentand,thus,canbegintocontemplatepotentialmethodsofprimary
disease prevention. And finally, we have now identified approximately 100 MS-associated genes and can envision
utilizingthiskindinformationtoguidefuturetherapeuticinnovations,toassesswho,withinapopulationofindivid-
uals,isatriskofdevelopingthisillness,andtodeterminethemostappropriatetherapyforaspecificpatient-basedon
individualgeneticmake-up.
However,inevitably,withsuchrapidadvancesinknowledge,itbecomesincreasinglydifficultforindividualprac-
titionerstokeepabreastoftherelevantdevelopmentsinwidelydiversefieldsofstudy.Itisthepurposeofthisvolume
tocollectinoneplacethenecessaryinformationforphysicianstobothunderstandandappreciatethesignificanceof
thelatestdevelopmentsinourunderstandingofthediseasewecallMS.Tothisend,thisvolumeincludes30chapters
x PREFACE
devotedtocoveringindepthvarioussubjectareasrelevanttoourcurrentunderstandingofMS.Thus,severalchapters
aredevotedtocoveringtheimportantclinicalaspectsofMS.Forexample,theepidemiologyofMS,itspresentationin
adults and children, its clinical course, and its prognosis are all considered at length. Other chapters are devoted
todiagnosticconsiderations,includingtheclinicalcriteriaand theappropriateuse ofancillarytesting(spinalfluid
analysis, neurophysiology, and neuroimaging) for making the correct diagnosis. The differential diagnosis of MS
isdiscussedindetail,bothgenerallyandalsowithafocusplacedonthoseconditionswithanuncertainrelationship
toMS(e.g.,acutedisseminatedencephalomyelitis,neuromyelitisoptica,andtheacuteinflammatorymyelopathies).
BecauseofthecurrentimportanceofMRIbothinthediagnosisofMSandinmonitoringdiseaseactivity,special
emphasisisplacedontheuseofthistechnique.
Severalchaptersaredevotedtothepathology,pathophysiology,genetics,andimmunologyofMS.Theseinclude
discussionsofimmunefunctionanditsregulationinMS,thegeneticbasisofMSinbothitsrelapsingandprogressive
forms,thepotentiallycausativeroleofinfectiousagentsandautoimmunityinMSpathogenesis,thegoodandbad
aspectsofinflammationinthenervoussystem,andthepathophysiologyofinjurytothemyelinandtheaxonsandthe
useofanimalmodelsinelucidatingthesemechanisms.Finally,thetreatmentofMS(bothnowandinthefuture)is
considered,includingtheuseofdisease-modifyingtherapies,corticosteroids,symptomaticmanagementstrategies,
andthetreatmentofacuteattacks.Moreover,considerationisalsogiventohowthedesignofclinicaltrialsandcertain
keydesignconcepts(e.g.,validity,reliability,replicability,andoutcomeassessment)affect,orshouldaffect,oureval-
uationoftheefficacyandsafetyforthedifferenttherapiesnowavailableandhowwecanappropriatelyincorporate
thisclinicaltrialdataintoclinicalpractice.
Itishopedthat,withthisvolume,boththeinterestedreaderandthebusypractitionerwillfindauseful,thorough,
readilyaccessible,andeasilyunderstandableguidetothebreadthofourmostrecent,butrapidlyexpanding,knowl-
edgeaboutMS.
DouglasS.Goodin,MD
SanFrancisco,California
Contributors
M.Absinta G.Criste
NeuroimagingResearchUnit,Departmentof DepartmentofNeurosciences,LernerResearch
Neurology,SanRaffaeleScientificInstitute, Institute,ClevelandClinic,Cleveland,OH,USA
Vita-SaluteSanRaffaeleUniversity,Milan,Italy
G.Cutter
O.Aktas DepartmentofBiostatistics,UniversityofAlabama,
DepartmentofNeurology,MedicalFaculty,Heinrich- Birmingham,AL,USA
HeineUniversity,Du€sseldorf,Germany
T.M.DeAngelis
CorinneGoldsmithDickinsonCenterforMultiple
B.L.Banwell
Sclerosis,MountSinaiMedicalCenter,NewYork,
DivisionofNeurology,DepartmentofPediatrics,
NY,USA
Children’sHospitalofPhiladelphia,Philadelphia,
PA,USA
J.Derwenskus
DepartmentofNeurology,FeinbergSchool
F.Barkhof
ofMedicine,NorthwesternUniversity,
DepartmentofRadiologyandNuclearMedicine,
Chicago,IL,USA
VUUniversityMedicalCenter,Amsterdam,
TheNetherlands
R.Dutta
DepartmentofNeurosciences,LernerResearch
A.Charil Institute,ClevelandClinic,Cleveland,OH,USA
NeuroimagingResearchUnit,Departmentof
Neurology,SanRaffaeleScientificInstitute, K.Fernando
Vita-SaluteSanRaffaeleUniversity,Milan,Italy NMRResearchUnit,InstituteofNeurology,
London,UK
O.Ciccarelli
DepartmentofBrainRepairandRehabilitation,UCL M.Filippi
InstituteofNeurology,QueenSquare,London,UK NeuroimagingResearchUnit,Departmentof
Neurology,SanRaffaeleScientificInstitute,
Vita-SaluteSanRaffaeleUniversity,Milan,Italy
G.Comi
DepartmentofNeurology,ClinicalNeurophysiology
J.M.Gelfand
andNeurorehabilitation,UniversityHospitalSan
DepartmentofNeurology,UniversityofCalifornia,
Raffaele,Milan,Italy
SanFrancisco,USA
C.Confavreux(deceased)
G.Giovannoni
ServicedeNeurologieA,EDMUSCoordinatingCenter,
CentreforNeuroscienceandTrauma,BlizardInstitute,
INSERMU842,HoˆpitalNeurologiquePierre
BartsandTheLondonSchoolofMedicineand
Wertheimer,Lyon,France
Dentistry,London,UK
B.A.C.Cree D.S.Goodin
DepartmentofNeurology,UniversityofCalifornia, DepartmentofNeurology,UniversityofCalifornia,
SanFrancisco,USA SanFrancisco,USA
xii CONTRIBUTORS
C.T.Harp A.Miller
DepartmentofMicrobiology-Immunologyand CorinneGoldsmithDickinsonCenterforMultiple
InterdepartmentalImmunobiologyCenter,Feinberg Sclerosis,MountSinaiMedicalCenter,NewYork,NY,
SchoolofMedicine,NorthwesternUniversity,Chicago, USA
IL,USA
D.Miller
H.-P.Hartung NMRResearchUnit,InstituteofNeurology,
DepartmentofNeurology,MedicalFaculty,Heinrich- London,UK
HeineUniversity,Du€sseldorf,Germany
S.D.Miller
DepartmentofMicrobiology-Immunologyand
R.T.Johnson
InterdepartmentalImmunobiologyCenter,Feinberg
DepartmentofNeurology,JohnsHopkinsUniversity
SchoolofMedicine,NorthwesternUniversity,
SchoolofMedicineandBloombergSchoolofPublic
Chicago,IL,USA
Health,Baltimore,MD,USA
M.Naegele
L.Kappos
InstituteforNeuroimmunologyandClinicalMultiple
DepartmentofBiomedicine,UniversityHospitalBasel,
SclerosisResearch,CenterforMolecularNeurobiology
Basel,Switzerland
Hamburg,UniversityMedicalCenterHamburg-
Eppendorf,Hamburg,Germany
B.C.Kieseier
DepartmentofNeurology,MedicalFaculty,Heinrich-
A.Noronha
HeineUniversity,Du€sseldorf,Germany
DepartmentofNeurology,UniversityofChicago,
Chicago,IL,USA
A.Kutzelnigg
CentreforBrainResearch,MedicalUniversityof P.W.O’Connor
Vienna,Vienna,Austria MultipleSclerosisClinic,St.Michael’sHospital,
Toronto,Canada
H.Lassmann
CentreforBrainResearch,MedicalUniversityof J.Oh
Vienna,Vienna,Austria MultipleSclerosisClinic,St.Michael’sHospital,
Toronto,CanadaandDepartmentofNeurology,
L.Leocani JohnsHopkinsUniversity,Baltimore,MD,USA
DepartmentofNeurology,ClinicalNeurophysiology
andNeurorehabilitation,UniversityHospitalSan D.T.Okuda
Raffaele,Milan,Italy ClinicalCenterforMultipleSclerosis,Departmentof
NeurologyandNeurotherapeutics,UTSouthwestern
C.Lubetzki MedicalCenter,Dallas,TX,USA
CentredeRecherchedel’InstitutduCerveauetdela
MoelleE´pinie`re,Salpeˆtrie`reHospital,UMRS975,Paris, A.P.Robinson
France DepartmentofMicrobiology-Immunologyand
InterdepartmentalImmunobiologyCenter,Feinberg
F.D.Lublin SchoolofMedicine,NorthwesternUniversity,Chicago,
DepartmentofNeurologyandCorinneGoldsmith IL,USA
DickinsonCenterforMultipleSclerosis,MountSinai
Hospital,NewYork,NY,USA M.A.Rocca
NeuroimagingResearchUnit,Departmentof
R.Martin Neurology,SanRaffaeleScientificInstitute,
NeuroimmunologyandMSResearch,NeurologyClinic, Vita-SaluteSanRaffaeleUniversity,Milan,Italy
UniversityHospital,Zurich,Switzerland
M.Rovaris
T.Menge NeuroimagingResearchUnit,Departmentof
DepartmentofNeurology,MedicalFaculty,Heinrich- Neurology,SanRaffaeleScientificInstitute,Vita-Salute
HeineUniversity,Du€sseldorf,Germany SanRaffaeleUniversity,Milan,Italy
CONTRIBUTORS xiii
E.Sa´nchezAliaga B.Trapp
DepartmentofRadiologyandNuclearMedicine,VU DepartmentofNeurosciences,LernerResearch
UniversityMedicalCenter,Amsterdam,TheNetherlands Institute,ClevelandClinic,Cleveland,OH,USA
N.Scolding B.M.J.Uitdehaag
InstituteofClinicalNeurosciences,FrenchayHospital, DepartmentofNeurology,VUUniversityMedical
Bristol,UK Center,Amsterdam,TheNetherlands
J.H.Simon A.Venkatesan
OregonHealthandSciencesUniversityandPortlandVA DepartmentofNeurology,JohnsHopkinsUniversity
MedicalCenter,Portland,OR,USA SchoolofMedicineandBloombergSchoolofPublic
Health,Baltimore,MD,USA
B.Stankoff
CentredeRecherchedel’InstitutduCerveauetdela S.Vukusic
MoelleE´pinie`re,Salpeˆtrie`reHospital,UMRS975, ServicedeNeurologieA,EDMUSCoordinatingCenter,
Paris,France INSERMU842,HoˆpitalNeurologiquePierre
Wertheimer,Lyon,France
J.Swanton
NMRResearchUnit,InstituteofNeurology,London,UK B.G.Weinshenker
DepartmentofNeurology,MayoClinic,Rochester,
A.Thompson MN,USA
DepartmentofBrainRepairandRehabilitation,UCL
InstituteofNeurology,QueenSquare,London,UK D.M.Wingerchuk
DepartmentofNeurology,MayoClinic,Scottsdale,
A.Toosy AZ,USA
Department of Brain Repair and Rehabilitation,
UCL Institute of Neurology, Queen Square,
London, UK
HandbookofClinicalNeurology,Vol.122(3rdseries)
MultipleSclerosisandRelatedDisorders
D.S.Goodin,Editor
©2014ElsevierB.V.Allrightsreserved
Chapter1
Immune regulation of multiple sclerosis
HANS-PETERHARTUNG*,ORHANAKTAS,TILMENGE,ANDBERNDC.KIESEIER
DepartmentofNeurology,MedicalFaculty,Heinrich-HeineUniversity,D€usseldorf,Germany
Multiple sclerosis (MS) is a chronic, inflammatory, adaptive immune responses. While it has clearly been
demyelinating disease of the central nervous system shown that TLRs are critical in host defense against a
(CNS). It is regarded as an autoimmune disease and a varietyofpathogens,theyhavealsobeenimplicatedin
complexinterplayofgeneticandenvironmentalfactors the etiology of allergies and various autoimmune dis-
governs an individual’s susceptibility to the disease eases. InMS most ofthe current insights to aputative
(Comabella and Khoury, 2011). For a long time, MS role of TLRs in this disease have been derived from
was believed to be exclusively driven by T cells; this EAE studies (Racke and Drew, 2009). Hence, TLR3
hypothesis was based on observations made from an stimulation was observed to have protective effects in
important animal model, experimental autoimmune EAE as a consequence of an increased expression of
encephalomyelitis(EAE).Thisviewhasbeenchallenged interferon-b (IFN-b) (Touil et al., 2006). In addition,
in recent years. Insights into the role of the innate TLR4-deficient mice displayed a more severe EAE
immune system as well as an increased understanding course (Marta et al., 2008) whereas Myd88-deficient
ofBcellsinMSofferanindepthviewtothecomplexity mice were resistant to the disease (Prinz et al., 2006;
ofthisdisease(Mixetal.,2010). Martaetal.,2008).Theseresultssuggestthatsignaling
through the Myd88-independent pathway, which pro-
motestheexpressionoftypeIIFNs,couldexhibitapro-
INNATEIMMUNERESPONSES
tective role in EAE, whereas signaling through the
Myd88-dependent pathway, which activates NF-kB
Autoimmune diseases, specifically MS, are driven by
andleadstothesecretionofproinflammatorycytokines,
the actions of adaptive immune cells targeting self
would exacerbate the autoimmune disease. Studies on
antigens. The innate immune system plays a key role
the tyrosine phosphatase SHP-1, which inhibits the
in the initiation and propagation of tissue inflamma-
Myd88-dependent pathway but not the TRIF-mediated
tion. Characteristically, innate immune responses
pathway (O’Neill, 2008), point in the same direction.
consist of all the immune defense mechanisms that do
Thus, in a recent study, deficient expression of SHP-1
not require immunologic memory. The strategy of the
atboththeproteinandmRNAlevelswasfoundinmac-
innateimmuneresponseisnottorecognizeeverypossi-
rophagesfromMSpatients(Christophietal.,2009).The
bleantigen,butrathertofocusonafewhighlyconserved
decreasedexpressionofSHP-1ledtohigherpresenceof
structures present in large groups of microorganisms,
inflammatorycytokines(tumornecrosisfactor-a(TNF-
such as bacterial lipopolysaccharide, peptidoglycan,
a),interleukin-6(IL-6))andchemokines(CCL2,CCL7)
and bacterial DNA (Medzhitov and Janeway, 2000).
followingTLRstimulation.Furthermore,SHP-1silenced
Thesemoleculesserveasligandstoarecentlydiscovered
macrophages from healthy controls also exhibited
groupofsurfacemolecules,theso-calledpatternrecog-
enhanced inflammatory responses (Christophi et al.,
nitionreceptors(PRRs),suchasCD14,b -integrins,and
2
2009)(Fig.1.1).
complement receptors (CR1/CD35, CR2/CD21). In the
Following the recognition of pathogens, the task of
defense of microbial patterns, one group of PRRs, the
presentingantigensofcell-associatedmicrobesforrec-
Toll-like receptors (TLR), are of critical importance
ognitionbyTlymphocytesisperformedbyspecificmol-
(Moynagh,2005;PasareandMedzhitov,2005).Activa-
ecules that are encoded bygenescomprising themajor
tionofTLRsresultintheregulationofbothinnateand
*Correspondenceto:Hans-PeterHartung,DepartmentofNeurology,MedicalFaculty,Heinrich-HeineUniversity,Moorenstrasse
5,Du€sseldorf,Germany.Tel:þ49-211-8117880,E-mail:[email protected]
