Current Concepts in Autoimmunity and Chronic Inflammation

287 Pages·2006·4.97 MB·English

by  F. Melchers, A. R. Rolink (auth.), Andreas Radbruch Ph.D., Peter E. Lipsky MD (eds.)

305
Current Topics
in Microbiology
and Immunology
Editors
R.W.Compans,Atlanta/Georgia
M.D.Cooper,Birmingham/Alabama
T.Honjo,Kyoto·H.Koprowski,Philadelphia/Pennsylvania
F.Melchers,Basel·M.B.A.Oldstone,LaJolla/California
S.Olsnes,Oslo·M.Potter,Bethesda/Maryland
P.K.Vogt,LaJolla/California·H.Wagner,Munich
A. Radbruch and P.E. Lipsky (Eds.)
Current Concepts
in Autoimmunity
and Chronic
Inflammation
With29Figuresand18Tables
123
AndreasRadbruch,Ph.D.
DeutschesRheumaforschungszentrumBerlin(DRFZ)
Schumannstr.21/22
10117Berlin
Germany
e-mail:[email protected]
PeterE.Lipsky,MD
NationalInstituteofArthritisandMusculoskeletalandSkinDiseases
9000RockvillePike
Bethesda,MD20892-1560
USA
e-mail:[email protected]
CoverfiguresbyKatrinMoser(chapterManzetal.,thisvolume):
BrdU(green)labeledlong-livedandBrdU-negativeshort-livedplasmacells(blue)inthespleenof
NZB/Wmice.Bcellsareshowninred.
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Preface
The immune system has been known to be capable of distinguishing self
fromnon-selfsincethepioneeringworkofPaulErhlichmorethanacentury
ago.Originallydescribedinexperimentsstudyingbloodtransfusioncompat-
ibility,theprincipleof“horrorautotoxicus”isstillvalid,althoughtodaythe
phenomenonisusuallydescribedintermsoftoleranceorignorance.Agreat
dealhasbeenlearnedaboutthevariousprocessespreventingself-reactivity
normally.Theseincludeprocessesthatoperateduringimmunecellontogeny
andsubsequentlyonreactivityofmaturelymphocytesintheperiphery.They
encompassmechanismsthatareintrinsictopotentiallyreactivelymphocytes
andcanresultincentralorperipheraldeletionorthealterationoffunctional
potential. In addition, there are influences that are extrinsic to potentially
auto-reactive lymphocytes, including the function of regulatory cells, dif-
ferentiationstateofantigen-presentingcells,availabilityofself-antigen,the
cytokineandchemokinemilieu,aswellasthetraffickingpatternsinvolved
in generating productive immune interactions. It is clear that the immune
systemdevotesaconsiderableefforttotheavoidanceofthedevelopmentof
potentiallypathogenicself-reactivity.
Despitethis,thedevelopmentofself-reactivityisrelativelycommon.Al-
thoughthedevelopmentofautoimmunediseaseislessfrequent,autoimmune
diseases,suchasrheumatoidarthritis,multiplesclerosis,systemiclupusery-
thematosus,psoriasis,thyroiditis,andmyastheniagravis,arealltoocommon,
andcancauseconsiderablemorbidityandevenmortality.Thatthebreakdown
ofself/non-selfdiscriminationcanresultinautoimmunityandinsomecir-
cumstancesautoimmunediseasehasbeenknownformorethat50years.In
mostcircumstances,however,theprecisemechanismunderlyingthedevel-
opmentofautoimmunediseaseisunknown.Althoughmanyelegantanimal
models of autoimmune disease have been developed, some of which result
from a single genetic defect, in most circumstances the relevance of these
animalmodelstohumanautoimmunediseaseremainsuncertain.
Therehasbeengreatprogressinthelastfewyearsinthedevelopmentof
more precise knowledge of the control of the function of the immune sys-
VI Preface
tem. Awareness of the complex interactions of the innate and the adaptive
immunesystem,theroleofapoptosisinregulatingtheevolutionofimmune
reactivity,aswellastheroleofvariousregulatorycellsinshapingandlimiting
immunereactivityhaspermittedthedevelopmentofabetterunderstanding
ofimmunesystembiology.Newinsightshavenotonlycomefromtraditional
immunologicstudies,butalsofromgeneticanalysesofbothimmunerespon-
siveness and autoimmune disease. In addition, new insights have emerged
fromstudiesofthecontrolofcellsignaling,biochemicalanalysisoftheregu-
lationofcellulardifferentiation,aswellasthedetailedanalysisofthebiology
andbiochemistryoftheplethoraofeffectormoleculesinvolvedinregulating
theexpressionofimmunereactivity.
Thewealthofnewinsightshaspromptedare-assessment ofthemecha-
nismscontrollingself/non-selfdiscriminationandthespecificabnormalities
thatresultinabreakdownofthisfundamentalandessentialprotectiveprop-
erty of animals. The goal of this volume is to utilize the wealth of new in-
formationtore-assessself/non-selfdiscriminationwiththeexpectationthat
viewing this old challenge with more modern eyes may generate novel in-
sights.Itisanticipatedthatnewhypothesesmayemergeaboutthecontrolof
autoimmunity,andthatnovelpotentialtargetsmayberecognizedaspotential
pointsofinterventiontotreatorevenpreventautoimmunedisease.
December2005 PeterE.LipskyandAndreasRadbruch
ListofContents
BCellTolerance—HowtoMakeItandHowtoBreakIt................... 1
F.MelchersandA.R.Rolink
BreakingIgnorance:TheCaseoftheBrain ........................... 25
H.Wekerle
NaturallyArisingFoxp3-ExpressingCD25+CD4+RegulatoryTCells
inSelf-ToleranceandAutoimmuneDisease........................... 51
S.Sakaguchi,R.Setoguchi,H.Yagi,andT.Nomura
SexHormonesandSLE:InfluencingtheFateofAutoreactiveBCells ......... 67
J.F.G.Cohen-Solal,V.Jeganathan,C.M.Grimaldi,E.Peeva,and
B.Diamond
Innate(Over)immunityandAdaptiveAutoimmuneDisease ............... 89
M.RecherandK.S.Lang
CanUnresolvedInfectionPrecipitateAutoimmuneDisease?...............105
D.J.B.Marks,N.A.Mitchison,A.W.Segal,andJ.Sieper
TheSystemicAutoinflammatoryDiseases:
InbornErrorsoftheInnateImmuneSystem ..........................127
S.BrydgesandD.L.Kastner
InefficientClearanceofDyingCellsandAutoreactivity ..................161
U.S.Gaipl,A.Sheriff,S.Franz,L.E.Munoz,R.E.Voll,J.R.Kalden,and
M.Herrmann
TheImportanceofTCellInteractionswithMacrophages
inRheumatoidCytokineProduction ...............................177
F.M.Brennan,A.D.Foey,andM.Feldmann
TCellActivationasStarterandMotorofRheumaticInflammation ..........195
A.Skapenko,P.E.Lipsky,andH.Schulze-Koops
VIII ListofContents
SignallingPathwaysinBCells:ImplicationsforAutoimmunity .............213
T.DörnerandP.E.Lipsky
ImmunologicalMemoryStabilizingAutoreactivity .....................241
R.A.Manz,K.Moser,G.-R.Burmester,A.Radbruch,andF.Hiepe
GeneticsofAutoimmuneDiseases:AMultistepProcess ..................259
M.Johannesson,M.Hultqvist,andR.Holmdahl
SubjectIndex................................................277
ListofContributors
(Addressesstatedatthebeginningofrespectivechapters)
Brennan,F.M. 177 Manz,R.A. 241
Brydges,S. 127 Marks,D.J.B. 105
Burmester,G.-R. 241 Melchers,F. 1
Mitchison,N.A. 105
Cohen-Solal,J.F.G. 67 Moser,K. 241
Munoz,L.E. 161
Dörner,T. 213
Diamond,B. 67 Nomura,T. 51
Feldmann,M. 177 Peeva,E. 67
Foey,A.D. 177
Franz,S. 161 Radbruch,A. 241
Recher,M. 89
Gaipl,U.S. 161 Rolink,A.R. 1
Grimaldi,C.M. 67
Sakaguchi,S. 51
Herrmann,M. 161 Schulze-Koops,H. 195
Hiepe,F. 241 Segal,A.W. 105
Holmdahl,R. 259 Setoguchi,R. 51
Hultqvist,M. 259 Sheriff,A. 161
Sieper,J. 105
Jeganathan,V. 67 Skapenko,A. 195
Johannesson,M. 259
Voll,R.E. 161
Kalden,J.R. 161
Kastner,D.L. 127 Wekerle,H. 25
Lang,K.S. 89 Yagi,H. 51
Lipsky,P.E. 195,213
CTMI(2006)305:1–23
(cid:1)c Springer-VerlagBerlinHeidelberg2006
BCellTolerance—HowtoMakeItandHowtoBreakIt
F.Melchers1,2((cid:1))·A.R.Rolink3
1DepartmentofCellBiology,Biozentrum,UniversityofBasel,
Klingelbergstrasse50–70,4056,Basel,Switzerland
[email protected];[email protected]
2CampusCharite,MaxPlanckInstituteforInfectionBiology,
Schumannstrasse21–22,10117 Berlin, Germany
3CenterforBiomedicine,UniversityofBasel,DKBW,
DevelopmentalandMolecularImmunology,
Mattenstrasse28,4058Basel,Switzerland
1 Introduction ........................................... 2
2 RepertoireSelectionsbythepre-BCellReceptor .................. 6
3 GenerationofImmature,sIgM+BCells......................... 7
4 NegativeandPositiveSelection,andIgnorance
oftheDevelopingImmatureBCellRepertoires................... 9
5 NegativeSelectionandEditing .............................. 10
6 Ignorance ............................................. 12
7 PositiveSelection........................................ 13
8 PeripheralBCellsWithoutsIgExpression ...................... 14
9 RescueofAutoreactiveBCellsbyTCell-IndependentAntigens
ofTypeI,TLR–Ligand–Antigen-Complexes ..................... 15
10 AutoreactionRescuedbyIgnorance ........................... 16
11 BreakingtheToleranceofMature,PeripheralBCellRepertoires....... 17
12 ConsequencesofBreakingBCellTolerance—AutoimmuneDiseases.... 19
References.................................................. 20
Abstract Aseriesofcheckpointsforantigenreceptorfitness andspecificity during
B cell development ensures the elimination or anergy of primary, high-avidity –
autoantigen-reactive B cells. Defects in genes encoding molecules with which this