Table Of ContentApoptosis and Autoimmunity
Editedby
M.HerrmannandJ.R. Kalden
ApoptosisandAutoimmunity.FromMechanismstoTreatments.
EditedbyJ.R.Kalden,M.Herrmann
Copyright©2003WILEY-VCHVerlagGmbH&Co.KGaA,Weinheim
ISBN:3-527-30442-8
Further titles of interest
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Stewart,C.C./Nicholson,J.K.A.(Eds.)
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Freshney,R.I.
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AManualof Basic Technique
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Krauss,G./Cooper,B.L./Schönbrunner,N.
Biochemistry of Signal Transduction and Regulation
Building Blocks andFineChemicals
2001, ISBN3-527-30378-2
Apoptosis and Autoimmunity
Edited by
M. Herrmann and J.R. Kalden
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ISBN 3-527-30442-8
V
Preface
More than 100 years ago Paul Ehrlich coined the expression ‘horror autotoxicus’
implicating the existenceof autoimmune diseases.After the firstdescriptionof an
autoimmune disease of the thyroid, it soon became obvious that autoimmunity in
principle is a self-limiting process, which in certain situations might proceed in
an autoaggressive disease situation, when stringent control mechanisms have
failed or are dysregulated. Despite of extensive research activities over the past de-
cades, the etiology of autoimmune diseases is still enigmatic. Different hypoth-
eses have been postulated, although these only partially explain the phenomenon
of‘autoimmunity’.
More recently, the relationship between autoimmunity and apoptosis has been
the focus of much research activity. Apoptosis as a genetically predetermined pro-
cessisnotonly avital mechanismsustaining homeostasisinthe regulation ofim-
mune reactivity, but, in addition to being an important factor in general cell phy-
siology, produces pronounced morphological changes of cells and the breakdown
of cellular constituents by nucleolytic and proteolytic cleavage, resulting in the
persisting presence of potential autoantigens. This book presents an up-to-date
discussionon apoptosisand its rolein autoimmunity.
We would like to express our appreciation and gratitude to the authors for their
outstanding contributions and cooperation. We also gratefully acknowledge the
continuous support of Andreas Sendtko and his colleagues at Wiley-VCH in the
realization ofthis book.
Erlangen, July 2002 Martin Herrmann
Joachim R. Kalden
ApoptosisandAutoimmunity.FromMechanismstoTreatments.
EditedbyJ.R.Kalden,M.Herrmann
Copyright©2003WILEY-VCHVerlagGmbH&Co.KGaA,Weinheim
ISBN:3-527-30442-8
VII
Contents
Preface V
ListofContributors XVII
Part1 GeneralFeaturesofApoptosis 1
1 Apoptosis andAutoimmunity 3
Keith Elkon
1.1 Introduction 3
1.2 Autoimmune DiseasesAssociatedwith Targeted Cell Destruction 5
1.2.1 What isthe Modeof Cell Death? 5
1.2.2 What Cellsand What EffectorPathways are Responsible
forCell Death? 6
1.3 Autoimmune DiseasesAssociatedwith Enhanced Cell Growth
and Survival 7
1.4 Autoimmune DiseasesAssociatedwith Abnormal Processing
ofDying Cells 7
1.5 Conclusions 9
1.6 References 10
2 CaspaseKnockouts: MattersofLifeandDeath 13
Saquib Lakhani, Binfeng Lu and Richard A. Flavell
2.1 Death, Developmentand Immune Function 13
2.2 Apoptotic Pathways: fromNematode to Mammals 15
2.3 Triggering a Killer: General Aspects of CaspaseActivation 16
2.4 Caspase-1and -11: Morethan MediatorsofInflammatory
Cytokines? 17
2.5 Caspase-8and the FAS Signaling Pathway 19
2.6 Caspase-3:The Chief Executioner? 21
2.7 Caspase-9:MitochondrialActivation and the Apoptosome 22
2.8 Caspase-2:A Duality of Function 24
2.9 Caspase-12:Responding to Stress 25
2.10 Compensatory CaspaseActivation:A Caveat to Knockout Analysis 26
2.11 Caspases:Morethan Simple Killers 27
2.12 ConcludingRemarks 28
2.13 References 29
ApoptosisandAutoimmunity.FromMechanismstoTreatments.
EditedbyJ.R.Kalden,M.Herrmann
Copyright©2003WILEY-VCHVerlagGmbH&Co.KGaA,Weinheim
ISBN:3-527-30442-8
VIII Contents
Part2 ClearanceofApoptotic Cells 37
3 Anti-inflammatory andImmunoregulatoryEffects ofApoptotic Cells 39
Reinhard E. Voll,Martin Herrmann,IruteGirkontaite, WasilisKolowos
and Joachim R. Kalden
3.1 Introduction 39
3.2 Anti-inflammatory EffectsofApoptotic Cells
on Monocytes/Macrophages 40
3.3 The Role of Anti-inflammatory Cytokines for the Inhibition
ofPro-inflammatory Cytokine Production 45
3.4 Monocyte/Macrophage Receptorsreceivingthe Anti-inflammatory
Signal fromApoptotic Cells 46
3.5 Intracellular Signaling EventsCausing the Anti-inflammatory
State inMacrophages 48
3.6 ApoptoticCellsImpairMHCClassII SurfaceExpression
onMonocytes 48
3.7 Influence ofApoptoticCellsonDCFunctioninAllogeneicMLR 49
3.8 The PresenceofApoptoticCellscanShift the T CellResponse
h
towardsT 2 50
h
3.9 ApoptoticCellsSuppressDelayed-typeHypersensitivity(DTH)
InVivo 51
3.10 NecrosisandInflammation 51
3.11 Implications ofthe Anti-inflammatory andImmunodulatory
EffectsofApoptoticCellsforHealth andDisease 53
3.11.1 ApoptosisandPregnancy 53
3.11.2 ApoptosisandIrradiation 53
3.11.3 ApoptosisandCancer 53
3.11.4 ApoptosisandInfections 54
3.11.5 ApoptosisandBloodTransfusions 54
3.12 References 55
4 ComplementandApoptosis 57
Dror Mevorach
4.1 Introduction 57
4.2 ProgrammedCellDeath (PCD) 57
4.3 Complement 59
4.4 Complement andApoptosis 62
4.4.1 RoleofComplement inthe ExecutionPhase 62
4.4.2 Complement ActivationbyApoptoticCells 65
4.5 Apoptosis,Complement andAutoimmunity 68
4.6 References 70
5 SolubleFactorsthatBindtoDyingCellsControltheOutcome
ofCorpseDisposal:
TheRoleofPentraxins,CollectinsandAutoantibodies 79
Patrizia Rovere-Querini
Contents IX
5.1 Introduction 79
5.2 Soluble FactorsInvolvedin Apoptotic Cell Recognition
and Internalization 76
5.2.1 CorpseClearance at Rest: Collectins 79
5.2.2 CorpseClearanceat Rest:CationicFactorsandOtherPS-binding
Moieties 81
5.2.3 CorpseClearanceduring AcuteInflammation: Pentraxins 82
5.3 CorpseClearanceinAutoimmunePatients:Autoantibodies 86
5.4 Conclusions 88
5.5 Acknowledgements 89
5.6 References 89
6 TheRoleofATP-bindingCassetteTransportersintheClearance
ofApoptotic Cells:ATaleofTwoSystems 97
VéroniqueRigot and Giovanna Chimini
6.1 Introduction 97
6.2 The Family ofABC Transporters 97
6.3 The CaseofABCA1 in Mammals 99
6.3.1 ABCA1 andReverseCholesterolTransport 102
6.3.2 ABCA1 and Engulfment 103
6.4 The CaseofCED-7in C. elegans 104
6.5 The Model 106
6.6 References 107
7 InnateImmunityandApoptosis:
CD14-dependentClearanceofApoptotic Cells 111
ChristopherD. Gregoryand AndrewDevitt
7.1 Introduction: CD14, A Multifunctional Moleculeinvolved
in Innate Immune Responses 111
7.1.1 Background 111
7.1.2 MolecularStructureandDistributionofCD14 111
7.1.3 CD14asanLPS Receptorthat Signals LPS Responses 112
7.1.4 CD14BindsMultiple andDiverseLigands 113
7.2 Evidencethat Apoptotic Cells Interact with CD14 114
7.2.1 61D3, a CD14 MonoclonalAntibody that BlocksApoptotic
Cell Clearance 114
7.2.2 ExogenousExpressionofCD14 in Non-myeloidCells 114
7.2.3 ApoptoticCell-associatedLigandsofCD14 116
7.3 Mechanisms:Conceptualizing CD14’sRoleinApoptotic
CellClearance 119
7.3.1 CD14asaPRR that RecognizesApoptoticCell-associated
MolecularPatterns(ACAMPs) 119
7.3.2 DifferentialCD14Signaling following Ligand Binding 121
7.4 Conclusions:RelativeImportanceofCD14inApoptotic
CellClearance 122
7.5 References 124
X Contents
Part3 AutoimmunityCausedbyDefective Execution ofApoptosis
orDefective ClearanceofApoptotic Cells 133
8 AutoimmuneLymphoproliferative Syndromes(ALPS) 135
FrédérikRieux-Laucat,Françoise leDeistand AlainFischer
8.1 Introduction 135
8.2 DeathReceptorsandSignaling ofApoptosis 135
8.3 ClinicalandImmunological BasisofALPS 138
8.3.1 Definitions 138
8.3.2 ClinicalPresentation 138
8.3.2.1 Lymphoproliferation 138
8.3.2.2 Autoimmune Manifestations 139
8.3.2.3 OtherClinical Manifestations 140
8.3.3 LaboratoryFindings 140
8.3.3.1 Immunological Data 140
8.3.3.2 Pathological Findings 140
8.3.4 Treatment 141
8.4 GeneticandMolecularBasesofALPS 141
8.4.1 ALPS 0 142
8.4.2 ALPS Ia 142
8.4.3 ALPS Ib 145
8.4.4 ALPS II 145
8.4.5 ALPS III 146
8.5 MechanismofAutoimmunity inALPS 147
8.6 Conclusion 148
8.7 References 149
9 InfectionandInflammation asCofactors forAutoimmunity
ofSystemicLupusErythematosus Patients 157
Hanns-Martin Lorenz
9.1 Introduction 157
9.2 InfectionandAutoimmunity 157
9.3 Infection,Inflammation andSLE:TheoryandPracticalAspects 159
9.3.1 TheoreticalConsiderationsforthe PathogenesisofSLE 159
9.3.2 PracticalAspectsinHuman SLE 163
9.4 Conclusions 164
9.5 References 165
10 Apoptosis inRheumatoid Arthritis 169
Yuji Yamanishi and Gary S. Firestein
10.1 Introduction 169
10.2 ApoptosisinRA Synovium 171
10.3 ApoptosisinSynovialFluid T Cells 172
10.4 Regulation ofApoptosisbyCytokines 173
10.5 p53Mutations inRA SynoviumandFibroblast-likeSynoviocytes 174
10.5.1 The RoleandRegulation ofp53TumorSuppressorProtein 174
Contents XI
10.5.2 p53ProteinExpressioninInflammation 175
10.5.3 p53Mutations inRA SynovialTissue 176
10.5.4 PossibleMechanismofOccurrenceofp53Mutations 176
10.5.5 Functionofp53Mutations inRA Synovial Cells 177
10.6 Fas-FasLigand (FasL)ApoptoticPathway inRA 177
10.6.1 FasandFasL 177
10.6.2 Fas-FasLExpressioninSynovium 178
10.6.3 Fas-FasLExpressioninSynovial FluidCells 178
10.6.4 sFas 178
10.6.5 sFasL 179
10.6.6 Fas-MediatedApoptosis 179
10.7 Therapeutic TargetofMoleculesforInducing Apoptosis
inSynovialTissues 180
10.7.1 Fas-FasLandRelatedMolecules 180
10.7.2 NuclearFactor(NF)-(cid:1)BandRelatedMolecules 181
10.7.3 p53TumorSuppressorGene 182
10.7.4 Proteasome 182
10.8 Conclusion 182
10.9 References 183
11 SystemicLupusErythematosus 187
Thomas D. Beyer, SusanneKuenkele,Udo S. Gaipl,WasilisKolowos,
Reinhard E. Voll,Irith Baumann, Joachim R. Kalden
and Martin Herrmann
11.1 Introduction 187
11.2 InvolvementofBCellsinthe DevelopmentofSLE 187
11.3 InvolvementofT Cellsinthe DevelopmentofSLE 188
11.4 GeneticFactorsforthe DevelopmentofSLE 189
11.5 Animal Modelsforthe Immunogenicity ofDying Cells 189
11.6 PhagocytosisofApoptoticCells 190
11.7 ReducedPhagocytosisofApoptoticCellsinSLE Patients
Challenges T CellTolerance 190
11.7.1 IncreasedApoptosisinSLEPatients? 190
11.7.2 ReducedPhagocytosisofApoptoticCellsbyInVitro
GeneratedMacrophagesfromSLEPatients 191
11.7.3 Hypothesis:AccumulationofSecondaryNecroticCellsChallenges
T CellToleranceinSLE 191
11.8 The GerminalCenterReaction 193
11.9 ReducedPhagocytosisofApoptoticCellsinSLE PatientsChallenges B
CellTolerance 196
11.9.1 The NumberofTingibleBodyMacrophagesisReduced
inthe GerminalCentersofSLEPatients 196
11.9.2 AccumulationofApoptoticCell-DerivedNuclearFragments
inthe GerminalCentersofSLEPatients 197
