Table Of ContentApoptosis and Autoimmunity
Edited by
M. Herrmann and J.R. Kalden
Apoptosis and Autoimmunity. From Mechanisms to Treatments.
Edited by J.R. Kalden, M. Herrmann
Copyright © 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
ISBN: 3-527-30442-8
Further titles of interest
Stuhler, G. / Walden, P. (Eds.)
Cancer Immune Therapy
Current and Future Strategies
2000, ISBN 3-527-30441-X
Stewart, C.C. / Nicholson, J.K.A. (Eds.)
Immunophenotyping
Cytometric Cellular Analysis
2000, ISBN 0-471-23957-7
Freshney, R.I.
Culture of Animal Cells
A Manual of Basic Technique
2000, ISBN 0-471-34889-9
Krauss, G. / Cooper, B.L. / Schönbrunner, N.
Biochemistry of Signal Transduction and Regulation
Building Blocks and Fine Chemicals
2001, ISBN 3-527-30378-2
Edited by
M. Herrmann and J.R. Kalden
Apoptosis and Autoimmunity
Prof. Dr. Dr. Joachim R. Kalden
University of Erlangen-Nuremberg
Department of Internal Medicine III
and Institute for Clinical Immunology
Krankenhausstraße 12
91054 Erlangen, Germany
Dr. Dr. Martin Herrmann
University of Erlangen-Nuremberg
Institute for Clinical Immunology
Krankenhausstraße 12
91054 Erlangen, Germany
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© 2003 WILEY-VCH Verlag GmbH & Co. KGaG,
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This book was carefully produced. Nevertheless,
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More than 100 years ago Paul Ehrlich coined the expression ‘horror autotoxicus’
implicating the existence of autoimmune diseases. After the first description of 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-
cess is not only a vital mechanism sustaining homeostasis in the regulation of im-
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
discussion on apoptosis and its role in 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 of this book.
Erlangen, July 2002
Martin Herrmann
Joachim R. Kalden
V
Preface
Apoptosis and Autoimmunity. From Mechanisms to Treatments.
Edited by J.R. Kalden, M. Herrmann
Copyright © 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
ISBN: 3-527-30442-8
Preface
V
List of Contributors
XVII
Part 1
General Features of Apoptosis
1
1
Apoptosis and Autoimmunity
3
Keith Elkon
1.1
Introduction
3
1.2
Autoimmune Diseases Associated with Targeted Cell Destruction
5
1.2.1
What is the Mode of Cell Death?
5
1.2.2
What Cells and What Effector Pathways are Responsible
for Cell Death?
6
1.3
Autoimmune Diseases Associated with Enhanced Cell Growth
and Survival
7
1.4
Autoimmune Diseases Associated with Abnormal Processing
of Dying Cells
7
1.5
Conclusions
9
1.6
References
10
2
Caspase Knockouts: Matters of Life and Death
13
Saquib Lakhani, Binfeng Lu and Richard A. Flavell
2.1
Death, Development and Immune Function
13
2.2
Apoptotic Pathways: from Nematode to Mammals
15
2.3
Triggering a Killer: General Aspects of Caspase Activation
16
2.4
Caspase-1 and -11: More than Mediators of Inflammatory
Cytokines?
17
2.5
Caspase-8 and the FAS Signaling Pathway
19
2.6
Caspase-3: The Chief Executioner?
21
2.7
Caspase-9: Mitochondrial Activation and the Apoptosome
22
2.8
Caspase-2: A Duality of Function
24
2.9
Caspase-12: Responding to Stress
25
2.10
Compensatory Caspase Activation: A Caveat to Knockout Analysis
26
2.11
Caspases: More than Simple Killers
27
2.12
Concluding Remarks
28
2.13
References
29
VII
Contents
Apoptosis and Autoimmunity. From Mechanisms to Treatments.
Edited by J.R. Kalden, M. Herrmann
Copyright © 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
ISBN: 3-527-30442-8
Part 2
Clearance of Apoptotic Cells
37
3
Anti-inflammatory and Immunoregulatory Effects of Apoptotic Cells
39
Reinhard E. Voll, Martin Herrmann, Irute Girkontaite, Wasilis Kolowos
and Joachim R. Kalden
3.1
Introduction
39
3.2
Anti-inflammatory Effects of Apoptotic Cells
on Monocytes/Macrophages
40
3.3
The Role of Anti-inflammatory Cytokines for the Inhibition
of Pro-inflammatory Cytokine Production
45
3.4
Monocyte/Macrophage Receptors receiving the Anti-inflammatory
Signal from Apoptotic Cells
46
3.5
Intracellular Signaling Events Causing the Anti-inflammatory
State in Macrophages
48
3.6
Apoptotic Cells Impair MHC Class II Surface Expression
on Monocytes
48
3.7
Influence of Apoptotic Cells on DC Function in Allogeneic MLR
49
3.8
The Presence of Apoptotic Cells can Shift the Th Cell Response
towards Th2
50
3.9
Apoptotic Cells Suppress Delayed-type Hypersensitivity (DTH)
In Vivo
51
3.10
Necrosis and Inflammation
51
3.11
Implications of the Anti-inflammatory and Immunodulatory
Effects of Apoptotic Cells for Health and Disease
53
3.11.1
Apoptosis and Pregnancy
53
3.11.2
Apoptosis and Irradiation
53
3.11.3
Apoptosis and Cancer
53
3.11.4
Apoptosis and Infections
54
3.11.5
Apoptosis and Blood Transfusions
54
3.12
References
55
4
Complement and Apoptosis
57
Dror Mevorach
4.1
Introduction
57
4.2
Programmed Cell Death (PCD)
57
4.3
Complement
59
4.4
Complement and Apoptosis
62
4.4.1
Role of Complement in the Execution Phase
62
4.4.2
Complement Activation by Apoptotic Cells
65
4.5
Apoptosis, Complement and Autoimmunity
68
4.6
References
70
5
Soluble Factors that Bind to Dying Cells Control the Outcome
of Corpse Disposal:
The Role of Pentraxins, Collectins and Autoantibodies
79
Patrizia Rovere-Querini
Contents
VIII
5.1
Introduction
79
5.2
Soluble Factors Involved in Apoptotic Cell Recognition
and Internalization
76
5.2.1
Corpse Clearance at Rest: Collectins
79
5.2.2
Corpse Clearance at Rest: Cationic Factors and Other PS-binding
Moieties
81
5.2.3
Corpse Clearance during Acute Inflammation: Pentraxins
82
5.3
Corpse Clearance in Autoimmune Patients: Autoantibodies
86
5.4
Conclusions
88
5.5
Acknowledgements
89
5.6
References
89
6
The Role of ATP-binding Cassette Transporters in the Clearance
of Apoptotic Cells: A Tale of Two Systems
97
Véronique Rigot and Giovanna Chimini
6.1
Introduction
97
6.2
The Family of ABC Transporters
97
6.3
The Case of ABCA1 in Mammals
99
6.3.1
ABCA1 and Reverse Cholesterol Transport
102
6.3.2
ABCA1 and Engulfment
103
6.4
The Case of CED-7 in C. elegans
104
6.5
The Model
106
6.6
References
107
7
Innate Immunity and Apoptosis:
CD14-dependent Clearance of Apoptotic Cells
111
Christopher D. Gregory and Andrew Devitt
7.1
Introduction: CD14, A Multifunctional Molecule involved
in Innate Immune Responses
111
7.1.1
Background
111
7.1.2
Molecular Structure and Distribution of CD14
111
7.1.3
CD14 as an LPS Receptor that Signals LPS Responses
112
7.1.4
CD14 Binds Multiple and Diverse Ligands
113
7.2
Evidence that Apoptotic Cells Interact with CD14
114
7.2.1
61D3, a CD14 Monoclonal Antibody that Blocks Apoptotic
Cell Clearance
114
7.2.2
Exogenous Expression of CD14 in Non-myeloid Cells
114
7.2.3
Apoptotic Cell-associated Ligands of CD14
116
7.3
Mechanisms: Conceptualizing CD14’s Role in Apoptotic
Cell Clearance
119
7.3.1
CD14 as a PRR that Recognizes Apoptotic Cell-associated
Molecular Patterns (ACAMPs)
119
7.3.2
Differential CD14 Signaling following Ligand Binding
121
7.4
Conclusions: Relative Importance of CD14 in Apoptotic
Cell Clearance
122
7.5
References
124
Contents
IX
Part 3
Autoimmunity Caused by Defective Execution of Apoptosis
or Defective Clearance of Apoptotic Cells
133
8
Autoimmune Lymphoproliferative Syndromes (ALPS)
135
Frédérik Rieux-Laucat, Françoise le Deist and Alain Fischer
8.1
Introduction
135
8.2
Death Receptors and Signaling of Apoptosis
135
8.3
Clinical and Immunological Basis of ALPS
138
8.3.1
Definitions
138
8.3.2
Clinical Presentation
138
8.3.2.1
Lymphoproliferation
138
8.3.2.2
Autoimmune Manifestations
139
8.3.2.3
Other Clinical Manifestations
140
8.3.3
Laboratory Findings
140
8.3.3.1
Immunological Data
140
8.3.3.2
Pathological Findings
140
8.3.4
Treatment
141
8.4
Genetic and Molecular Bases of ALPS
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
Mechanism of Autoimmunity in ALPS
147
8.6
Conclusion
148
8.7
References
149
9
Infection and Inflammation as Cofactors for Autoimmunity
of Systemic Lupus Erythematosus Patients
157
Hanns-Martin Lorenz
9.1
Introduction
157
9.2
Infection and Autoimmunity
157
9.3
Infection, Inflammation and SLE: Theory and Practical Aspects
159
9.3.1
Theoretical Considerations for the Pathogenesis of SLE
159
9.3.2
Practical Aspects in Human SLE
163
9.4
Conclusions
164
9.5
References
165
10
Apoptosis in Rheumatoid Arthritis
169
Yuji Yamanishi and Gary S. Firestein
10.1
Introduction
169
10.2
Apoptosis in RA Synovium
171
10.3
Apoptosis in Synovial Fluid T Cells
172
10.4
Regulation of Apoptosis by Cytokines
173
10.5
p53 Mutations in RA Synovium and Fibroblast-like Synoviocytes
174
10.5.1
The Role and Regulation of p53 Tumor Suppressor Protein
174
Contents
X
