Cancro BLyS Ligands and Receptors

1. Auflage 2009
ISBN: 978-1-60327-013-7
Verlag: Humana Press
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 284 Seiten

Reihe: Contemporary Immunology

Discovery of the BLyS (also known as BAFF) family of ligands and receptors has yielded a paradigm shift in our view of B-lymphocyte selection, survival, activation, and homeostasis. Previously, the B-cell antigen receptor (BCR) was viewed as the sole mediator of these parameters, in which BCR signals were not only dominant but were also linearly related to consequent outcomes. However, appreciating that BLyS signaling is an equal partner in establishing and maintaining B-cell pools in- cated that additional regulatory complexity - apparently based on population density and homeostatic demands - had to be included in models of B-cell behavior. This mounting interest was ampli?ed by evidence of a clear relationship to autoim- nity. The resulting ?urry of research activity has yielded a wealth of information and insights, impacting basic concepts in B-cell tolerance and activation as well as revealing novel translational strategies for autoimmunity, neoplasia, and transplant tolerance. This book includes 12 chapters that together yield an overview of these advances and ideas. The initial excitement generated by associations with humoral autoimmunity, coupled with profound B lineage phenotypes in knockout mouse models, prompted immediate questions: What do these receptors and cytokines look like, how do they interact, what cells express them, and how does this inform our understating of their biology? Indeed, probing the structural features of BLyS family ligands and rec- tors has afforded substantial insight, as have studies directed toward understanding the basic biological actions of these molecules.

Autoren/Hrsg.

Cancro, Michael P.

Inhaltsverzeichnis

1;Preface;4
2;Acknowledgements;6
3;Contributors;9
4;Contents;7
5;1 The Beautiful Structures of BAFF, APRIL, and Their Receptors;12
5.1;1.1 Introduction;13
5.2;1.2 Multiple Forms of BAFF and APRIL;14
5.3;1.3 Structure of BAFF and APRIL;14
5.3.1;1.3.1 Structural Comparison to Other TNF Family Members ;14
5.3.2;1.3.2 BAFF Forms Virus-Like Particles;15
5.3.3;1.3.3 APRIL Binds to Proteoglycans;17
5.4;1.4 Receptor Binding;18
5.4.1;1.4.1 Structure of BCMA, TACI, and BAFF-R;18
5.4.2;1.4.2 Comparison of Ligand--Receptor Binding in the TNF Family;19
5.4.3;1.4.3 Structural Determinants of Binding Specificity;21
5.5;1.5 Receptor Signaling;22
5.5.1;1.5.1 Signaling Overview;22
5.5.2;1.5.2 TRAF Binding;23
5.6;1.6 Oligomerization-Dependent Signaling;24
5.7;1.7 Conclusions and Open Questions;25
5.8;References;26
6;2 BAFF Receptor Regulation of Peripheral B-Lymphocyte Survival and Development;30
6.1;2.1 Introduction;30
6.2;2.2 Peripheral B-Cell Development;31
6.3;2.3 BAFF/BR3 in B-Cell Survival and Development;36
6.4;2.4 Mechanisms of BR3-Mediated B-Cell Survival;37
6.5;2.5 Mechanisms of BAFF-Mediated Activation of Classical and Alternative NF-B Pathways;39
6.6;2.6 A Unified View of How BCR and BR3 Regulate B-Cell Development and Activation: BCR-Positive Regulation of BR3-Induced NF-B Activation;42
6.7;References;45
7;3 Regulation of B-Cell Self-Tolerance By BAFF and the Molecular Basis of Its Action;53
7.1;3.1 Regulation of Self-Reactive B Cells by BAFF;54
7.1.1;3.1.1 The Requirement for B-Cell Self-Tolerance;54
7.1.2;3.1.2 Self-Tolerance Checkpoints During B-Cell Development;54
7.1.2.1;3.1.2.1 Immature Bone Marrow B Cells;54
7.1.2.2;3.1.2.2 Immature to Mature B-Cell Transition in the Periphery;55
7.1.2.3;3.1.2.3 Marginal Zone B-Cell Development;56
7.1.3;3.1.3 Points of Action of BAFF and BAFF-R During B-Cell Development;57
7.1.4;3.1.4 BAFF and the Regulation of B-Cell Self-Tolerance Checkpoints;58
7.1.4.1;3.1.4.1 Immature Bone Marrow B Cells;58
7.1.4.2;3.1.4.2 Immature to Mature B-Cell Transition in the Periphery;59
7.1.5;3.1.5 Marginal Zone B-Cell Development;60
7.2;3.2 Signalling BAFF-Dependent B-Cell Survival;61
7.2.1;3.2.1 The NF- B Signalling Pathways;61
7.2.1.1;3.2.1.1 The Canonical NF-B Pathway;62
7.2.1.2;3.2.1.2 The Alternative NF-B Pathway;63
7.2.2;3.2.2 The Contribution of the Canonical NF- B Pathway to B-Cell Survival;63
7.2.3;3.2.3 The Alternative NF- B Pathway Is the Major Contributor to B-Cell Survival Downstream of BAFF-R;64
7.2.3.1;3.2.3.1 TRAF Proteins Are Fundamental Regulators of NF-B2 Signalling;64
7.2.3.2;3.2.3.2 Unravelling the Proximal Signalling Events That Allow TRAFs to Suppress NF-B2 Signalling;65
7.2.3.3;3.2.3.3 BAFF Is an Obligate Survival Factor for B Cells Because It Reverses the Suppression of NF-B2;67
7.2.4;3.2.4 Other Intracellular Mediators of B-Cell Survival Initiated by BAFF;67
7.2.4.1;3.2.4.1 Increasing Glycolysis;68
7.2.4.2;3.2.4.2 Modulation of Pro- and Anti-apoptotic Proteins;68
7.3;3.3 Conclusions;68
7.4;References;69
8;4 Role of BAFF and APRIL in Antibody Production and Diversification;74
8.1;4.1 Introduction ;74
8.2;4.2 Role of BAFF and APRIL in B-Cell Survival and Activation;75
8.2.1;4.2.1 Structure of BAFF and APRIL;75
8.2.2;4.2.2 Expression of BAFF and APRIL;75
8.2.3;4.2.3 BAFF and APRIL Receptors;76
8.2.4;4.2.4 BAFF and APRIL Signaling;76
8.2.5;4.2.5 Role of BAFF and APRIL in B-Cell Survival;77
8.2.6;4.2.6 Role of BAFF and APRIL in B-Cell Activation and Differentiation;78
8.3;4.3 Role of BAFF and APRIL in Antibody Production;79
8.3.1;4.3.1 Regulation of Adaptive Immune Responses by DCs;79
8.3.2;4.3.2 Role of Specific DC Subsets;80
8.3.3;4.3.3 DC Regulation of TD Antibody Responses;81
8.3.4;4.3.4 Function of BAFF and APRIL in TD Antibody Responses;82
8.3.5;4.3.5 Role of TI Antibody Responses in Protective Immunity;83
8.3.6;4.3.6 Dendritic Cell Regulation of TI Antibody Responses;84
8.3.7;4.3.7 Function of BAFF and APRIL in TI Antibody Responses;85
8.4;4.4 Role of BAFF and APRIL in Antibody Diversification;87
8.4.1;4.4.1 Processes Mediating Antibody Diversification;87
8.4.2;4.4.2 Mechanism and Requirements of Class Switching;88
8.4.3;4.4.3 CD40L Signaling in TD Class Switching;90
8.4.4;4.4.4 BAFF and APRIL Signaling in TI Class Switching;91
8.5;4.5 Role of BAFF and APRIL in Antibody Disorders;92
8.5.1;4.5.1 Autoimmune Disorders;92
8.5.2;4.5.2 Immunodeficiencies;93
8.6;4.6 Conclusions;94
8.7;References;94
9;5 Signal Transduction by Receptors for BAFF and APRIL;102
9.1;5.1 Proximal Signaling by BAFF and APRIL Receptors;102
9.1.1;5.1.1 Recruitment of Adaptor Molecules;102
9.1.2;5.1.2 TRAF-Binding Sites in the TNF Receptor Family;103
9.1.3;5.1.3 TRAF-Binding Sites in BAFFR;104
9.1.4;5.1.4 TRAF-Binding Sites in BCMA;105
9.1.5;5.1.5 TRAF-Binding Sites in TACI;105
9.1.6;5.1.6 Lipid Raft Movement of BAFFR and TACI;106
9.1.7;5.1.7 TRAF Degradation Induced by BAFF and APRIL Receptors;106
9.1.8;5.1.8 BAFFR Recruitment of Act1 and TRAF3;107
9.1.9;5.1.9 CAML Binding to TACI;108
9.2;5.2 Kinase Regulation by BAFF Receptors;108
9.2.1;5.2.1 Inhibition of PKC Nuclear Translocation by BAFF;108
9.2.2;5.2.2 Activation of Phosphatidyl Inositol-3 Kinase (PI-3K)/Akt and PKC /Akt Signaling Pathways by BAFF;110
9.2.3;5.2.3 Regulation of the MEK/ERK/Bim Signaling Pathway by BAFF;112
9.2.4;5.2.4 Upregulation of Pim2 by BAFF;113
9.2.5;5.2.5 Induction of Proteins Controlling Cell Cycle by BAFF;113
9.3;5.3 NF-kB Activation by BAFF and APRIL ;113
9.3.1;5.3.1 Two Pathways of NF-kB Activation;114
9.3.2;5.3.2 Challenges to Determination of Which Pathways Are Activated by BAFF and APRIL;114
9.3.3;5.3.3 Activation of NF-kB by BAFFR;115
9.3.4;5.3.4 NF-kB Activation by TACI;117
9.3.5;5.3.5 NF-kB Activation by BCMA;118
9.3.6;5.3.6 Adaptor Proteins Involved in BAFF-Mediated NF-kB Activation;118
9.4;5.4 Conclusions;119
9.5;References;119
10;6 TACI Signaling and Its Role in Immunity;124
10.1;6.1 Initial Characterization of TACI;124
10.2;6.2 Ligands;125
10.3;6.3 Patterns of Expression of TACI;126
10.4;6.4 Signaling Events;126
10.5;6.5 Physiologic Role of TACI;127
10.6;6.6 Negative vs. Positive Signaling by TACI;128
10.7;6.7 Mechanism of Action in T-Independent II Immunity;129
10.8;6.8 Reverse Signaling: TACI as Ligand;130
10.9;6.9 TACI Expression by Monocytes;131
10.10;6.10 Conclusions;131
10.11;References;131
11;7 The BAFF/APRIL System in Autoimmunity;134
11.1;7.1 Introduction;135
11.2;7.2 The BAFF/APRIL Ligands/Receptors System;136
11.2.1;7.2.1 BAFF and APRIL;136
11.2.1.1;7.2.1.1 Structure;136
11.2.1.2;7.2.1.2 Expression;138
11.2.2;7.2.2 BAFF and APRIL Receptors;139
11.3;7.3 Physiological Role of BAFF and APRIL;142
11.4;7.4 The BAFF/APRIL System and B-Cell Tolerance;143
11.4.1;7.4.1 Elements of B-Cell Tolerance;143
11.4.1.1;7.4.1.1 B-Cell Development and Maturation;143
11.4.1.2;7.4.1.2 B-Cell Tolerance;144
11.4.2;7.4.2 High BAFF Levels and Mechanisms of B-Cell Tolerance;145
11.5;7.5 The BAFF/APRIL System in Autoimmunity;147
11.5.1;7.5.1 BAFF/APRIL and T Cells;147
11.5.1.1;7.5.1.1 BAFF and T-Cell Activation;147
11.5.1.2;7.5.1.2 BAFF and Regulatory T Cells;148
11.5.2;7.5.2 B-Cell-Specific Lupus in BAFF Tg Mice;149
11.6;7.6 The BAFF/APRIL System and Autoimmunity in Humans;150
11.6.1;7.6.1 BAFF and SLE;151
11.6.1.1;7.6.1.1 Serum Levels of BAFF and SLE;151
11.6.1.2;7.6.1.2 A Possible Association Between BAFF and Activity of SLE;151
11.6.2;7.6.2 BAFF and Sj'gren's Syndrome (SS);151
11.6.2.1;7.6.2.1 Serum BAFF in SS;151
11.6.2.2;7.6.2.2 Non-lymphoid and Lymphoid Cells Express BAFF in SS;152
11.6.2.3;7.6.2.3 Elevated BAFF Levels May Explain the Lack of Efficacy of Anti-TNF Therapies in SS;152
11.6.3;7.6.3 BAFF and Other Autoimmune Diseases;152
11.6.4;7.6.4 BAFF Receptors Expression and Autoimmune Diseases;153
11.6.5;7.6.5 APRIL and Human Autoimmunity;153
11.6.5.1;7.6.5.1 The APRIL--TACI Axis;153
11.6.5.2;7.6.5.2 APRIL and SLE or RA;154
11.6.6;7.6.6 BAFF Secretion by Resident Cells in Target Organs of Autoimmunity: A New Concept;154
11.6.7;7.6.7 BAFF: A Possible Bridge Between Innate and Adaptive Immunity in Autoimmune Diseases;154
11.7;7.7 Targeting BAFF and/or APRIL: Progress and Challenges;155
11.8;7.8 Conclusion;158
11.9;References;159
12;8 Systemic Immune-Based Rheumatic Diseases: Blissless States of BLySfulness;170
12.1;8.1 Introduction ;170
12.2;8.2 BLyS and Its Receptors;171
12.2.1;8.2.1 General Properties of BLyS;171
12.2.2;8.2.2 Systemic and Local BLyS Expression;172
12.2.3;8.2.3 BLyS Receptors;174
12.2.4;8.2.4 Consequences of BLyS Binding to Surface BLyS Receptors;174
12.2.4.1;8.2.4.1 Consequences of BLyS Binding to B Cells;174
12.2.4.2;8.2.4.2 Consequences of BLyS Binding to Dendritic Cells (DCs);176
12.2.5;8.2.5 A Proliferation-Inducing Ligand (APRIL), the Confounding Relative of BLyS;177
12.3;8.3 BLyS/BLyS Receptor Deficiency In Vivo;179
12.3.1;8.3.1 BLyS-Deficient Mice;179
12.3.2;8.3.2 BLyS Receptor Deficiency;179
12.3.2.1;8.3.2.1 BCMA-Deficient Mice;179
12.3.2.2;8.3.2.2 TACI-Deficient Mice;180
12.3.2.3;8.3.2.3 BAFFR-Deficient Mice;181
12.4;8.4 BLyS Overexpression In Vivo;181
12.4.1;8.4.1 BLyS Overexpression In Vivo in Mice ;181
12.4.2;8.4.2 BLyS Overexpression In Vivo in Human SIRDs ;183
12.4.2.1;8.4.2.1 BLyS Overexpression in SLE;183
12.4.2.2;8.4.2.2 BLyS Overexpression in RA;183
12.4.2.3;8.4.2.3 BLyS Overexpression in Sj'gren's Syndrome;184
12.4.2.4;8.4.2.4 BLyS Overexpression in Other SIRDs;184
12.5;8.5 Therapeutic Targeting of BLyS;185
12.5.1;8.5.1 Elimination/Neutralization of BLyS in Murine Disease;185
12.5.2;8.5.2 Therapeutic Neutralization of BLyS in Human Disease;186
12.5.2.1;8.5.2.1 Treatment with Belimumab (Anti-BLyS mAb);187
12.5.2.2;8.5.2.2 Treatment with Atacicept (TACI--Ig Fusion Protein);188
12.5.2.3;8.5.2.3 Treatment with BR3-Fc Fusion Protein;189
12.5.2.4;8.5.2.4 Treatment with AMG 623;189
12.6;8.6 BLyS Antagonism as Part of Combination Therapy;189
12.7;8.7 Concluding Remarks;191
12.8;References;191
13;9 The Role of BAFF and APRIL in Regulating Human B-Cell Behaviour: Implications for Disease Pathogenesis;203
13.1;9.1 Introduction ;203
13.2;9.2 BAFF and APRIL: Ligands of the TNF Family;204
13.3;9.3 Functions of BAFF;206
13.3.1;9.3.1 B-Cell Survival and Proliferation;206
13.3.1.1;9.3.1.1 Murine B Cells;206
13.3.1.2;9.3.1.2 Human B Cells;206
13.3.2;9.3.2 Class Switch Recombination;207
13.3.2.1;9.3.2.1 Human B Cells;207
13.3.2.2;9.3.2.2 Murine B Cells;208
13.4;9.4 Aberrant Expression of BAFF, APRIL, and BAFF Receptors in Human Disease;210
13.4.1;9.4.1 Autoimmunity and Related Diseases;210
13.5;9.5 B-Cell Malignancies;211
13.6;9.6 TACI Mutations in Immunodeficiency;213
13.7;9.7 Genetics of TACI Mutation in Humoral Immunodeficiencies;213
13.8;9.8 Functional Implications of TNFRSF13b Mutations in B-Cell Responses;215
13.9;9.9 Conclusions;218
13.10;References;219
14;10 Translation of BAFF Inhibition from Mouse to Non-human Primate and Human;229
14.1;10.1 Blocking BAFF in Mice;230
14.1.1;10.1.1 BAFF and BAFF/APRIL Blockade in Normal Mice;230
14.1.2;10.1.2 Impact of BAFF and BAFF/APRIL Blockade in Models of Human Disease;232
14.2;10.2 Comparison of BAFF Antagonists in Non-human Primates;234
14.3;10.3 Clinical Aspects of BAFF Inhibition;238
14.3.1;10.3.1 BAFF Overexpression in Autoimmune Disorders in Man;238
14.3.1.1;10.3.1.1 Rheumatoid Arthritis (RA);238
14.3.1.2;10.3.1.2 Systemic Lupus Erythematosus (SLE);239
14.3.1.3;10.3.1.3 Sjögren Syndrome (SS);240
14.3.1.4;10.3.1.4 Other Disorders;241
14.3.2;10.3.2 Clinical Experience with BAFF Antagonists;241
14.3.2.1;10.3.2.1 Belimumab;241
14.3.2.2;10.3.2.2 Atacicept;243
14.3.2.3;10.3.2.3 Briobacept;244
14.3.2.4;10.3.2.4 AMG-623;244
14.3.2.5;10.3.2.5 Combination Therapy;246
14.4;10.4 From Mice to Humans;246
14.5;References;248
15;11 BLyS/BR3 Receptor Signaling in the Biologyand Pathophysiology of Aggressive B-Cell Lymphomas;252
15.1;11.1 LBCL and MCL: Representative Aggressive NHL-Bs;252
15.2;11.2 Large B-Cell Lymphoma;253
15.3;11.3 Mantle-Cell Lymphoma;255
15.4;11.4 Abnormal BLyS Expression in NHL-Bs;256
15.5;11.5 BLyS Signaling Pathway in NHL-Bs;257
15.6;11.6 NF- B Signaling Pathways ;257
15.7;11.7 NFAT Signal Pathway;259
15.8;11.8 BLyS Expression Regulation;259
15.9;11.9 Mechanisms of BLyS Signaling in NHL-B-Cell Survival and Proliferation;261
15.10;11.10 BLyS As a Therapeutic Target in NHL-B Treatment;262
15.11;References;264
16;12 Tipping the Scales of Survival: The Role of BLySin B-Cell Malignancies;271
16.1;12.1 Introduction ;271
16.1.1;12.1.1 B-Cell Growth and Transformation;271
16.1.2;12.1.2 BLyS and Its Receptors in B-Cell Biology;272
16.1.3;12.1.3 Summary;275
16.2;12.2 BLyS in B-Cell Malignancies: Growth and Survival;275
16.2.1;12.2.1 B-Cell Non-Hodgkin's lymphoma (NHL );275
16.2.2;12.2.2 B-Cell Chronic Lymphocytic Leukemia (CLL);277
16.2.3;12.2.3 Multiple Myeloma (MM);278
16.2.4;12.2.4 Hodgkin's Lymphoma (HL);279
16.2.5;12.2.5 Summary;280
16.3;12.3 BLyS in B-Cell Malignancies: Regulatory Control of BLyS Expression and Its Clinical Relevance;280
16.3.1;12.3.1 Regulation of BLyS Expression;281
16.3.2;12.3.2 Clinical Significance of BLyS Levels;282
16.3.3;12.3.3 Clinical Targeting of BLyS;282
16.4;12.4 Concluding Remarks;283
16.5;References;283
17;Index;289