BLyS Ligands and Receptors (eBook)

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