B Cell Receptor Signaling (eBook)

Tomohiro Kurosaki, MD, PhD, is a professor at WPI Immunology Frontier Research Center at Osaka University, Japan Jürgen Wienands, PhD, is a professor of Cellular and Molecular Immunology at the University of Göttingen, Germany

Preface 6
Regulatory Signal Networks of the B Cell Antigen Receptor 6
Contents 9
Part I Initiation of B Cell Receptor Signaling 11
475 Assembly and Function of the Precursor B-Cell Receptor 12
Abstract 12
1 Introduction 13
2 The Structure of the Pre-BCR 14
3 Assembly of the Pre-BCR 17
4 Initiation of Pre-BCR Signaling 19
5 Signaling Downstream of the Pre-BCR 23
6 Regulation of Proliferation and Differentiation at the Pre-B-Cell Stage 28
7 Concluding Remarks 29
References 30
482 Receptor Dissociation and B-Cell Activation 35
Abstract 35
1 Introduction 36
2 The Structure of the BCR Complex 36
3 The Resting BCR and Models of Its Activation 38
3.1 The Monomeric BCR and the CLM 38
3.2 The Monomeric BCR and the Conformation-Induced Oligomerization Model 39
3.3 The Higher Organization of the Lymphocyte Membrane 40
3.4 The Oligomeric BCR and the DAM Hypothesis 40
3.4.1 Dissociation Activation of the BCR 42
3.4.2 Unsolved Questions 44
The Assembly of the BCR Monomer and the Formation of BCR Oligomers 44
The Dissociation of Oligomeric BCR and Signal Initiation 46
References 48
476 Molecular Mechanisms of B Cell Antigen Gathering and Endocytosis 52
Abstract 52
1 Introduction 53
2 B Cell Antigen Gathering 54
2.1 Access of B Cells to Antigen in Vivo 54
2.2 B Cell Antigen Gathering in Immune Synapses 55
2.3 Antigen Extraction from Immune Synapses 57
3 BCR-Mediated Antigen Endocytosis 58
3.1 The Initiation of Clathrin-Mediated Antigen Endocytosis 59
3.2 BCR Signaling and the Regulation of Endocytosis 60
3.3 Conversion of CCPs into Intracellular Vesicles 61
3.4 Trafficking Through the Endosomal Pathway 62
3.5 Endocytosis and the Regulation of BCR Signaling 63
4 Perspectives 65
Acknowledgments 65
References 66
Part II BTKs, Adaptors, and Effector Systemin B Cell Receptor Signaling 71
478 BTK Signaling in B Cell Differentiation and Autoimmunity 72
Abstract 72
1 Introduction 74
2 BTK Structure and Activity 76
2.1 BTK Structure 76
2.2 Regulation of BTK Expression 78
3 Role of BTK in B Cell Development in the Bone Marrow 79
3.1 The Pre-BCR Checkpoint 79
3.2 X-Linked Agammaglobulinemia (XLA) 80
3.3 The Xid Phenotype: Role of BTK in the Regulation of Pre-B Cell Proliferation 81
3.4 The Xid Phenotype: Role of Btk in the Initiation of Ig L Chain Recombination 82
4 BTK and B Cell Receptor Signaling 83
4.1 Activation of BTK in the IgM-BCR Signaling Pathway 83
4.2 Activation of BTK in the IgG-BCR Signaling Pathway 85
4.3 BTK Downstream Targets in the BCR Signaling Pathway 86
4.4 BTK and the Interconnection of BCR Signaling with Other Pathways 87
5 Role of BTK in Mature B Cells 89
5.1 BTK Is Essential for Peripheral B Cell Differentiation 89
5.2 Btk-Deficient B Cells Are Less Responsive in Vitro 90
5.3 In Vivo B Cell Responses in BTK-Deficient Mice 91
5.4 Immunity to Influenza in BTK-Deficient Mice 93
5.5 BTK Deficiency and Natural Resistance to Pathogens 95
6 BTK and Autoimmune Disease 96
6.1 Role of Btk in Pathogenesis of Autoimmune Disease 96
6.2 BTK Inhibitors in Autoimmunity 98
7 Concluding Remarks 100
Acknowledgements 101
References 101
480 The Memory Function of the B Cell Antigen Receptor 111
Abstract 111
1 Introduction 112
2 Subpopulations of Memory B Cells with Distinct Characteristics 113
3 B Cell Antigen Receptors on Memory B Cells 115
4 Tyrosine-Based Signal Amplification of mIgG-Containing BCRs in Memory B Cells 116
5 Additional Features of mIgG-Containing BCRs 119
6 The Antigen--BCR Interaction and MBC Reactivation 120
Acknowledgements 122
References 122
484 PI3K Signaling in Normal B Cells and Chronic Lymphocytic Leukemia (CLL) 126
Abstract 126
1 PI3K Family 127
2 Mechanism of PI3K Signaling in B Cells 128
2.1 Activation of PI3K by the BCR and CD19 128
2.2 Atypical Activation of PI3K delta by Chemokine Receptors in B Cells 129
2.3 BAFF Signals via PI3K to Promote B Cell Survival 129
2.4 Pdk1, Akt, and Btk Are PIP3 Binding Proteins in B Cells 130
3 Role of PI3K in B Cell Development and Function 130
3.1 PI3K alpha and PI3K delta Act Redundancy in Bone Marrow B Cells 130
3.2 P110 delta is the Main PI3K Isoform in Mature B Cells 131
3.3 PI3K delta Regulates Marginal Zone B Cell Development 132
4 Chronic Lymphocytic Leukemia 132
4.1 BCR Signaling in CLL Pathogenesis 132
4.2 Role of Chemokine Signaling in CLL 134
4.3 Role of PI3K in T Cells in CLL 137
4.4 Targeting BTK and PI3K delta : Redundant or Synergistic? 138
5 Perspective: Targeting PI3K in Other B Cell Cancers 139
Acknowledgments 139
References 140
477 Role of Calcium Signaling in B Cell Activation and Biology 146
Abstract 146
1 Introduction 147
2 Initial Ca2+ Signaling Pathway: Ca2+ Release from ER Store 148
3 Sustained Ca2+ Signaling Pathway: Store-Operated Ca2+ Entry (SOCE) 151
3.1 STIM1 and STIM2 ER Ca2+ Sensor
3.2 SOCE Channel 154
3.3 SOCE Regulator 154
4 Negative Regulation of Ca2+ Signaling Pathway 155
4.1 Negative Regulation of Initial Ca2+ Mobilization 155
4.2 Negative Regulation of SOCE 157
5 Physiological Function of BCR-Mediated Ca2+ Signaling 158
5.1 Defective ER Ca2+ Release and Immune Disease 158
5.2 Ca2+ Inhibitory Signals and Immune Diseases 161
5.3 Physiological Role of SOCE in B Cells 163
6 Decoding BCR-Triggered Ca2+ Signals 164
7 Conclusions 166
References 166
Part III Connection Between Cytoplasmicand Nuclear Events 178
479 Roles of the NF- kappa B Pathway in B-Lymphocyte Biology 179
Abstract 179
1 Introduction 181
2 NF- kappa B in B-Cell Development and Survival 184
2.1 NF- kappa B Function in Early B Lymphopoiesis 184
2.2 NF- kappa B Function in Immature B Cells 184
2.3 Role of NF- kappa B in Survival of Mature B Cells 186
3 NF- kappa B in B-Cell Activation 187
3.1 Control of Cell Proliferation and Survival of Activated B Cells by NF- kappa B 187
3.2 Involvement of NF- kappa B in CSR 189
3.3 Function of NF- kappa B in GC B Cells 189
4 Receptor-Mediated Activation of NF- kappa B in B Lymphocytes 190
4.1 The Ubiquitin System 190
4.2 Non-degradation Roles of the Ubiquitin System in the Activation of IKK Complex 191
4.3 Roles of the Ubiquitin System in Alternative NF- kappa B Activation 195
4.4 BCR-Mediated NF- kappa B Activation 196
5 NF- kappa B in B-Cell Malignancies 199
5.1 CARMA1 Mutations 199
5.2 Chromosomal Translocation of MALT1 and BCL10 200
5.3 MyD88 Mutations 200
5.4 Chronic Active BCR Signaling 201
5.5 Inactivation of A20 201
6 Conclusions 202
References 202
481 MAP Kinase Cascades in Antigen Receptor Signaling and Physiology 212
Abstract 212
1 Introduction 213
2 The MEK--ERK Pathway in Early B Cell Development 216
3 The ERK Pathway in the Differentiation of Mature B Cells 218
4 The JNK Pathway 220
5 The P38 Pathway 223
6 Other MAPKs 225
7 Conclusions 226
Acknowledgments 226
References 226
4820 Erratum to: B Cell Receptor Signaling 233
Erratum to:& #6