Front Cover 1
Mast Cells and Basophils 4
Copyright Page 5
Contents 8
Contributors 20
Preface 26
Acknowledgements 28
SECTION ONE: DEVELOPMENT OF MAST CELLS AND BASOPHILS 30
Chapter 1. Regulation of Mast Cell and Basophil Development by Stem Cell Factor and Interleukin-3 32
Introduction 32
SCF a Ligand for the c-kit Receptor 33
Multiple Effects of SCF in Mast Cell Biology 34
SCF can Regulate Mast Cell Function In Vitro and In Vivo 36
Interleukin-3 38
Using IL-3 -/- Mice to Assess the Role of IL-3 in Mast Cell and Basophil Development 39
Summary 42
Acknowledgements 43
References 43
Chapter 2. Gain-of-function Mutations of c-kit in Human Diseases 50
Introduction 50
Loss-of-function Mutation of c-kit 50
Stomach Lesions of W/W' and Sl/Sld Mice 52
Gain-of-function Mutation of c-kit in Mast Cell Neoplasms 52
Sporadic Gastrointestinal Stromal Tumours 54
Familial GIST 55
Conclusion 56
References 56
Chapter 3. Modulation of Mast Cell Development from Embryonic Haematopoietic Progenitors by Eotaxin 60
Chemokines and their Receptors Play Diverse Roles as Mediators of Inflammation 60
Chemokines Participate in Multiple Mast Cell and Basophil Functions 61
Chemokine Secretion by Mast Cells 64
Eotaxin 65
Results 66
Discussion 69
References 73
Chapter 4. Regulation and Dysregulation of Mast Cell Survival and Apoptosis 80
Introduction 80
Regulation of Mast Cell Survival and Apoptosis by Growth Factors 81
Regulation of Mast Cell Survival and Apoptosis by Death Receptors 83
Regulation of Mast Cell Survival and Apoptosis by Perforin, Nitric Oxide and Bacterial Toxins 85
Regulation of Mast Cell Survival and Apoptosis by Irradiation and Chemical Agents 86
Perspective: Apoptosis and Mast Cell Disease 86
References 87
SECTION TWO: PHENOTYPIC AND ULTRASTRUCTURAL FEATURES OF MAST CELLS AND BASOPHILS 90
Chapter 5. Ultrastructural Features of Human Basophil and Mast Cell Secretory Function 92
Introduction 92
Mechanism(s) of Histamine and CLC-P Secretion from Human Basophils, of Histamine Secretion from Human Mast Cells In Vitro and of TNF-a and Chymase Secretion from Rat Peritoneal Cells 94
Histamine Secretion from Human Mast Cells In Vivo 101
Heparin Secretion from Human Mast Cells In Vitro 104
The Vesiculovacuolar Organelle, a New Endothelial Permeability Structure 107
Acknowledgements 112
References 112
Chapter 6. Human Dendritic Mast Cells 118
Introduction 118
The Morphology of Human Dendritic Mast Cells 118
Functional Aspects and Future Lines of Research 122
Concluding Remarks 123
References 123
Chapter 7. The Phenotypic Similarities and Differences Between Human Basophils and Mast Cells 126
Introduction 126
Morphology 127
Membrane Receptors 127
Cytoplasmic Contents 130
Mast Cell Phenotypes in Tissues 133
The Involvement of Mast Cells and Basophils in Asthma and Drug Reactions 134
Acknowledgements 136
References 136
Chapter 8. Interactions Between Nerves and Mast Cells in Amphibians 146
Introduction 146
Morphology of Frog Mast Cells 146
Frog Mast Cells and Peripheral Nervous System 149
Occurrence of Mast Cells in the Central and Peripheral Nervous Systems of Mammals 156
Concluding Remarks 156
References 157
SECTION THREE: SIGNAL TRANSDUCTION IN MAST CELLS AND BASOPHILS 160
Chapter 9. Sequential Protein Kinase Activation and the Regulation of Mast Cell Cytokine Production 162
Introduction 162
Signalling Through Mast Cell Surface Receptors 162
MAPK Family Members 164
Transcriptional Regulation of TNF-a Production 167
Stem Cell Factor Receptor (c-kit) 168
Differentiation Signalling and Function of Mast Cells Derived from Bone Marrow and Embryonic Stem Cells 170
Identification of a Critical Role for MEKK2 in JNK Activation and Cytokine Production 171
Summary 171
Acknowledgements 172
References 173
Chapter 10. FceRI-mediated Induction of TNF-a Gene Expression in Mast Cell Lines 178
Introduction 178
Chromosomal Location and Gene Structure of TNF-a 179
Regulation of TNF-a Gene Expression in Non-mast Cell Lines 181
FceRI-dependent Regulation of TNF-a Production 184
Concluding Remarks 189
References 191
Chapter 11. Regulation of Mast Cell Degranulation by SHIP 198
Introduction 198
Structure and Binding Partners of SHIP 199
Biological Properties of SHIP 200
Properties of the SHIP Knockout Mouse 201
The Role of SHIP in FceRI-induced Degranulation of Mast Cells 202
The Role of SHIP in Steel Factor-induced Signalling in Mast Cells 204
The Role of SHIP in Thapsigargin-induced Signalling in Mast Cells 205
A Model of IgE-induced Degranulation 206
Major Questions Remaining 207
Summary and Conclusions 208
Acknowledgements 208
References 208
SECTION FOUR: REGULATION OF MAST CELL AND BASOPHIL SIGNALLING AND SECRETION 212
Chapter 12. Immunoreceptor Tyrosine-based Inhibition Motif-dependent Negative Regulation of Mast Cell Activation and Proliferation 214
Introduction 214
SIRP-a can Negatively Regulate FceRI-dependent Mast Cell Activation 216
Fc.RIIB can Negatively Regulate c-kit-dependent Mast Call Proliferation 217
Conclusion 218
Acknowledgements 219
References 219
Chapter 13. Perspectives on the Regulation of Secretion from Human Basophils and Mast Cells 224
Introduction 224
Regulation of FceRI Expression 224
Desensitization 227
Modification of Basophil Function by IL-3 230
Summary 233
References 233
Chapter 14. Interactions between Secretory IgA and Human Basophils 238
Introduction 238
Structure and Metabolism of sIgA 239
Pathophysiology of sIgA 241
sIgA-mediated Basophil Activation 241
Receptors for sIgA 243
Clinical Relevance of sIgA-mediated Basophil Activation 245
Concluding Remarks 246
Acknowledgements 246
References 246
Chapter 15. Regulation of Mast Cell Secretion by Interferon-.and Nitric Oxide 250
Introduction 250
Interferon and Mast Cells 250
Do Mast Cells Produce Interferon-.? 253
Nitric Oxide and Nitric Oxide Synthases 253
Nitric Oxide Effects on Mast Cells 254
Do Mast Cells Produce Nitric Oxide? 255
How does Nitric Oxide Regulate Mast Cells? 256
Nitric Oxide and Mast Cells In Vivo-Clinical Implications Conclusion: Mast Cells, Interferon-y and Nitric Oxide in Cell Interactions and Disease 257
Conclusion: Mast Cells, Interferon-. and Nitric Oxide in Cell Interactions and Disease 258
Acknowledgements 259
References 259
SECTION FIVE: STRUCTURE AND FUNCTION OF MAST CELL PROTEASES 262
Chapter 16. Human and Mouse Mast Cell Tryptases 264
Introduction 264
Identification and Cloning of Human Tryptase Genes 265
Identification and Cloning of Mouse Tryptase Genes 266
Biochemical Features of Human and Mouse Tryptases 267
Expression of Mouse and Human Tryptases in Cells and Tissues 271
Function of Human and Mouse Tryptases 273
Tryptase Metabolism 276
Concluding Remarks 277
References 278
Chapter 17. Expression, Function and Regulation of Mast Cell Granule Chymases During Mucosal Allergic Responses 286
Introduction 286
Investigating the Response of mMCP-1-/-Mice to Gastrointestinal Nematodes 287
Regulation of the Expression of mMCP- 1 in mBMMC 292
Discussion 297
Acknowledgements 300
References 300
Chapter 18. Structure and Function of Human Chymase 304
Introduction 304
General Properties 304
X-ray Crystal Structure of rHC 308
The Extended Substrate-binding Site of Human Chymase 310
Modelling of the Human Chymase-angiotensin I Interaction 312
Summary 315
Acknowledgements 316
References 316
Chapter 19. Structure and Function of Human Mast Cell Tryptase 320
Introduction 320
Distribution and Secretion in Disease 320
Structure and Physicochemical Properties 323
Non-human Tryptases 324
Regulation of Tryptase Activity 325
Peptide Substrates 325
Protein Substrates 326
Actions on Cells and Tissues 327
Cellular Receptors for Tryptase 329
Tryptase as a Therapeutic Target 330
Acknowledgements 331
References 331
SECTION SIX: NERVE-MAST CELL INTERACTIONS: PHYSIOLOGY AND PATHOLOGY 340
Chapter 20. Mast Cell–Nerve Interactions: Possible Significance of Nerve Growth Factor 342
Evidence for Mast Cell–Nerve Interactions 343
Possible Role of NGF 346
Acknowledgement 349
References 349
Chapter 21. Nerve Growth Factor, Mast Cells and Allergic Inflammation 354
Nerve Growth Factor: Early Discovery and Emerging Data 354
NGF and the Nervous System 355
NGF and the Endocrine System 356
NGF and the Immune System 356
NGF and Mast Cells 357
NGF and Inflammation 360
NGF and Allergic Responses 361
Behavioural Influence on NGF Levels and Allergic Responses 363
Possible Future Directions 364
Acknowledgements 365
References 365
Chapter 22. Interactions Between Neurotrophins and Mast Cells 370
Definition and Basic Aspects of Neurotrophins 370
Mast Cells as a Source of Neurotrophic Factors 372
Effects of Neurotrophins on Mast Cells 372
Evidence that NGF is also a Human Mast Cell Growth Factor 373
Neurotrophin Receptors on Mast Cells 376
Clinical Findings Suggesting Mast Cell and Neurotrophin Activity 377
Mast Cells and Neurotrophins: Open Issues 378
Acknowledgement 379
References 379
Chapter 23. Modulation of Peripheral Neurotransmission Associated with Mast Cell Activation 384
Sensory (Afferent) Nervous System 385
Enteric Nervous System 388
Sympathetic Nervous System 389
Parasympathetic Nervous System 390
Summary 391
References 393
Chapter 24. Regulation of Gastrointestinal Mucin Production by Nerve–Mast Cell Interactions 396
Introduction 396
Neuronal Mediation of Mucin Secretion 397
Effects of Stress on Colonic Mucin and Prostaglandin Release 397
Role of Corticotropin-releasing Factor in Stress-induced Colonic Mucin Secretion 399
Neurotensin is an Important Mediator of Colonic Stress Responses 399
Mast Cells as a Major Link of Stress-mediated Mucin Secretion 400
CRF and NT as Mediators of Intestinal Mast Cell Activation During Stress 402
Clinical Implications 403
References 404
SECTION SEVEN: MAST CELLS AND BASOPHILS IN HOMEOSTASIS AND HOST DEFENCE 408
Chapter 25. Mast Cell–Enterobacteria Interactions during Infection 410
Introduction 410
Protective Role of Mast Cells Against Bacterial Infection 411
Mast Cell Phagocytosis of Bacteria 412
Molecular Basis for Mast Cell-Enterobacteria Recognition 414
Mast Cell Activation Via CD48 420
Interactions of Human Mast Cells with Enterobacteria 421
Final Thoughts 421
Acknowledgements 423
References 423
Chapter 26. Human Mast Cells and Basophils in Immune Responses to Infectious Agents 426
Introduction 426
Mast Cells in Host Defence Against Bacterial Infections 427
Mast Cells and Basophils in Helicobacterpylori Infection 428
Leukotrienes in the Defence against Bacterial and Viral Infections 428
Activation of Human Basophils and Mast Cells by Protein A 429
Activation of Human Basophils and Mast Cells by Protein L 431
Activation of Human Basophils by Pepstatin A 433
Endogenous Superallergen Protein Fv in Viral Hepatitis 435
Activation of Human Basophils and Mast Cells by HIV-1 Glycoprotein gp120 437
The 'Three Faces' of Mast Cells and Basophils in the Immune Response to Infectious Agents 439
Acknowledgements 440
References 440
Chapter 27. Differential Regulation of Mast Cell Mediator Secretion by Bacterial Products 448
Introduction 448
Receptors for Bacteria on Mast Cells 448
Selective Mast Cell Responses to Specific Bacterial Products 450
Combined Signals Alter and Enhance Mast Cell Responses 455
Bacteria- and Bacterial Product-mediated Signalling Events in Mast Cells 459
Conclusions 461
References 461
Chapter 28. The Role of Mast Cells, Basophils and Interleukin-3 (IL-3) in Immune Responses to Parasites: Studies with Mast Cell- and IL-3-Deficient Mice 468
Introduction 468
Studies of Parasite Infection in Genetically Mast Cell-deficient Mice 469
Assessing the Role of IL-3 in Host Responses to Nematodes using IL-3 -/- Mice 472
Kitw/Kit w-v, IL-3 -/- Mice Exhibit a Profound Impairment of Basophilia, Mucosal Mast Cell Development and Immunity During Infection with Strongyloides venezuelensis 474
Summary 476
Acknowledgements 478
References 478
SECTION EIGHT: MAST CELLS IN ATHEROSCLEROSIS AND CARDIAC DISEASES 482
Chapter 29. Human Heart Mast Cells: Immunological Characterization In Situ and In Vitro 484
Introduction 484
Isolation of HHMC and their Characterization In Situ 485
Histamine, Proteolytic Enzymes and Proteoglycans Synthesized by HHMC 488
Prostaglandins and Cysteinyl Leukotrienes Synthesized De Novo by HMMC 489
Immunological and Non-immunological Stimuli that Activate HHMC In Vitro 491
Mast Cells and Regulation of Coagulation and Fibrinogenolysis 493
HHMC in Systemic and Cardiac Anaphylaxis and in Anaphylactoid Reactions 494
HHMC and Atherosclerosis 494
HHMC in Patients with Myocarditis and Hyper-eosinophilia 496
HHMC and Angiogenesis in the Heart 496
HHMC and Myocardial Ischaemia 497
HHMC in Idiopathic and Ischaemic Cardiomyopathy 497
Perspective and Conclusions 498
Acknowledgements 499
References 499
Chapter 30. Mast Cells in Atherosclerotic Human Coronary Arteries: Implications for Coronary Fatty Streak Formation, Plaque Ulceration and Control of Local Haemostatic Balance 508
Introduction 508
Atherosclerosis is a Disorder of Lipid Metabolism in the Arterial Intima with a Strong Inflammatory Component 509
Circulating Mast Cell Progenitors also find their way in to the Arterial Intima 510
Immunohistochemical Observations on Mast Cells in the Human Coronary Arterial Intima 511
Potential Mechanisms by Which Mast Cells may Play a Role in Atherogenesis 515
Conclusion and Future Directions 521
Acknowledgements 522
References 522
Chapter 31. Role of Mast Cells in Endogenous Fibrinolysis and Related (Patho)physiological Processes 526
Introduction 526
Contribution of Mast Cells to Fibrinogen Extravasation and Fibrin Formation 527
Mast Cell-dependent Fibrinolysis: Role of Tryptase and Chymase 527
The Mast Cell as Site of tPA Expression 528
Human Mast Cells Express the Urokinase Receptor (uPAR, CD87) 529
Functional Significance of MC-tPA: Mast Cells are 'Pro-fibrinolytic' Cells 529
Molecular Basis of Mast Cell Dependent Fibrinolysis: Role of Inhibitors (PAIs) 530
Fibrin-independent Plasminogen Activation 530
Clinical Significance 530
Mast Cells Accumulate at the Site of Thrombosis 531
SCF Regulates Expression and Release of tPA in Mast Cells 531
Concluding Remarks and Future Directions 532
Acknowledgement 532
References 532
Chapter 32. Mast Cells in Myocardial Ischaemia and Reperfusion 536
Introduction 536
Mast Cells in Normal Hearts 537
The Mast Cell as a Source of Cytokines 538
Mast Cell Degranulation Following Myocardial Ischaemia 540
Mast Cells in Healing Myocardial Infarcts 542
Mast Cell Precursors Infiltrate the Healing Heart 543
SCF Induction Following Myocardial Ischaemia/Reperfusion 544
Macrophages are the Main Source of SCF Following Myocardial Ischaemia 545
Potential Role of Mast Cells in Healing 546
The Mast Cell in Myocardial Ischaemia/Reperfusion: Friend or Foe? 546
Acknowledgement 547
References 547
SECTION NINE: LEUKOTRIENES, CYTOKINES AND CHEMOKINES IN ALLERGIC DISORDERS 552
Chapter 33. Lipid Mediators from Mast Cells and Basophils in Allergic Diseases 554
Introduction 554
Arachidonic Acid Pools in Human Mast Cells and Basophils 556
Phospholipase A 2 in Human Mast Cells and Basophils 557
Extracellular Effects of Mast Cell-derived Secretory PLA 2 558
PAF and Related Phospholipids 560
Concluding Remarks 562
Acknowledgements 562
References 563
Chapter 34. Regulation and Function of Human Intestinal Mast Cells 570
Introduction 570
Effector Functions of Human Intestinal Mast Cells 572
Regulation of Human Intestinal Mast Cell Functions 577
Clinical Implications 579
Future Directions 586
References 586
Chapter 35. Differential Regulation of Basophil Functions by Chemokines 596
Basophil Phenotype and Functions 596
Chemokines 599
Acknowledgement 604
References 604
Chapter 36. Chemokine Receptors on Human Mast Cells 608
Chemokines 608
Mast Cells 615
Chemokine Receptors on MC 617
Concluding Remarks 620
Acknowledgement 620
References 620
Chapter 37. Release and Cleavage of Stem Cell Factor by Human Mast Cells 626
Introduction 626
Stem Cell Factor Expression in Human Mast Cells 627
Stem Cell Factor-Protease Interactions 629
Biological Effects of SCF1-166 and SCF1-159 on HLMC and HSMC 631
Conclusions 632
Acknowledgements 633
References 633
Chapter 38. SCF-Induced Chemokine Production, Allergic Airway Inflammation and Airway Hyper-reactivity 638
Introduction 638
SCF-Induced Mast Cell Activation, Inflammation and Airway Hyper-reactivity 639
Regulation of SCF Production 641
Initiation of Cytokine/Chemokine Production by SCF in Mast Cells and Eosinophils 642
Structural Cell-derived SCF Contributes to Disease Progression: Differential Activation of Mast Cells by Soluble versus Membrane SCF 644
Summary 645
References 646
SECTION TEN: CLINICAL IMPLICATIONS OF HISTAMINE H1 RECEPTOR ANTAGONISTS 652
Chapter 39. Pharmacological Profile of Mizolastine, a Novel Histamine H1 Receptor Antagonist 654
Histamine and its Receptor Subtypes 654
Specificity and Selectivity of Mizolastine for H~ Histamine Receptor Subtypes 655
Antihistaminergic Effects of Mizolastine 657
Allergic Reaction 658
Anti-anaphylactic Properties of Mizolastine 659
Immune System-mediated Inflammatory Reaction in Allergy 660
Anti-allergic Effects of Mizolastine 662
Other Pharmacological Effects of Mizolastine 664
Conclusion 667
Acknowledgement 667
References 668
Chapter 40. Adenosine-Induced Enhancement of Mast Cell Mediator Release in Asthma and COPD 670
Introduction 670
The Bronchoconstrictor Effect of Adenosine in Asthma 671
The Airway Response to Adenosine in COPD 673
Adenosine Receptors on Mast Cells 673
Concluding Comments 674
References 676
Chapter 41. Neural Activation and Inflammation in Allergic Rhinitis 680
Introduction 680
Neurogenic Inflammation 681
Neural Hyper-responsiveness 683
Nerve Growth Factor 687
Summary and Conclusion 688
References 689
Chapter 42. Antihistaminic and Anti-inflammatory Effects of Mizolastine 694
Introduction 694
Pharmacokinetics of Mizolastine 695
Clinical Efficacy of Mizolastine 695
Anti-inflammatory effects of Mizolastine 696
Concluding Remarks 698
References 698
Chapter 43. Electrophysiological and Molecular Basis for the Adverse Cardiovascular Effects of Histamine H, Receptor Antagonists 702
Introduction 702
Cardiotoxicity of Second-generation Antihistamines 703
Conclusions 713
Acknowledgements 713
References 713
Index 718
Color Plate Section 737