Advances in Immunology (eBook)

Cover 1
Contents 6
Contributors 10
Chapter 1: New Insights into Adaptive Immunity in Chronic Neuroinflammation 12
1. Introduction: Multiple Sclerosis Is a Heterogeneous Inflammatory Disease of the Nervous System 13
2. Experimental Autoimmune Encephalomyelitis as a Model for MS 14
3. Current Knowledge About Induction and Perseveration of Chronic Neuroinflammation 16
3.1. General considerations 16
3.2. CD4+ T helper cells in chronic neuroinflammation 16
3.3. CD8+ T cells in neuroinflammation: A never-ending controversy 26
3.4. B cells and antibody-mediated immune responses in chronic neuroinflammation 28
4. Therapeutic Approaches to Chronic Neuroinflammation 31
4.1. General considerations 31
4.2. Current therapeutic concepts 32
4.3. New therapeutic concepts 34
Acknowledgments 40
References 40
Chapter 2: Regulation of Interferon-gamma During Innate and Adaptive Immune Responses 52
1. Introduction 54
2. IFN-gamma-Producing Cells 56
2.1. NK cells 56
2.2. NKT cells 56
2.3. CD8 T cells 57
2.4. CD4 T cells play multiple roles in adaptive immunity 57
3. Signaling Pathways Controlling IFN-gamma Production by NK Cells 59
3.1. NK receptors provide a dynamic rheostat to control NK cell responses 59
3.2. IL-12 is a potent activator of IFN-gamma production in NK cells 60
3.3. IL-15 and IL-2 regulate NK cell development and contribute to IFN-g production 62
3.4. TGF-beta is a negative regulator of IFN-gamma production and NK cell development 62
4. Control of IFN-gamma Production by NKT Cells 63
5. Signaling Pathways in the Differentiation of CD4 and CD8 T Cells 64
5.1. Naive T cells require antigen stimulation for proliferation and effector commitment 64
5.2. T cells require cytokine signals for sustained IFN-gamma expression 65
5.3. Other factors influencing Th1 lineage commitment 68
5.4. TGF-beta and IL-6 negatively regulate IFN-gamma production and Th1 development 69
5.5. IFN-gamma production by memory T cells in response to cytokine stimulation 70
6. Transcription Factors Downstream of the TCR, Activating NK Receptors, and Cytokine Receptors 71
6.1. Factors downstream of the TCR, costimulatory, and activating NK receptors 71
6.2. STATs are activated in response to cytokine receptor signaling 79
6.3. T-box family members are crucial for IFN-gamma secretion 81
7. Epigenetic Processes Govern Plasticity of Cell Fate Choices and Help to Identify Distal Regulatory Elements 83
8. Transcriptional Regulatory Elements Within the Ifng Gene 85
8.1. Regulatory elements within the Ifng promoter and gene 85
8.2. Identification of candidate distal regulatory elements in the Ifng locus 88
9. Functional Analysis of Candidate Distal Regulatory Elements in the Ifng Locus 93
10. Conclusions and Future Directions 95
Acknowledgments 53
References 53
Chapter 3: The Expansion and Maintenance of Antigen-Selected CD8+ T Cell Clones 114
1. Background 116
1.1. Introduction 116
1.2. Subsets of antigen-selected CD8+ T cells: Central memory, effector memory, and effector cells 117
1.3. Central memory CD8+ T cells generate new effector CD8+ T cells 118
1.4. Current models for development of antigen-stimulated CD8+ T cells 119
2. The Behavior of the CD8+ T Cell in Persistent Viral Infections 122
2.1. Persistent CD8+ T cell stimulation and expansion: "Inflationary" epitopes 122
2.2. Cellular senescence despite continued clonal expansion 124
2.3. Clonal persistence versus clonal succession 125
2.4. Molecular requirements for clonal persistence 125
3. Clarifying the Role of IL-2 in the Clonal Expansion and Effector Differentiation of the CD8+ T Cell 126
3.1. Is IL-2 "the" or "a" mediator of CD8+ T cell clonal expansion? 126
3.2. CD8+ T cell clonal expansion without IL-2R signaling 127
4. Coreceptors Mediating IL-2-Independent CD8+ T Cell Clonal Expansion 129
4.1. CD27 129
4.2. Other coreceptors 131
5. Modifying the Antiproliferative Effects of Types I and II IFN 131
5.1. The effects of types I and II IFN on CD8+ T cells 132
5.2. Regulating IFN-gammaR expression 132
5.3. Stat1 as a "Switch" determining the effects of types I and II IFN on proliferation 133
6. Transcriptional Control of Replicative Senescence: Bmi-1, Blimp-1, and BCL6/BCL6b 134
7. A Refined Model for CD8+ T Cell Clonal Expansion: Sequential Phases of CD27-Dependent Self-Renewal and IL-2-Dependent Differentiation 137
8. Clinical Extensions of the TCR/CD27 Pathway: Adoptive CD8+ T Cell Therapy 138
Acknowledgments 53
References 53
Chapter 4: Inherited Complement Regulatory Protein Deficiency Predisposes to Human Disease in Acute Injury and Chronic Inflammatory States 152
1. Altered Self Triggers Innate Immunity 154
1.1. Acute injury 154
1.2. Debris accumulation 155
2. Regulation of the Alternative Complement Pathway 156
2.1. Overview of activation 156
2.2. Regulation of the alternative complement pathway 159
2.3. Regulatory proteins 159
3. Lessons from Homozygous Complement Regulatory Protein Deficiencies 164
3.1. Plasma proteins FH and FI 164
3.2. Membrane proteins MCP and Crry 164
4. Complement and Atypical Hemolytic Uremic Syndrome 165
4.1. Hemolytic uremic syndrome 165
4.2. Factor H 166
4.3. FH-related genes 168
4.4. Membrane cofactor protein: CD46 168
4.5. Factor I 170
4.6. Factor B 170
4.7. Disease penetrance 171
5. Complement and Age-Related Macular Degeneration 171
5.1. Age-related macular degeneration 171
5.2. Factor H 172
5.3. Factor B/C2 174
6. Immunopathogenesis of aHUS and AMD 174
6.1. Atypical HUS 174
6.2. Age-related macular degeneration 177
7. Treatment of aHUS and AMD 178
7.1. Treatment options for aHUS 178
7.2. Treatment options for AMD 179
8. Conclusions: Lessons and Implications 179
References 53
Chapter 5: Fc-Receptors as Regulators of Immunity 190
1. Introduction 191
2. The Family of Activating and Inhibitory FcRs 192
3. Activating and Inhibitory FcR Signaling Pathways 194
4. The Role of Activating and Inhibitory FcRs on Innate Immune Effector Cells 196
5. Modulation of Antibody Activity 199
6. Activating and Inhibitory FcR Expression on DCs 201
7. FcgammaRIIB as a Master Regulator of Humoral Tolerance and Plasma Cell Survival 203
8. Summary and Outlook 206
Acknowledgments 53
References 53
Index 216
Contents of Recent Volumes 222
Color Plate Section 227