Antigen Presenting Cells From Mechanisms to Drug Development/Edited by Harald Kropshofer and Anne B. Vogt

Comentario:

Contents:
VI
2.3 Antigen Entry via the Skin 35
2.4 Systemic Dissemination of Antigens/Infectious
Microorganisms 38
2.5 Antigen Presenting Cells in the Liver 39
2.5.1 Dendritic Cells 39
2.5.2 Kupffer Cells 41
2.5.3 Liver Sinusoidal Endothelial Cells 42
2.6 Conclusion 44
3 Antigen Processing in the Context of MHC Class I Molecules 51
Frank Momburg 51
3.1 Tracing the Needle in the Haystack: The Efficiency of Antigen
Processing and Presentation by MHC Class I Molecules 51
3.2 The “Classical” Route: Loading of MHC Class I Molecules With
Peptides Generated in the Cytoplasm 53
3.2.1 Cytosolic Peptide Processing by Proteasomes and other Proteases 53
3.2.1.1 Structure and Function of the Proteasomal Core and Interferoninduced
Subunits 56
3.2.1.2 Targeting Proteins for ATP-dependent Degradation by
26S Proteasomes 56
3.2.1.3 Cleavage Properties of (Immuno)Proteasomes 57
3.2.1.4 Peptide Processing by Nonproteasomal Cytosolic Peptidases 59
3.3 Crossing the Border – Peptide Translocation into the ER by TAP 60
3.3.1 Structure and Function of TAP 60
3.3.2 Substrate Specificity of TAP 62
3.3.3 TAP-independent Peptide Entry into the ER 63
3.4 Fitting in the Best: TAP-associated Peptide Loading Complex
Optimizes MHC-I Peptide Binding 63
3.4.1 Structure of MHC-I Molecules 64
3.4.2 Early Steps in the Maturation of MHC-I Molecules 64
3.4.3 Structure and Molecular Interactions of Tapasin 66
3.4.4 Optimization of Peptide Loading in the TAP-associated Loading
Complex 67
3.5 On the Way Out: MHC-I Antigen Processing along the Secretory
Route 70
3.6 Closing the Circle – Cross-presentation of Endocytosed Antigens by
MHC-I Molecules 73
3.6.1 Phagosome-to-cytosol Pathway of MHC-I Peptide Loading 73
3.6.2 Endolysosomal Pathway of MHC-I Peptide Loading 76
4 Antigen Processing for MHC Class II 89
Anne B. Vogt, Corinne Ploix and Harald Kropshofer
4.1 Introduction 89
4.2 Types of Antigen Presenting Cells 90
Contents
VII
4.2.1 Macrophages, B Lymphocytes and DCs 90
4.2.2 Tissue-resident APCs 91
4.2.3 Maturation State of APCs 92
4.2.3.1 Immature APCs 92
4.2.3.2 Mature APCs 92
4.3 Antigen Uptake by APCs 93
4.3.1 Macropinocytosis 93
4.3.2 Phagocytosis 94
4.3.3 Receptors for Endocytosis 95
4.4 Generation of Antigenic Peptides 97
4.4.1 Reduction of Disulfide Bonds: GILT 97
4.4.2 Regulation of the Proteolytic Milieu 98
4.4.3 Protease/MHC Interplay in Antigen Processing 99
4.5 Assembly of MHC II Molecules 102
4.5.1 Structural Requirements of MHC II 102
4.5.2 Biosynthesis of MHC II 103
4.5.3 Chaperones for Peptide Loading 104
4.5.3.1 HLA-DM/H2-DM 104
4.5.3.2 HLA-DO/H2-DO 107
4.6 Export of MHC II and Organization on the Cell Surface 109
4.6.1 Membrane Microdomains 109
4.6.2 Tubular Transport 112
4.7 Viral and Bacterial Interference 114
4.8 Concluding Remarks 116
5 Antigen Processing and Presentation by CD1 Family Proteins 129
Steven A. Porcelli and D. Branch Moody
5.1 Introduction 129
5.2 CD1 Genes and Classification of CD1 Proteins 129
5.3 Structure and Biosynthesis of CD1 Proteins 130
5.3.1 Three-dimensional (3D) Structures of CD1 Proteins 132
5.3.2 Molecular Features of CD1–Lipid Complexes 133
5.3.3 CD1 Pockets and Portals 135
5.4 Foreign Lipid Antigens Presented by Group 1 CD1 136
5.5 Self Lipid Antigens Presented by CD1 137
5.6 Group 2 CD1-restricted T Cells 138
5.6.1 Antigens Recognized by Group 2 CD1-restricted T Cells 139
5.7 Tissue Distribution of CD1 Proteins 140
5.8 Subcellular Distribution and Intracellular Trafficking of CD1 140
5.8.1 Trafficking and Localization of CD1a 141
5.8.2 Trafficking and Localization of CD1b 141
5.8.3 Trafficking and Localization of CD1c 143
5.8.4 Trafficking and Localization of CD1d 144
5.8.5 Trafficking and Localization of CD1e 145
Contents
5.9 Antigen Uptake, Processing and Loading in the CD1 Pathway 146
5.9.1 Cellular Uptake of CD1-presented Antigens 146
5.9.2 Endosomal Processing of CD1-presented Antigens 147
5.9.3 Accessory Molecules for Endosomal Lipid Loading of CD1 148
5.9.4 Non-endosomal Loading of Lipids onto CD1 Molecules 149
5.10 Conclusions 150
Part III Antigen Presenting Cells’ Ligands Recognized by
T- and Toll-like Receptors 157
6 Naturally Processed Self-peptides of MHC Molecules 159
Harald Kropshofer and Sebastian Spindeldreher
6.1 Introduction 159
6.2 Milestone Events 160
6.2.1 Nomenclature 160
6.2.1.1 Autologous Peptides 160
6.2.1.2 Endogenous Peptides 161
6.2.1.3 Natural Peptides Ex Vivo and In Vitro 161
6.2.2 Extra Electron Density Associated to MHC Molecules 162
6.2.3 Acidic Peptide Elution Approach 163
6.2.4 First Natural Foreign Peptides on MHC Class II 165
6.2.5 First Natural Viral Epitopes on MHC Class I 165
6.2.6 Self-peptide Sequencing on MHC Class I:
the First Anchor Motifs 166
6.2.7 First Murine MHC Class II-associated Self-peptides: Nested Sets 167
6.2.8 First Human MHC Class II-bound Self-peptides:
Hydrophobic Motifs 169
6.3 Progress in Sequence Analysis of Natural Peptides 172
6.3.1 Edman Microsequencing 172
6.3.2 Electrospray Ionization Tandem Mass Spectrometry 173
6.3.3 Automated Tandem Mass Spectrometry 175
6.3.4 MAPPs: MHC-associated Peptide Proteomics 176
6.4 Natural Class II MHC-associated Peptides from
Different Tissues and Cell-types 177
6.4.1 Peripheral Blood Mononuclear Cells 177
6.4.2 Myeloid Dendritic Cells 178
6.4.3 Medullary Thymic Epithelial Cells 179
6.4.4 Splenic APCs 181
6.4.5 Tumor Cells 181
6.4.6 Autoimmunity-related Epithelial Cells 182
6.5 The CLIP Story 183
6.5.1 CLIP in APCs Lacking HLA-DM 184
6.5.2 Flanking Residues and Self-release of CLIP 184
6.5.3 CLIP in Tetraspan Microdomains 185
VIII Contents
6.5.4 CLIP as an Antagonist of TH1 Cells 188
6.6 Outlook: Natural Peptides as Diagnostic or Therapeutic Tools 189
7 Target Cell Contributions to Cytotoxic T Cell Sensitivity 199
Tatiana Lebdeva, Michael L. Dustin and Yuri Sykulev 199
7.1 Introduction 199
7.2 Intercellular Adhesion Molecule 1 (ICAM-1) 200
7.2.1 Adhesion Molecules on the Surface of APC and Target Cells 200
7.2.2 ICAM-1 Structure and Topology on the Cell Surface 200
7.2.3 ICAM-1 as Co-stimulatory Ligand and Receptor 201
7.2.4 ICAM-1-mediated Signaling 203
7.2.5 Role of ICAM-1 in Endothelial Response to Leukocytes 206
7.2.6 ICAM-1 Association with Lipid Rafts 206
7.3 Major Histocompatability Complex (MHC) 208
7.3.1 MHC Molecules 208
7.3.2 Molecular Associations of MHC-I Molecules 208
7.3.3 Association of MHC-I and ICAM-1 211
7.3.4 Could APC and Target Cells Play an Active Role in Ag
Presentation? 212
7.3.5 Identical pMHCs are Clustered in the Same Microdomain 212
7.3.6 Identical pMHC can be Recruited to the Same Microdomain
During Target Cell–T Cell Interaction 213
7.3.7 Co-clustering of MHC and Accessory Molecules 213
7.3.8 Role of Cytoskeleton 214
7.4 Conclusion 215
8 Stimulation of Antigen Presenting Cells:
from Classical Adjuvants to Toll-like Receptor (TLR) Ligands 221
Martin F. Bachmann and Annette Oxenius
8.1 Synopsis 221
8.2 Pathogen-associated Features that Drive
Efficient Immune Responses 221
8.3 Composition and Function of Adjuvants 222
8.4 TLR Protein Family in Mammals 224
8.4.1 TLR4 226
8.4.2 TLR2 227
8.4.3 TLR5 227
8.4.4 TLR11 228
8.4.5 TLR12 and TLR13 228
8.4.6 Nucleic Acids as PAMPs 228
8.4.6.1 TLR3 228
8.4.6.2 TLR7 and TLR8 229
8.4.6.3 TLR9 229
Contents IX
8.4.7 Compartmentalization of Sensing Renders
the Nucleic Acid PAMPs 229
8.5 TLR Signaling 230
8.5.1 Signal Transduction Across the Membrane 231
8.5.2 MyD88-dependent Pathways 231
8.5.3 MyD88-independent Pathways 232
8.6 TLR-independent Recognition of PAMPs:
Nods, PKR and Dectin-1 233
8.6.1 Nods 233
8.6.2 PKR (IFN-inducible dsRNA-dependent Protein Kinase) 234
8.6.3 Dectin-1 234
8.7 Therapeutic Potential of TLRs and their Ligands 235
8.8 Conclusion 237
Part IV The Repertoire of Antigen Presenting Cells 245
9 Evolution and Diversity of Macrophages 247
Nicholas S. Stoy
9.1 Evolution of Macrophages: Immunity without Antigen
Presentation 247
9.1.1 Introduction 247
9.1.2 Drosophila: a Window into Innate Immunity 247
9.1.3 Evolution of Adaptive Immunity: Macrophages in a New Context 255
9.2 Diversity of Macrophages in Mammalian Tissues 257
9.2.1 Classifying Heterogeneity 257
9.2.2 Phenotypic Manipulations and Transdifferentiations: Routes to and
from Macrophages 258
9.2.3 Function-related Markers’ in Macrophages and DCs 262
9.2.4 Macrophage Phenotypic Diversity in Response to Microbial
Challenge 266
9.2.5 Interactions between Tissue Microenvironments and Macrophages
Generate Diversity 283
9.2.6 Sequential and Regulatory Changes in Macrophage Phenotypes:
Limiting Pro- and Antiinflammatory Responses 292
9.2.6.1 Pre-TLR and TLR Regulation of Immune Responses 293
9.2.6.2 Signal Transduction in the Regulation of Immune Responses 294
9.2.6.3 Regulation of Immune Responses by Cytokines and other Bioactive
Molecules 299
9.2.6.4 Regulation of Immune Responses by Decoys 300
9.2.6.5 Regulation of Immune Responses by the Adaptive Immune
System 300
9.2.6.6 Regulation of Immune Responses by Apoptosis 301
X Contents
9.2.6.7 Interaction of Regulatory Mechanisms during Immune
Responses 301
9.2.7 Macrophage Diversity: an Overview 302
10 Macrophages – Balancing Tolerance and Immunity 331
Nicholas S. Stoy 331
10.1 Balancing Tolerance and Immunity 331
10.1.1 Introduction 331
10.1.2 Macrophage Phenotypes: Effects on Immunity and Tolerance 332
10.1.3 Concept of Innate (Peripheral) Tolerance 334
10.1.4 Concept of Adaptive Tolerance 335
10.1.5 Innate Tolerance: Receptors, Responses and Mechanisms 342
10.1.6 Incorporating NK and NT Cells into the Innate Tolerance/Innate
Immunity Paradigm 349
10.1.7 Definitions and Terminology 354
10.2 Ramifications of the Paradigm: Asthma 356
10.3 Ramifications of the Paradigm: Autoimmunity 362
10.4 Summary and Conclusions: Towards Immune System Modeling
and Therapeutics 378
11 Polymorphonuclear Neutrophils as Antigen-presenting Cells 415
Amit R. Ashtekar and Bhaskar Saha
11.1 Introduction 415
11.2 PMN as Antigen-presenting Cells 417
11.2.1 Basic Criteria of an APC for T Cells 417
11.2.2 Acquisition of Antigens 418
11.2.3 Antigen Processing 420
11.2.4 Expression of MHC Class I/II and Co-stimulatory Molecules 424
11.2.5 Delivery of Second Signal 427
11.2.6 Alteration in Cytokine Milieu 430
11.3 Evolution of Newer Thoughts as PMN March to a Newer
Horizon 434
12 Microglia – The Professional Antigen-presenting Cells of the CNS? 441
Monica J. Carson
12.1 Introduction: Microglia and CNS Immune Privilege 441
12.1.1 What are Microglia? 441
12.1.2 Is Immune Privilege Equivalent to Immune Isolation? 442
12.2 Do Microglia Differ from Other Macrophage Populations? 444
12.2.1 Microglia are Likely of Mesodermal Origin 444
12.2.2 Parenchymal Microglia are not the only Myeloid Cells in the CNS 444
12.2.3 In Contrast to other Macrophages, Parenchymal Microglia are not
Readily Replaced by Bone Marrow Stem Cells 444
Contents XI
12.2.4 Microglia Display Stable Differences in Gene Expression that
Distinguish them from Other Macrophage Populations 446
12.2.5 Morphology is not a Reliable Parameter to Differentiate Microglia
from Other Macrophage Populations 447
12.3 To What Extent is Microglial Phenotype Determined by the CNS
Microenvironment? 448
12.4 Microglia versus Macrophages/Dendritic Cells as Professional
Antigen-presenting Cells 449
12.4.1 In vitro and Ex Vivo Assays of Antigen-presentation 449
12.4.2 Culture Conditions can have Profound Effects on Microglia Effector
Functions as Assayed In Vitro 450
12.4.3 In Vivo Assays of Antigen-presentation 451
12.4.4 Antigen-presentation by Microglia is Necessary to Evoke or Sustain
Neuroprotective T Cell Effector Function 451
12.4.5 Why were Microglia Unable to Initiate Protective T Cell
Responses? 453
12.5 TREM-2 Positive Microglia may Represent Subsets Predisposed to
Differentiate into Effective Antigen-presenting Cells 454
12.6 Are Microglia the “Professional Antigen-presenting Cell of the
CNS?” 456
13 Contribution of B Cells to Autoimmune Pathogenesis 461
Thomas D rner and Peter E. Lipsky
13.1 Introduction 461
13.2 Autoimmunity and Immune Deficiency 463
13.2.1 Basic Mechanisms Providing Diversity to the B Cell Receptor 463
13.2.2 Ig V Gene Usage by B Cells of Healthy Individuals 465
13.2.3 Potential Abnormalities in Molecular Mechanisms Underlying
IgV Gene Usage in Systemic Autoimmune Diseases 465
13.2.4 Lack of Molecular Differences in V(D)J Recombination in Patients
with Systemic Autoimmune Diseases 466
13.2.5 Receptor Editing/Revision and Autoimmunity 467
13.2.6 Selective Influences Shaping the Ig V Gene Repertoire in
Autoimmune Diseases 469
13.2.6.1 IgV Gene Usage by Autoantibodies 469
13.2.7 Role of Somatic Hypermutation in Generating Autoantibodies 470
13.3 Disturbed Homeostasis of Peripheral B Cells in Autoimmune
Diseases 472
13.4 Signal Transduction Pathways in B Cells 473
13.4.1 B Cell Function Results from Balanced Agonistic and
Antagonistic Signals 474
13.4.1.1 Altered B Cell Longevity can Lead to Autoimmunity 474
13.4.1.2 Altered B Cell Activation can Lead to Autoimmunity 476
13.4.1.3 Inhibitory Receptors of B Cells 477
XII Contents
13.4.1.4 Inhibitory Receptor Pathways and Autoimmunity 480
13.5 B Cell Abnormalities Leading to Rheumatoid Arthritis 482
13.5.1 Activated B Cells may Bridge the Innate and
Adaptive Immune System 483
13.5.2 “Humoral Imprinting” in Rheumatoid Arthritis 484
13.5.3 Indications of Enhanced B Cell Activity in RA 485
13.5.4 T Cell Independent B Cell Activation 486
13.6 Depleting anti-B Cell Therapy as a Novel Therapeutic Strategy 487
14 Dendritic Cells (DCs) in Immunity and Maintenance of Tolerance 503
Magali de Heusch, Guillaume Oldenhove and Muriel Moser
14.1 Introduction 503
14.2 Dendritic Family 503
14.3 DCs at Various Stages of Maturation 504
14.4 Immature DCs 505
14.5 Homing of DCs into Secondary Lymphoid Organs 505
14.6 DCs as Adjuvants 507
14.7 DC Subsets 508
14.7.1 Classical DCs 508
14.7.2 Plasmacytoid DCs 508
14.8 DCs in T Cell Polarization 509
14.9 Tolerogenic DC 510
14.10 Mechanisms of Tolerance 512
14.10.1 Lack of Co-stimulation 512
14.10.2 Peripheral Deletion of Autoreactive T Cells 512
14.10.3 Dynamics of Cellular Contacts 512
14.10.4 Induction of Regulatory T Cells 513
14.11 CD28-B7 Bidirectional Signaling 514
14.12 Crosspriming 515
14.13 Cross-presentation and Cross-tolerization 515
14.14 DC as Regulators of T Cell Recirculation 516
14.15 DC-based Immunotherapy of Cancer 517
14.16 Conclusion 517
15 Thymic Dendritic Cells 523
Kenneth Shortman and Li Wu
15.1 Thymic Dendritic Cells 523
15.2 Localisation and Isolation of Thymic DC 523
15.3 Pickup of Antigens by Thymic DC 524
15.4 Subtypes of Thymic DC 525
15.5 Major Thymic cDC Population 525
15.6 Minor Thymic cDC Population 526
15.7 Thymic pDC 527
15.8 Maturation State and Antigen Processing Capacity of Thymic DC 527
Contents XIII
15.9 Cytokine Production by Thymic DC 528
15.10 DC of the Human Thymus 529
15.11 Turnover Rate and Lifespan of the Thymic DC 530
15.12 Endogenous versus Exogenous Sources of Thymic DC 530
15.13 Lineage Relationship and Differentiation
Pathways of Thymic cDC 531
15.14 Lineage Relationships and Developmental
Pathways of Thymic pDC 532
15.15 Thymic cDC do not Mediate Positive Selection 533
15.16 Thymic cDC and Negative Selection 533
15.17 Role of pDC in the Thymus 535
Part V Antigen Presenting Cell-based Drug Development 539
16 Antigen Presenting Cells as Drug Targets 541
Siquan Sun, Robin Thurmond and Lars Karlsson
16.1 Introduction 541
16.2 Roles of DC in disease 542
16.2.1 Transplantation 542
16.2.2 Autoimmune Diseases 542
16.2.3 Allergy/Asthma 543
16.2.4 Cancer 543
16.3 Marketed Drugs Affecting APC function 544
16.4 New Potential APC Drug Targets 547
16.4.1 APC Activation 547
16.4.2 Antigen Presentation 550
16.4.3 Co-stimulation 553
16.4.4 Cell Adhesion 555
16.4.5 APC Chemotaxis 557
16.4.6 APC Survival 558
16.4.7 Intracellular Signaling 559
16.4.8 APC Depletion 560
16.5 APC per se as Drugs – DC-based Immunotherapy Therapy 561
16.5.1 DC-based Cancer Vaccines 561
16.5.2 Targeting and Activating DC In Vivo 562
16.5.3 DC-based Immunotherapy for Transplantation and
Autoimmune Diseases 563
16.6 Conclusion 564
Glossary 585
Index 599

Download/Descarga:

Antigen Presenting Cells.PDF

.