Antigen Presenting Cells – From Mechanisms to Drug Development

Born in 1962, Harald Kropshofer gained his PhD in 1993 from the University of Tubingen. He subsequently did his post doc at the German Cancer Research Center, Heidelberg, before becoming senior scientist and group leader there in 1997. In 2000 he gained his lecturing qualification at the University of Heidelberg and in the same year joined the Basel Institute for Immunology as the Group leader in Antigen Presentation. He has been working at F. Hoffmann La Roche, Basel, since 2002, where he is currently Head of Applied Immunology. Dr. Kropshofer is a recipient of, among others, the Otto Westphal Award from the German Society for Immunology, the Robert Koch Award for Postdoctoral Scientists, and the Georges Koehler Award from the German Society for Immunology. He has filed three patents, and has around fifty publications to his name. Born in 1967, Anne Barbara Vogt gained her doctorate in 1995 from the University of Tubingen, before doing her post doc at the German Cancer Research Center, Heidelberg. From 2000 to 2001, she was Group leader at the Basel Institute for Immunology, joining F. Hoffmann La Roche in 2002, where she is currently Group leader at the Roche Center for Medical Genomics. Dr. Vogt is the recipient of several fellowships and of the Langener Wissenschaftspreis from the Paul Ehrlich Institute and the Georges Koehler Award, given by the German Society for Immunology. She has filed three patents, and has some 40 publications to her name.

Preface. List of Contributors. List of Abbreviations. Color Plates. Part I: Antigen Presentation in the Immune System. 1 Some Old and Some New Findings on Antigen Processing and Presentation (Emil R. Unanue). 1.1 Introduction. 1.2 HEL Processing. 1.3 Selection of Peptide Segments of HEL. 1.4 HEL: Conformational Isomers. 1.5 Negative Selection and Peripheral Activation to HEL Peptides. 1.6 Response to HEL Immunization in the Draining Lymph Node. Part II: Molecular Mechanisms of Antigen Processing. 2 Antigen Entry Routes Where Foreign Invaders Meet Antigen Presenting Cells (Percy A. Knolle). 2.1 Introduction. 2.2 Antigen Entry via the Gastrointestinal Tract. 2.3 Antigen Entry via the Skin. 2.4 Systemic Dissemination of Antigens/Infectious Microorganisms. 2.5 Antigen Presenting Cells in the Liver. 2.6 Conclusion. 3 Antigen Processing in the Context of MHC Class I Molecules (Frank Momburg). 3.1 Tracing the Needle in the Haystack: The Efficiency of Antigen Processing and Presentation by MHC Class I Molecules. 3.2 The Classical Route: Loading of MHC Class I Molecules With Peptides Generated in the Cytoplasm. 3.3 Crossing the Border Peptide Translocation into the ER by TAP. 3.4 Fitting in the Best: TAP associated Peptide Loading Complex Optimizes MHC I Peptide Binding. 3.5 On the Way Out: MHC I Antigen Processing along the Secretory Route. 3.6 Closing the Circle Cross presentation of Endocytosed Antigens by MHC I Molecules. 4 Antigen Processing for MHC Class II (Anne B. Vogt, Corinne Ploix and Harald Kropshofer). 4.1 Introduction. 4.2 Types of Antigen Presenting Cells. 4.3 Antigen Uptake by APCs. 4.4 Generation of Antigenic Peptides. 4.5 Assembly of MHC II Molecules. 4.6 Export of MHC II and Organization on the Cell Surface. 4.7 Viral and Bacterial Interference. 4.8 Concluding Remarks. 5 Antigen Processing and Presentation by CD1 Family Proteins (Steven A. Porcelli and D. Branch Moody). 5.1 Introduction. 5.2 CD1 Genes and Classification of CD1 Proteins. 5.3 Structure and Biosynthesis of CD1 Proteins. 5.4 Foreign Lipid Antigens Presented by Group 1 CD1. 5.5 Self Lipid Antigens Presented by CD1. 5.6 Group 2 CD1 restricted TC ells. 5.7 Tissue Distribution of CD1 Proteins. 5.8 Subcellular Distribution and Intracellular Trafficking of CD1. 5.9 Antigen Uptake, Processing and Loading in the CD1 Pathway. 5.10 Conclusions. Part III: Antigen Presenting Cells' Ligands Recognized by T and Toll like Receptors. 6 Naturally Processed Self peptides of MHC Molecules (Harald Kropshofer and Sebastian Spindeldreher). 6.1 Introduction. 6.2 Milestone Events. 6.3 Progress in Sequence Analysis of Natural Peptides. 6.4 Natural Class II MHC associated Peptides from Different Tissues and Cell types. 6.5 The CLIP Story. 6.6 Outlook: Natural Peptides as Diagnostic or Therapeutic Tools. 7 Target Cell Contributions to Cytotoxic T Cell Sensitivity (Tatiana Lebdeva, Michael L. Dustin and Yuri Sykulev). 7.1 Introduction. 7.2 Intercellular Adhesion Molecule 1 (ICAM 1). 7.3 Major Histocompatability Complex (MHC). 7.4 Conclusion. 8 Stimulation of Antigen Presenting Cells: from Classical Adjuvants to Toll like Receptor (TLR) Ligands (Martin F. Bachmann and Annette Oxenius). 8.1 Synopsis. 8.2 Pathogen associated Features that Drive Efficient Immune Responses. 8.3 Composition and Function of Adjuvants. 8.4 TLR Protein Family in Mammals. 8.5 TLR Signaling. 8.6 TLR independent Recognition of PAMPs: Nods, PKR and Dectin 1. 8.7 Therapeutic Potential of TLRs and their Ligands. 8.8 Conclusion. Part IV: The Repertoire of Antigen Presenting Cells. 9 Evolution and Diversity of Macrophages (Nicholas S. Stoy). 9.1 Evolution of Macrophages: Immunity without Antigen Presentation. 9.2 Diversity of Macrophages in Mammalian Tissues. 10 Macrophages Balancing Tolerance and Immunity (Nicholas S. Stoy. 10.1 Balancing Tolerance and Immunity. 10.2 Ramifications of the Paradigm: Asthma. 10.3 Ramifications of the Paradigm: Autoimmunity. 10.4 Summary and Conclusions: Towards Immune System Modeling and Therapeutics. 11 Polymorphonuclear Neutrophils as Antigen presenting Cells (Amit R. Ashtekar and Bhaskar Saha). 11.1 Introduction. 11.2 PMN as Antigen presenting Cells. 11.3 Evolution of Newer Thoughts as PMN March to a Newer Horizon. 12 Microglia The Professional Antigen presenting Cells of the CNS? (Monica J. Carson). 12.1 Introduction: Microglia and CNS Immune Privilege. 12.2 Do Microglia Differ from Other Macrophage Populations? 12.3 To What Extent is Microglial Phenotype Determined by the CNS Microenvironment? 12.4 Microglia versus Macrophages/Dendritic Cells as Professional Antigen presenting Cells. 12.5 TREM 2 Positive Microglia may Represent Subsets Predisposed to Differentiate into Effective Antigen presenting Cells. 12.6 Are Microglia the Professional Antigen presenting Cell of the CNS??. 13 Contribution of B Cells to Autoimmune Pathogenesis (Thomas D rner and Peter E. Lipsky). 13.1 Introduction. 13.2 Autoimmunity and Immune Deficiency. 13.3 Disturbed Homeostasis of Peripheral B Cells in Autoimmune Diseases. 13.4 Signal Transduction Pathways in B Cells. 13.5 B Cell Abnormalities Leading to Rheumatoid Arthritis. 13.6 Depleting anti B Cell Therapy as a Novel Therapeutic Strategy. 14 Dendritic Cells (DCs) in Immunity and Maintenance of Tolerance (Magali de Heusch, Guillaume Oldenhove and Muriel Moser). 14.1 Introduction. 14.2 Dendritic Family. 14.3 DCs at Various Stages of Maturation. 14.4 Immature DCs. 14.5 Homing of DCs into Secondary Lymphoid Organs. 14.6 DCs as Adjuvants. 14.7 DC Subsets. 14.8 DCs in TC ell Polarization. 14.9 TolerogenicDC. 14.10 Mechanisms of Tolerance. 14.11 CD28 B7 Bidirectional Signaling. 14.12 Crosspriming. 14.13 Cross presentation and Cross tolerization. 14.14 DC as Regulators of TC ell Recirculation. 14.15 DC based Immunotherapy of Cancer. 14.16 Conclusion. 15 Thymic Dendritic Cells (Kenneth Shortman and Li Wu). 15.1 Thymic Dendritic Cells. 15.2 Localisation and Isolation of Thymic DC. 15.3 Pickup of Antigens by Thymic DC. 15.4 Subtypes of Thymic DC. 15.5 Major Thymic cDC Population. 15.6 Minor Thymic cDC Population. 15.7 Thymic pDC. 15.8 Maturation State and Antigen Processing Capacity of Thymic DC. 15.9 Cytokine Production by Thymic DC. 15.10 DC of the Human Thymus. 15.11 Turnover Rate and Lifespan of the Thymic DC. 15.12 Endogenous versus Exogenous Sources of Thymic DC. 15.13 Lineage Relationship and Differentiation Pathways of Thymic cDC. 15.14 Lineage Relationships and Developmental Pathways of Thymic pDC. 15.15 Thymic cDC do not Mediate Positive Selection. 15.16 Thymic cDC and Negative Selection. 15.17 Role of pDC in the Thymus. Part V: Antigen Presenting Cell based Drug Development. 16 Antigen Presenting Cells as Drug Targets (Siquan Sun, Robin Thurmond and Lars Karlsson). 16.1 Introduction. 16.2 Roles of DC in disease. 16.3 Marketed Drugs Affecting APC function. 16.4 New Potential APC Drug Targets. 16.5 APC per se as Drugs DC based Immunotherapy Therapy. 16.6 Conclusion. Glossary. Index.