Mucosal Immunology

In Memoriam

Preface to the First Edition

Preface to the Second Edition

Preface to the Third Edition

Preface to the Fourth Edition

Historical Aspects of Mucosal Immunology

Volume 1

• Section A. Development and Organization of the Mucosal Immune System

• Chapter 1. Overview: The Mucosal Immune System

• Introduction
• Mucosal Microbiota
• Epithelial Cells as Essential Partners of the Mucosal Immune System
• Antigen Uptake and Presentation in the Mucosal Immune System
• Mucosal T Cells and Cell-Mediated Immunity
• Mucosal Immunity and Homeostasis
• Unique Features of Individual Components of the Mucosal Immune System and Their Integration
• Global Impact of Mucosal Immunity in Vaccine Initiatives
• The Future

• Chapter 2. Development and Physiology of the Intestinal Mucosal Defense

• Development of Mucosal Defense
• The Development of Mucosal Immunity Continues during the Postnatal Period
• Physiology of Mucosal Defense
• Macromolecular Absorption
• Physiologic Transport
• Barriers Preventing Pathologic Transport

• Chapter 3. Development of Gut-Associated Lymphoid Tissues

• Introduction: Gut-Associated Lymphoid Tissues
• Lymph Node and Peyer’s Patch Organogenesis
• Solitary Intestinal Lymphoid Tissues

• Chapter 4. Structure, Organization, and Development of the Mucosal Immune System of the Respiratory Tract

• Introduction and Basic Anatomy of Lymphoid Tissues in the Respiratory Tract
• Lymphoid Architecture of NALT
• NALT Development
• Antigen Acquisition in NALT
• Immune Responses in NALT
• NALT and Nasal Tolerance
• Lymphoid Architecture of BALT
• BALT Development
• Antigen Acquisition in BALT
• Immune Responses in BALT
• BALT and Asthma
• BALT and Chronic Obstructive Pulmonary Disease
• BALT and Autoimmunity
• BALT and Pulmonary Malignancy

• Chapter 5. The Mucosal Microbiome: Imprinting the Immune System of the Intestinal Tract

• Composition of the Intestinal Microbiome
• Factors Influencing the Intestinal Microbiome
• Sensing of the Microbiota by the Intestinal Immune System
• Influence of the Microbiota on Immune Development and Function
• Outlook

• Chapter 6. The Microbiome at Other Mucosal Sites

• Introduction
• The Oral Microbiome
• The Airway Microbiome
• The Ocular Microbiome
• The Genital Microbiome
• Conclusions

• Chapter 7. Endogenous Microbiota of the Genitourinary Tract

• Introduction
• Early Studies of VMB on the Basis of Culture and Microscopy
• Molecular Microbiologic Investigations of VMB
• Modulation of the Vaginal Mucosal Immune Response by VMB
• Molecular Analysis of Male Genitourinary Tract Microbiota
• Conclusions

• Chapter 8. Gnotobiology and the Study of Complex Interactions between the Intestinal Microbiota, Probiotics, and the Host

• Introduction: Microbiota and Microbiomes
• Gnotobiology as a Tool: A Historical Perspective
• Microbiota Perturbations in Human Disease
• Mechanisms of Immunomodulation by Specific Members of the Intestinal Microbiota
• Mechanisms of Immunomodulation by Probiotics
• Conclusion

• Chapter 9. Mucosal Immunity in Invertebrates

• Introduction
• Innate Immunity of Invertebrates
• Conclusions

• Chapter 10. Comparative Phylogeny of the Mucosa-Associated Lymphoid Tissue

• Introduction
• The Phylogeny of Immune Systems
• General Characteristics of Mucosa-Associated Lymphoid Tissue in the Major Vertebrate Lineages
• Conclusions

• Chapter 11. Ontogeny of Mucosal Immunity and Aging

• Ontogeny of Muscosal Immunology
• Aging
• Association of Ontogeny Profiles with Disease
• Conclusions

• Chapter 12. Epithelial Cells: Structure, Transport, and Barrier Function

• Introduction
• Structural Organization of the Intestine
• Intestinal Epithelial Cell Types
• Epithelial Polarity
• The Paracellular Barrier
• Transepithelial Transport
• Molecular Architecture of Tight Junctions
• Measuring Barrier Function
• Ex vivo and In vitro Measures of Barrier Function
• Barrier Function and Disease Pathogenesis
• Models Linking Intestinal Barrier Loss to Experimental IBD
• Intestinal Barrier Loss Promotes Compensatory Immunoregulatory Processes
• Conclusion

• Chapter 13. M Cells: Specialized Antigen Sampling Cells in the Follicle-Associated Epithelium

• Fundamentals of Structure and Function of Intestinal Epithelium
• Structure and Cellular Composition of Intestinal Absorptive Epithelium
• Functions of Intestinal Absorptive Epithelium
• The FAE of GALTs
• Morphological Identification of M Cells
• Markers for Identification of M Cells
• Ontogeny of M Cells
• M Cell Differentiation
• Functions of Intestinal M Cells
• M Cells in Other Mucosa-Associated Lymphoid Tissues
• Conclusion

• Chapter 14. Mucins and Mucus

• Introduction
• Biosynthesis and Structure of Mucins
• Differentiation of Mucus Producing Cells and Regulation of Mucin Gene Expression
• Functional Properties of Mucins
• Subversion of Mucin Barriers by Mucosal Pathogens and Parasites
• Mucins in Human Mucosal Inflammatory Diseases
• Future Challenges

• Chapter 15. Innate Humoral Defense Factors

• Introduction
• Pattern-Recognition Molecules
• Lysozyme and HAMLET
• Lactoferrin
• Peroxidases
• Other Factors

• Chapter 16. Defensins in Enteric Mucosal Immunity

• Antimicrobial Peptides and Innate Immunity
• Cathelicidins
• Defensins: Three Families of Cysteine-Rich AMPs
• Mucosal Antimicrobial Proteins and Peptides
• Mechanisms of α-Defensin Bactericidal Action
• The Intestinal Epithelium
• Paneth Cells
• α-Defensin Biosynthesis
• Paneth Cell α-Defensins
• Paneth Cell α-Defensins and Innate Mucosal Immunity
• Paneth Cell Defects and Mucosal Immunity

• Chapter 17. Mucosal Immunoglobulins

• Introduction
• Igs of the External Secretions
• IgA STRUCTURE AND ARRANGEMENT OF COMPONENT CHAINS
• Biosynthesis and Assembly of IgA
• IgA Metabolism

• Chapter 18. Phylogeny and Comparative Physiology of Mucosal Immunoglobulins

• Introduction
• Phylogeny of Mucosal Ig’s in Jawed Vertebrates
• Phylogeny of Polymeric Ig’s
• Phylogeny of the Polymeric Ig Receptor, the Epithelial Transporter of Mucosal Ig’s
• Comparative Physiology of Mucosal Ig’s
• Conclusions

• Chapter 19. Immunoglobulin Transport and Immunoglobulin Receptors

• Introduction
• Transport of Polymeric Ig by pIgR
• Structure and Function of pIgR
• Regulation of pIgR Expression
• Organization and Regulation of the PIGR Gene
• pIgR Trafficking and Signals
• Regulation of pIgR Trafficking
• Hepatobiliary Transport of IgA
• Transport of IgG by the FcRn
• Structure and Function of FcRn
• Transcytosis of IgG by FcRn
• Physiological Importance of FcRn-Mediated IgG Transcytosis
• Exploitation of the FcRn–IgG Interaction for Therapeutic Purposes at Mucosal Surfaces
• Systemic Functions of FcRn
• Conclusions

• Chapter 20. Fc Receptors in Mucosal Immunology

• Introduction
• Leukocyte IgA Receptors
• FCα/μR
• Nonleukocyte IgA Receptors
• FCR-Mediated IgE Activity in Mucosal Secretions

• Chapter 21. Biological Activities of IgA

• Introduction
• Biological Properties of IgA
• IgA and Maintenance of Homeostasis

• Chapter 22. Microbial Evasion of IgA Functions

• Introduction
• Specific IgA Proteases
• Other Microbial Proteases with IgA-Cleaving Activity
• Effect of Microbial Glycosidases on IgA
• IgA-Binding Proteins
• Conclusions

• Chapter 23. The Regulation of IgA Production

• Variable IgA Production in Mammals
• Immune Geography and Lymphoid Structures Regulating IgA Production
• T Cell-Dependent IgA Responses upon Colonization with a Microbiota
• T Cell-Independent IgA Generation in Isolated Lymphoid Follicles
• IgA Generation in Lamina Propria: Innate and Adaptive Crossroad
• Heterogeneity of IgA Induction and Responses

• Section B. Inductive and Effector Cells and Tissues of the Mucosal Immune System

• Chapter 24. Overview: Inductive and Effector Cells and Tissues of the Mucosal Immune System
• Chapter 25. Mucosal Dendritic Cells: Origins, Subsets, and Biology

• Introduction
• Origins of DCs
• DCs Are Specialized Sentinels That Capture Antigens and Activate Naïve T Cells after Migrating to the Draining LNs
• Dendritic Cells Can Directly Determine the Nature of the Ensuing Lymphocyte Response
• Gastrointestinal Tract DCs
• Respiratory Tract DCs
• Genitourinary Tract DCs
• General Conclusions

• Chapter 26. Mucosal Macrophages in Defense and Regulation

• Introduction
• Ontogeny of Mucosal Macrophages
• Phenotype of Resident Intestinal Macrophages
• Defense and Regulatory Functions of Intestinal Macrophages
• Role of Macrophages in Gastrointestinal Neoplasia
• Intestinal Macrophages in Mucosal Infections

• Chapter 27. Role of Epithelial Cells in Antigen Presentation

• Introduction to Antigen Presentation and Function in Adaptive Immunity
• Antigen Transport and Presentation by the Intestinal Epithelium
• Conclusion

• Chapter 28. Microbial Sensing and Regulation of Mucosal Immune Responses by Intestinal Epithelial Cells

• Epithelial Cells Comprise Functionally Different Cell Types
• Interaction of Epithelial Cells with the External World: Microbes
• Interaction of Epithelial Cells with the Internal World: Immune Cells
• Conclusions

• Chapter 29. Epithelial Cell Regulation of Immune Responses in the Lung

• Introduction
• Asthma: A Th2 Cell-Mediated Disease with Alterations of ECs
• Alterations to the Barrier Function of the Airway Epithelium Leads to Allergic Sensitization
• Alterations in the Differentiation Program of Airway Epithelial Cells in Asthma
• Epithelial Cells Sense Danger and Activate DCs
• Epithelial Threshold for Allergen Recognition is Crucial in Causing Allergic Sensitization
• An Interplay between Airway Epithelium and Dendritic Cells Controls Asthma Development
• Defective Epithelial Cell Responses Contribute to Decreased Viral Clearance
• Bronchial Epithelial Cells Produce Endogenous Danger Signals
• Epithelial Cells Can Also Dampen Inflammation
• Conclusion

• Chapter 30. Signaling Mechanisms Regulating Innate Immune Responses

• Introduction
• PRR-Initiated Signaling Pathways
• Mechanisms for Inhibiting PRR Signaling
• Future Perspectives

• Chapter 31. The Mucosal B Cell System

• Introduction
• Immune-Inductive Lymphoid Tissue
• Activation of B Cells in Malt
• Regulatory Mechanisms of the Mucosal B Cell System
• Homing Mechanisms for Malt-Derived B Cells
• Distribution and Properties of Plasma Cells In Human Exocrine Tissues
• Ontogeny of Mucosal Plasma Cells
• Impact of Immunodeficiency on the Mucosal B Cell System
• Conclusions

• Chapter 32. Regulation and Function of Mucosal IgA and IgD

• Introduction
• Nature and Function of Mucosal IgA and IgD
• Mechanisms of Mucosal IgA and IgD Responses
• Pathways Underlying Mucosal IgA and IgD Responses
• Concluding Remarks

• Chapter 33. Mucosal B Cell Differentiation and Regulation

• Introduction
• Induction of Mucosal IgA Responses in Mucosal-Associated Lymphoid Tissue
• Dependence of MALT on the Microbiota
• IgA CSR and SHM
• IgA Switch Factors and Signals That Influence Mucosal Antibody Formation
• Ig Light Chain Drifting in the IgA Response
• GCs and IgA B Cell Differentiation
• The Role of DCs in Mucosal IgA Responses
• The Role of Nonhematopoietic Cells in IgA B Cell Differentiation
• T Cell-Dependent and -Independent Mucosal B Cell Responses
• IgA B Cell Responses Are Synchronized in the GALT
• Re-Utilization of GCs in PPs
• Follicular Helper CD4 T Cells in MALT
• B Cell Subsets Responsible for Mucosal IgA Responses
• Long-Term Memory in Mucosal IgA Responses
• A Proposed Model for IgA B Cell Differentiation

• Chapter 34. Effector CD4+ T Cells in the Intestines

• Discovery of Effector T Cells
• Effector T Cell Development and Functions
• T Cell Lineage Plasticity within the Intestines
• Induction of Intestinal Effector T Cells by the Gut Microbiota
• Intestinal Effector T Cell Responses to Enteric Infection
• Therapeutic Targeting of Effector T Cells
• Conclusion

• Chapter 35. Intraepithelial TCRαβ T Cells in Health and Disease

• Introduction
• Hallmarks of TCRαβ⁺ Epi-T Cells
• Development of TCRαβ Epi-T Cell Subsets
• Post-Thymic Migration of TCRαβ Epi-T Cell Progenitor Cells
• Local Adaptation of Gut-Specific TCRαβ Epi-T Cells
• Beneficial and Pathogenic Roles of TCRαβ Epi-T Cells
• Concluding Remarks

• Chapter 36. Mucosal-Resident T Lymphocytes with Invariant Antigen Receptors

• Introduction
• INKT and MAIT Cells Share Unusual Properties
• Pathways for Activating INKT Cells
• INKT Cells and Intestinal Immunity
• INKT Cells and Lung Immunity
• INKT Cells and the Commensal Flora
• Methodologic Issues in Analyzing MAIT Cells
• Phenotype and Distribution of MAIT Cells
• Pathways for Activating MAIT Cells
• MAIT Cells in Intestine and Lung Immunity
• Summary and Conclusions

• Chapter 37. Mucosal T Cell Receptor γδ Intraepithelial T Cells

• γδ T Cells and Mucosal Tissues
• γδ IELs in Context
• Innate-like T Cell Development
• Thymic Selection of Innate-like IELs
• IEL Pre-programming
• Atypical IEL Responsiveness
• Mucosal γδ T Cells and Infection
• Mucosal γδ T Cell Responses to Nonmicrobial Challenge
• Mucosal γδ T Cell Replenishment
• MALT Pathobiology as Informed by Mucosal γδ T Cells

• Chapter 38. Intestinal Regulatory CD4+ T Cells

• Types of CD4⁺ Regulatory T Cells
• Development of Regulatory CD4⁺ T Cells
• Networks of Regulatory T Cells in the Intestine
• Conclusion

• Chapter 39. Effector Cells of the Mucosal Immune System: Innate Lymphoid Cells

• Introduction
• ILC1 or IFN-γ Producing ILC
• ILC2 or IL-5/IL-13-Producing ILC
• ILC3 or IL-17/IL-22-Producing ILCs
• Conclusion

• Chapter 40. Lymphocyte Trafficking to Mucosal Tissues

• Lymphocyte Trafficking Circuits
• The Nuts and Bolts of Lymphocyte Trafficking
• The Multistep Model of Leukocyte Migration
• Lymphocyte Trafficking in and out of the LN
• Lymphocyte Trafficking into Peripheral Tissue
• Tissue-Selective Lymphocyte Trafficking to Mucosal Surfaces
• Mechanism of T Cell Imprinting
• Systemic T Cell Immunity and Flexibility in Tissue-Selective Imprinting
• Lymphocyte Trafficking and Oral Tolerance
• Lymphocyte Trafficking in Disease
• Targeting Lymphocyte Trafficking as a Therapeutic Strategy
• Conclusion

• Chapter 41. Mechanisms of Oral Tolerance to Soluble Protein Antigens

• A Definition of Oral Tolerance
• Other Dominant Suppressive T Cell Populations

• Chapter 42. Gut Microbiota and Intestinal Adaptive Immunity

• Introduction
• Lamina Propria Adaptive Lymphocytes
• Intraepithelial Lymphocytes and the Microbiota
• Conclusion and Future Directions

• Chapter 43. Mast Cells, Basophils and Mucosal Immunity

• Introduction
• Mast Cell and Basophil Development and Characteristics
• New Tools to Understand the Function of Mast Cells and Basophils
• Mast Cell and Basophil Functions—Role in Disease Processes
• Conclusions

• Chapter 44. Mucosal Eosinophils

• Introduction
• Regulation of Eosinophils
• Eosinophil Products
• Beneficial Role of Eosinophils
• Detrimental Role of Eosinophils in Inflammatory Disease States
• Summary and Concluding Remarks

• Chapter 45. The Neutrophil

• Introduction
• Neutrophil Structure
• Functions
• Conclusions
• Disclosure

• Chapter 46. Neuronal Regulation of Mucosal Immune Responses

• Innervation and Immunity in the Gastrointestinal Tract
• Sympathetic Regulation of the Mucosal Immune System
• The Parasympathetic Control of the Gut Immune System
• Noncholinergic, Nonadrenergic Receptors: Relevance for Gut
• Future Perspectives and Clinical Implications

• Section C. Mucosal Immunity and Infections

• Chapter 47. Overview: Mucosal Immunity and Infections

• The Distinctive Patterns of Mucosal Responses to Commensals and Pathogens
• Reponses to a Pathogen Causing Chronic and Deceptively Asymptomatic Infection
• A "Semipathogenic" Escherichia coli Organism Implicated in Crohn’s Disease

• Chapter 48. Bacterial Adhesion to Intestinal Mucosa

• Introduction
• Adhesion of Bacteria to Mucus
• Bacteria Adhesion to M Cells
• Adhesion to Intestinal Epithelium

• Chapter 49. Bacterial Interactions with Mucosal Epithelial Cells

• Antibacterial Features of Mucosal Environments
• Interactions of Bacterial Pathogens with the Respiratory Tract
• Bacterial Interactions with the Gastrointestinal Tract
• Summary

• Chapter 50. Discriminating Pathogens from Commensals at Mucosal Surfaces

• Introduction
• Active Immune Stimulation by Luminal Bacteria Keeps Them away from Host Cells
• Immune Hyporesponsiveness to Commensals
• Commensals Actively Dampen Gut Immune Response
• Pathogens Express Virulence Factors that Enable Them to Invade the Host and to Contact Intestinal Epithelial Cells
• Pathogens Elicit Danger Signals Sensed by the Host
• Pathogens Dampen Immune Activation for Their Own Survival at the Expense of Host Integrity
• Conclusion

• Chapter 51. Helicobacter pylori Infection of the Gastric Mucosa

• Epidemiology and Transmission of H. pylori Infection in Humans
• Sites of H. pylori Colonization
• Role of Mucus
• H. pylori
-Associated Gastritis, Peptic Ulcers, and Gastric Adenocarcinoma
• Virulence Factors of H. pylori
• Models for Studying H. pylori-Induced Gastritis and Gastric Adenocarcinoma
• Mucosal Immune Responses to Chronic H. pylori Infection
• Vaccine Development: Approaches, Experience, and Prospects
• Concluding Remarks

• Chapter 52. Innate Lymphoid Cells in Mucosal Homeostasis, Infections, Autoimmune Disorders, and Tumors

• Introduction: Recognition of ILC Complexity
• ILC Differentiation: Cytokines and Transcription Factors
• ILCs are Tissue-Resident Lymphocytes That Respond to Local Cytokine Microenvironment
• Microbiota and Nutrition in ILC Development
• A Role for ILC1 Subsets in Inflammatory Bowel Disease
• ILC2 Play a Major Role in Immune Responses to Helminth Infections
• Diversity and Plasticity of Gastrointestinal ILC3
• ILC3: Friend or Foe?
• ILCs and Adaptive Responses: Redundant or Complementary?
• ILCs in Viral Infections
• Future Directions

• Chapter 53. Virus Infection of Airway Epithelial Cells

• Susceptibility of the Epithelium to Respiratory Viral Infection
• Acute Epithelial Responses to Respiratory Viral Infection: Inducing the "Antiviral State"
• Acute Epithelial Responses to Respiratory Viral Infection: Cytokine Networks in Normal Host Defense
• Acute Epithelial Responses to Respiratory Viral Infection: T-Helper Type 2 (Th2)-Associated Cytokines
• Interplay between Virus Infection, Epithelial Type 2 Cytokines, and the Development of Chronic Airway Disease
• Concluding Remarks

• Chapter 54. Parasitic Infection of the Mucosal Surfaces

• Introduction
• Parasites
• Models of Mucosal-Associated Parasitic Infections
• Innate Immune Responses
• Adaptive Immune Responses
• Immune Effector Mechanisms
• Microbiota–Parasite Interactions in the Intestine
• Concluding Remarks

• Section D. Mucosal Vaccines

• Chapter 55. Mucosal Vaccines: An Overview

• Rationale for Mucosal Vaccination
• Mucosal Adjuvants
• Duration of Responses: Mucosal Memory
• Mucosal Tolerance
• Routes of Mucosal Vaccine Administration
• The Future of Mucosal Vaccination

• Chapter 56. Vaccines against Bacterial Enteric Infections

• Introduction
• Immune Responses Induced by Enteric Infections or Oral Vaccines
• Determinants for Choice of Vaccination Route for Protecting against Mucosal Pathogens
• Choice of Mucosal Vaccination Route
• Licensed Vaccines against Bacterial Enteric Infections
• Other Bacterial Enteric Vaccines in the Pipeline
• "Developing Country Ecology Barriers" to Oral Vaccines
• Mucosal Adjuvants for Oral Vaccines against Bacterial Enteric Infections
• Alternative Vaccine Approaches
• Immune Correlates of Protection Related to Oral Vaccines
• Conclusions

• Chapter 57. Acute Gastroenteritis Viruses

• Rotaviruses
• Human Caliciviruses
• Astroviruses
• Perspective

• Chapter 58. Respiratory Bacterial Vaccines

• Introduction
• Diphtheria Vaccine
• Pertussis Vaccine
• Haemophilus Influenzae
Vaccine
• Pneumococcal Vaccine

• Chapter 59. Respiratory Virus Vaccines

• Introduction
• Virology
• Clinical Features and Epidemiology
• Pathogenesis
• Immune Responses to Respiratory Virus Infection
• Respiratory Virus Vaccines
• New Developments in Mucosal Vaccination
• Concluding Remarks

• Chapter 60. Mucosal Immunity and Vaccines Against Simian Immunodeficiency Virus and Human Immunodeficiency Virus

• Introduction: The Global Human Immunodeficiency Virus Epidemic
• HIV Transmission and Infection in the Mucosa
• Mucosal Immune Defense Against HIV-1
• Models of HIV Infection and Related Vaccine Studies
• Future Studies

• Chapter 61. Mucosal Adjuvants: New Developments and Challenges

• Introduction
• Bacterial Enterotoxins as Mucosal Adjuvants
• Other Bacterial Toxins with Mucosal Adjuvant Properties
• Toll-Like Receptor Ligands
• Cytokines
• Challenges and Future Direction

• Chapter 62. Use of CpG Oligonucleotides as Mucosal Adjuvants

• Introduction
• Overview of Mucosal Adjuvants
• Effect of CpG ODN on the Mucosal Immune System
• Comparison of CpG ODN with Other Adjuvants
• Clinical Trials Involving Mucosal Delivery of CpG ODN

• Chapter 63. Antigen Delivery Systems I: Nonliving Microparticles, Liposomes, and Immune-Stimulating Complexes (ISCOMs)

• Introduction
• Barriers to Mucosal Immunization
• Mucosal Vaccination
• Routes of Mucosal Immunization
• Adjuvants
• Mechanisms of Adjuvanticity
• Mucosal Adjuvants
• Particulate Adjuvants
• Immune-stimulating Complexes (ISCOMs)
• Liposomes
• Microparticles
• Future Perspectives

• Chapter 64. Antigen Delivery System II: Development of Live Attenuated Bacterial Vectors

• Introduction
• Attenuated Bacterial Antigen Delivery Systems
• Recombinant Attenuated Bacterial Vaccine Antigen Delivery Systems
• Invasive Bacterial Vector Delivery Systems
• Noninvasive Mucosal Colonizing Bacterial Delivery Systems
• Recombinant Attenuated Bacterial DNA Vaccine Delivery Systems
• Bacterial Genera Being Developed for DNA Vaccine Delivery
• Other Issues of Importance
• Concluding Thoughts

Volume 2

• Section D. Mucosal Vaccines

• Chapter 65. Mucosal Vaccines from Plant Biotechnology

• Introduction
• Mucosal Vaccines for Humans
• Plant-Based Mucosal Animal Vaccines
• Conclusions

• Chapter 66. Filling the Immunological Gap: Recombinant Viral Vectors for Mucosal Vaccines

• Introduction
• Routes of Mucosal Vaccine Delivery
• Poxvirus Vectors
• Canarypox Vectors
• Potential Promise of Poxviral Vectors and HIV-1
• Recombinant Adenovirus Vectors
• RAd5 and HIV-1 Step Study: Guilty and Condemned or Wrongfully Used and Prematurely Convicted?
• Rare Serotype and Simian Adenovirus Vectors
• Rhesus Cytomegalovirus Vectors—Breaking the Rules and Protecting against SIV via Mucosal Effector Memory T Cells
• Respiratory Mucosal Vaccination Strategies against Intracellular Bacterial Infection
• Choice of Virus-Based Vector Platforms for Respiratory Mucosal Vaccination
• Respiratory Mucosal Vaccination against Pulmonary Tuberculosis
• Respiratory Mucosal "Boosting" or "Vaccine-less" Strategies to Modulate T Cell Geography for Enhanced Protection against Respiratory Pathogens
• Human Papillomavirus Pseudovirions: Targeting the Vaginal Mucosa
• Going Global and Challenges for Mucosal Vaccines: Tropical Barrier
• Conclusions

• Chapter 67. DNA Vaccines for the Induction of Immune Responses in Mucosal Tissues

• Introduction
• Brief History of DNA Vaccines
• DNA Vaccines Encode for Antigens Synthesized by Transduced Cells
• The Immune Response to DNA Vaccines
• Safety of DNA Vaccines
• Approaches Increasing DNA Vaccine Efficacy
• Targeting of DNA Vaccine to M Cells and DCs
• Conclusion

• Chapter 68. Mucosal Veterinary Vaccines: Comparative Vaccinology

• Introduction
• Respiratory Vaccines
• Vaccines for Genital Infections
• Enteric Vaccines
• Passive Immunity
• Vaccination of Farmed Fish
• Conclusions

• Chapter 69. Mucosal Vaccines for Dental Diseases

• Dental Caries
• Introduction to Periodontal Diseases
• Conclusions

• Chapter 70. Parenteral Immunization and Protection from Mucosal Infection

• Parenteral Immunization and Mucosal Immunity
• The Polio Paradigm
• Respiratory Infections
• Gastrointestinal Infections
• Typhoid
• Shigella
• Genitourinary Infections
• Conclusion

• Chapter 71. Passive Immunization: Toward Magic Bullets

• Passive Immunity: A Historical Perspective
• Role of Antibodies in Protection Against Pathogens
• Naturally Acquired Passive Immunity
• Artificial Induction of Passive Immunity
• Production System for Recombinant Antibodies
• Passive Administration of Antibodies
• Passive Immunity: Toward the Future

• Section E. Immunodeficiency

• Chapter 72. Overview: Mucosal Immunity and Immunodeficiency

• IgA Deficiency
• The Impact of SIV/HIV Infection on Mucosal Immune Function

• Chapter 73. IgA Deficiency and Other Immunodeficiencies Causing Mucosal Immunity Dysfunction

• Selective IGA Deficiency

• Chapter 74. Malnutrition, Immunodeficiency, and Mucosal Infection

• Introduction
• Influence of Nutrients in Priming and Development of the Gastrointestinal Immune System
• Role of Nutrition in the Development of the Microbiota
• Malnutrition, Nutrient Deficiency, and Infection
• Summary

• Chapter 75. Human/Simian Immunodeficiency Virus Transmission and Infection at Mucosal Sites

• Mucosal Transmission
• Events in the Mucosa Following Infection
• Conclusions

• Chapter 76. Simian Immunodeficiency Virus Infection and Mucosal Immunity

• Introduction: The Evolution of HIV from SIV
• SIV in Its "Natural Hosts" and the Origins of HIV
• Susceptible Hosts
• SIV Transmission in Mucosal Tissues
• Vaginal SIV Transmission
• Rectal SIV Transmission
• Mucosal Pathogenesis of SIV
• Microbial Translocation
• Innate Mucosal Immunity in SIV-Infected Macaques
• Innate Lymphoid Cells
• γδ T Cells
• Adaptive Immune Responses to SIV
• Mucosal Th17 Cells in SIV Infection
• Mucosal CD8⁺ T Cell Responses in SIV
• Mucosal Humoral Responses to SIV
• SIV Macaque Models for Vaccine Testing
• Viral Challenges for Vaccine Testing
• Correlates of Protection from SIV Vaccines
• Future Directions for SIV Models for HIV Research

• Chapter 77. Microbial Translocation and the Effects of HIV/SIV Infection on Mucosal Barrier Function

• Introduction
• HIV/SIV Infection Induces a Barrier Defect of the Intestinal Mucosa
• Structural Correlates of the HIV-Induced Barrier Defect of the Intestinal Mucosa
• Mucosal Barrier Impairment by Loss of Immunological Defenses
• Mechanisms of the HIV-Induced Intestinal Mucosal Barrier Defect
• Microbial Translocation and Systemic Immune Activation
• Systemic Immune Activation, Disease Progression, and Comorbidity

• Section F. Gastrointestinal and Hepatic Diseases

• Chapter 78. Overview: Gastrointestinal and Hepatic Diseases

• Inflammatory Bowel Diseases
• Celiac Disease
• Pancreatitis
• Immunologic Diseases of the Liver and Biliary Tract

• Chapter 79. Experimental Models of Gastrointestinal Inflammatory Diseases

• Introduction
• Final Common Pathways of Experimental Mucosal Inflammation
• Representative Models of Mucosal Inflammation
• Conclusions

• Chapter 80. Immunopathology of Celiac Disease

• Clinical and Histological Presentations of Celiac Disease
• Predisposing Genes
• Adaptive Immune Response to Gluten in CD
• Innate Immunity and Licensing of Cytotoxic T Lymphocytes in CD
• Gluten-Free Diet and Development of Novel Therapies
• Conclusion

• Chapter 81. Ulcerative Colitis

• Introduction
• The Genetic Basis of UC
• Microbiome Abnormalities in UC
• Epithelial Cell Function in UC
• Genetic Defects Affecting Epithelial Barrier Function
• Additional Genetic Abnormalities Associated with UC
• Experimental Models of Th2 Colitis and UC
• Immunopathogenesis of UC
• Summary

• Chapter 82. Crohn’s Disease

• Introduction
• Clinical Aspects of CD
• Clinical Presentation
• Extraintestinal Manifestations
• Diagnosis: Blood and Stool Tests, Endoscopy, Imaging, and Pathology
• Clinical Management and Natural Course
• Quality of Life and Mortality
• Treatment
• Pathogenesis
• Genetic Susceptibility
• Environmental Factors
• The Commensal Microflora
• Nonimmune Defense Mechanisms and the Intestinal Barrier
• The Mucosal Immune System in CD Pathogenesis

• Chapter 83. Allergic Inflammatory Diseases of the Gastrointestinal Tract

• Introduction
• Clinical Aspects
• Pathogenesis
• Conclusions

• Chapter 84. IgE-Mediated Food Allergy

• Epidemiology of Food Allergy
• Clinical Manifestations of IgE-Mediated Food Allergy
• Diagnosing Food Allergic Disorders
• Immune Basis of Food Allergy
• Features of Food Allergens
• Factors Influencing Allergic Sensitization
• Pathophysiology of Allergic Reactions to Foods
• Treatment
• Conclusion

• Chapter 85. Autoimmune Enteropathy and IPEX Syndrome

• Introduction
• Pathophysiological Considerations
• Clinical Considerations

• Chapter 86. Protein-Losing Enteropathies

• Serum Protein Metabolism and Protein-Losing Enteropathy
• Results of Metabolic Studies
• Gastrointestinal Disease Mechanisms Resulting in Protein-Losing Enteropathy
• Protein-Losing Enteropathy in Representative Diseases of the Gastrointestinal Tract
• Lymphocytic Blockage as a Cause of Protein-Losing Enteropathy: Intestinal Lymphangiectasia
• Features of Secondary Intestinal Lymphangiectasia

• Chapter 87. Liver and the Biliary Tract

• Introduction
• The Lmphoid Liver
• Antigen Presenting Cells and Liver
• Hepatocytes and Biliary Epithelial Cells
• Immune-Mediated Liver Injury
• Autoimmune Liver Diseases
• Autoimmune Hepatitis
• Primary Biliary Cirrhosis
• Primary Sclerosing Cholangitis

• Chapter 88. Immune Mechanisms of Pancreatitis

• Introduction
• Role of Zymogen Activation in Pancreatitis
• Role of Innate Immunity in Pancreatitis
• Role of Adaptive Immunity in Pancreatitis
• Mechanisms of Inflammatory Pathway Activation in Pancreatitis
• Conclusions: A Working Hypothesis of Pancreatitis Pathogenesis

• Chapter 89. Gastrointestinal Lymphoma

• Introduction
• Extranodal Marginal Zone B Cell Lymphoma of Mucosa-Associated Lymphoid Tissue
• Immunoproliferative Small-Intestinal Disease
• Diffuse Large B Cell Lymphoma
• Primary Follicular Lymphoma of Small Intestine
• Burkitt Lymphoma
• Enteropathy-Associated T Cell Lymphoma
• CD4 Positive Small T Cell Lymphoma of the Intestine
• Intestinal NK/T Cell Lymphoma

• Chapter 90. Systemic Manifestations of Mucosal Diseases: Trafficking of Gut Immune Cells to Joint, Liver, and Pancreas

• Physiology of Lymphocyte Recirculation
• Molecular Mechanisms of Lymphocyte Recirculation
• Lymphocyte Homing to Gut, Synovium, Liver, and Pancreas
• Interconnected Immune Systems of the Gut and Joints
• Molecular Interactions of Mucosal Mononuclear Cells with Vascular Endothelium
• Therapeutic Aspects
• Conclusions

• Chapter 91. Intestinal Inflammation and Cancer of the Gastrointestinal Tract

• Introduction
• Colitis-Associated Colorectal Carcinogenesis
• Molecular Genetics of Colorectal Cancer
• Transcription Factors Involved in CAC
• Cytokines Involved in CAC
• Microbiota and Colorectal Cancer
• Murine Models of Colorectal Cancer
• Conclusions and Future Perspectives

• Section G. Respiratory Tract

• Chapter 92. Overview: Mucosal Immunity and Disease of the Respiratory Tract
• Chapter 93. Mechanisms of Experimental Mouse Models of Airway Hyperresponsiveness

• Introduction
• Asthma Pathogenesis
• Asthma Heterogeneity and Disease Endotypes
• Characteristics of Mouse Models of Experimental Asthma
• Assessment and Characteristics of the Experimental Allergic Asthma Phenotype in Mice
• Lessons Learned from Mouse Models of Asthma
• Other Factors Regulating the Asthma Phenotype
• Conclusions

• Chapter 94. The Mucosal Immune Response to Respiratory Viruses

• Introduction
• Antiviral Soluble Innate Immunity
• Innate Natural Antibodies and Antiviral Immunity
• Natural Killer Cells and Antiviral Immunity of the Lung
• Activation of Antiviral Cellular Innate Immunity by Stimulation of Pattern Recognition Receptors
• Dendritic Cells Bridge Innate and Adaptive Antiviral Immunity
• Lung Dendritic Cells and Induction of Immunity to Respiratory Virus Infections
• Controversial Role of pDCs in Antiviral Immunity
• Long-term Adaptive Memory to Respiratory Virus
• Inducible Bronchus-Associated Lymphoid Tissue Forms after Respiratory Viral Infection
• Concluding Remarks

• Chapter 95. Local Immune Responses in Tuberculosis

• Lung Predilection in Humans
• Lung Predilection in Mouse Models
• Dormancy and Reactivation of TB
• Vaccination and Immunotherapy
• Conclusions

• Chapter 96. Asthma: Clinical Aspects and Mucosal Immunology

• Introduction
• Patholophysiological Features of Asthma and Role of Constituent Cells
• The Role of Epithelial-Mesenchymal Signaling in the Origins of Asthma
• Asthma in Adolescence in Relation to Natural History
• Principles of Asthma Treatment
• Identification of Biomarkers for Th2 Responsiveness
• The Future: Time to Rethink Asthma Pathogenesis

• Chapter 97. Chronic Obstructive Pulmonary Disease

• Introduction
• Innate Immunity in COPD
• DCs: Linking Innate and Adaptive Immunity in COPD
• Adaptive Immunity in COPD

• Section H. Oral Cavity, Upper Airways, and Head and Neck

• Chapter 98. Mucosal Immunity in the Oral Cavity, Upper Respiratory Tract, and Adjacent Areas: An Overview
• Chapter 99. Ocular Mucosal Immunity

• Architecture of Ocular Mucosal Defenses
• Induction of Ocular Mucosal Immunity
• Overview

• Chapter 100. Nasal Immunity, Rhinitis, and Rhinosinusitis

• Defense Mechanisms of the Upper Airways
• Common Cold, Acute Rhinosinusitis, and Associated Lower Airway Disease Exacerbations
• Allergic Rhinitis
• Chronic Rhinosinusitis and Nasal Polyposis

• Chapter 101. Middle Ear and Eustachian Tube Mucosal Immunology

• Introduction
• Mucosal Immune Characteristics of the Tubotympanum
• Otopathogens
• Immunoregulation in the Middle Ear
• Local Immune Response in Middle Ear Mucosa
• Mucosal Immunization to Prevent Middle Ear Infection
• Conclusion
• Dedication

• Chapter 102. Immunology of Diseases of the Oral Cavity

• Introduction
• Mechanisms of Immunity in the Oral Cavity
• Dental Diseases: Immunology of Dental Caries in Humans
• Immunology of Periodontal Diseases
• Oral Mucosal Diseases
• Oral Manifestations of Systemic Diseases
• Sjögren’s Syndrome
• Oral Manifestations of HIV Disease

• Chapter 103. Immunobiology of the Tonsils and Adenoids

• Introduction
• Immunological Cytoarchitecture of the Palatine Tonsils and Adenoids
• Homeostatic Interference of Pathogens and Allergens by the Commensal Microbiota
• Tonsils as a Putative Source of Autoantibodies
• Tonsillectomy and Hodgkin’s Lymphoma
• Dissemination of Activated Tonsillar B Cells to Distant Secretory Effector Sites
• Immunological Effect of Tonsillectomy and Adenoidectomy
• Inflammation- and Age-Related Changes of Tonsillar Immune Function
• Vaccination against Pathogens by the Nasal Route
• Conclusions

• Section I. Genitourinary Tract and Mammary Gland

• Chapter 104. Urogenital Tract and Mammary Gland: Overview

• Origin and Transport of Antibodies in Genital Tract Secretions
• Phenotypic and Functional Characteristics of Cells in the Genital Tract
• Induction of Immune Responses in the Genital Tract
• Urinary Tract
• Milk Immunoglobulins

• Chapter 105. IgA Nephropathy and Related Diseases

• Introduction
• Disease Presentation
• Structure and Subclasses of Human IgA
• Synthesis and Catabolism of IgA
• Glycosylation of Circulatory IgA1
• O
-Glycosylation of IgA1 in IgAN
• Biosynthesis of IgA1 O-Glycans
• Pathogenic Pathways in IgAN
• Glycan Deficiencies in Other Diseases
• Possible Approaches for Developing Disease-Specific Treatment and Biomarkers

• Chapter 106. Urinary Tract Infections and the Mucosal Immune System

• Introduction
• Urinary Tract Infection
• Innate Immune Mechanisms Control the Antimicrobial Mucosal Defense
• Activation of Innate Immunity in the Urinary Tract
• Effectors of the Innate Host Defense
• Genetic Determinants of Innate Immune Responsiveness and Host Resistance in the Murine UTI Model
• Human Disease Susceptibility and Innate Immune Genetics
• Genetic Variants Affecting Adaptive Immunity
• Coevolution of Bacteria and Host: Effects on the Innate Immune Response
• Conclusions

• Chapter 107. Animal Models of Immunity to Female Genital Tract Infections and Vaccine Development

• Introduction
• Chlamydia
• Gonorrhea
• HSV-Type 2
• Conclusions

• Chapter 108. Mucosal Immunity in the Human Female Reproductive Tract

• Introduction
• Cells of the Immune System in the Female Reproductive Tract
• Window of Vulnerability
• Cell–Cell Communication
• Immune Protection in Genital Tract Secretions
• Inductive and Effector Sites in the FRT
• Novel Concepts in Reproductive Immunology
• Conclusions

• Chapter 109. Human Male Genital Tract Immunity

• Introduction
• Immuno-Anatomy of the Human Male Genital Tract
• Natural Immune Defense of the Human Male Genital Tract
• Effects of Hormones on Immunity of the Male Urogenital Tract
• Genital Tract Vaccination Studies and Prospects for Future Research
• Conclusions

• Chapter 110. Endocrine Regulation of the Mucosal Immune System in the Female Reproductive Tract

• Introduction
• Influence of Sex Hormones on Immune Cells in the FRT
• Influence of Sex Hormones on Cytokines, Chemokines and Antimicrobials
• IgA and IgG Transport in the FRT
• Epithelial–Stromal Interactions in the FRT
• Antigen Presentation in the Uterus and Vagina
• Induction of Immune Responses in the FRT
• Role of Sex Hormones and Cytokines in Regulating Reproductive Tract Responsiveness to Sexually Transmitted Infections
• Conclusions

• Chapter 111. Immunologically Mediated Male and Female Reproductive Failure

• Why Don’t Men Develop Autoimmunity to Sperm?
• Under What Conditions Do Men Develop Autoimmunity to Sperm?
• Why Don’t Women Develop an Immunity to Sperm?
• Pathogenesis of Infertility due to ASAs
• Embryo–Endometrial Interactions during Implantation

• Chapter 112. Immunity to Sexually Transmitted Infections

• Immunoglobulins and Immune Cells in the Genital Tract
• Immunology of Specific Infections
• Conclusions

• Chapter 113. Maternal Genital Tract Infection: Implications for the Fetus and Newborn

• Infectious Agents and the Mucosal Immune Response: Relevance to Passive and Active Protection of the Infant
• Specific Pathogens and the Role of Maternal Genital Tract Immune Responses (Table 3)
• Other Maternal Genital Tract Conditions Associated with Adverse Outcome for the Fetus and Newborn
• Summary

• Chapter 114. Immunity at the Maternal–Fetal Interface

• Introduction
• Structure of the Maternal–Fetal Interface
• Immunology of the Maternal–Fetal Interface
• Contribution of Immune Cells to Complications of Pregnancy
• Conclusions

• Chapter 115. Amniotic Fluid and the Fetal Mucosal Immune System

• Introduction
• Development of the Amniotic and Chorionic Cavities and the Placenta
• Production of Chorionic and Amniotic Fluids
• Metabolism of Amniotic Fluid
• Immunological Factors in Amniotic Fluid
• Innate Immunity
• Cytokines, Chemokines, and Other Modulatory and Growth Factors
• Nonspecific Antimicrobial Factors
• Humoral Immunity
• Increased Activity of the Immune System in African Americans
• Pathological Conditions Involving Amniotic Fluid
• Antiretroviral Drugs and Amniotic Fluid

• Chapter 116. The Mammary Gland in Mucosal and Regional Immunity

• Introduction
• The MG and Its Secretions
• The Level and Origin of Lacteal Igs
• The Immune Response of the MG
• The Role of Lacteal Secretions in Passive Immunity

• Chapter 117. Human Milk: Its Components and Their Immunobiologic Functions

• Introduction
• Components
• Immunobiologic Functions
• Active and Long-term Effects of Breast-Feeding on the Infant’s Immune System
• Conclusion

Appendix I. Collection and Processing of Human Mucosal Secretions

Appendix II. Collection and Processing of External Secretions and Tissues of Mouse Origin

Appendix III. Collection, Handling, and Analysis of Specimens for Studies of Mucosal Immunity in Animals of Veterinary Importance

Index

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