Section A Basic Sciences Underlying Allergy and Immunology
Microbial Pattern Recognition by the Innate Immune System
Resident Cellular Responses of Innate Immunity
Infiltrative Cellular Responses of Innate Immunity
Innate Instruction of Adaptive Immune Responses
Homeostasis in the Innate Immune System
The Adaptive Immune Response in Allergic Disease
Components of the Adaptive Immune System
Features of the Adaptive Immune Response
Mechanisms of Diseases Involving Adaptive Immunity: Hypersensitivity Reactions
3 Immunoglobulin Structure and Function
B Lymphocytes and the Humoral Immune Response
Immunoglobulin Structure and Gene Rearrangement
Immunoglobulins and Human Disease
Peripheral Tolerance Mechanisms
Antigen Presentation, Dendritic Cells, and Immune Tolerance
Transforming Growth Factor-β and Immune Tolerance
IL-10 and IL-10–Secreting Treg Cells
Therapeutic Application of Treg Cells
Breg Cells and Allergen Tolerance
Histamine Receptor 2 as a Major Player in Peripheral Tolerance
Immune Tolerance Induced in Sublingual Immunotherapy
Novel Allergen Immunotherapy Vaccines and Evidence for Induction of Peripheral Tolerance
5 Cytokines in Allergic Inflammation
Introduction: Definition, Evolution of Cytokine Biology, and Nomenclature
Cytokine Production in Innate Immunity
6 Cellular Adhesion in Inflammation
Selectins and Selectin Ligands
Immunoglobulin Gene Superfamily
Galectins, Cadherins, and ORMDL3
Leukocyte Adhesion to Endothelium and Migration Across Endothelium
Leukocyte Adhesion to the Extracellular Matrix in Tissues
Regulation of Adhesion Molecule Expression
Human Disease Associated With Adhesion Molecule Deficiency
Adhesion Molecules in Human Allergic Inflammation
Potential Side Effects of Adhesion-Based Therapy: Progressive Multifocal Leukoencephalopathy
Chemokine Receptors and Signaling
Regulatory Mechanisms for the Chemokine Response
Targeting the Chemokine System as a Therapeutic Strategy
Introduction to the Complement System
Receptors and Biologic Functions
Regulation of Complement Activation
Disorders Associated With Complement Activation
Disorders Associated With Complement Deficiency
Management of Complement Deficiencies
Laboratory Assessment of Complement
9 Lipid Mediators of Hypersensitivity and Inflammation
Generation of Lipid Mediator Precursors by Phospholipase A2
10 Molecular Biology and Genetic Engineering
DNA Rearrangement: Genetic Recombination
Innate Lymphoid Cell Development
Innate Lymphoid Cell Plasticity
Identification of Innate Lymphoid Cell 2s
Cytokine and Growth Factor Production by ILC2s
ILC2s and Type 2 Inflammation in Preclinical Disease Models
ILC2 in Human Allergic Diseases
13 Antigen-Presenting Dendritic Cells
Dendritic Cell Terminology and Heterogeneity
Integrated Function of Dendritic Cells in the Immune Response
Role for Dendritic Cells in Allergic Sensitization in Humans
Dendritic Cells in Allergic Asthma
14 Biology of Mast Cells and Their Mediators
Mast Cell Ultrastructure and Mediators
Mechanisms of Mast Cell Activation
Mast Cells in Allergic Diseases and Asthma
Functional and Phenotypic Markers
Pharmacologic Modulation of Secretion
Basophil Involvement in Disease
Eosinophil Morphology, Production, and Tissue Distribution
Eosinophil Recruitment and Accumulation
Eosinophil Activation and Effector Functions
Role of Eosinophils in Host Defense and Disease
Mediators Released by Activated Neutrophils
Neutrophil Clearance and Death
18 Biology of Monocytes and Macrophages
Monocytes and Macrophage Subsets in the Lung
Origins of Monocytes and Macrophages
Macrophage Activation and Polarization
Anatomy of the Airway Epithelium
Barrier Function of the Airway Epithelium
Airway Epithelium Repair Processes
Airway Epithelium Immune Responses
The Airway Epithelium in Asthma
Influence of Asthma Medications on the Asthmatic Epithelium
20 Airway Smooth Muscle in Asthma
Cellular and Molecular Mechanisms Regulating Smooth Muscle Cell Growth
Factors Regulating Airway Smooth Muscle Growth in Asthma
Signaling Pathways Affecting Airway Smooth Muscle Growth and Proliferation
Airway Smooth Muscle Contraction, Airway Hyperresponsiveness, and Relaxation
21 Pathophysiology of Allergic Inflammation
Antiinflammatory Mechanisms in Allergy
22 Genetics and Epigenetics in Allergic Diseases and Asthma
Approaches to Study the Genetics of Common Disease
Genetics of Self-Reported and Doctor-Diagnosed Allergic Disease
Current Understanding of Allergic Disease Genetics
Missing Heritability in Allergic Disease
Functional Genomics Approaches, Translating Genetic Association Signals
Epigenetics and Allergic Disease
Methods for High-Dimensional Molecular Data Analysis
24 Immunobiology of IgE and IgE Receptors
IgE Structure and Mechanisms of IgE Isotype Switching
FcεRI, the High-Affinity IgE Receptor
CD23, the Low-Affinity IgE Receptor
Relationships With Other Systems
25 Neuronal Control of Airway Function in Allergy
Allergen-Induced Airway Neuromodulation
Clinical Allergy and the Neural Hypersensitive State
Section B Aerobiology and Allergens
26 The Structure and Function of Allergens
Pathogen-Derived Allergens and Autoallergens
Allergens and the Epithelial-Dendritic Cell Axis
27 Aerobiology of Outdoor Allergens
Introduction (Aeroallergen Sources)
General Principles of Allergen Aerobiology
Impact of Climate Change on Aeroallergens
Relevance of Indoor Allergens to Asthma and Other Allergic Diseases
Sources and Characteristics of Indoor Allergens
Other Airborne Allergens and Airborne Endotoxin
Avoidance Measures for Indoor Allergens
29 Preparation and Standardization of Allergen Extracts*
Manufacture of Allergen Extracts
Stability of Allergen Extracts
Standardization of Allergen Extracts in the United States
Susceptibility to Air Pollutants
Management of Pollution Exposures
31 Effect of the Food Matrix and Processing on the Allergenic Activity of Foods
Development of Food Processing
Processing-Induced Modification of Food Proteins
Impact of Processing on Food Allergens
Future of Food Allergy Research
32 Structure of the Skin and Cutaneous Immunology
Cells and Structure of the Skin
Immune Dysregulation and Skin Disease
Epidermal Barrier Abnormalities
Patient Evaluation, Diagnosis, and Differential Diagnosis
Introduction and Historical Perspective
Definitions and Classifications
Diseases Associated With Urticaria: Differential Diagnosis
36 Hereditary Angioedema and Bradykinin-Mediated Angioedema
Patient Evaluation, Diagnosis, and Differential Diagnosis
37 Immune Complexes and Allergic Disease
Immunochemical Factors in Immune Complex Bioactivity
Immune Complex Interaction With Fc Receptor-Bearing Cells
Immune Complexes and Induction of the Immune Response
Endothelial Cells, Cell Adhesion Molecules, and Cytokines
Animal Models of Antibody-Mediated and Immune Complex–Mediated Tissue Damage
Methods of Detecting Circulating Immune Complexes
Diseases Mediated by Circulating Immune Complexes
38 Allergic and Immunologic Diseases of the Eye
Anatomy and Physiology of the Eye
Conjunctival Provocation Testing
Other Immunologic Diseases of the Eye
39 The Nose and Control of Nasal Airflow
Anatomy of the Nose and Paranasal Sinuses
40 Allergic and Nonallergic Rhinitis
41 Rhinosinusitis and Nasal Polyps
Acute and Chronic Rhinosinusitis Without Nasal Polyps
Chronic Rhinosinusitis With Nasal Polyps
42 Development, Structure and Physiology in Normal Lung and in Asthma
Interpretation of Pulmonary Function Tests
43 Respiratory Tract Mucosal Immunology
Epithelium as a Component of the Innate Immune System
Nonstructural Innate Immune Mechanisms in the Lung
Immunologic Tolerance as a Default Pathway of Mucosal Immunity
Allergic Immune Reactions in the Respiratory Tract
Microbes in the Early Programming of Mucosal Homeostasis
44 Airway Mucus and Mucociliary System
Epithelial Cells Lining Conducting Airways and Submucosal Glands
Nasal Passages and Submucosal Glands
Ciliated Cell Differentiation and Function
Role of Submucosal Glands in Mucociliary Clearance
Therapeutic Approaches (Asthma/Chronic Obstructive Pulmonary Disease)
Therapeutic Approaches (Cystic Fibrosis)
45 Epidemiology of Asthma and Allergic Diseases
Definitions and Methods of Measurement
Natural History and Course of Asthma
46 Ontogeny of Immune Development and Its Relationship to Allergic Diseases and Asthma
A Paradigm for Developmental Origins
Epigenetic Perspectives on Immune Development
Nonlinear Layered Immune System Versus Linear Maturation
Tissue Signals: Limitations and Value of In Vitro Systems
Fetal Adaptive and Innate Immune Cell Development and Function
Perinatal and Postnatal Immune Maturation and Function
Early Life Immune Cell Phenotypic and Functional Associations With Risk for Allergic Disease
Impact of Environmental Exposures on Immune Maturation and Risk for Allergic Disease
Origins of Asthma: Risk Factors for Disease
Triggers of Asthma and Mechanisms of Action
Regulation of Cellular Inflammation
48 Mouse Models of Allergic Airways Disease
Characteristics of Animal Models of Allergic Asthma
Characteristics and Assessment of the Allergic Asthma Phenotype
Dissecting Mechanisms in Mouse Models of Allergic Asthma
Using Mouse Models to Investigate Genetic Influences on Asthma
Influence Across the Lifecourse
49 Diagnosis of Asthma in Infants and Children
Clinical Features (Wheezing and Asthma Phenotypes)
Risk Factors for Asthma Development in Childhood and Adolescence
Patient Evaluation, Diagnosis, and Differential Diagnosis
50 Management of Asthma in Infants and Children
51 Diagnosis of Asthma in Adults
Overdiagnosis and Underdiagnosis of Asthma
Airway Inflammation and Remodeling
Assessment of Asthma Control and Future Risks of Events
Evaluation of Asthma-Related Quality of Life
Phenotyping and Endotyping of Asthma
Special Considerations in Regard to Asthma Diagnosis
Differential Diagnosis: Conditions That May Mimic Asthma
52 Management of Asthma in Adolescents and Adults
Principles of Asthma Management
Assessment of Asthma and Disease Control
Establishment of a Partnership in Care
Control of Environmental Factors and Comorbid Conditions
The Role and Contribution of Fungal Disease in Asthma Severity
Medications for the Treatment of Asthma
Step Care Approach to Asthma Management and Control
Approaches to Treatment of Severe Asthma
Step-Up and Step-Down Considerations
Management of an Asthma Exacerbation
53 Emergency Treatment and Approach to the Patient with Acute Asthma
54 Approach to the Patient with Exercise-Induced Bronchoconstriction
Epidemiology and Immunopathology
Patient Evaluation and Diagnosis
55 Asthma and Allergic Diseases During Pregnancy
General Therapeutic Principles
Atopic Dermatitis and Other Dermatoses
56 Occupational Allergy and Asthma
Patient Evaluation, Diagnosis, and Differential Diagnosis
Socioeconomic Impact and Medicolegal Aspects
Specific Agents Causing Occupational Asthma and Rhinitis
Allergic Bronchopulmonary Aspergillosis
59 Immunologic Nonasthmatic Diseases of the Lung
Granulomatosis With Polyangiitis
Eosinophilic Granulomatosis With Polyangiitis
Antiglomerular Basement Membrane Antibody Disease
60 Approach to the Patient with Chronic Cough
Epidemiology, Pathogenesis, and Etiology
Unexplained Chronic Cough in Adults
61 Bronchial and Nasal Challenge Testing
Indirect Airway Hyperresponsiveness
Nonselective Challenges: Clinical Utility
Other Allergen Challenge Methods
Standardization of Lung Imaging
Radiation Exposure in Lung Imaging
Use of Imaging as a Biomarker of Therapeutic Response
63 Aerosols and Aerosol Drug Delivery Systems
Definition and Types of Aerosols
Definitions for Commonly Used Terms in Aerosol Delivery
Factors That Affect Aerosol Deposition
Section F Gastrointestinal Tract
64 Gastrointestinal Mucosal Immunology
Gastrointestinal Structure and Function
Organization of the Gastrointestinal Immune Tissue
Innate Immunity in the Gastrointestinal Tract
Adaptive Immunity in the Gastrointestinal Tract
65 Eosinophilic Gastrointestinal Disorders
Eosinophilic Gastritis and Gastroenteritis
66 Clinical Significance of Immunoglobulin E
Normal Immunoglobulin E Production
Immunoglobulin E in Allergic Disease
Immunoglobulin E in Infectious and Parasitic Disease
Immunoglobulin E in Nonatopic Diseases
Environmental Exposures and Immunoglobulin E
67 In Vivo Methods for the Study and Diagnosis of Allergy
Pathophysiology of the Skin Response
Factors That Affect Skin Tests
Skin Tests Used for Nondiagnostic Purposes
68 Approach to the Patient with Recurrent Infections
The Medical History in Immunodeficiency
Laboratory Tests for Screening Patients With Recurrent Infections
69 Primary Immunodeficiency Diseases
Cellular and Humoral Immunodeficiencies
Syndromic Combined Immunodeficiencies (Table 69.4)
Antibody Deficiency Syndromes (Table 69.7)
Diseases of Immune Dysregulation (Table 69.8)
Disorders of Phagocytic Cells (Table 69.9)
Defects of Innate Immunity (Table 69.10)
Autoinflammatory Disorders (Table 69.11)
Complement Component Deficiencies (Table 69.12)
Phenocopies of Primary Immunodeficiency Diseases (Table 69.13)
70 Treatment of Primary Immunodeficiency Diseases
General Management Strategies in Primary Immunodeficiency Diseases
Immunoglobulin G Replacement Therapy
Allogeneic Hematopoietic Cell Transplantation
Disease-Specific Considerations
71 HIV Infection and Allergic Disease
Immunopathogenesis of HIV Infection: Background
Immune Dysregulation Related to HIV Infection
Clinical Phenotypes of Allergic Disease in HIV Infection
Treatment of Atopic Disease in HIV-Infected Patients
72 Laboratory Tests for Allergic and Immunodeficiency Diseases
Humoral Immune Responses Important in Allergic and Immunodeficiency Disease
Immunologic Methods for Quantifying Antigens and Antibodies
Assays for Antigens and Antibodies
Immunochemical Methods for Measurement of Immunoglobulin E Protein
Immunochemical Methods for Measurement of Allergen-Specific Immunoglobulin G Antibody
Immunglobulin G Subclass Protein and Antibodies
Other Analytes of Interest in Allergic Disorders and Asthma
Quantification of Environmental Allergens
Laboratory Methods in Cellular Immunology
73 Eosinophilia and Eosinophil-Related Disorders
Allergic and Immunologic Disorders
Skin and Soft Tissue Disorders
Medication- and Toxin-Related Eosinophilia
Hematologic and Neoplastic Disorders
Renal and Urinary Tract Disorders
Rare Hypereosinophilic Syndromes
Other Rare Causes of Eosinophilia
Pathologic Effects of Increased Mast Cells
Patient Evaluation, Diagnosis, and Differential Diagnosis
Clinical Features (Phenotypes)
Prescription of Epinephrine for Outpatient Use
Epidemiology of Adverse Drug Reactions
Immunomechanisms of Drug Allergy
Immunopathologic Features of Drug Allergy
78 Hypersensitivity to Aspirin and Other Nonsteroidal Antiinflammatory Drugs
Introduction and Historical Note
Cross-Reactive Nonsteroidal Antiinflammatory Drug Hypersensitivity
Allergic (or Immunologically Mediated) Types of Nonsteroidal Antiinflammatory Drug Hypersensitivity
Definitions and Historical Perspective
Pathophysiology of Food Allergy
Clinical Manifestations of Food Allergy
Diagnosis and Management of Food Allergy
Natural History of Food Allergy
80 Reactions to Food and Drug Additives
Prevalence of Reactions to Additives
Diagnosis of Adverse Reactions to Additives
Food and Drug Additives Known or Suspected to Cause Adverse Reactions
81 Oral Food Challenge Testing
Indications for Oral Challenge Testing
Risk and Treatment of Oral Food Challenges
Food Allergy Risk Factors and Prevention
83 Adverse Reactions to Vaccines
Putting Adverse Reactions to Vaccines in Perspective
Immunoglobulin E–Mediated Reactions to Vaccines
Non–Immunoglobulin E–Mediated Reactions to Vaccines
Adverse Reactions to Vaccines for Biologic Agents Used as Weapons
Controversies Regarding Long-Term Consequences of Vaccination
Vaccination Relative to Immunocompromise and Immunoglobulin Preparations
Vaccination During Pregnancy and Breastfeeding
84 Allergen Control for Prevention and Management of Allergic Diseases
Measurement of Allergen Exposure
Rationale for the Use of Allergen Control for Prevention and Management of Allergic Disease
Clinical Effectiveness of Allergen Control Measures
Allergen Control in the Prevention of Allergic Disease
85 Injection Immunotherapy for Inhalant Allergens
Clinical Efficacy of Subcutaneous Allergen Immunotherapy
Immunologic Response to Inhalant Injection Immunotherapy (Box 85.1)
Practical Considerations in Allergen Immunotherapy
Alternative Extracts and Methods of Administration (Box 85.5)
86 Sublingual Immunotherapy for Inhalant Allergens
Effects on Natural History of Allergic Disease
87 Principles of Pharmacotherapeutics
Basic Principles of Clinical Pharmacology
88 Precision Medicine in Allergic Disorders
Precision Medicine: Brief History and Definition
Evidence-Based vs. Precision Medicine
Precision Medicine in Allergic Disorders: Role of Omics
Immune Profiling of Allergic Disorders
Pharmacogenomics and Drug Dosing
The Precision Medicine Revolution: CRISPR-Based Therapies
Precision Medicine and Racial Ancestry in Allergic Disorders
Machine Learning in Precision Medicine
Challenges in Precision Medicine
Extent of Nonadherence in Asthma and Other Diseases
Interventions to Improve Adherence
90 Anti-Immunoglobulin E Therapy
Omalizumab Disease-Specific Effects
91 Cytokine-Specific Therapy in Asthma
92 Histamine and Antihistamines
Molecular Basis of Histamine Action
Histamine in Immune Response Regulation
Clinical Pharmacology of H1 Antihistamines
β2-Receptor Structure and Activation
Efficacy of Inhaled β2-Agonists
94 Xanthines, Phosphodiesterase Inhibitors, and Chromones
Xanthines and Phosphodiesterase Inhibitors
Airway Cholinergic Hyperresponsiveness
Cholinergic Nervous System as a Target for Anticholinergic Agents
Pharmacology of Anticholinergic Agents
Short-Acting Anticholinergic Agents in Obstructive Lung Diseases
Long-Acting Anticholinergic Agents for Treating Chronic Obstructive Pulmonary Disease
Tiotropium for Treating Asthma
Anticholinergic Agents for Treating Rhinitis
Effects of Glucocorticoids on Asthmatic Inflammation
Effects of Glucocorticoids on Inflammatory Cells
Glucocorticoids Spare Innate Immune Responses
Effects of Glucocorticoids on Cell Recruitment to the Airways
Effects of Glucocorticoids on Airway Structural Cells
Cross-Talk Between the Adrenergic System and Glucocorticoids
Inflammatory Gene Expression and Nuclear Factor-κB
Chromatin and Histone Modifications Regulate Inflammatory Gene Expression
Mechanisms of Glucocorticoid Action
Relative Steroid-Insensitive Asthma
Evidence of Mechanisms in Clinical Studies
Obesity and Relative Glucocorticosteroid Insensitivity
Smoking and Oxidative Stress in Relative Glucocorticosteroid Insensitivity
Infections and Relative Glucocorticosteroid Insensitivity
Clustering on Clinical Features and on Omics
97 Antileukotriene Therapy in Asthma
Therapeutic Strategies to Inhibit Leukotrienes
Leukotriene Antagonism in Asthma
Treatment Trials in Chronic Asthma
Leukotriene Antagonists in Asthma Treatment Guidelines
98 Unconventional Theories and Unproven Methods in Allergy
Unconventional Theories of Allergic Disease
Allergic Toxemia or Tension Fatigue Syndrome
Multiple Food and Chemical Sensitivities: Idiopathic Environmental Intolerance
Candida Hypersensitivity Syndrome
Inappropriate Diagnostic Tests
Therapies Based on Controlled Environmental Exposures
Current Versus Historical Practices
99 Complementary and Alternative Medicine
Overview of Complementary and Alternative Medicine Therapy for Allergic Rhinitis and Asthma