Cover
Title page
Clinical Immunology Principles and Practice
Copyright
Table of Contents
Preface To The 1st Edition
Preface To The 6th Edition
List Of Contributors
Dedication
1
The Human Immune Response
The Host-Microbe Interaction
Adaptive and Innate Immunity
Cells of the Immune System
Granulocytes
Lymphocytes
Antigen-Presenting Cells
Basis Of Adaptive Immunity
Clonal Basis of Immunologic Memory
Antigen-Binding Molecules
Immunoglobulins and T-Cell Receptors
Receptor Selection
Immunoglobulin Class Switching
Major Histocompatibility Complex
Antigen Presentation
Lymphocyte Adhesion and Trafficking
Lymphocyte Activation
Cell-Mediated Immune Responses
T-Cell Subsets
CD4 T Cells, Cytokines, and Chemokines
CD8 T Cells
Antibody-Mediated Immune Responses
Complement and Immune Complexes
Apoptosis and Immune Homeostasis
Mechanisms of Immunologic Diseases
Host Immune Defenses Summarized
References
2
Organization of the Immune System
IMMUNE CELL DEVELOPMENT
Ontogeny of the Cells of the Immune System
Tools Essential to an Understanding of Immune Cell Biology
Hematopoiesis and Lymphopoiesis
Characteristics of Hematopoietic Stem Cells
Regulation of Hematopoietic and Lymphopoietic Cell Growth and Differentiation
Cytokines That Affect the Growth and Maintenance of Pluripotent and Multipotent Stem Cells
Cytokines That Inhibit Hematopoietic Stem Cell Growth
Cytokines Affecting Development and Differentiation of Specific Cell Lineages
Mature Cells of the Immune System
Antigen Presenting Cells
Monocytes-Macrophages
Dendritic Cells
Neutrophils.
Eosinophils.
Basophils and mast cells.
Polymorphonuclear Granulocytes
Platelets and Erythrocytes
Lymphocytes
T cells.
T cell subsets.
B cells and plasma cells.
Innate Lymphoid Cells
Natural killer cells.
Non-cytotoxic innate immune cells.
Major Lymphoid Organs
Bone Marrow
Thymus
Peripheral Development of Hematopoietic and Lymphoid Cells
Secondary Lymphoid Organs
Systemic Immune System
Spleen
Lymph Nodes and Lymphatics
Gastrointestinal Tract
Adipose Tissue
Epithelial Innate Immunity and Commensal Organisms
New Modalities to Study Immune System Development and Function
Acknowledgments
References
3 Innate Immunity
Barriers To Infection
Skin and Mucosa
Antimicrobial Proteins and Peptides
Humoral Innate Immunity
The Acute Phase Response
The Complement System
Complement Deficiency Diseases
Cellular Innate Immunity
Polymorphonuclear Leukocytes
Monocytes and Macrophages
Neutrophil and Macrophage Microbicidal Mechanisms
Microbicidal Molecules
Reactive Oxygen Intermediates
Neutrophil Extracellular Traps
Reactive Nitrogen Intermediates
Dendritic Cells
Natural Killer Cells
Intraepithelial Lymphocytes, B-1 and MZ B Cells, Innate Lymphoid Cells, and Mast Cells
Intraepithelial Lymphocytes
B1 and Marginal Zone B Cells
Innate Lymphoid Cells
Mast Cells
Activating Innate Immunity
Pattern Recognition Receptors
Toll-Like Receptors
NOD-Like Receptors
RIG-I–Like Receptors
C-Type Lectin Receptors
Scavenger Receptors
Receptor for Advanced Glycation End Products
Inflammasomes
Innate Immunity In Clinical Practice
References
4
Antigen Receptor Genes, Gene Products, and Co-Receptors
Paratopes And Epitopes
The B-Cell and T-Cell Receptor Antigen Recognition Complex
Immunoglobulins and T-Cell Receptor Structures
The Immunoglobulin Domain, the Basic Immunoglobulin Superfamily Building Block
Idiotypes and Isotypes
The V Domain
Antigen Recognition and the Fragment Antigen Binding
Effector Function and the Fragment Crystallizable
Gm Allotype System
Immunoglobulin Classes and Subclasses
Immunoglobulin M
Immunoglobulin G
Immunoglobulin A
Immunoglobulin E
Immunoglobulin D
T-Cell Receptor αβ and γδ
T-Cell Receptor αβ
T-Cell Receptor γδ
Ligand Recognitions
Binding to Peptide-Major Histocompatibility Complex
T-Cell Receptor Binding Affinity
Atypical Antigens
Superantigens
Immunoglobulin Gene Organization
The κ Locus
The λ Locus
The H-Chain Locus
Class Switch Recombination
Somatic Hypermutation
Activation-Induced Cytidine Deaminase
Diversity and Constraints on Immunoglobulin Sequence
The T-Cell Receptor αδ-Chain Locus
The T-Cell Receptor β-Chain Locus
The T-Cell Receptor γ-Chain Locus
Allelic Exclusion
B-Cell Receptor Complex: Structure And Function
Membrane-Bound Immunoglobulin
Signal Transduction and the Immunoglobulin-α/β (CD79a/CD79b) Heterodimer
Clinical Consequences of Disruptions in B-Cell Receptor Signaling
B-Cell Receptor Co-Receptors
Co-Receptors That Positively Regulate B-Cell Receptor Signaling
CD21
CD19
CD21–CD19 Co-Receptor Complex
Co-Receptors That Negatively Regulate B-Cell Receptor Signaling
FcγRIIB
CD22
The T-Cell Receptor/CD3 Complex
CD3 Proteins
Stoichiometry of the T-Cell Receptor/CD3 Complex
Assembly and Cell-Surface Expression of the T-Cell Receptor/CD3 Complex
Clinical Consequences of Altered or Missing Functions of the T-Cell Receptor/CD3 Complex
Early Events in T-Cell Receptor/CD3 Signaling
T-Cell Co-Receptors: CD4 and CD8
CD4: Structure and Binding to Major Histocompatibility Complex Class II Molecules
CD8: Structure and Binding to Major Histocompatibility Complex Class I Molecules
Co-Stimulatory and Inhibitory T-Cell Molecules: The CD28 Family
CD28 and Cytotoxic T-Lymphocyte-Associated Antigen-4
Program Death-1
REFERENCES
5
The Major Histocompatibility Complex
Genomic Organization of the Major Histocompatibility Complex
Structure And Function Of The Human Leukocyte Antigen Molecules
Classical Human Leukocyte Antigen Class I Molecules
MICA and MICB
Nonclassical Human Leukocyte Antigen-E, -F, and -G
Class II Human Leukocyte Antigen Molecules
Nonclassical Human Leukocyte Antigen -DM and -DO
Proteasome Elements Within the Class II Region
Principles of Peptide Presentation
Selection by Self-Peptides in the Thymus
Evolutionary Considerations Driving the Separate Functions of Class I and Class II
Generation and Selection of Polymorphisms Biological Consequences
Human Leukocyte Antigens in Infections, Transplantation, Autoimmunity, and Cancer
Human Leukocyte Antigen in Infections
Human Leukocyte Antigen in Transplantation
Human Leukocyte Antigen in Autoimmunity
Human Leukocyte Antigen in Cancer
Human Leukocyte Antigen Class I Molecules Regulate Natural Killer Cell Responses
Human Leukocyte Antigen and Disease Associations
Ankylosing Spondylitis
Narcolepsy
Type 1 Diabetes
Rheumatoid Arthritis
Multiple Sclerosis
Celiac Disease
Drug Hypersensitivity and Pharmacogenomics
Carbamazepine
Nevirapine
Abacavir
Methods of Detecting Human Leukocyte Antigen Polymorphisms. The Human Leukocyte Antigen Typing Problem
DNA-Based Typing Techniques: Sequence-Specific Oligonucleotide Probes, Sequence-Specific Primer, and Sequencing-Based Typin ...
Next-Generation Sequencing and Its Potential Impact on Human Leukocyte Antigen Typing
Human Leukocyte Antigen Nomenclature
Future Learning and Resources
References
6
Antigens and Antigen Presentation
Antigens
Antigens for Antibodies
Carbohydrate Antigens
Antigens as Ligands for T-Cell Receptors
Major Histocompatibility Complex Restriction
Alloantigens
Superantigens
Antigen-Presenting Cells
Cells that Present Antigens to B cells: Follicular Dendritic Cells
Cells that Present Antigens to T Cells
Antigen Acquisition
Antigen Processing
Class I Major Histocompatibility Complex Trafficking
Antigen Processing for Class II-Restricted T Cells
Predicting Epitopes for T-Cell Receptor
Antigen Presentation
Microbial Interference with Antigen Processing and Presentation
Clinical Relevance
Translational Research in Antigen Processing and Presentation
References
7
B-Cell Development and Differentiation
G
eneration of a Functioning Antigen Receptor Is Key to the Viability of a B Cell
Tyrosine Kinases Play Key Roles in B-Cell Development
Cell-Surface Antigens Associated with B-Cell Development
Transcription Factors and Epigenetic Mechanisms Controlling B-Cell Differentiation
MicroRNAs, Long Noncoding RNAs, and B-Cell Development
Modulation of B-Cell Development by Chemokines, Cytokines, and Hormones
Organization of the Peripheral Lymphoid Organs
The Spleen
B-Cell Development in the Periphery
B-Cell Activating Factor of the Tumor Necrosis Family and a Proliferation-Inducing Ligand Play Key Roles in the Development ...
Marginal Zone B Cells
B1 B Cells
Differentiation and the Response to Antigen
T-Independent Responses
T-Dependent Responses
Germinal Center Reaction
Molecular Mechanism of Somatic Hypermutation and Class Switch Recombination
Somatic Hypermutation
Class Switch Recombination
Both Somatic Hypermutation and Class Switch Recombination Require Activation-Induced Cytidine Deaminase
B-Cell Memory
Ectopic Lymphoid Tissue and B-Cell Development
B-Cell Functions in Addition to Antibody Production
References
8
Immunoglobulin Function
Antigen Binding and Molecular Identity
Physical Aspects of Binding
Immunological Specificity
Protein Epitopes
Carbohydrate Epitopes
Immune Complexes in Vivo
Correlations between CH Region Structure and Antibody Function
Functions Mediated by Antibody Alone
Virus Neutralization and Immunity
Neutralization of Toxins and Enzymes
Functions Mediated by Antibody and Additional Molecules or Cells
Complement Activation
Receptors for Fc Regions
Antibodies as Surrogate Ligands
Functional Properties of Engineered Antibody Molecules
Monoclonal Antibodies
Recombinant Antibodies
References
9
T-Cell Development
T-Cell Development
Thymus: The Site of T-Cell Development
Early T-Cell Development
Early Thymic Progenitors Encounter Notch Ligands
Other Key Transcriptional Regulators
Fate Commitment Occurs at the Double-Negative Stage
T-Cell Receptor Gene Rearrangement Begins at DN2
γδ T Cells Diverge at DN3
Beta Selection Generates αβ T Cells
Positive and Negative Selection
Positive Selection Generates an “MHC-Restricted” T-Cell Pool
Negative Selection Generates a “Self-Tolerant” T-Cell Pool
Role of Peptide:MHC in Negative and Positive Selection
CD4 and CD8 T-Cell Characteristics are set in the Thymus
Specialized Lymphocytes
Tolerance
Autoimmunity Results From the Lack of Tolerance (AIRE, FoxP3)
Migration of Thymocytes into the Periphery
Thymic Atrophy
References
10
T-Cell Activation and Tolerance
The T-Cell Antigen Receptor Complex
Activation of Protein Tyrosine Kinases by the T-Cell Receptors and the Role of the Immunoreceptor Tyrosine-Based Activation ...
Second Messenger Cascades Downstream of the T-Cell Receptor–Stimulated Protein Tyrosine Kinases
Integration of Second-Messenger Pathways by Adaptor Proteins
Coreceptors Transduce Signals That Are Integrated With T-Cell Receptor Signals
Counterbalanced Costimulatory and Coinhibitory Signals Determine T-Cell Response Thresholds
Spatial and Temporal Distribution of T-Cell Receptor Signaling Proteins
Tolerance
Central Tolerance/Clonal Deletion
Peripheral Mechanisms of Tolerance
Immune Privilege
T-Cell Anergy
Regulation
Summary And Future Directions
References
11
Helper T-Cell Subsets and Control of the Inflammatory Response
Activation
Clonal Expansion
Trafficking
Differentiation of CD4 Th Subsets
Naïve T Cells
Effector Cell Phenotypes
Th1
Th2
Th17
Th9
Th22
Regulatory T Cells
Adaptive Tregs
Tr1 Cells
Follicular Helper T Cells
Memory T Cells
General Considerations in Effector T-Cell Differentiation
Termination of T-Cell Responses
Cell Death Pathways in T-Cell Homeostasis
Action of Inhibitory Receptors
Cytokine-Mediated Inhibition
Summary of Therapeutic Regulation of T-Cell Responses for Treatment of Immune-Mediated Diseases
References
12
Cytotoxic T Lymphocytes and Natural Killer Cells
Effector Functions/Mechanisms
Cytotoxicity
Perforin–Granzyme Pathway
Death Receptor–Induced Apoptosis
Cytokines
Cytotoxic T Cells
Development and Tissue Distribution of Cytotoxic T Lymphocytes
The Cytotoxic T-Lymphocyte Response
Initial Activation
Cross-Presentation and Priming
Contraction of Effector Populations
Maintenance of Memory Cells
CD4 T-Cell Help
Detection and Analysis of Cytotoxic T-Lymphocyte Function
Natural Killer Cells
Properties of Natural Killer Cells
Tissue Distribution and Diversity of Natural Killer Cells
Cytokine Regulation of Natural Killer–Cell Activation, Function, and Homeostasis
Natural Killer–Cell Receptors
Natural Killer–Cell Receptor Signaling
Natural Killer Receptors That Recognize Major Histocompatibility Complex Class I Molecules
Killer Cell Immunoglobulin-Like Receptors in Humans
The Ly49 Family in Rodents
CD94/NKG2 Family
NKG2D
Natural Killer–Cell Receptors That Recognize Non–Major Histocompatibility Complex I Molecules
Natural Killer–Cell Licensing and Self-Tolerance
Specific Natural Killer–Cell Functions
Control of Viral Infections
Control of Malignant Cells
Role of Natural Killer Cells in Hematopoietic Stem Cell Transplantation
Natural Killer Cell Memory
Interactions of Cytotoxic T Lymphocyte and Natural Killer Cells in the Immune Response
Evasion of the Cytotoxic Response
Viruses
Tumor Cells
References
13
Regulatory Immune Cells
CD4 Regulatory T Cells
Thymus-Derived Regulatory T Cells
Thymus-Derived Treg Express the Transcription Factor Foxp3
Maintenance of Foxp3+ Tregs
Suppressive Function of Foxp3+ Tregs
Tr1 Cells
Treg-of-B cells
Other Subsets of FOXP3− Regulatory T Cells
Suppressive Non–T Cells
Clinical Relevance of Regulatory T Cells
Autoimmunity
Allergic Disease
Transplantation
Tumor Immunity
Infectious Disease
Translational Research
References
14 Cytokines and Cytokine Receptors
Cytokine Classification
Type I and II Cytokine Receptors (Hematopoietin Family and Interferon Receptors)
Ligand and Receptor Structure
Family Members and Their Actions
Homodimeric Receptors
Cytokine Receptors Utilizing gp130
Interleukin-6.
Interleukin-11.
Interleukin-27.
Cytokine Receptors Utilizing the βc Chain
Interleukin-3.
Interleukin-5.
Granulocyte–Macrophage-CSF.
Cytokine Receptors Utilizing the γc Chain
Interleukin-2.
Interleukin-4.
Interleukin-7.
Interleukin-9.
Interleukin-15.
Interleukin-21.
Other Heterodimeric Receptors
Interleukin-12.
Interleukin-23.
Interleukins-35 and -39.
Interleukin-13.
Interleukin-31.
Thymic Stromal:Lymphopoietin.
Interferons
Type I Interferons
Interferon-γ
Interleukin-10 and related cytokines.
Interleukin-10
Interleukin-19, Interleukin-20, Interleukin-22, Interleukin-24, and Interleukin-26.
IFN-λs.
Signaling
Janus Kinases
STATs
Attenuation of Type-I and Type-II Cytokine Signaling
The TNF Cytokine and Receptor Superfamily
Ligand and Receptor Structure
Family Members and Their Actions
Tumor Necrosis Factor, Lymphotoxin-α, and Receptors
Fas Ligand (FasL) and Its Receptor, Fas/APO-1/CD95
CD40 Ligand and CD40
OX40 Ligand and OX40
TL1A and DR3
Other TNF-Family Cytokines
Signaling
Death Domains: TRADD and FADD
Clinical Relevance
Interleukin-1/Toll-like Receptor Family
Ligand and Receptor Structure
Family Members and Their Actions
Interleukin-1
Interleukin-18
Interleukin-33
Interleukin-36
Interleukin-37
Interleukin-38
Other Members of the Interleukin-1 Family
Signaling
Clinical Relevance
Interleukin-17 Receptors
Ligand and Receptor Structure
Signaling
Clinical Relevance
Cytokines Activating Receptor Tyrosine Kinases
Ligand and Receptor Structure
Family Members and Their Actions
KIT and Stem Cell Factor
Colony Stimulating Factor Receptor 1 (CSF-1R) and CSF1
FLT and FLT3-L
Signaling
Clinical Relevance
Transforming Growth Factor-b Ligand and Receptor Families
Ligand and Receptor Structure
TGF-β Family Members and Their Actions
Signaling
Clinical Relevance
Other Cytokines
Interleukin-14
Interleukin-16
Interleukin-32
Interleukin-34
Conclusions and Summary
References
15
Chemokines and Chemokine Receptors
Chemokines
Chemokine Receptors
Atypical Chemokine System Components
Immunologic Classification
Chemokine Presentation Mechanisms
Chemokine Activation of Chemotactic Signaling Pathways
Regulation of Chemokine Action
Leukocyte Responses to Chemokines
Chemokine Regulation of Hematopoiesis
Chemokine Regulation of the Immune Response
Innate Immunity
Platelet-Derived Chemokines
Myeloid Cell Trafficking
NK Cells
Dendritic Cells and Transition to the Adaptive Immune Response
Adaptive Immunity
Afferent Trafficking to Secondary Lymphoid Tissue
Migration Within Lymph Node Microenvironments
Efferent Trafficking
Tissue-Specific Lymphocyte Homing
Clinical Correlates
Chemokines and Disease
HIV/AIDS
Malaria
WHIM syndrome
Atherosclerosis
Kaposi Sarcoma
Autoimmunity
Acute Neutrophil-Mediated Inflammatory Disorders
Transplant Rejection
Allergic Airway Disease
Cancer
Therapeutic Applications
Chemokines and Chemokine Receptors as Targets for Drug Development
Chemokines as Biological Response Modifiers
Conclusion
Acknowledgments
References
16
Lymphocyte Adhesion and Trafficking
Early Lymphocyte Precursor Trafficking to the Primary Lymphoid Organs
Migration of Naive Mature Lymphocytes from Blood to the Secondary Lymphoid Organs
Activated Lymphocytes Display Selective Tissue Homing Patterns
Distinct Recirculation Routes in the Spleen
Inflammation-Induced Changes in Leukocyte Trafficking
Molecular Mechanisms Involved in Leukocyte Extravasation from Blood Into Tissues
The Adhesion Cascade
Receptors and Their Ligands in Leukocyte–Endothelial Cell Interaction
Selectins and Their Ligands
Chemokines and Their Receptors
Integrins and Their Immunoglobulin Superfamily Ligands
Other Homing-Associated Molecules
Intraorgan Lymphocyte Localization
Cell Trafficking Within Lymphatics
Clinical Implications
Immunodeficiencies
Autoimmune or Inflammatory Diseases
Multiple Sclerosis
Inflammatory Bowel Diseases
Cancer
Adhesion Molecules as Diagnostic Targets
Immunodeficiency Disorders
Soluble Adhesion Molecules
Imaging
Therapeutic Applications of Adhesion-Modulating Therapies
Antibodies and Small-Molecular Drugs
Adhesion-Modulating Drugs in Clinical Use
References
17
Death Pathways and Immunogenicity
Cell Death and Damage-Associated Molecular Patterns—The Concept Of Necroinflammation
Regulated Cell Death Regulates its Immunogenicity in an Active Manner
Signaling Pathways of Regulated Cell Death
Apoptosis
Pyroptosis
Necroptosis
Ferroptosis
Distinction of Other Regulated Necrosis Pathways—Mitochondrial Permeability Transition-Induced Regulated Necrosis and Parth ...
Concluding Remarks and Implications for Solid-Organ Transplantations
ACKNOWLEDGMENTS and Conflict Of Interest Statement
References
18 Human Genomics in Immunology
Genome Annotation
Human Variation
Clinical Impact of Human Variation
Comparative Genomics
Functional Genomics
Applying Human Genomics to Discovery of Disorders of the Human Immune System
Finding Disease-Causing Variants by Analyzing Deep Sequence Data
Interpreting Variants Discovered Through Gene Sequencing
Future Directions
References
19 Regulatory RNA in Immunologic Diseases
Classes of Regulatory RNAs
lncRNAs and the Development and Function of the Immune System
lncRNAs and Immune-Mediated Disease
Links between IFNG-AS1 and Brucellosis, Inflammatory Bowel Disease, and Systemic Lupus Erythematosus
GATA3-AS1 and Allergy
lncRNAs, NUCLEAR FACTOR KAPPA B (NF-κB), and the Pathogenesis of Rheumatoid Arthritis
lncRNAs and Systemic Lupus Erythematosus
miRNAs
Enhancer RNAs
Genome-Wide Association Studies
References
20 Immunometabolism
Glycolysis And Pentose Phosphate Pathway
Glutaminolysis
Fatty Acid Oxidation and Fatty Acid Synthesis
Tricarboxylic Acid Cycle and Electron Transport Chain
Immune Cell Metabolism
Adaptive Immune Cell Metabolism
T-Cell Metabolism
B Cell Metabolism.
Innate Immune Cell Metabolism
Natural Killer Cell Metabolism.
Mast Cell Metabolism.
Eosinophil Metabolism.
Basophil Metabolism.
Neutrophil Metabolism.
Macrophage Metabolism.
Dendritic Cell Metabolism.
Aberrations in Immunometabolism in Immune-Mediated Diseases
Immunometabolism-Based Targeted Treatment
Conclusions and Future Directions
References
21 Immune Deficiencies at the Extremes of Age
Infancy and the Generation of an Immune System
Innate Immune Development
Adaptive Immune Development
Infancy and Functional Differentiation of Adaptive Immune Cells
Infant Immune Development and the Microbiome
Clinical Consequences for Childhood Vaccination
Older age and Immune Cell Generation
T-cell Population Homeostasis
Inflammation, Aging, and the Aging Host Environment
Cellular Defects in Immune Aging
Clinical Consequences of Immune Aging—Immunodeficiency, Autoimmunity, and Accelerated Degenerative Diseases
Strategies and Interventions on the Horizon
References
22 The Microbiota in Immunity and Inflammation
Overview of Our Nonmammalian “Self”
Prokaryotes
Viruses
Fungi
The Immune System Facilitates Microbial Colonization
Prenatal Development of the Immune System
Reproductive Tract Microbiota and the Immune System in Perpetuation of the Species
Passive Acquisition of Antimicrobial Immunity
Microbiota-Dependent Maturation of The Intestinal Immune System
Gut-Associated Lymphoid Tissues
Innate Lymphoid Cells
Invariant Natural Killer T Cells
Regulatory T Cells
CD4 T-Helper Cells
Mucosal Antibody-Secreting Cells (ASC)
Immune Consequences of Early Microbial Manipulation
Immune System—Microbiota CROSSTALK in Intestinal Inflammation
Gastrointestinal Infection
Inflammatory Bowel Disease
Extraintestinal Manifestations of Gut Microbiota–Immune System Interaction
Cancer and the Microbiota
Microbiota–Immune System Interactions in Cancer Susceptibility and Development
The Microbiota in Cancer Immunotherapy
The Skin Microbiota and The Immune System
Skin Microbes Maintain Barrier Integrity in the Steady State
Skin Microbes in Chronic Inflammatory Disease
The Respiratory Tract Microbiota In Health And Disease
The Shaping of the Healthy Respiratory Microbiota
Microbes as Therapy
Summary
References
23 Immunology of the Skin
Molecules Primarily Associated with Innate Immunity and Skin
Pattern Recognition Receptors
Antimicrobial Peptides
Cytokines and Chemokines in the Skin
Cytokine Signaling
Cytokine-Related Autoinflammatory Diseases
Cellular Components of the Cutaneous Adaptive Immune Response
Dendritic Cells
Epidermal Langerhans Cells
Dermal Dendritic Cells
T-Cell Subpopulations and the Skin
Th1 Responses
Th2 Responses
Th17 Responses
Regulatory T Cells
CD8 T-Cell Immunity
γδ T Cells
Mast Cells
Events Involved in the Generation of a Prototypic Innate and Adaptive Immune Response in the Skin
Antibodies and Skin
Urticaria
Hyper-Immunoglobulin E Syndrome
Environmental Challenges and the Skin-Associated Lymphoid Tissue
Chemicals
Solar Ultraviolet Radiation
References
24 Immunology of Mucosal Surfaces
The Innate Mucosal Defense System
Cells and molecules that contribute to innate defense of the mucosa include the physical barrier provided by epithelial cel ...
Defensins and Other Mucosal Antimicrobial Peptides
Mucosal Innate Lymphoid Cells
The Common Mucosal Immune System
Mucosa-Associated Lymphoid Tissue as an Inductive Site
Gut-Associated Lymphoid Tissues
Nasopharyngeal-Associated Lymphoid Tissues (NALTs)
Other Sites for Mucosal Induction of an Immune Response
Lymphocyte Homing into Mucosal Compartments
Lymphocyte Homing in the Gastrointestinal Tract
Lymphocyte Homing in Nasopharyngeal-Associated Lymphoid Tissues and Lung-Associated Tissues
The Common Mucosal Immune System Revisited
Induction of Mucosal Immunity
Mucosal Antigen-Presenting Cells
CD4 T-Helper Cell Subsets in Mucosal Immunity
B-Cell Isotype Switching and Immunoglobulin A Plasma Cell Differentiation
Vaccine Development And Mucosal Immune Responses
Lessons From Studies of Bacterial Enterotoxins
Cellular Targets of Vaccine Adjuvants Can Shape the Immune Response
Potential Central Nervous System Targeting Is a Safety Concern with Nasal Vaccines
New Mucosal Adjuvants and Delivery Systems
Nontoxic Derivatives of Bacterial Enterotoxins
Nucleic Acid Toll-Like Receptor Ligands
Mucosal Cytokines and Innate Factors as Adjuvants
Transgenic Plants
Synthesis and Functions of Secretory Antibodies
In external secretions, adult levels of SIgA are reached considerably earlier (1 month to 2 years) than in the serum (adole ...
IgA-Mediated Inhibition of Microbial Adherence
Neutralization by SIgA of Viruses, Enzymes, and Toxins
Anti-Inflammatory Actions Mediated by SIgA Antibodies
IgA Deficiency
Mucosal Cytotoxic T Lymphocytes
M cells have specific receptors for mucosal virus that allow certain viruses, such as reoviruses, to enter the cells in bot ...
Respiratory Viruses and Mucosal Cytotoxic T Lymphocytes
Mucosal AIDS Models for Cytotoxic T-Lymphocyte Responses
Other Mucosal Cytotoxic T-Lymphocyte Systems
Mucosal Immune Responses in Early Life and Aging
References
25 Host Defenses to Viruses
Viral Entry and Infection
Innate Immunity to Viruses
Adaptive Immunity to Viruses
Immunological Memory
Immune Evasion and Immunity to Chronic Viral Infections
Outcomes of Virus Infection: Immunity or Immunopathology
Immunopathology and Autoimmunity
Translational Research Opportunities
Conclusions
Acknowledgments
References
26 Host Defenses to Intracellular Bacteria
Balance of Protection and Pathology Defines The Chronic Nature of Intracellular Bacterial Infection
Intracellular Bacterial Infections of Clinical Relevance
Granulomatous Infections
Tuberculosis
Leprosy
Nontuberculous Mycobacteria
Typhoid or Enteric Fever
Gastroenteritis
Listeriosis
Brucellosis
Lymphogranuloma Venerum
Melioidosis
Tularemia
Nongranulomatous Infections
Legionnaires’ Disease or Legionellosis
Chlamydial Urethritis, Cervicitis, and Conjunctivitis
Trachoma
Chlamydia pneumoniae
Typhus
Rocky Mountain Spotted Fever, Ehrlichiosis
Bartonella
Sepsis, Staphylococcus aureus, and Pseudomonas aeruginosa
Granuloma Pathology as Hallmark of Intracellular Bacterial Infection
Role of the Facultative Intracellular Niche in Sepsis and Pneumonia
The Interdependence of Innate and Adaptive Immunity in Protection Against Intracellular Bacteria
Innate Immune Mechanisms as First-Line Defense
Cytokines as Mediators of Defense Against Intracellular Bacteria
IFN-γ, TNF, IL-12, and IL-18
Proinflammatory Cytokines and Phagocyte Attraction
Cytokine-Induced Host-Protective Mechanisms
Effector Molecules
Apoptosis and Autophagy
Nutrient Deprivation
Evasion From, Interference With, and Resistance to Microbial Killing
Strategies Against Toxic Effector Molecules
Intraphagosomal Survival
Phenotypic Plasticity of the Infected Cell
Training of Innate Immunity
Escape into Cytoplasm
T Lymphocytes as Specific Mediators of Acquired Resistance
CD4 T Cells
CD8 T Cells
Unconventional T Cells
T-Cell Memory and Regulation of Immune Responses
B Cells
Regulatory T Cells
Innate Lymphoid Cells
Concluding Remarks
Acknowledgments
References
27 Host Defenses to Extracellular Bacteria Including Spirochetes
Clearance and Nonspecific Host Defenses at Mucosal Epithelial Surfaces
Normal Microbiota as Host Defense
Host Defenses to Extracellular Bacteria Including Spirochetes
Innate Immune Responses
Early Pathogen Recognition and Antimicrobial Peptides
Complement
Phagocytic Cell Recruitment and Pathogen Clearance
Adaptive Immune Responses to Extracellular Bacteria and Spirochetes
T Cell–Mediated Responses
B Cell–Mediated Responses
Immunoglobulins
Host Risk Factors for Local and Systemic Invasion by Extracellular Pathogens and Spirochetes
Deleterious Host Responses
Inflammation and Autoimmunity
Sepsis
Translational Research Opportunities
References
28 Host Defenses to Fungi
Fungal Recognition Pathways and their Contribution to Human Antifungal Host Defense
Immune Responses to Yeast Fungi
Mucosal Candidiasis
Invasive Candidiasis
Cryptococcosis
Patients AT RISK for Yeast Infections due to Genetic or PHARMACOLOGICAL Factors
Mucosal Candidiasis
Invasive Candidiasis
Cryptococcosis
Immune Responses to Molds
Aspergillosis
Agents of Mucormycosis
Patients AT RISK for Invasive Mold Infections due to Genetic or PHARMACOLOGICAL Factors
Immune Responses to Dimorphic Fungi
Histoplasmosis
Coccidioidomycosis
Blastomycosis
Patients AT RISK for Endemic Mycoses due to Genetic or PHARMACOLOGICAL Factors
Summary
Acknowledgments
References
29 Host Defenses to Protozoa
Plasmodium SPP.
Pathogenesis
Innate Immunity
Adaptive Immunity
Evasion of Host Immunity
Toxoplasma gondii
Pathogenesis
Innate Immunity
Adaptive Immunity
Evasion of Host Immunity
Leishmania SPP.
Pathogenesis
Innate Immunity
Adaptive Immunity
Evasion of Host Immunity
Trypanosoma cruzi
Pathogenesis
Innate Immunity
Adaptive Immunity
Evasion of Host Immunity
Entamoeba histolytica
Pathogenesis
Innate Immunity
Evasion of Host Immunity
Giardia duodenalis
Pathogenesis
Innate Immunity
Adaptive Immunity
Evasion of Host Immunity
Cryptosporidium SPP.
Pathogenesis
Innate Immunity
Adaptive Immunity
Evasion of Host Immunity
Trichomonas vaginalis
Pathogenesis
Innate Immunity
Adaptive Immunity
Evasion of Host Immunity
References
30 Host Defenses to Helminth Infection
Spectrum of Host–Parasite Interactions
Prototypical Host Responses to Helminths
Helminths and Epithelial Cells
Helminths and Innate Lymphoid Cells
Helminths and Dendritic Cells
Helminths and Macrophages
Helminths and T Cells
Helminths and B Cells
Helminths and Eosinophils
Helminths and Basophils/Mast Cells
Helminths and Neutrophils
Protective Immunity Against Helminths
Pathology Associated with Immune Responses in Parasitic Helminth Infection
Immune Complexes
Autoantibodies and Molecular Mimicry
Granulomatous Reactions
Fibrosis
Toll-Like Receptors
Immediate Hypersensitivity Responses
Wound Healing
Lymphangiogenesis
Carcinogenesis
Epileptogenesis
Mechanisms of Evasion and Immune Regulation by Helminth Parasites
Parasite-Derived Factors
Host-Related Factors
Regulatory T and B Cells
Hyporesponsive T Cells
Modulation of Antigen-Presenting Cell Function
Apoptosis
Helminths and The Microbiota
Regulation of Allergy, Autoimmunity, and Metabolic Diseases in Helminth Infection
Helminth Therapy for Inflammatory Diseases
Vaccines Against Helminth Parasites
References
31 Emerging Pandemic Infectious Disease Threats
Introduction
Human Betacoronavirus
Microbiology and Clinical Expression
Immunopathogenesis
Treatment and Prevention
Passive Antibody Transfer
Experimental Vaccines
Immune Enhancement
Flaviviruses—Dengue and Zika Virus Disease
Microbiology
Clinical Expression
Immunopathogenesis
Treatment and Prevention
Ebola
Microbiology
Clinical Expression
Immunopathogenesis
Treatment and Prevention
Alphainfluenzavirus—Pandemic Influenza
Microbiology
Clinical Expression
Immunopathogenesis
Treatment and Prevention
Vaccines
Antiviral Therapy
Summary
Emerging Bacterial Threats
Microbiology and Clinical Manifestation
Vaccine Development and Treatment
References
32 Approach to the Evaluation of the Patient With Suspected Immunodeficiency
Evaluating Suspected Defects in Antibody Response
Evaluating Suspected T-Cell Defects
Newborn Screening for Severe Combined Immune Deficiency
Evaluating Suspected Natural Killer Defects
Evaluating Immune Defects Involving Macrophage Activation
Evaluating Suspected Toll-Like Receptor Defects
Evaluating Suspected Phagocyte Dysfunction Syndromes
Evaluating Suspected Complement Disorders
Conclusions
References
33 Primary Antibody Deficiencies
Clinical Manifestations
Principles of Diagnosis and Treatment
Diagnostic Tests and Their Interpretation
Replacement Therapy With Human Immunoglobulin
X-Linked Agammaglobulinemia
Diagnosis
Clinical Manifestations
Origin and Pathogenesis
Treatment and Prognosis
Autosomal Agammaglobulinemia
Origin and Pathogenesis
The PreB-Cell Receptor and Signal Transduction Axis
E47
LRRC8
PIK3R1
Other Agammaglobulinemia Conditions
Diagnosis and Treatment
Hyper-Immunoglobulin Syndrome
Diagnosis
Hyper-Immunoglobulin Syndrome Type 1: CD40L (CD154) Deficiency
Hyper-Immunoglobulin Syndrome Type 2: Activation-Induced Cytidine Deaminase dysfunction
Hyper-Immunoglobulin Syndrome Type 3: CD40 Deficiency
Hyper-Immunoglobulin Syndrome Type 4: As Yet Unknown Causes
Hyper-Immunoglobulin Syndrome Type 5: Uracil-DNA Glycosylase Deficiency
NEMO and IKBA Mutations
INO80 and MHSH6
Clinical Manifestations
CD40-CD154 Axis (HIGM1, HIGM3, NEMO)
AID-UNG Axis (HIGM2 and HIGM5)
Origin and Pathogenesis
CD40-CD154 Axis (HIGM1, HIGM3, and NEMO)
Treatment and Prognosis
Selective Immunoglobulin A Deficiency
Diagnosis
Clinical Manifestations
Origin and Pathogenesis
Treatment and Prognosis
Common Variable Immunodeficiency and Common Variable Immunodeficiency-Like Disorders
Diagnosis
Clinical Manifestations
Origin and Pathogenesis
The Major Histocompatibility Complex
The CD19 (CVID3), CD81 (CVID6), CD21 (CVID7) B-Cell Co-Receptor Complex
The BAFF, BAFFR (CVID4), and TACI (CVID2) axis
CD20 (CVID5)
ICOS (CVID1)
LRBA (CVID8) and CTLA-4 axis
Interleukin-21
PKCδ Deficiency
TWEAK Deficiency
NF-κB1 (CVID12) and NF-κB2 (CVID10) Deficiency
PI3K Mutations
BLK, IRF2BP2 (CVID13), and IKAROS (CVID14)
Other Genes
Kabuki syndrome
Treatment and Prognosis
Selective Immunoglobulin G Subclass Deficiencies
Diagnosis
Clinical Manifestations
Origin and Pathogenesis
Treatment and Prognosis
Antibody Deficiency with Normal Serum Immunoglobulin Levels
Selective Light Chain Deficiency
Transient Hypogammaglobulinemia of Infancy
Diagnosis
Clinical Manifestations
Treatment and Prognosis
Frontiers in Research
References
34 Primary T-Cell Immunodeficiencies
Severe Combined Immune Deficiency—General Considerations
Scid Due to Metabolic Defects Affecting Survival of T-Cell Progenitors
Adenosine Deaminase Deficiency
Reticular Dysgenesis
Scid Due to Defects of Cytokine-Mediated Signaling
X-Linked Severe Combined Immune Deficiency
Interleukin-7 Receptor Deficiency
JAK3 Deficiency
Scid Due to Defects of V(D)J Recombination
Defects of Recombination Activating Genes (RAG) 1 and RAG2
ARTEMIS Deficiency
DNA-PKcs Deficiency
DNA Ligase IV Deficiency
Cernunnos/XLF Deficiency
Scid Due to Defects of The Cd3/Tcr Complex
Scid Due to Other Hematopoietic Defects
Coronin-1A Deficiency
RAC2 Gain-of-Function Mutations
SCID With Multiple Intestinal Atresia
Veno-Occlusive Disease With Immunodeficiency
Scid Due Non-Hematopoietic Defects
Complete DiGeorge Syndrome
Charge Syndrome
FOXN1 Deficiency
PAX1 Deficiency
Combined Immune Deficiency—Definition
Cid Due to Metabolic Defects
Purine Nucleoside Phosphorylase Deficiency
Cytidine 5-Triphosphate Synthase 1 Deficiency
CID Due to Defects of TCR-Mediated Signaling
Deficiency of the Zeta-Associated Protein of 70 kDa (ZAP-70)
LCK Deficiency
Deficiency of the IL-2 Inducible Tyrosine Kinase (ITK)
STK4 Deficiency
RHOH Deficiency
T-Cell Receptor α Constant (TRAC) Chain Deficiency
CID Due to Defects of Nuclear Factor-κB (NF-κB) Signaling
Cid Due to Defects of Major Histocompatibility Complex Molecule Expression
CID Due to Defects of Co-Stimulatory Molecules
Defects of CD40 Ligand and CD40
ICOS and ICOS Ligand (ICOSLG) Deficiency
OX40 Deficiency
CD27 and CD70 Deficiency
CID Due to Defects of Dna Repair and DNA Replication
CID Associated With Cytoskeletal Defects
Wiskott-Aldrich Syndrome and Related Disorders
Dedicator of Cytokinesis 8 (DOCK8) Deficiency
DOCK2 Deficiency
Moesin Deficiency
CID Due to Defects of Clathrin-Mediated Endocytosis and Iron Internalization
CID With Immune-Osseous Dysplasia
Cartilage Hair Hypoplasia
Schimke Syndrome
Phosphoglucomutase 3 (PGM3) Deficiency
Other Immuno-Osseous Dysplasias
CID Associated With Prominent Immune Dysregulation
Other Forms of Cid Due to Defects of Transcription Factors
Management of Patients with CID
References
35 Genetic Disorders of Interferons-, Interleukin-17, Interleukin-18, and Nuclear Factor-κB-Mediated Immunity
Genetic Disorders of Interferon-γ-Dependent Immunity and Mendelian Susceptibility to Mycobacterial Disease
Genetic Disorders Predisposing to Tuberculosis
Genetic Disorders Of The TLR3 Pathway in Herpes Simplex Virus-1 Encephalitis
Genetic Disorders of Other Interferon-Inducing Pathways in Other Severe Viral Infections
Genetic Etiologies of Life-Threatening Influenza Pneumonitis
Genetic Etiologies in Human Papillomaviruses
Human Genetic Basis of Fulminant Viral Hepatitis
Hypomorphic Mutations of IKBKG/NEMO
Genetic Disorders of IKKα/IKKβ
Hypermorphic Mutations of Nuclear factor-κB Inhibitor Alpha (NFKBIA/IκBα)
LUBAC Deficiency: HOIL1/RBCK1 and HOIP/RNF31 deficiencies
IRAK4 and MYD88 Deficiency
TIRAP Deficiency
Genetic Disorders of Interleukin-17-Mediated Immunity and Chronic Mucocutaneous Candidiasis
Conclusion
Acknowledgments
References
36 Hemophagocytic Lymphohistiocytosis
Epidemiology
Pathophysiology
Genetics
Diagnosis
Other Manifestations
Distinctive Clinical Contexts
Hemophagocytic Lymphohistiocytosis in the Context of a Rheumatologic Disease (R-HLH)
Hemophagocytic Lymphohistiocytosis in the Context of Malignancy (M-HLH)
Hemophagocytic Lymphohistiocytosis in the Context of Immune Compromise (IC-HLH)
Hemophagocytic Lymphohistiocytosis in the Context of Immune-activating Therapies (Rx-HLH)
Treatment
HLH-94 Protocol
Salvage Therapy
Targeted Therapy
Allogeneic Hematopoietic Stem Cell Transplantation
Summary
References
37 Autoinflammatory Syndromes
Epidemiology
SIGNS and Symptoms
Familial Mediterranean Fever
Cryopyrin-Associated Periodic Syndrome
Tumor Necrosis Factor Receptor–Associated Periodic Syndrome
Mevalonate Kinase Deficiency
Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis Syndrome
Schnitzler Syndrome
Pathogenesis
Familial Mediterranean Fever
Cryopyrin-Associated Periodic Syndrome
Tumor Necrosis Factor Receptor–Associated Periodic Syndrome
Mevalonate Kinase Deficiency
Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis Syndrome
Schnitzler Syndrome
Laboratory Tests
Diagnosis
Familial Mediterranean Fever
Cryopyrin-Associated Periodic Syndrome
Tumor Necrosis Factor Receptor–Associated Periodic Syndrome
Mevalonate Kinase Deficiency
Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis Syndrome
Schnitzler Syndrome
Autoinflammation of Unknown Origin
Treatment
Colchicine
Inhibition of Interleukin-1
Inhibition of Interleukin-6
Inhibition of Tumor Necrosis Factor
Corticosteroids
Simvastatin
Other Immunosuppressive Drugs
Other Treatments
Amyloidosis
Conclusions
References
38
Immune Regulatory Disorders
Clinical Features of Immune Regulatory Disorders
The Genetics of Immune Regulatory Disorders
Somatic or Mosaic Genetic Defects and Immune Dysregulation
General Diagnostic Testing Approach to Immune Regulatory Disorders
Adjunctive Diagnostic Tests
Additional Workup
Specific Immune Regulatory Disorders
Regulatory-T-Cell (Treg)/Effector-T-Cell (Teff) Axis Defects
Nonmalignant Lymphoproliferation
Conclusions
References
39 Neutrophils and Neutrophil Disorders
Neutrophils
Production of Macrophages and Granulocytes
Evolution of Neutrophil Granules
Disorders of Neutrophil Production
Severe Congenital Neutropenia and Cyclic Neutropenia
Shwachman-Bodian-Diamond Syndrome
Autoimmune Neutropenia
Primary Autoimmune Neutropenia
Secondary Autoimmune Neutropenia
Alloimmune Neonatal Neutropenia
Defects of Leukocyte Adhesion
Leukocyte Adhesion Defect-1
Leukocyte Adhesion Defect-2
Leukocyte Adhesion Defect-3
Chronic Granulomatous Disease
The NADPH Oxidase and Its Activity
Mutations Leading to CGD
X-Linked CGD
Autosomal Recessive CGD
Clinical Manifestations of CGD
Diagnosis of CGD
Treatment of CGD
Myeloperoxidase Deficiency
Primary MPO Deficiency
Secondary or Acquired MPO Deficiency
Specific Granule Deficiency
Chediak-Higashi Syndrome
Hyper-IgE Recurrent Infection, or Job Syndrome
Facial, Skeletal, and Dental Abnormalities
Infections and Immunological Characteristics
DOCK8 Deficiency (Autosomal Recessive Hyper-IgE Syndrome)
GATA2 Deficiency (Monomac Syndrome)
Assessment of Neutrophil Function
Isolation of Neutrophils
Neutrophil Adherence
Neutrophil Chemotaxis
Expression of Surface Antigens
Neutrophil Degranulation
Generation of Reactive Oxygen Species
Western Blot for Measuring NADPH Oxidase
Translational Research
Acknowledgment
References
40 Complement and Complement Disorders
Overview: an Evolutionary and Historical Perspective
Complement Pathways
Classical Pathway
Lectin Pathway
Alternative Pathway
Membrane Attack Complex
Regulation of Complement Activation
C1 Esterase Inhibitor
Regulators of the C3 and C5 Convertases
Factor I
Soluble Regulatory Proteins, C4b-Binding Protein, and FH
Membrane Regulatory Proteins
Properdin
Regulators of the Membrane Attack Complex
Soluble Membrane Attack Complex Inhibitors: Vitronectin and Clusterin
Membrane Attack Complex Inhibitor CD59
Complement Receptors
C1q Receptors
Complement Receptor 1 (CR1, CD35)
Complement Receptor 2 (CR2, CD21)
Complement Receptors 3 and 4
Complement Receptor of the Immunoglobulin Superfamily (CRIg)
C5a and C3a Receptors
Complement in Host Defense and Immunity
Complement in Host Defense
Complement in Inflammation
Pathogen Evasion of Complement
Role of Complement in Adaptive Immunity
Effects of Complement on the Humoral Immune Response
Complement and T-Cell Biology
The Intracellular Complement System (Complosome)
Role of Complement in Clearance of Apoptotic Cells
Targeted and Restricted Activation of the Complement System
Complement Deficiencies
Genetics and Incidence
Classical Pathway Deficiencies
C1 Deficiency
C4 Deficiency
C2 Deficiency
Lectin Pathway Deficiencies
Alternative Pathway Deficiencies
C3 Deficiency
Acquired C3 Deficiency: Genetic Deficiencies of FH and FI and C3 and C4 Nephritic Factors
Deficiencies of Complement Receptors
Deficiencies of CR1 (CD35) and CR2 (CD21)
Leukocyte Adhesion Deficiency: CR3 and CR4 Deficiency
Deficiencies of Regulatory Proteins
Hereditary Angioedema: C1-INH Deficiency
Paroxysmal Nocturnal Hemoglobinuria: Decay-Accelerating Factor and CD59 Deficiency
Control of Localized Complement Activation: Atypical Hemolytic–Uremic Syndrome, Age-Related Macular Degeneration
Complement in Disease
Measurement of Complement in a Clinical Setting
Role of Complement in Specific Immunological Diseases
Systemic Lupus Erythematosus (Chapter 52)
Antiphospholipid Syndrome (Chapter 61)
Rheumatoid Arthritis (Chapter 53)
Vasculitis (Chapters 59 and 60)
Immunological Renal Diseases (Chapter 68)
Asthma (Chapters 43)
Neurological Disease
Ischemia/Reperfusion Injury
Complement-Based Therapeutics
References
41 Human Immunodeficiency Virus Infection and Acquired Immunodeficiency Syndrome
US Perspective
HIV Immunopathogenesis
HIV Life Cycle
HIV Infection Through Mucosa
Chronic Immune Activation
HIV Latency and HIV Reservoirs
Anti-HIV Immunity
Innate Immunity In HIV Infection
Clinical Features
Acute HIV Infection
Chronic HIV Infection
End-Stage HIV Infection: AIDS
Long-Term Non-Progressors/Elite Controllers
Diagnosis and Monitoring of Hiv Infection
Diagnostic Tests
HIV Immunoassays
HIV Nucleic Acid Amplification Tests
Point-of-Care Diagnostic Tests
Monitoring Tests
CD4 T-Cell Count
HIV Viral Load
Drug Resistance: HIV Genotype Versus Phenotype
Testing for Viral Tropism and Abacavir Hypersensitivity
Treatment
Antiretroviral Therapy: Attacking the Life Cycle of HIV
When to Start Therapy
Antiretroviral Agents
Reverse Transcriptase Inhibitors, Protease Inhibitors, and Integrase Inhibitors
Entry Inhibitors: Fusion Inhibitors, CCR5 Blockers, Attachment and Post-Attachment Inhibitors
Immunoreconstitution After Therapy
Return of T Cells: Memory T Cells, Then Naïve T Cells
Immune Reconstitution Inflammatory Syndrome
Hyperallergenic State Associated With Immunoreconstitution
Prevention
Prevention of Mother-to-Child Transmission
Prevention of Sexual Transmission
Male Medical Circumcision
Pre-Exposure Prophylaxis
Expanded Treatment With Antiretroviral Therapy
Hiv Vaccines: Clinical Trials
Preventive Vaccines
Therapeutic Vaccines
Future for HIV Vaccines
Translational Research Needs and Conclusions
ACKNOWLEDGMENTS
REFERENCES
42 Autoantibody-Mediated Phenocopies of Primary Immunodeficiency Diseases
Overview of Pathophysiology
Anti-GM-CSF Autoantibodies and Pulmonary Alveolar Proteinosis
Anti IFN-Γ Autoantibodies and Susceptibility to Intracellular Pathogens
Anti-IL-17 And Anti-IL-22 Autoantibodies and Chronic Mucocutaneous Candidiasis
Anti-IL-6 Autoantibodies and Bacterial Infections
Management
Conclusions
Acknowledgments
References
43 Allergic Airway Diseases
Clinical Presentation of Allergic Airway Disease
Chronic Rhinitis and Rhinosinusitis
Epidemiology and Clinical Presentation
Diagnosis
Therapy
Asthma
Epidemiology and Clinical Presentation
Diagnosis
Therapy
Other Airway Allergic Disease Syndromes
Extrinsic Eosinophilic Syndromes
Tropical Eosinophilic Pneumonias
Allergic Bronchopulmonary Aspergillosis
Acute and Chronic Eosinophilic Pneumonia
Hypersensitivity Pneumonitis
Intrinsic Eosinophilic Syndromes
Hypereosinophilic Syndrome
Eosinophilic Granulomatosis and Polyangiitis
Immunologic Mechanisms of Allergic Airway Disease
Type I (Immediate) Hypersensitivity
Cell-Mediated Features of Immediate Hypersensitivity
Contributing Immune Mechanisms in Allergic Airway Disease
Environmental Factors and Allergic Disease Initiation
Novel Pathways to Therapy in Inflammatory Airway Disease
References
44 Mast Cells and Mast Cell Disorders
Mast Cell Biology
Mast Cell Origin and Early Development
Mast Cell Homing
Mast Cell Heterogeneity
Mast Cell Activation
Mast Cell Mediators
Preformed Mediators
Histamine
Mast Cell Proteases
Tryptase
Tryptase isoforms.
Pathophysiology and diagnostic function.
Hereditary α-tryptasemia.
Proteoglycans and Heparin
Newly Formed Mediators
Lipid Mediators
Prostaglandins
Leukotrienes
Platelet-Activating Factor
Cytokines and Chemokines
Normal Mast Cell Function
Immune Response to Infection
Innate Immunity
Adaptive Immunity
Immune Tolerance
Mast Cell Homeostasis
Mast Cell Related Disease
Role of Mast Cells in Allergic Disease
Anaphylaxis
Asthma
Aspirin-Exacerbated Respiratory Disease
Allergic Rhinitis
Food Allergy
Role of Mast Cells in Nonallergic Disease
Mast Cell Disorders
Mastocytosis
Mast Cell Activation Syndrome
Basophils and Related Disorders
References
45 Eosinophils and Eosinophilic Disorders
Eosinophil Biology
Eosinophil Life Cycle
Eosinophil Structure
Eosinophil Activation and Degranulation
Role of Eosinophils in Homeostasis
Eosinophilia and Eosinophilic Disorders
Definition of Eosinophilia
Diagnostic Approach to the Patient With Eosinophilia
Eosinophilia by Organ System
Dermatologic and Soft Tissue Disorders
Pulmonary Disorders
Gastrointestinal Disorders
Renal and Genitourinary Disorders
Cardiac Disorders
Neuromuscular Disorders
Drug and Toxin-Related Eosinophilia
Infectious and Immune Causes of Eosinophilia
Hematologic and Neoplastic Causes of Eosinophilia
Hypereosinophilic Syndromes
Myeloid Hypereosinophilic Syndromes
Lymphoid Hypereosinophilic Syndromes
Overlap Hypereosinophilic Syndromes
Associated Hypereosinophilic Syndromes
Familial Hypereosinophilic Syndromes.
Idiopathic Hypereosinophilic Syndromes.
Therapy of Eosinophil-Associated Disorders
General Treatment Approach
Approach to Therapy of Hypereosinophilic Syndromes
Myeloid Hypereosinophilic Syndromes
Idiopathic Hypereosinophilic Syndromes
Lymphoid Hypereosinophilic Syndromes
Overlap Hypereosinophilic Syndromes
Eosinophilic Gastrointestinal Disorders
Eosinophilic Granulomatosis with Polyangiitis
Familial Eosinophilia
HEus
References
46 Urticaria, Angioedema, and Anaphylaxis
Definition
Epidemiology
Genetics
Clinical Patterns
Etiopathophysiology
Mast Cell–Dependent Mechanisms
Allergic Urticaria
Autoimmune Urticaria
Immune Complex–Mediated Urticarial Rash
Mast-Cell Activation via MRGPRX2 Receptors
Mast Cell and Basophil Releasability in Urticaria
Skin Response to Mast Cell Activation in Chronic Urticaria
Mast Cell–Independent Mechanisms of Urticaria
Nonsteroidal Anti-Inflammatory Drugs
Food-Induced Pseudoallergic Reactions in Chronic Spontaneous Urticaria
Bradykinin-Mediated Angioedema
Clinical Classification
Spontaneous Urticaria
Acute Spontaneous Urticaria
Chronic Spontaneous Urticaria
Chronic Inducible Urticarias
Mechanical Urticaria
Symptomatic Dermographism
Delayed-Pressure Urticaria
Vibratory Angioedema
Thermal or Ultraviolet-Induced Urticaria
Cold Urticaria
Heat Urticaria
Solar Urticaria
Other Patterns of Inducible Urticaria
Cholinergic Urticaria
Aquagenic Urticaria
Contact Urticaria
Differential Diagnosis of Urticaria
Urticarial Vasculitis
Angioedema Without Wheals
Angioedema Caused by C1 Inhibitor Deficiency
Angioedema With Normal C1 Inhibitor
Histamine-Mediated Angioedema (without wheals).
Idiopathic.
Drug-induced.
Bradykinin-Mediated Angioedema.
Hereditary.
Drug-induced.
Acquired.
Idiopathic.
Autoinflammatory Syndromes Presenting With Urticarial Rash
Acquired
Schnitzler Syndrome.
Hereditary (Cryopyrin-Associated) Periodic Syndromes
Work-up in Patients with Urticaria
Work-Up of Acute Urticaria
Work-Up in Chronic Inducible Urticarias
Work-Up in Chronic Spontaneous Urticarias
The Diagnosis of Autoimmune Chronic Spontaneous Urticaria
Management of Urticaria
General Measures
First-Line Therapy
Second-Line Therapy
Third-Line Therapy
Fourth-Line Therapy
Management of Hereditary Angioedema
Treatment of the Acute Attack
Short-Term Prophylaxis
Long-Term Prophylaxis
Gene Therapy
Anaphylaxis
Epidemiology of Anaphylaxis
Pathophysiology of Anaphylaxis
Etiology of Anaphylaxis
Food-Induced Anaphylaxis
Drug-Induced Anaphylaxis
Perioperative Anaphylaxis
Insect Sting–Induced Anaphylaxis
Other Rare Causes of Anaphylaxis
Anaphylaxis in Clonal Mast-Cell Disorders
Clinical Diversity of Anaphylaxis
Diagnosis of Anaphylaxis
Management of Anaphylaxis
Prevention of Anaphylaxis
Translational Research Opportunities
References
47 Allergic Reactions to Stinging and Biting Insects
Entomological Aspects1,2
Apidae1
Vespidae3
Ants (Formicidae)2
Allergens in Hymenoptera Venoms
Clinical Picture
Normal Local Reactions
Large Local Reactions
Systemic Reactions
Systemic Toxic Reactions
Unusual Reactions
Epidemiological Aspects
Prevalence of Allergy to Hymenoptera
Risk Factors for Developing Hymenoptera Allergy
Natural History of Hymenoptera Allergy and Risk Factors For Severe Reactions9,12
Mortality Caused by Hymenoptera Stings
Epidemiological Aspects of Allergic Reactions to Ant Stings
Diagnosis
Clinical History
Skin Tests14
Venom-Specific Serum Immunoglobulin E Antibodies
Sensitivity and Specificity of Skin Tests and sIgE
Cross-Reactivity
Cellular Tests15
Baseline Serum Tryptase
Sting Challenge Tests
Prevention
Treatment of Large Local Reactions
Treatment of Systemic Allergic Reactions
Venom Immunotherapy18
Indications
Dosage and Treatment Regimens
Adverse Reactions to Venom Immunotherapy
Efficacy of Venom Immunotherapy
Duration of Venom Immunotherapy
Risk Factors for Recurrence of Systemic Reactions after Stopping Venom Immunotherapy
ReferenceS
48 Atopic and Contact Dermatitis
Clinical Aspects of Atopic Dermatitis
Epidemiology
Natural History
Clinical Features
Complicating Features
Ocular Problems
Hand Dermatitis
Infections
Systemic Complications
Psychosocial Implications
Differential Diagnosis
Pathogenesis of Atopic Dermatitis
Genetics
Immune Abnormalities in Atopic Dermatitis
Immunohistology
Immune Pathways in Atopic Dermatitis
Epidermal Barrier Dysfunction
Management of Atopic Dermatitis
Identification and Elimination of Exacerbating Factors
Irritants
Allergens
Psychosocial Factors
Patient Education
Hydration
Moisturizers and Occlusives
Corticosteroids
Topical Calcineurin Inhibitors
Phosphodiesterase-4 Inhibitor
Antiinfective Therapy
Antipruritic Agents
Biologic therapy
Recalcitrant Disease
Hospitalization
Wet Wrap Therapy
Systemic Immunosuppressive Agents
Phototherapy and Photochemotherapy
Allergen-Specific Immunotherapy
Investigational Therapies
Intravenous Gammaglobulin
Omalizumab
Recombinant Human Interferon-γ
Probiotics
Other Biologics and Small Molecules in Clinical Trials
Prevention
Contact Dermatitis
Pathogenesis of Allergic Contact Dermatitis
The Genes
The Allergens
The Immune Response
Pathogenesis of Irritant Contact Dermatitis
Clinical Manifestations of Contact Dermatitis
Management of Allergic Contact Dermatitis
Identification of the Allergen
Allergen Avoidance and Treatment
Perspectives in Atopic Dermatitis and Allergic Contact Dermatitis
References
49 Food Allergy
Prevalence
Spectrum of Disease
Immunoglobulin E–Mediated Food Allergies
Mixed Immunoglobulin E/Non–Immunoglobulin E– and Non–Immunoglobulin E–Mediated Food Allergies
Pathophysiology
Properties of Food Allergens
The Allergic Response
Natural History
Diagnosis
Management
Treatment of a Reaction
Prevention of Food Allergy
Experimental Interventional Therapies
Oral Immunotherapy
Sublingual Immunotherapy
Epicutaneous Immunotherapy
References
50 Drug Hypersensitivity
Epidemiology
Immune System Recognition of Drugs
Risk Factors for Drug Allergy
Drug-Related Factors
Host Related Factors
Genetics of Drug Allergy
Hypersensitivity Reactions
Type I IgE-Mediated Hypersensitivity
Type II Antibody-Dependent Hypersensitivity
Type III Immune-Complex Hypersensitivity
Type IV Delayed-Type Hypersensitivity
Type IVa Reactions
Type IVb Reactions
Type IVc Reactions
Type IVd Reactions
Direct Mast Cell Activation
Mas-Related G Protein-Coupled Receptor-X2 (MRGPRX2)
Cytokine Release Syndrome
Diagnosis
Tryptase
Drug Challenges
Skin Prick and Intradermal Testing
Patch Testing
In Vitro Testing: Specific IgE and Basophil Activation Test
Management
Acute Treatment
Alternative Medications
Desensitization
Drug Challenges
Premedication Protocols
Delabeling Allergy After Negative Testing
Specific Drug Hypersensitivity
Antibiotics
Penicillins
Cephalosporins
Sulfonamide Antibiotics
Other Antibiotics
Aspirin and Nonsteroidal Anti-Inflammatory Drugs
NSAID-Exacerbated Respiratory Disease
Radiocontrast Media
Angiotensin-Converting Enzyme Inhibitors
Perioperative Anaphylaxis
Local Anesthetics
Chemotherapy
Biologics and Monoclonal Antibodies
Conclusion
References
51 Mechanisms of Autoimmunity
The Distinct Phases in the Development of Autoimmunity
Phase 1: Susceptibility
Incomplete Thymic Tolerance Induction Predisposes to Autoimmunity
Impaired Clearance and Tolerance Induction: Susceptibility Defect in Systemic Autoimmunity
Defective Production of Regulatory T Cells
Signaling Thresholds and Susceptibility to Autoimmunity
Infections and the Microbiome
Phase 2: Initiation
Dominance and Crypticity
High-Affinity Binding of Antigen to Ligands or Antibodies
Tissue-Specific Protease Expression
Posttranslational Modification of Autoantigens
Novel Antigen Cleavage During Cell Damage, Cell Death, or Inflammation
Autoantigen Alteration Caused by Mutation, Truncation, or Splicing
Antigen Mimicry
Phase 3: Propagation
Principles of Amplification
Acquisition of Adjuvant Properties by Disease-Specific Autoantigens
Role of Innate Immune Receptors in Amplification
Enhanced Autoantigen Expression in the Target Tissue
Translational Research
References
52 Systemic Lupus Erythematosus
Epidemiology
Mortality and Organ Damage
Immunopathogenesis
Autoantibodies
The Predisposed Host: Genetic Contributions
Antigen Presentation
Impaired Clearance of Apoptotic Debris
Lymphocyte Activation, Proliferation, and Function
Cytokine and Chemokine Regulation
Cell Survival
Target Organ Damage
Epigenetic Contributions
B Cells
Neutrophils
Dendritic Cells
T Cells
Hormonal Influences
Clinical Manifestations
Musculoskeletal Involvement
Arthritis and Arthralgia
Tendinitis
Myositis/Myalgia
Avascular Necrosis
Mucocutaneous Manifestations
Skin: Classification and Pathogenesis
Acute Cutaneous Systemic Lupus Erythematosus
Subacute Cutaneous Systemic Lupus Erythematosus
Chronic Cutaneous Systemic Lupus Erythematosus
Hair and Nail
Oral Lesions
Gastrointestinal Manifestations
Esophagus
Abdominal Pain/Vasculitis
Intestinal Pseudo-obstruction
Peritonitis
Pancreatitis
Liver
Protein-Losing Enteropathy
Pulmonary Involvement
Pleuritis
Lupus Pneumonitis
Pulmonary Hemorrhage
Chronic Diffuse Interstitial Lung Disease
Pulmonary Hypertension
Shrinking-Lung Syndrome
Cardiac Involvement
Myocardium
Valvular Heart Disease
Pericarditis
Coronary Artery Disease
Renal Involvement
Hematologic
Anemia
Leukopenia
Thrombocytopenia
Central and Peripheral Nervous System
NPSLE Nomenclature and Epidemiology
NPSLE Pathogenesis
NPSLE Assessment and Attribution
Drug-Induced Lupus
Treatment
Translational Research
Conclusions
References
53 Rheumatoid Arthritis
Epidemiology
Etiology and Pathogenesis
Environmental and Nongenetic Factors
Immunogenetics
Synovial Pathology
Increased Vascularity and Cell Migration
Organization of Lymphoid Tertiary Microstructures
Immunobiology of Rheumatoid Arthritis
Initiation of the Immune Response
Autoantigens in Rheumatoid Arthritis
The Discovery of Citrulline as a Key Target for Autoimmunity in Rheumatoid Arthritis
Lymphocyte Biology
Immune Regulation
Impact of the Inflammatory Response on Cartilage and Bone
Clinical Features
Disease Onset
Diagnosis
Classification Criteria
Laboratory Findings
The Preclinical Phase of Rheumatoid Arthritis
Treatment
Disease-Modifying Antirheumatic Drugs
Anti-Cytokine Therapy
Anti-T-Cell Therapy
Anti-B-Cell Therapy
Future Prospects for Therapy
References
54
Juvenile Idiopathic Arthritis
Etiology and Pathogenesis
Genetic Contribution
Polygenic Disorder
Human Leukocyte Antigen Associations
Nonhuman Leukocyte Antigen Associations
Environmental Factors
Immune Abnormalities
Autoantibodies
T-Helper Cells
Cytokines
Macrophage Activation Syndrome
Juvenile Idiopathic Arthritis Clinical Subtypes
Oligoarticular Juvenile Idiopathic Arthritis
Polyarticular Juvenile Idiopathic Arthritis
Psoriatic Arthritis
Enthesitis-Related Arthritis
Systemic Juvenile Idiopathic Arthritis
Laboratory Evaluation
Imaging Evaluation
Differential Diagnosis
Clinically Silent Complications
Treatment
Overview
Nonsteroidal Antiinflammatory Drugs
Glucocorticoids
Nonbiological Disease-Modifying Anti-Rheumatic Drugs
Biological Disease-Modifying Anti-Rheumatic Drugs
Treatment of Oligoarthritis (Arthritis of ≤4 Joints)
Treatment of Polyarthritis (Arthritis of ≥5 Joints)
Treatment of Arthritis Involving Specific Joints
Treatment of Erosive Arthritis
Treatment of Systemic Features of Systemic Arthritis
Treatment of Arthritis of Systemic Arthritis
Treatment of Uveitis
Duration of Therapy
Translational Research
References
55 Sjögren’s Syndrome
Etiopathogenesis
Environment
Hormones—Stress
Genetics—Epigenetics
Pathophysiology
Diagnosis and Classification
Medical History and Clinical Examination
Laboratory Work-Up
Evaluation of Lachrymal Gland Involvement—Ocular Dryness
Evaluation of Salivary Gland Involvement—Xerostomia/Parotid Gland Enlargement
Classification Criteria for Primary Sjögren Syndrome
Clinical Features
Glandular Manifestations
Extraglandular Manifestations
Musculoskeletal
Raynaud’s Phenomenon
Respiratory Tract Involvement
Hepatobiliary and Gastrointestinal Manifestations
Renal Involvement
Vasculitis
Neuropsychiatric Involvement
Lymphoproliferative Disease
Overlapping Autoimmune Entities and Comorbidities
Therapy
Glandular Manifestations
Extraglandular Manifestations
Arthralgias/Arthritis
Other Extraglandular Manifestations
Biologic Treatments
References
56
Scleroderma–Systemic Sclerosis
Prevalence and Epidemiology
Etiology and Pathogenesis
Environmental Factors
Pathology
Pathogenesis
Microangiopathy
Cellular and Humoral Immune Responses
Fibrosis: Cellular and Molecular Components
Clinical Features
Overview
Morphea
Symptoms
Clinical Course
Raynaud’s Phenomenon
Gastrointestinal Involvement
Pulmonary Involvement
Interstitial Lung Disease
Pulmonary Hypertension
Cardiac Involvement
Renal Involvement
Musculoskeletal Complications
Emotional Aspects
Approach to Treatment
Immunotherapy
Treatment of Fibrosis
Treatment of Vascular Disease
Treatment
Other Fibrosing Diseases
References
57 Inflammatory Muscle Diseases
Clinical Features
Classification
Etiology
Immunological Clues to Origin
Drugs and Toxins
Bacterial and Parasitic Diseases
Pathogenesis
Genetics
Natural History
Patient Management
Corticosteroids
Second-Line and Third-Line Immunosuppressive Therapies
Monitoring Disease Activity
Treatment-Resistant Myositis
Nonskeletal Muscle Involvement
Diagnostic Tools, Evaluation, and Differential Diagnosis
Pitfalls
References
58 Spondyloarthritis
Classification of Spondyloarthritis
Epidemiology
Pathogenesis
Genetics of Spondyloarthritis
Familial Aggregation
HLA-B27 and Spondyloarthritis
Other Major Histocompatibility Complex Genes and SpA Susceptibility
Non–Major Histocompatibility Complex Genes in Susceptibility to Spondyloarthritis
Genes and Severity of SpA
Infection
The Gut and Spondyloarthritis
Pathology of SpA
Clinical Features
Ankylosing Spondylitis
Musculoskeletal Symptoms
Extraarticular Manifestations
Uveitis.
Cardiac Manifestations.
Pulmonary Manifestations.
Renal Manifestations.
Osteoporosis.
Spondylodiscitis and Spinal Fractures.
Neurological Manifestations.
Fatigue and Psychosocial Manifestations.
AS in Women.
Reactive Arthritis
Juvenile Spondyloarthritis
Psoriatic Arthritis
Enteropathic Arthritis
Undifferentiated Spondyloarthritis
Measures of SpA Activity and Severity
Radiographic Imaging of Spondyloarthritis
Axial Spondyloarthritis
Psoriatic Arthritis
Disease Course and Prognosis
Ankylosing Spondylitis
Reactive Arthritis
Psoriatic Arthritis
Juvenile Spondyloarthritis
Treatment
Patient Education and Physiotherapy
Medical Treatment
Nonsteroidal Anti-Inflammatory Drugs
Disease-Modifying Anti-Inflammatory Drugs
Sulfasalazine.
Methotrexate.
Other DMARDs.
Corticosteroids.
Intraarticular/Intralesional Corticosteroids
Antibiotics
Tumor Necrosis Factor-α Blockers
Interleukin-17 Blockers
Interleukin-12/23 Blockers
Janus Kinase Inhibitors
Surgical Treatment of Ankylosing Spondylitis Complications
Conclusions and Research Opportunities
References
59 Small- and Medium-Vessel Primary Vasculitis
Epidemiology
Pathogenesis of Antineutrophil Cytoplasmic Antibody-Associated Vasculitides
The Pathogenic Role of ANCA in GPA and MPA
GENETICS
Epigenetics
Environmental and Infectious Triggers
Drug Induced Antineutrophil Cytoplasmic Antibody-Associated Vasculitides
Propylthiouracil
Hydralazine
Levamisole-Contaminated Cocaine
Loss of B- and T-Cell Tolerance in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis
Role of Neutrophils
Role of Complement
Pathogenesis of Kawasaki Disease
Pathogenesis of Polyarteritis Nodosa
Pathogenesis of Cryoglobulinemic Vasculitis
Pathogenesis of Eosinophilic Glomerulonephritis with Polyangiitis
Classification of Vasculitides
Diagnosis
Laboratory Investigations
Assessment
Damage Assessment in Vasculitis
Treatment
No Treatment/Symptom Relief
Target-Directed Therapies
Specific Therapies
Glucocorticoids
Other Immunosuppressive Therapies
Specific Immunotherapy
Other Therapies
Outcomes
Acknowledgments
References
60 Large Vessel Vasculitides
Epidemiology
Etiology and Pathogenesis
Innate Immune System Defects
Adaptive Immune System Defects
Defective T Regulatory Cells and Insufficient Immune Checkpoints in Giant Cell Arteritis
Clinical Features in Giant Cell Arteritis
Clinical Features in Polymyalgia Rheumatica
Clinical Features in Takayasu Arteritis
Diagnosis
Laboratory Tests
Tissue Biopsy
Diagnostic Imaging
Therapeutic Management
Induction Therapy
Maintenance Therapy
Revascularization Procedures
References
61 Antiphospholipid Syndrome
Epidemiology
Etiopathogenesis
Diagnosis
Clinical Manifestations
Laboratory Tests
Imaging Studies
Pathological Studies
Treatment
Asymptomatic Individuals
Venous and Arterial Thromboembolism
Pregnancy Morbidity
Other Clinical Manifestations of Antiphospholipid syndrome
Perioperative Management
Additional Therapeutic Considerations
Conclusions and Translational Research
References
62 Immunohematologic Disorders
Introduction
Immune-Mediated Hemolytic Anemia
Immunopathogenesis
Warm Autoimmune Hemolytic Anemia
Cold Agglutinin Diseases
Paroxysmal Cold Hemoglobinuria
Drug-Induced Immune Hemolysis
Diagnosis
Therapy
Immune-Mediated Neutropenia
Neonatal Alloimmune Neutropenia
Primary Autoimmune Neutropenia
Neutropenia Associated With Systemic Autoimmune or Lymphoproliferative Diseases
T-Cell Large Granular Lymphocyte Leukemia
Drug-Induced Immune Neutropenia
Immunopathogenesis
Regulation of Antineutrophil Antibody Production
Antibody Specificity
Impact of Antibodies and Immune Complexes on Neutrophil Survival
Myelopoiesis in Immune Neutropenia
Diagnosis
Clinical Presentation
Laboratory Findings
Detection of Antineutrophil Antibodies.
Clinical Use of Antineutrophil Antibody Studies.
Therapy
Overview
Colony-Stimulating Factors
Immunosuppressive Agents
Other Therapy
Prophylactic Antibiotics
Immune-Mediated Thrombocytopenias
Immune Thrombocytopenia
Pathogenesis
Laboratory Diagnosis
Therapy
Drug-Induced Thrombocytopenia
Neonatal Alloimmune Thrombocytopenia
Autoimmune MULTILINEAGE Cytopenias
References
63 Bullous Diseases of the Skin and Mucous Membranes
Introduction
Target Antigens and Disease Entities
Pemphigus Diseases
Pemphigoid Diseases and Dermatitis Herpetiformis
Epidemiology
Incidence
Genetics
Risk Factors
Comorbidities
Mortality
Clinical Presentations
Pemphigus
Pemphigus Vulgaris
Pemphigus Foliaceus
Paraneoplastic Pemphigus
Pemphigoid Diseases
Bullous Pemphigoid
Mucous Membrane Pemphigoid
Linear Immunoglobulin A Disease
Pemphigoid Gestationis
Anti-p200 Pemphigoid
Epidermolysis Bullosa Acquisita
Dermatitis Herpetiformis
Diagnosis
Pathophysiology
Pemphigus
Pemphigoid Diseases
Loss of Tolerance to Pemphigoid Disease Autoantigens and Production of Autoantibodies
Circulation of Autoantibodies
Autoantibody-Mediated Tissue Pathology
Experimental Models
Dermatitis Herpetiformis
Treatment
Pemphigus
Pemphigus Vulgaris und Pemphigus Foliaceus
Paraneoplastic Pemphigus
Pemphigoid Diseases
Bullous Pemphigoid
Pemphigoid Gestationis
Anti-p200 Pemphigoid
Mucous Membrane Pemphigoid
Epidermolysis Bullosa Acquisita
Dermatitis Herpetiformis
Acknowledgments
References
64 Immunology of Psoriasis
Clinical and Histologic Features of Psoriasis
Immune-Related Genetic Factors Predisposing to Psoriasis
Effector Cells and Immune Mechanisms Operating in Psoriasis
Plasmacytoid Dendritic Cells as Inducers of Primary Immune Responses in Psoriasis
Dendritic Cell Driving of T-Cell Responses in Psoriatic Skin
Activation of T Lymphocytes and Establishment of the Cytokine Milieu Influencing Keratinocyte Proliferation and Immune Func ...
Innate Immune Cells Are Fundamental for the Induction of Psoriatic Processes
Conclusions
References
65 Myasthenia Gravis
Disease Diagnosis and Classification
Neuromuscular Transmission
Differential Muscle Involvement in Myasthenia Gravis
Autoantigens In Myasthenia Gravis and Their Roles in Neuromuscular Transmission
Acetylcholine Receptor
Muscle-Specific Kinase
Low-density Lipoprotein Receptor-related Protein 4
Experimental Models to Study Myasthenia Gravis
Mechanisms of Immunopathogenesis
Role of Pathogenic B cells
Pathogenic Autoantibodies
Acetylcholine Receptor Autoantibodies
Complement Activation and Destruction of Neuromuscular Junction
Acceleration of Acetylcholine Receptor Degradation (Antigenic Modulation)
Receptor Blockade
Muscle-Specific Kinase Autoantibodies
Lrp4 Autoantibodies
Role of Thymus Pathology
Role of T cells
Epigenetic Factors: Role of miRNAs
Lymphocyte-Targeted Therapy
Induction of Tolerance
Treatment
Acetylcholinesterase Inhibitors
Corticosteroids
Thymectomy
Immunosuppressants
Intravenous Immunoglobulin and Plasma Exchange
Eculizumab
Therapies Under Development
Reducing Effector Activity: Moderation of Autoantibody Levels and Complement Inhibition
Moderating Proinflammatory Signals
Future Studies
References
66 Multiple Sclerosis
Clinical Subsets and Phenomonology
Relapsing-Remitting Multiple Sclerosis
Secondary Progressive Multiple Sclerosis
Primary Progressive Multiple Sclerosis
Diagnosis
Risk Factors
Genetic Risk Factors
Environmental Risk Factors
Geographic Prevalence Patterns
Vitamin D
Infection
Obesity
Cigarette Smoking
Sex Hormones
Microbiome
Pathologic Features of Multiple Sclerosis
White Matter Lesions
Gray Matter Lesions
Meningeal Inflammation
Immunopathogenesis
Animal Models of Multiple Sclerosis
Immune Dysregulation in Patients With Multiple Sclerosis
Disease-Modifying Therapies
Recombinant Interferon Beta
Glatiramer Acetate
Teriflunomide
Dimethyl Fumarate and Diroximel Fumarate
Fingolimod and Siponimod
Cladribine
Natalizumab
Alemtuzumab
B Cell–Depleting Monoclonal Antibodies
Future Directions
References
67 Autoimmune Peripheral Neuropathies
Acute Inflammatory Polyneuropathy: Guillain-Barré Syndrome(s)
Diagnosis
Antecedent Events
Immunopathology of Guillain-Barré Syndrome
Cellular Factors
Humoral Factors and Antiganglioside Antibodies
Molecular Mimicry: Relationship Between Campylobacter jejuni and Gangliosides
Chronic Inflammatory Demyelinating Polyneuropathy
Clinical Features and Disease Variants
Diagnosis
Immunopathogenesis
Multifocal Motor Neuropathy with Conduction Block
Polyneuropathies Associated with Monoclonal Gammopathies of Undetermined Significance
Antibodies to Myelin-Associated Glycoprotein (MAG) in Patients with igM MGUS (Anti-MAG Neuropathy)
Polyneuropathy, Organomegaly, Endocrinopathy, Myeloma, and Skin Changes (Poems Syndrome)
Cryoglobulinemic Neuropathy
Paraneoplastic Peripheral Neuropathies WITH Anti-HU OR CRMP-5 Antibodies
Autoimmune Autonomic Neuropathies
Possibly Autoimmune Small Fiber Sensory Neuropathies, Neuropathic Pain, and Neural Antibodies
Mononeuropathy Multiplex and Localized, Isolated Vasculitis of the Peripheral Nerves
Neuropathy with Viruses
Treatment
Guillain-Barré Syndrome
Supportive Care
Plasmapheresis
Intravenous Immunoglobulin
Chronic Inflammatory Demyelinating Polyneuropathy
Prednisone
Intravenous Immunoglobulin
Plasmapheresis
Polyneuropathy with Paraproteinemias
Multifocal Motor Neuropathy
Paraneoplastic Neuropathy
Vasculitic Neuropathies
HIV Neuropathies
Possibly Autoimmune Small-Fiber Sensory Neuropathies
Acknowledgments
References
68 Immunologic Renal Diseases
Hematuria
Proteinuria
Nephrotic Syndrome
Acute Nephritic Syndrome
Renal Biopsy
Minimal Change Disease
Clinical Features
Etiology and Pathogenesis
Pathology
Treatment
Focal Segmental Glomerulosclerosis
Etiology and Pathogenesis
Pathology
Treatment
Membranous Nephropathy
Etiology and Pathogenesis
Clinicopathological Features
Natural History
Treatment
Membranoproliferative Glomerulonephritis
Etiology and Pathogenesis
Pathology
Clinical Presentation
Treatment
Postinfectious Nephropathies
Viral Infections
Hepatitis B Virus
Hepatitis C Virus
Human Immunodeficiency Virus
Bacterial Infections
Poststreptococcal Glomerulonephritis
IgA Nephropathy
Pathology
Etiology and Pathogenesis
Natural History
Treatment
Antineutrophil Cytoplasmic Antibodies–Associated Renal Vasculitis
Pathology
Treatment and Prognosis
Anti-Glomerular Basement Membrane Antibody-Mediated Nephritis (Goodpasture Disease)
Lupus Nephritis
Pathogenesis
Clinical Features
Pathology
Treatment
Systemic Sclerosis (SSc, Scleroderma) Renal Disease
Renal Disease of Primary Sjögren Syndrome
Thrombotic Microangiopathies
References
69 Immunologic Mechanisms ofAtherosclerosis and Myocarditis
Immunological Mechanisms that Contribute to Atherosclerosis
Atherosclerosis Initiation
Lesion Progression
Lesion Complication
Therapeutic Implications of Inflammation in Atherosclerosis
Myocarditis: Immune Response that Damages the Heart
Immune Status of the Heart Under Homeostatic Conditions
Myocarditis
Infectious Myocarditis
Autoimmune Myocarditis
Autoimmune Myocarditis Associated With Infection
Autoimmune Myocarditis Without Known Infection
Myocarditis Associated With Systemic Autoimmune Diseases
Immune Checkpoint Blockade-Associated Myocarditis
Cardiac Allograft Rejection
Clinical Implications of Cardiac Inflammation
References
70 Autoimmune Thyroid Diseases
Graves Hyperthyroidism
Epidemiology
Etiology
Immunopathogenesis
Clinical Presentation
Investigation and Diagnosis of Graves Disease
Management of Graves Disease
Medical Management—Antithyroid Drugs
Definitive Treatment
Graves Ophthalmopathy
Epidemiology
Etiology
Immunopathogenesis
Diagnosis and Clinical Presentation
Treatment
Future Developments for Graves Hyperthyroidism and Ophthalmopathy
Autoimmune Hypothyroidism
Epidemiology
Etiology
Immunopathogenesis
Clinical Presentation
Investigation and Diagnosis
Management
Subclinical Hypothyroidism
Future Developments
Other Forms of Thyroiditis
Postpartum Thyroiditis
Immunomodulation And Thyroid Dysfunction
Alemtuzumab
Immune Checkpoint Inhibitors
TRANSLATIONAL RESEARCH
References
71 Type 1 Diabetes
Epidemiology and Natural History of T1DA
Pathogenesis: Nature and Nurture
Genes
β Cells
Environment—Outside and Inside
Treatment and Prevention
References
72 Immunologic Lung Diseases
Inflammation of Interstitial Lung Diseases
Idiopathic Interstitial Pneumonias
Idiopathic Pulmonary Fibrosis
Clinical Manifestations
Histopathology
Pathogenesis
Diagnosis
Treatment and Outcome
Acute Interstitial Pneumonia
Clinical Manifestations
Histopathology
Diagnosis
Treatment and Outcome
Desquamative Interstitial Pneumonitis
Clinical Manifestations
Histopathology
Diagnosis
Treatment and Outcome
Respiratory Bronchiolitis-Associated Interstitial Lung Disease
Clinical Manifestations
Histopathology
Diagnosis
Treatment and Outcome
Nonspecific Interstitial Pneumonitis
Clinical Manifestations
Histopathology
Treatment and Outcome
Cryptogenic Organizing Pneumonia
Clinical Manifestations
Histopathology
Diagnosis
Treatment and Outcome
Lung Involvement in Connective Tissue Diseases
Systemic Lupus Erythematosus
Acute Lupus Pneumonitis
Diffuse Alveolar Hemorrhage
Lupus Pleuritis
Interstitial Lung Disease
Pulmonary Vascular Disease
Respiratory Muscle Dysfunction
Rheumatoid Arthritis
Pleuritis and Pleural Effusions
Rheumatoid Nodules
Airway Disease
Interstitial Lung Disease
Systemic Sclerosis (Scleroderma)
Interstitial Lung Disease
Pulmonary Vascular Disease
Sarcoidosis
Epidemiology
Pathogenesis
Clinical Manifestations
Histopathology
Diagnosis
Treatment and Outcome
Hypersensitivity Pneumonitis
Conclusions
References
73 Chronic Obstructive Pulmonary Disease and Emphysema
Chronic Obstructive Pulmonary Disease Definition and Epidemiology
Clinical Presentation of Chronic Obstructive Pulmonary Disease
Chronic Obstructive Pulmonary Disease Clinical Subphenotypes
Chronic Bronchitis
Emphysema
Chronic Bronchitis with Emphysema Features
Clinical Aspects and Diagnosis of Chronic Obstructive Pulmonary Disease
Obstructive and Emphysema Phenotypes
Asthma-Chronic Obstructive Pulmonary Disease Overlap
Early Chronic Obstructive Pulmonary Disease
Immunological Mechanisms of Chronic Obstructive Pulmonary Disease
Evidence for Autoimmunity in Emphysema
Evidence for Type 2 Inflammation in Asthma Chronic Obstructive Pulmonary Disease Overlap
Therapy
References
74 Immunologic Ocular Disease
The Ocular Immune System
Immune Privilege
Tolerance
Inflammatory Diseases of the Eye
Uveitis and Intraocular Immune-mediated Inflammation
Spondyloarthropathies
Juvenile Idiopathic Arthritis
Fuchs Heterochromic Iridocyclitis
Tubulointerstitial Nephritis and Uveitis
Sarcoidosis
Behçet Disease
Birdshot Chorioretinopathy
Vogt-Koyanagi-Harada
Sympathetic Ophthalmia
Uveitis Treatment
Neuro-Ophthalmic Immune-Mediated Diseases
Optic Neuritis
Giant Cell Arteritis
Miller Fisher Variant of Guillain-Barré Syndrome
Myasthenia Gravis
Paraneoplastic Syndromes
Lambert-Eaton Myasthenic Syndrome
Autoimmune Retinopathies
Extraocular Immune-mediated Inflammation
Ocular Allergy
Sjögren Syndrome
Episcleritis and Scleritis
Corneal Transplant and Transplant Rejection
Emerging Topics in Immunologic Ocular Diseases
Commensal Microbiota in Ocular Immunology
Cancer Immunotherapy-Associated Ocular Complications
Gene Therapy
Summary
References
75 Immunologic Diseases of the Gastrointestinal Tract
76 Inflammatory Hepatobiliary Diseases
Autoimmune Hepatitis
Definition
Epidemiology
Risk Factors and Pathophysiology
Clinical Presentation and Biochemical Features
Serum Autoantibodies
Histology
Diagnostic Criteria
Therapy
Primary Biliary Cholangitis
Definition
Nomenclature
Epidemiology
Pathogenesis
Diagnosis, Clinical Features, and Prognosis
Serum Autoantibodies
Histology
Therapy
Primary Sclerosing Cholangitis
Definition
Epidemiology
Pathogenesis
Clinical Features and Diagnosis
Therapy
Overlap/Variant Syndromes
Immunoglobulin 4-Related Sclerosing Cholangitis
References
77 Lymphoid Leukemias
Acute Lymphoblastic Leukemia
Epidemiology and Etiology
Immunologic and Molecular Classification of ALL
Immunologic Classification
B-Cell Precursor Leukemias
T-Cell ALL
Genetic and Molecular Classification
Numeric Chromosomal Aberrations
Structural Genetic Aberrations
Molecular Subtypes of Clinical Relevance
B-Lineage ALL
T-Lineage ALL
Clinical Features
Special Diagnostic Tests
Principles of Therapy1
Prognostic Factors
Where Immunology Meets Oncology—Minimal Residual Disease
Course and Prognosis
Treatment Sequelae
Where Immunology Meets Oncology—Immunotherapy of B-linage acute lymphoblastic leukemia (B-cell precursor ALL)
Inotuzumab Ozogamicin
Blinatumomab
Chimeric Antigen Receptor T Cells
Future Perspectives
Chronic Lymphocytic Leukemia
Epidemiology
Pathogenesis and the Biology of Leukemic Lymphocytes
Clinical Features of CLL
Treatment
Immunologic Aspects of CLL
The Pathophysiologic Rationale
Immunologic Deficiencies
Autoimmune Phenomena
Other Malignancies
Conclusions
References
78 Lymphomas
Mature B-Cell Neoplasms
Lymphoplasmacytic Lymphoma
Mantle Cell Lymphoma
Follicular Lymphoma
Mucosa-Associated Lymphoid Tissue Lymphoma
Nodal Marginal Zone Lymphoma
Splenic Marginal Zone Lymphoma
Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
Primary Mediastinal Large B-Cell Lymphoma
Virally Associated B-Cell Lymphoproliferative Disorders
Burkitt Lymphoma
High-Grade B-Cell Lymphoma With MYC and BCL2 and/or BCL6 Rearrangements
T-Cell and NK-Cell Neoplasms
Overview of the Classification of T-Cell Neoplasms
Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type
Nodal T-Cell Lymphoma With TFH Phenotype: Angioimmunoblastic T-Cell Lymphoma
Peripheral T-Cell Lymphoma, Not Otherwise Specified
Anaplastic Large-Cell Lymphoma
Primary Cutaneous Anaplastic Large-Cell Lymphoma
Subcutaneous Panniculitis-Like T-Cell Lymphoma
Primary Cutaneous γ/δ T-Cell Lymphoma
Mycosis Fungoides and Sézary Syndrome
Intestinal T-cell Lymphoma
Hepatosplenic T-Cell Lymphoma
Adult T-Cell Leukemia/Lymphoma
Classic Hodgkin Lymphoma
Hodgkin Lymphomas
Classic Hodgkin Lymphoma, Nodular Sclerosis
Classic Hodgkin Lymphoma, Mixed Cellularity
Classic Hodgkin Lymphoma, Lymphocyte Depletion
Classic Hodgkin Lymphoma, Lymphocyte-Rich
Nodular Lymphocyte-Predominant Hodgkin Lymphoma
References
79 Monoclonal Gammopathies
Diagnosing a Monoclonal Gammopathy
Monoclonal Gammopathy of Undetermined Significance
Epidemiology
Clinical Presentation and Diagnosis
Differential Diagnosis
Management and Prognosis
Smoldering Multiple Myeloma
Epidemiology
Clinical Presentation and Diagnosis
Differential Diagnosis
Management and Prognosis
Multiple Myeloma
Epidemiology
Clinical Presentation and Diagnosis
Differential Diagnosis
Management and Prognosis
Plasma Cell Leukemia
Epidemiology
Clinical Presentation and Diagnosis
Differential Diagnosis
Management and Prognosis
Plasmacytoma
Epidemiology
Clinical Presentation and Diagnosis
Differential Diagnosis
Management and Prognosis
Immunoglobulin Light-Chain Amyloidosis
Epidemiology
Clinical Presentation and Diagnosis
Differential Diagnosis
Management and Prognosis
WaldenstrÖm Macroglobulinemia and Smoldering WaldenstrÖm Macroglobulinemia
Epidemiology
Clinical Presentation and Diagnosis
Differential Diagnosis
Management and Prognosis
Monoclonal Gammopathy of Clinical Significance
Monoclonal Gammopathy of Renal Significance
Light-Chain Deposition Disease
Monoclonal Gammopathy of Neurologic Significance
POEMS Syndrome
Distal, Acquired Demyelinating, Symmetric Neuropathy With M Protein
Sporadic Late-Onset Nemaline Myopathy
Monoclonal Gammopathy of Dermatologic Significance
Schnitzler Syndrome
Scleromyxedema
Necrobiotic Xanthogranuloma
Cryoglobulinemia
TEMPI Syndrome
Idiopathic Systemic Capillary Leak Syndrome (Clarkson Disease)
References
80 Immune Responses to Solid Tumors and Immune Checkpoint Therapy
Immune Checkpoints
CTLA-4
Anti-Programmed Death-1/Programmed Death-L1
Anti-Programmed Death-1 in Melanoma
Anti-Programmed Death-1/Programmed Death-L1 in Lung Cancer
Anti-Programmed Death-1/Programmed Death-L1 in Renal Cell Carcinoma
Anti-Programmed Death-1/Programmed Death-L1 in Urothelial Carcinoma
Anti-Programmed Death-1/Programmed Death-L1 in Skin Cancers
Anti-PD-1/PD-L1 in GI Malignancies
Anti-Programmed Death-1/Programmed Death-L1 in Head and Neck Tumors
Anti-Programmed Death-1/Programmed Death-L1 in Lymphoma
Anti-Programmed Death-1/Programmed Death-L1 in Cervical Carcinoma
Immunotherapy Combinations
Immune-Immune Combinations
Immune Checkpoint/Cytokine Combinations
Immune Checkpoint/Intratumoral Injection Combinations
Immune Checkpoint/Chemotherapy Combinations
Immune Checkpoint/Targeted Therapy Combinations
Biomarkers of Response
Programmed Death-L1 as a Biomarker
Microsatellite-Instability as a Biomarker
Tumor Mutational Burden as a Biomarker
Other Biomarkers
Toxicities from Immune-Checkpoint Inhibitors
Colitis
Myocarditis
Pneumonitis
Hypophysitis
Specific Safety Considerations
References
81 CAR T-Cell Therapy
Car Structure
Car T-Cell Toxicity
Antigen Loss and Heterogeneity
Targeting Hematologic Malignancies
Solid Tumors and Their Immunosuppressive Microenvironment
Combating the Tme by Gene Modification of Car T Cells
The Differentiation State and Subset Origin of the Infused T Cells is Important
Intrapatient Comparative Studies Can Best Identify Optimal Car T Cells
Off-the-Shelf Car T Cells
Summary
References
82 Immunoglobulin Therapy: Replacement and Immunomodulation
Replacement Therapy With Intravenous Immunoglobulin
Adverse Events Associated With Intravenous Immunoglobulin Therapy
Rate-Related Adverse Events
Central Nervous System–Related Adverse Events
Renal Adverse Events
Thromboembolic Events
Transfusion Reaction Caused by Antibodies Against Immunoglobulin A
Hemolysis Caused by Isoagglutinins (Anti-A and Anti-B Antibodies) in the Immunoglobulin Products
Other Adverse Reactions
Summary: Immunoglobulin Replacement in Treatment of Immune Deficiency
Mechanisms of Action of Immunoglobulin Therapy in Autoimmune and Inflammatory Diseases
Blockade of Fc Receptors of the Reticuloendothelial System
Interactions of Idiotype and Anti-Idiotype as Immune Modulation
The Role of the FcRn Receptor on Immune Modulation
Modulation of Immunoregulatory Function Through the Fc Receptor
Neutralizing Antibody Activity in Intravenous Immunoglobulin Against Bacterial Toxins
Modulation of Adhesion Molecules on Endothelial Cells and Antibodies in Intravenous Immunoglobulin to Cell-Surface Receptor ...
Modulation of Complement Effector Function
Effects of Immunoglobulin on the Regulatory T-Cell Pathways
Effects of Intravenous Immunoglobulin on B Cells
Summary: Intravenous Immunoglobulin in Treatment of Autoimmune and Inflammatory Diseases
References
83 Glucocorticoids
Mechanisms of Action
Genomic Actions of Glucocorticoids
Structure of the Cytosolic Glucocorticoid Receptor
Translocation Into the Nucleus
Interactions With Transcription Factors
The Cytosolic Glucocorticoid Receptor β Isoform
Post-Transcriptional and Post-Translational Mechanisms
Glucocorticoid Receptor Resistance
Nongenomic Actions of Glucocorticoids
Cytosolic Glucocorticoid Receptor–Mediated Nongenomic Actions
Nonspecific Nongenomic Actions
Specific Nongenomic Actions
Glucocorticoid Effects on Immune Cells
The Role of Endogenous Glucocorticoids in Inflammatory Arthritis
Therapeutic Use
Terminology
Low Dose
Medium Dose
High Dose
Very High Dose
Pulse Therapy
Alternate-Day Regimens
Glucocorticoid Withdrawal Regimens
Glucocorticoid Treatment Regimens: General Aspects
Glucocorticoids in Rheumatoid Arthritis: An Example
Low-Dose Maintenance Therapy
Glucocorticoid Pulse Therapy
Intraarticular Glucocorticoid Injections
Adverse Effects
Osteoporosis
Osteonecrosis
Myopathy
Cardiovascular Adverse Effects
Dermatological Adverse Effects
Gastrointestinal Adverse Effects
Infectious Diseases
Other Adverse Effects
Timing of Glucocorticoid Administration Matters
New Glucocorticoid Receptor Ligands on the Horizon
Selective Glucocorticoid Receptor Agonists
Long-Circulating Liposomal Glucocorticoids
References
84 Immunomodulating Drugs
Methotrexate
Pharmacokinetics of Methotrexate
Mechanisms of Action for Methotrexate
Adverse Effects
Sulfasalazine
Mechanisms of Action for Sulfasalazine
Adverse Effects
Azathioprine
Proposed Mechanisms of Action for Azathioprine
Adverse Effects
Cyclophosphamide
Mechanisms of Action of Cyclophosphamide
Adverse Effects
Other Nitrogen Mustard Derivatives
Leflunomide
Mechanisms of Action of Leflunomide
Adverse Effects
Mycophenolate Mofetil
Adverse Effects
Hydroxyurea
Oral Cyclosporine and Tacrolimus (FK506)
Adverse Effects
Topical Pimecrolimus and Tacrolimus (FK506)
Adverse Effects
Sirolimus
Imiquimod
Adverse Effects
5-Fluorouracil
Adverse Effects
Glatiramer
Adverse Effects
Fingolimod (FTY720)
Adverse Effects
Conclusions
References
85 Protein Kinase Antagonists
Structure and Function of Protein Kinases
A Short History of the Generation of Kinase Inhibitors
Targeting Cytokine Signaling
Jakinibs and the Type I/II Cytokine Receptor Family
IL-1 Family Receptors and Toll-Like Receptors
Targeting Kinases Involved in TNFR Signaling
Targeting Antigen- and Related Receptor Signaling
Lipid Kinases and Downstream Signaling
MAP Kinase Pathways
Conclusions
References
86 Biologic Response Modifiers
Immunomodulatory Cytokines
IL-2 (rIL-2, Aldesleukin)
Interferons
Interferon-α
Interferon-β
Interferon-γ
Inhibitors of Inflammatory Cytokines
Tumor Necrosis Factor-α Inhibitors
IL-1β Inhibitors
IL-6 Inhibitors
On the Horizon
Other Anti-IL-6 and sgp130:Fc Reagents
IL-23 and IL-17 Inhibitors
On the Horizon
IL-17 Inhibitors
On the Horizon
Inhibitors of Interferons
Complement and Kinin Pathway Inhibitors
Adhesion Molecule Inhibitors
Inhibitors of B-Cell Activation
On the Horizon
Other Inhibitors of B-Cell Activation
Inhibitors of T-Cell Activation
On the Horizon
IL-13 Inhibitors
On the Horizon
Recombinant Promoters of Treg Function
Inhibitors of Mast Cell Activation
Inhibitors of Eosinophil Activation
B-Cell and T-Cell Depleting Agents
References
87 Vaccines
Introduction
History of Vaccination
Accomplishments of Vaccination
Recent Changes in Vaccine Development Strategies
Human Papillomavirus
Malaria
Dengue
Adjuvants
Systems Biology Approach to Vaccination
Recent Responses to Epidemics and Pandemics
Ebola
Zika Virus
SARS-CoV-2
Current Recommendations
Present and Future Challenges
A Vaccine for HIV.
Improved Influenza Vaccines
Selected Unmet Vaccine Needs
Reflections on the Future of Vaccinology
Acknowledgments
References
88 Allergen Immunotherapy for Allergic Diseases
Historical Perspective
Allergen Immunotherapy for Allergic Rhinoconjunctivitis and Asthma: Place in Therapy
Allergen Avoidance and Pharmacotherapy
Allergen Immunotherapy
Evidence for Efficacy of Allergen Immunotherapy
Allergic rhinoconjunctivitis.
Allergic Bronchial Asthma.
Long-Term Benefits of Allergen Immunotherapy
Persistence of Benefit
Prevention of Asthma
Subcutaneous versus Sublingual Immunotherapy
Safety
Hymenoptera Venom Immunotherapy
Allergen Immunotherapy for Foods
Mechanisms of Allergen Immunotherapy
Mechanisms of Allergic Rhinitis
Mechanisms of Allergen Immunotherapy
Summary
Biomarkers of Response to Immunotherapy
Novel Therapeutic Approaches
References
89 Solid Organ Transplantation: Rejection, Immunosuppression, and Tolerance
The Immune Response in Organ Transplantation
Innate Immunity and Ischemia Reperfusion Injury
Clinical Implications
Activation of the Adaptive Immune Response
Signal 1: Recognition of Alloantigen
Signal 2: Costimulation
Signal 3: T-Cell Proliferation and Differentiation
Acute T Cell–Mediated Rejection
Clinical Implications
Antibody-Mediated Rejection
Clinical Implications
Late Allograft Failure
Viral-Mediated Kidney Allograft Injury
Clinical Implications
Immunosuppressive Management
Signal 1: Blockade of Antigen Recognition
Rabbit Antithymocyte Globulin
Alemtuzumab (Campath-1H)
Anti-CD20 Monoclonal Antibody (Rituximab)
Signal 2: Costimulatory Blockade: CTLA4Ig and Anti-CD40L
Signal 3: Blockade of Proliferation and Differentiation
Anti-IL-2R (CD25) Monoclonal Antibody (Basiliximab)
Corticosteroids
Antiproliferative Agents
Calcineurin Inhibitors
Mammalian Target of Rapamycin Inhibitors
Desensitization and Antibody-Mediated Rejection Treatments
Tolerance
Clinical Protocols in Tolerance Induction
Molecule-Based Protocols
Full Chimerism
Mixed Chimerism
Regulatory T Cells
Biomarkers of Rejection or Tolerance
New Frontiers in Organ Supply For Transplantation: Xenotransplantation
References
90 Allogeneic Transplantation for Immunodeficiency
Hematopoietic Stem Cell Transplantation: General Considerations
Sources of Hematopoietic Stem Cells for Transplantation
Donor Selection and Manipulation of the Graft
Hematopoietic Stem Cell Transplantation From a Related Human Leukocyte Antigen–Identical Donor
Hematopoietic Stem Cell Transplantation From a Haploidentical Donor
Hematopoietic Stem Cell Transplantation From Matched Unrelated Donors
Hematopoietic Stem Cell Transplantation Using Unmanipulated Cord Blood
Principles of Conditioning and Effect on Hematopoietic and Immune Reconstitution
Complications of Hematopoietic Stem Cell Transplantation
Acute Graft-Versus-Host Disease
Chronic Graft-Versus-Host Disease
Prevention of GvHD
Treatment of Graft-Versus-Host Disease
Infections
Toxicity Related to Conditioning Regimen
Hematopoietic Stem Cell Transplantation forv Severe Combined Immunodeficiency
General Considerations
Survival Following Hematopoietic Stem Cell Transplantation for Severe Combined Immunodeficiency
Quality and Kinetics of T-Cell Immune Reconstitution
Reconstitution of B- and NK-Cell Immunity
Complications Following Hematopoietic Stem Cell Transplantation for Severe Combined Immunodeficiency
Hematopoietic Stem Cell Transplantation for Combined Immunodeficiencies Other Than Severe Combined Immunodeficiency
Wiskott-Aldrich Syndrome
Disorders Associated With Hemophagocytic Lymphohistiocytosis
Phagocytic Cell Disorders
Regulatory T-Cell Defects
Interferon-γ Pathway Disorders
Future Directions for Hematopoietic Stem Cell Transplantation in the Treatment of Primary Immune Deficiency
References
91 Gene Therapy for Primary Immune Deficiency Diseases
Gene Transfer to Hematopoietic Stem Cells
Clinical Trials of Gene Therapy for Primary Immune Deficiencies
The Role of Cytoreductive Conditioning to Facilitate Engraftment
Adenosine Deaminase-Deficient Severe Combined Immune Deficiency (Chapter 34)
X-linked Severe Combined Immune Deficiency (Chapter 34)
Chronic Granulomatous Disease (Chapter 39)
Wiskott-Aldrich Syndrome (Chapter 34)
Leukocyte Adhesion Defect-1 (Chapter 39)
Gene Therapy Considerations for other Primary Immune Deficiencies
Gene Editing for Gene Therapy of Primary Immune Deficiencies
Use of Pluripotent Stem Cells as a Source of Hematopoietic Stem Cells for Gene Therapy of Primary Immune Deficiencies
Gene Therapy for Primary Immune Deficiencies Involving Serum Protein Deficiencies
Advancing Gene Therapy for Primary Immune Deficiencies From Experimental to Standard of Care
Conclusion
References
92 Hematopoietic Stem Cell Transplantation for Malignant Diseases
Immune Mechanisms Related to Allo-Hematopoietic Stem Cell Transplantation
Histocompatibility
Graft-versus-Host Disease
Clinical Aspects of Acute Graft-versus-Host Disease
Autologous Graft-versus-Host Disease
Clinical Aspects of Chronic Graft-versus-Host Disease
Graft-versus-Tumor Responses
Adjuvant Therapy With Hematopoietic Stem Cell Transplantation
Clinical Hematopoietic Stem Cell Transplantation
Sources of Hematopoietic Stem Cells
Hematological Recovery
Conditioning Regimens
Dose-Intensive and Reduced-Intensity Chemotherapy
Hematopoietic Stem Cell Transplantation for Individual Diseases
Acute Myelogenous Leukemia
Myelodysplastic Syndromes
Chronic Myelogenous Leukemia
Myeloproliferative Diseases
Acute Lymphoblastic Leukemia
Chronic Lymphocytic Leukemia
Multiple Myeloma
Non-Hodgkin Lymphoma
Low-Grade Non-Hodgkin Lymphoma
Aggressive Non-Hodgkin Lymphoma
Hodgkin Lymphoma
Solid Tumors
Future Directions
References
93 Flow Cytometry
Instrumentation
Fluorescence Reagents
Data Analysis
Gating
Data Display
Positive–Negative Discrimination
Compensation
Quality Control
Methods
Practical Applications of Flow Cytometry
Immunophenotyping Studies
Intracellular Evaluation
Cellular Activation
Intracellular Cytokine Detection
Cell Cycle Analysis
Apoptosis Detection
Peptide–Major Histocompatibility Complex Multimers
Conclusion
Acknowledgment
References
94 Assessment of Functional Immune Responses in Lymphocytes
T-Cell Response
Measurement of T-Cell Function Via Activation Markers
Assessment of Cellular Viability In Lymphocytes
Measurement of T-Cell Competence Via Proliferation
Measurement of Cell-Mediated Cytotoxicity
Assessing Function of Exhausted T Cells
T-Cell ELISPOT for Measuring T-Cell Function Through Cytokine Production
Natural Killer Cell Activation and Function
Natural Killer Cell Cytotoxicity
Evaluation of Regulatory T-Cell Function
Assessment of Signaling and Dna Repair Pathways In Lymphocytes Via Phosphoflow Cytometry
Assessment of B-Cell Function
Summary
References
95 Assessment of Neutrophil Function
Isolation of Neutrophils
Clinical Indications and Implications
Principles and Interpretation of Laboratory Assessment
Histochemical Analysis of Neutrophils
Clinical Indications and Implications
Principle and Interpretation of Laboratory Assessment
Analysis of Granule Constituents
Clinical Indications and Implications
Principles and Interpretation of Laboratory Assessment
Neutrophil Adherence
Clinical Indications and Implications
Principles and Interpretation of Laboratory Assessment
Neutrophil Chemotaxis
Clinical Indications and Implications
Principles and Interpretation of Laboratory Assessment
Expression of Surface Antigens
Clinical Indications and Implications
Principles and Interpretation of Laboratory Assessment
Neutrophil Degranulation
Clinical Indications and Implications
Principles and Interpretation of Laboratory Assessment
Generation of Reactive Oxygen Species
Clinical Indications and Implications
Principles and Interpretation of Laboratory Assessments
Western Blot Analysis of Nadph Oxidase Protein Subunits
Clinical Indications and Implications
Principles and Interpretation of Laboratory Assessments
Conclusions
Acknowledgment
References
96 Assessment of Human Allergic Diseases
Biological Properties of Immunoglobulin E
Clinical Importance of Total Serum Immunoglobulin E
Clinical Importance of Allergen-Specific Immunoglobulin E
Clinical History
Diagnostic Methods
Initial Clinical Laboratory Tests
In Vivo Provocation Testing
Skin Tests
Variables that Influence Skin Test Responses
Relationship Between Puncture and Intradermal Skin Test Responses
Conjunctival, Bronchial, and Nasal Provocation Tests
Oral Food Challenge Tests
In Vitro Testing
Total Serum Immunoglobulin E
Total Immunoglobulin E Measurements After Therapeutic Anti– Immunoglobulin E Administration
Allergen-Specific Immunoglobulin E
Allergen
Calibration
Single-Plex, Multiallergen, and Multiplex Assays
Allergen-Specific Immunoglobulin G
Mast-Cell Tryptase
References
Appendix 1 Selected CD Molecules and Their Characteristics
Appendix 2 Laboratory Reference Values