Clinical Immunology: Principles and Practice

Cover
Clinical Immunology
Copyright Page
Preface to the First Edition
Preface to the Fifth Edition
List of Contributors
Dedication
Part One: Principles of Immune Response
Chapter 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 Immunological 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 Immunological Diseases
Host Immune Defenses Summarized
Multiple-Choice Questions
References
Chapter 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
Polymorphonuclear Granulocytes
Neutrophils
Eosinophils
Basophils and Mast Cells
Platelets and Erythrocytes
Lymphocytes
T Lymphocytes
Subpopulations of T Cells
B Cells and Plasma Cells
Innate Lymphoid Cells
Natural Killer Cells
Noncytotoxic Innate Immune Cells
Major Lymphoid Organs
Bone Marrow
Thymus
Development of Hematopoietic and Lymphoid Cells
Secondary Lymphoid Organs
Systemic Immune System
Spleen
Lymph Nodes and Lymphatics
Adipose Tissue
Mucosal Immune System
Gastrointestinal Tract
Respiratory Tract
Genital Tract
Skin
Commensal Organisms/Toll-Like Receptors
Acknowledgments
References
Multiple-Choice Questions
Chapter 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
Intraepithelial Lymphocytes, Innate Lymphoid Cells, B1 and MZ B Cells, and Mast Cells
Activating Innate Immunity
Pattern Recognition Receptors
Toll-Like Receptors
NOD-Like Receptors
RIG-I–Like Receptors
C-Type Lectin Receptors
Scavenger Receptors
Inflammasomes
Innate Immunity in Clinical Practice
Multiple-Choice Questions
References
Chapter 4: Antigen Receptor Genes, Gene Products, and Coreceptors
Paratopes and Epitopes
The BCR and TCR Antigen Recognition Complex
Immunoglobulins and TCR Structures
The Ig Domain, the Basic IgSF Building Block
Idiotypes and Isotypes
The V Domain
Antigen Recognition and Fab
Effector Function and Fc
Gm Allotype System
Ig Classes and Subclasses
IgM
IgG
IgA
IgE
IgD
TCR αβ and γδ
TCR αβ
TCR γδ
Ligand Recognition
Binding to pMHC
TCR 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 TCR αδ Chain Locus
The TCR β Chain Locus
The TCR γ Chain Locus
Allelic Exclusion
B Cell Receptor Complex: Structure and Function
Membrane-Bound Immunoglobulin
Signal Transduction and the Ig-α/β (CD79a/CD79b) Heterodimer
Clinical Consequences of Disruptions in BCR Signaling
BCR Coreceptors
Coreceptors That Positively Regulate BCR Signaling
CD21
CD19
CD21–CD19 Coreceptor Complex
Coreceptors That Negatively Regulate BCR Signaling
FcγRIIB
CD22
The TCR–CD3 Complex
CD3 Proteins
Stoichiometry of the TCR–CD3 Complex
Assembly and Cell-Surface Expression of the TCR–CD3 Complex
Early Events in TCR–CD3 Signaling
T-Cell Coreceptors: CD4 and CD8
CD4: Structure and Binding to MHC Class II Molecules
CD8: Structure and Binding to MHC Class I Molecules
Costimulatory and Inhibitory T-Cell Molecules: the CD28 Family
CD28 and CTLA-4
PD-1
Multiple-Choice Questions
References
Chapter 5: The Major Histocompatibility Complex
Genomic Organization of the MHC
Structure and Function of the HLA Molecules
Classic HLA Class I Molecules
MICA and MICB
Nonclassic HLA-E, HLA-F, and HLA-G
Classic Class II HLA Molecules
Nonclassic HLA-DM and HLA-DO
Proteosome 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
Hlas in Infections, Transplantation, Autoimmunity, and Cancer
HLA in Infections
HLA in Transplantation
HLA in Autoimmunity
HLA in Cancer
HLA 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 HLA Polymorphisms: HLA Typing
DNA-Based Typing Techniques: SSO, SSP, and SBT
Next-Generation Sequencing
HLA Nomenclature
Future Learning and Resources
Multiple-Choice Questions
References
Chapter 6: Overview of T-Cell Recognition
Antigens
Antibodies and T-Cell Receptors Recognize Antigens
Innate Receptors Recognize Pathogen-Associated Molecular Patterns or Danger Signal Ligands
The Nature of Antigen Recognition by Immunoglobulin and T-Cell Receptor Differs
Antigens for B Cells
Coupling of B-Cell and T-Cell Epitopes Permits Highly Focused Adaptive Responses
Superantigens
Antigen-Presenting Cells
Cells That Present Antigens to B Cells: Follicular Dendritic Cells
Cells That Present Antigens to T Cells
MHC-Restricted Recognition of Antigen
Class I MHC
Class II MHC
MHC Class II Antigen Presentation
Invariant Chain
Class II Peptide Loading
HLA-DM and Peptide Exchange
Selection of Immunodominant Peptides
HLA-DO
Targeting of Antigen into the MHC Class II Processing Pathway
MHC Class I–Restricted Antigen Presentation
The Proteasome
Import of Antigenic Peptides Into the Endoplasmic Reticulum and Final Trimming
The Peptide Loading Complex
Cross-Presentation of Antigens for Recognition by CD8 T Cells
The MHC-Presented Peptidome
Cryptic Viral or Tumor-Associated Peptides Presented by MHC Class I Molecules
Pathogen Evasion Strategies
Tumor Escape From Immune Surveillance
Potential Role of “Peptide Editing” of Presented Peptides on Self Tolerance and Autoimmunity
Summary
Acknowledgement
Multiple-Choice Questions
References
Chapter 7: B-Cell Development and Differentiation
B-Cell Development Begins in the Primary Lymphoid Organs
Generation 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 Controlling B-Cell Differentiation
MicroRNAs and B-Cell Development
Modulation of B-Cell Development by Chemokines, Cytokines, and Hormones
B-Cell Development in the Periphery
BAFF and APRIL Can Play Key Roles in the Development of Mature B Cells
B Cells and the Response to Antigen
T Cell–Independent Antigens
T Cell–Dependent Antigens
Organization of Peripheral Lymphoid Tissues
The Spleen
B-1 Cells
Germinal Centers
B-Cell Functions in Addition to Antibody Production
Molecular Mechanism of Somatic Hypermutation and Class-Switch Recombination
Somatic Hypermutation
Class-Switch Recombination
Both SHM and CSR Require Activation-Induced Cytidine Deaminase
B-Cell Memory
Memory B Cells
Plasma Cells
Ectopic Lymphoid Tissue and B-Cell Development
Multiple-Choice Questions
References
Chapter 8: T-Cell Development
Thymus: the Site of T-Cell Development
Lineage Commitment
The Common Lymphoid Progenitor
The Early Thymic Progenitor
Double-Negative Thymocytes
Fate Commitment
Transcriptional Regulation of Commitment to T-Cell Lineage
Notch
Notch Ligand
T-Cell Factor 7
Enhancer Binding Protein GATA-3
B-Cell Chronic Lymphocytic Lymphoma/ Lymphoma 11B (Bcl11b)
T-Cell Receptor Rearrangement and β Selection
γδ T cells
αβ T cells
β Selection and the Appearance of Double-Positive Thymocytes
Positive and Negative Selection
Positive Selection
Negative Selection
Role of the Major Histocompatibility Complex in Negative Selection and Positive Selection
CD4 and CD8 T-Cell Determination
Transition From Double-Positive to Single-Positive CD4 or CD8 Thymocytes
Factors That Dictate CD4 Versus CD8 Commitment
Migration of Thymocytes Into the Periphery
Multiple-Choice Questions
References
Chapter 9: 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–colony-stimulating factor.
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.
Interleukin-35.
Interleukin-13.
Interleukin-31.
Thymic stromal lymphopoietin.
Interferons
Type I Interferons
Interferon-α/β.
Interferon-γ.
Interleukin-10 and related cytokines.
Signaling
Janus Kinases
Signal Transducer and Activator of Transcription (STAT)
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 and Its Receptor Fas/APO-1/CD95
CD40 Ligand and CD40
Other TNF-Family Cytokines
Signaling
Death Domains: TNF Receptor-Associated Death Domain and FAS-Associated Death Domain
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
Stem Cell Factor
Colony-Stimulating Factor 1
Signaling
Transforming Growth Factor-β Ligand and Receptor Families
Ligand and Receptor Structure
TGF-β Family Members and Their Actions
Signaling
SMADs
R-SMADs.
C-SMADs.
I-SMADs.
SMAD pathways.
Other TGF-β–Activated Pathways
Clinical Relevance
Other Cytokines
Interleukin-14
Interleukin-16
Interleukin-32
Therapeutic Targeting of Cytokines and Cytokine Receptors
Conclusions and Summary
Multiple-Choice Questions
References
Chapter 10: Chemokines and Chemokine Receptors
Introduction
Molecular Organization of the Chemokine System
Chemokine Receptors
Atypical Chemokine System Components
Immunological Classification
Chemokine Presentation Mechanisms
Leukocyte Responses to Chemokines
Chemokine Signaling Pathways
Regulation of Chemokine Action
Chemokine Regulation of Hematopoiesis
Bone Marrow
Thymus
Tissue
Chemokine Regulation of the Immune Response
Innate Immunity
Platelet-Derived Chemokines
CXCL8 and CXCR2
Natural Killer 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
Chemokines and Disease
Opposite Effects of CCR5 in HIV and West Nile Virus Infection
Malaria
WHIM Syndrome
Atherosclerosis
Kaposi’s Sarcoma
Autoimmunity
Acute Neutrophil-Mediated Inflammatory Disorders
Transplant Rejection
Allergic Airway and Intestinal Disease
Cancer
Therapeutic Applications
Chemokines and Chemokine Receptors as Targets for Drug Development
Chemokines as Biological Response Modifiers
Conclusion
Acknowledgments
Multiple-Choice Questions
References
Chapter 11: 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
LAD I
LAD II
LAD III
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
Multiple-Choice Questions
References
Chapter 12: T-Cell Activation and Tolerance
The T-Cell Antigen Receptor Complex
Activation of Protein Tyrosine Kinases by the TCR and the Role of the ITAMs
Second Messenger Cascades Downstream of the TCR-Stimulated PTKs
Integration of Second-Messenger Pathways by Adaptor Proteins
Coreceptors Transduce Signals That Are Integrated With TCR Signals
Counterbalanced Costimulatory and Coinhibitory Signals Determine T-Cell Response Thresholds
Spatial and Temporal Distribution of TCR Signaling Proteins
Tolerance
Central Tolerance/Clonal Deletion
Peripheral Mechanisms of Tolerance
Immune Privilege
T-Cell Anergy
Regulation
Summary and Future Directions
Multiple-Choice Questions
References
Chapter 13: Regulated Necrosis and Its 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
Caspase-Dependent Cell Death
Apoptosis
Pyroptosis
Caspase-Independent Regulated Necrosis
Necroptosis
Ferroptosis
Mitochondrial Necrosis
MPT-RN
Parthanatos
Concluding Remarks and Implications for Solid-Organ Transplantations
Acknowledgements
Multiple-Choice Questions
References
Chapter 14: The Microbiota in Immunity and Inflammation
Overview of Our Nonmammalian “Self”
Prokaryotes
Viruses
Fungi
Immune Preparations for Microbial Colonization
Prenatal Development of the Immune System
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 B Cells
Immune Consequences of Early Microbial Manipulation
Immune System—Microbiota Cross-Talk 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
Multiple-Choice Questions
References
Part Two: Host Defense Mechanisms and Inflammation
Chapter 15: 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
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
Multiple-Choice Questions
References
Chapter 16: 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 (Tfh)
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
Multiple-Choice Questions
References
Chapter 17: Cytotoxic T Lymphocytes and Natural Killer Cells
Effector Functions/Mechanisms
Cytotoxicity
Perforin–Granzyme Pathway
Death Receptor–Induced Apoptosis
Cytokines
Cytotoxic T Cells
The Development and Tissue Distribution of CTLs
The CTL Response
Initial Activation
Cross-Presentation and Priming
The Contraction of Effector Populations
The Long-Term Maintenance of Memory Cells
CD4 T-Cell Help
Detection and Analysis of CTL Function
Natural Killer Cells
Properties of NK Cells
Tissue Distribution and Diversity of NK Cells
Cytokine Regulation of NK-Cell Activation, Function, and Homeostasis
NK-Cell Receptors
NK-Cell Receptor Signaling
NK Receptors That Recognize MHC-I Molecules
Killer Cell Immunoglobulin-Like Receptors in Humans
The Ly49 Family in Rodents
CD94 and NKG2 Family
NKG2D
NK Cell Receptors That Recognize Non-MHC I Molecules
NK-Cell Licensing and Self-Tolerance
Specific NK-Cell Functions
Control of Viral Infections
Control of Malignant Cells
Role of NK Cells in Hematopoietic Stem Cell Transplantation
NK-Cell Memory
Interactions of CTL and NK Cells in the Immune Response
Evasion of the Cytotoxic Response
Viruses
Tumor Cells
Multiple-Choice Questions
References
Chapter 18: Regulatory Immune Cells
CD4 Regulatory T Cells
Thymus-Derived Regulatory T Cells
Thymus-Derived Tregs Express the Transcription Factor Foxp3
Maintenance of Foxp3+ Tregs
Suppressive Function of Foxp3+ Tregs
Tr1 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
Multiple-Choice Questions
References
Chapter 19: Host Defenses in Skin
Innate Immunity and Skin
Pattern Recognition Receptors
Cutaneous Production of Cytokines and Chemokines
Types of Cytokines and Chemokines
Phases of Active Cutaneous Cytokine Secretion
Initiation.
Amplification.
Resolution.
Antimicrobial Peptides
Adaptive Immunity and Skin
Dendritic Cells
Epidermal Langerhans Cells
Dermal Dendritic Cells
T Cells and Immune Responses in Skin
Phases of the Cell-Mediated Immune Response in Skin
Sensitization/immunization phase.
Elicitation/effector phase.
Skin Resident T-Cell Subpopulations
Th1 responses.
Th2 responses.
Th17 responses.
Regulatory T cells.
CD8 T-cell immunity.
γδ T cells.
Cytokines and Chemokines and the Adaptive Immune Response in Skin
Mast Cells and Skin
Antibodies and Skin
Ultraviolet Radiation and Cutaneous Immunity
Multiple-Choice Questions
References
Chapter 20: Host Defenses at Mucosal Surfaces
The Innate Mucosal Defense System
Epithelial Cells and Other Effectors of the Mucosal Physical Barrier
Defensins and Other Mucosal Antimicrobial Peptides
Mucosal Innate Lymphoid Cells
A Common Mucosal Adaptive Immune System
MALT as an Inductive Site
Gut-Associated Lymphoreticular Tissues
Nasal-Associated Lymphoid Tissues
Other Sites for Mucosal Induction of an Immune Response
Lymphocyte Homing Into Mucosal Compartments
Lymphocyte Homing in the GI Tract
Lymphocyte Homing in NALTs 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 IgA 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
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
Polymeric Immunoglobulin Receptor and plgA Transport
IgA-Mediated Inhibition of Microbial Adherence
Neutralization by sIgA of Viruses, Enzymes, and Toxins
Antiinflammatory Actions Mediated by SIgA Antibodies
IgA Deficiency
Mucosal CTLs
Enteric Viruses and Mucosal CTLs
Respiratory Viruses and Mucosal CTLs
Mucosal AIDS Models for CTL Responses
Other Mucosal CTL Systems
Mucosal Immune Responses in Early Life and Aging
Multiple-Choice Questions
Correct Order:
References
Chapter 21: The Human Complement System:
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 MAC Inhibitors: Vitronectin and Clusterin
Membrane MAC 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 Activation
Role of Complement in Clearance of Apoptotic Cells
Targeted Activation of Complement for Opsonization
Complement Deficiencies
Genetics and Incidence
CP Deficiencies
C1 Deficiency
C4 Deficiency
C2 Deficiency
LP Deficiencies
AP Deficiencies
C3 Deficiencies
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: DAF 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 51)
Antiphospholipid Syndrome (Chapter 61)
Rheumatoid Arthritis (Chapter 52)
Vasculitis (Chapters 58, 59)
Immunological Renal Diseases (Chapter 68)
Asthma (Chapter 41)
Neurological Disease
Ischemia/Reperfusion Injury
Complement-Based Therapeutics
Multiple-Choice Questions
References/Bibliography
Chapter 22: Phagocyte Deficiencies
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’s 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 Determination of NADPH Oxidase Defect
Translational Research
Acknowledgment
Multiple-Choice Questions
References
Chapter 23: Mast Cells, Basophils, and Mastocytosis
Development and Distribution of Mast Cells
Mast Cell Development and Survival
Homing, Distribution, and Heterogeneity of Mast Cells
Development and Distribution of Basophils
Biological Mediators Produced by Mast Cells and Basophils
Preformed Mediators
Newly Synthesized Mediators
Cytokines, Chemokines, and Growth Factors
Mechanisms of Activation of Mast Cells and Basophils
FcεRI-Mediated Activation (and Inhibition of IgE-Dependent Activation)
Non–IgE-Mediated Activation
Mast Cells and Basophils in Disease and Host Defense
Allergic Disease
Anaphylaxis
Asthma
Allergic Rhinitis
Atopic Dermatitis
Mast Cells and Basophils in Immunity
Mast Cells in Other Diseases
Mast Cell Roles in Normal Physiology
Mastocytosis and Other Mast Cell Disorders
Epidemiology
Pathogenesis
Clinical Features
Classification
Diagnosis
Treatment
Prognosis
Summary and Future Research Directions
Multiple-Choice Questions
References
Chapter 24: Eosinophils and Eosinophilia
Production and Distribution of Eosinophils
Eosinophilopoiesis
Eosinophil Adherence Mechanisms
Eosinophil Chemoattractants
Structure of Eosinophils
Cell-Surface Receptors and Proteins
Constituents of Eosinophils
Cationic Granule Proteins
Cytokines and Chemokines
Activated Eosinophils
Mechanisms of Eosinophil Degranulation
Functions of Eosinophils
Roles in Host Defense
Roles in Disease Pathogenesis
Other Eosinophil Functions
Eosinophilia and Eosinophilic Disorders
Infectious Diseases Associated With Eosinophilia
Helminth Parasites
Other Infections: Protozoa and Fungi
Human Immunodeficiency Virus and Retroviral Infections
Allergic Diseases Associated With Eosinophilia
Myeloproliferative and Neoplastic Disease
Hypereosinophilic Syndromes
Eosinophilia With Tumors or Leukemias
Organ System Involvement and Eosinophilia
Pulmonary Eosinophilias
Skin and Subcutaneous Diseases
Gastrointestinal Diseases
Rheumatological Disorders
Immunological Disorders
Endocrine Diseases
Other Causes of Eosinophilia
Evaluation of Eosinophilia
Multiple-Choice Questions
References
Part Three: Host Defenses to Infectious Agents
Chapter 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
Multiple-Choice Questions
References
Chapter 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 (Table 26.1)
Granulomatous Infections
Tuberculosis
Leprosy
Atypical Mycobacterial Infections
Typhoid or Enteric Fever
Gastroenteritis
Listeriosis
Brucellosis
Lymphogranuloma Venereum
Melioidosis
Tularemia
Nongranulomatous Infections
Legionnaires’ Disease or Legionellosis
Chlamydial Urethritis, Cervicitis, and Conjunctivitis
Trachoma
Chlamydia Pneumoniae
Typhus
Rocky Mountain Spotted Fever, Ehrlichiosis
Bartonella
Granuloma Pathology as Hallmark of Intracellular Bacterial Infection
The Interdependence of Innate and Adaptive Immunity in Protection Against Intracellular Bacteria
Innate Immune Mechanisms as First-Line Defense
Macrophage Training by Epigenetic Mechanisms
Cytokines as Mediators of Defense Against Intracellular Bacteria
IFN-γ, TNF-α, 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
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
Concluding Remarks
Acknowledgments
Multiple-Choice Questions
References
Chapter 27: Host Defenses to Extracellular Bacteria
Clearance and Nonspecific Host Defenses at Mucosal Epithelial Surfaces
Normal Microbiota as Host Defense
Antimicrobial Peptides and Antimicrobial Proteins
Recognition of Extracellular Bacteria and Activation of the Immune System
Pattern Recognition Receptors
Complement
Dendritic Cells
Macrophages
Polymorphonuclear Leukocytes
Innate Lymphoid Cells
Lymphocytes
Immunoglobulins
Mechanism of Immune Evasion and Disease by Extracellular Bacteria
Host Risk Factors for Local and Systemic Invasion by Extracellular Pathogens
Deleterious Host Responses
Inflammation and Autoimmunity
Sepsis
Enhancement of Immune Responses to Extracellular Bacteria (Vaccines and Immunomodulation)
Translational Research Opportunities
Multiple-Choice Questions
References
Chapter 28: Host Defenses to Spirochetes
Clinical Manifestations
Lyme Disease
Diagnosis
Treatment
Venereal Syphilis
Diagnosis
Treatment
Host Defenses to B. burgdorferi
Innate Immune Responses
Early Pathogen Recognition
Phagocytic Cell Recruitment and Spirochetal Clearance
Complement
Adaptive Immune Responses
T Cell–Mediated Responses
B Cell–Mediated Responses
Host Defenses to T. pallidum
Innate Immune Responses
Early Pathogen Recognition
Phagocytic Cell Recruitment and Spirochetal Clearance
Complement
Adaptive Immune Responses
T Cell–Mediated Responses
B Cell–Mediated Responses
Translational Research
Conclusions
Multiple-Choice Questions
References
Chapter 29: Host Defenses to Fungal Pathogens
Clinically Relevant Fungal Organisms
Aspergillus fumigatus
Candida albicans
Cryptococcus neoformans
Host Defense Against Fungi by Epithelial Cells
The Fungal Cell Wall
The Innate Immune Response to Fungal Pathogens
Role of Neutrophils
Role of Macrophages
Role of Dendritic Cells
Pattern Recognition Receptors
Toll-Like Receptor
C-Type Lectin Receptor
Collaboration Between TLRs and CLRs
CARD9
The Inflammasome
Memory of Innate Immune Cells
Linking the Innate Immune Response to Adaptive Immune Response
The Adaptive Immune Response to Fungal Pathogens
CD4 T Cells
Th1 Cells
Th2 Cells
Th17 Cells
CD8 T Cells
B Cells
Natural Killer Cells
Genetic Susceptibilities to Invasive Fungal Infections
Summary
Multiple-Choice Questions
References
Chapter 30: Host Defenses to Protozoa
Plasmodium spp.
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
Toxoplasma gondii
Pathogenesis
Innate Immunity
Adaptive Immunity
Evasion of Host Immunity
Entamoeba histolytica
Pathogenesis
Innate Immunity
Adaptive Immunity
Evasion of Host Immunity
Giardia lamblia
Pathogenesis
Innate Immunity
Adaptive Immunity
Evasion of Host Immunity
Cryptosporidium parvum and Cryptosporidium hominis
Pathogenesis
Innate Immunity
Adaptive Immunity
Evasion of Host Immunity
Trichomonas vaginalis
Pathogenesis
Innate Immunity
Adaptive Immunity
Evasion of Host Immunity
Multiple-Choice Questions
References
Chapter 31: Immune Responses 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 Apc 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
Multiple-Choice Questions
References
Part Four: Immunological Deficiencies
Chapter 32: Approach to the Evaluation of the Patient With Suspected Immunodeficiency
Epidemiology—Primary Immunodeficiencies Are Not Uncommon
Primary Versus Secondary Immunodeficiency
Evaluating Patients for Immunodeficiency
Exploring the Medical History
Age and Environment
Immunization and Previous Infections
Comorbid Conditions
Use of Medications
Family and Social Histories
Physical Examination Findings
Laboratory Testing for Immune Function
Immunology Testing
Serum Immunoglobulin Levels
B-Cell Function: Specific Antibody Production
Evaluation of Cellular Immunity
Lymphocyte subset enumeration.
B-cell panels and NK-cell panels.
Lymphocyte functional analysis.
Phagocytes
Complement
Innate Immunity: Interferon-γ Levels, Toll-Like Receptor Assay
Molecular Testing for Primary Immune Defects
Conclusions
Illustrative Cases
Case 1
Case 2
Case 3
Case 4
Multiple-Choice Questions
References
Chapter 33: Human Genomics in Immunology
Genome Annotation
Human Variation
Clinical Impact of Human Variation
Comparative Genomics
Functional Genomics
Applying Human Genomics to Understanding Disorders of the Human Immune System
Multiple-Choice Questions
References
Chapter 34: 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 Pre–B-Cell Receptor and Signal Transduction Axis
TCF3
LRRC8
PIK3R1
Diagnosis and Treatment
Hyper-IgM Syndrome
Diagnosis
HIGM Syndrome Type 1: CD40L (CD154) Deficiency
HIGM Syndrome Type 2: AID Dysfunction
HIGM Syndrome Type 3: CD40 Deficiency
HIGM Syndrome Type 4: As yet Unknown Causes
HIGM Syndrome Type 5: UNG Deficiency
NEMO
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 IgA Deficiency
Diagnosis
Clinical Manifestations
Origin and Pathogenesis
Treatment and Prognosis
Common Variable Immunodeficiency and CVID-Like Disorders
Diagnosis
Clinical Manifestations
Origin and Pathogenesis
The Major Histocompatibility Complex
The CD19 (CVID3), CD81 (CVID6), CD21 (CVID7) B-Cell Coreceptor Complex
The BAFF–BAFFR (CVID4)–TACI (CVID2) Axis
CD20 (CVID5)
ICOS (CVID1)
The LRBA (Cvid8)–CTLA-4 Axis
PKCδ Deficiency
TWEAK Deficiency
NF-κB1 (CVID12) and NF-κB2 (CVID10) Deficiency
PI3K Mutations
Other Genes: BLK, IRF2BP2, IKAROS
Kabuki Syndrome
Treatment and Prognosis
Selective IgG 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
Multiple-Choice Questions
References
Chapter 35: Primary T-Cell Immunodeficiencies
T-Cell Immunodeficiencies
Severe Combined Immunodeficiency
Combined Immunodeficiency
Omenn Syndrome
Severe Combined Immune Deficiency
SCID With T-Cell Lymphopenia (T−B+)
γc (IL-2Rγ) Deficiency
JAK3 Deficiency
IL-7Rα Deficiency
CD45 Deficiency
CD3–TCR Complex Defects
SCID With T-Cell Lymphopenia and Syndromic Features
Coronin-1A Deficiency
FOXN1 Deficiency (Combined Immunodeficiency With Alopecia Totalis)
SCID With T-Cell and B-Cell Lymphopenia (T−B−)
RAG1/2 Deficiency
Artemis Deficiency
SCID With T-Cell and B-Cell Lymphopenia (T−B−) and Syndromic Features
DNA-PKcs Deficiency
DNA Ligase IV Deficiency
Cernunnos Deficiency
AK2 Deficiency (Reticular Dysgenesis)
Adenosine Deaminase Deficiency
Combined Immunodeficiency (SCID Phenotype)
ZAP-70 Deficiency
MHC Class II Deficiency (Bare Lymphocyte Syndrome)
MHC Class I Deficiency
DOCK2 Deficiency
CD3γ Deficiency
CARD11/BCL10/MALT1 (CBM) Complex Deficiencies
Combined Immunodeficiency (SCID Phenotype) and Syndromic Features
TTC7A Deficiency (MIA Syndrome)
Calcium Channel Defects (ORAI-1, STIM-1 Deficiencies)
Combined Immunodeficiencies With Variable Severity (Non-SCID)
Combined Immunodeficiency With Immune Dysregulation
IL-2Rα (CD25) Deficiency
FOXP3 Deficiency
IL-10 and IL-10Rα and IL-10Rβ Deficiencies
IKK2 Deficiency
DOCK8 Deficiency
RHOH Deficiency
Combined Immunodeficiency With EBV-Induced Lymphoproliferation
Combined Immunodeficiency With Immune Dysregulation and Syndromic Features
PNP Deficiency
DiGeorge Syndrome
Wiskott-Aldrich Syndrome
Ataxia Telangiectasia (Louis-Bar Syndrome)
Combined Immunodeficiency With Immunoosseous Dysplasia
Cartilage Hair Hypoplasia
Schimke Immunoosseous Dysplasia
Roifman Syndrome
SPENCDI–Roifman Immunoskeletal Syndrome
Combined Immunodeficiency With Bone Marrow Failure
IKAROS Deficiency
Dyskeratosis Congenita
Moesin Deficiency (MSN Deficiency)
Progressive T-Cell or Combined Immunodeficiency
STAT1 Dysfunction
RelB Deficiency
STK4 (Mst1) Deficiency
Diagnosis, Management, and Treatment of T-Cell and Combined Immunodeficiency
Newborn Screening
Isolation
Hematopoietic Stem Cell Transplantation
Donor Source
Conditioning
Prophylaxis and Treatment of Graft versus Host Disease
Gene Therapy
Gene Editing
Conclusions
References
Multiple-Choice Questions
Chapter 36: Immunodeficiencies at the Interface of Innate and Adaptive Immunity
Mendelian Susceptibility to Mycobacterial Disease: Genetic Disorders of the IFN-γ Circuit
Complete IFN-γR1 and IFN-γR2 Deficiencies
Autosomal Recessive Partial IFN-γR1 and IFN-γR2 Deficiencies
Autosomal Dominant Partial IFN-γR1 and IFN-γR2 Deficiencies
Complete IL-12Rβ1 and IL-12P40 Deficiencies
Autosomal Dominant Partial STAT1 Deficiency
Complete and Partial IRF8 Deficiency
AR Complete ISG15 Deficiency
AR Complete TYK2 Deficiency
NEMO and CYBB Deficiencies
Inherited Disorders of IFN-γ– and IFN-α/β–Mediated Immunity
AR Complete and Partial STAT1 Deficiency
Genetic Disorders of the TLR3–IFN-α, IFN-β, and IFN-λ Pathway
TLR3 Deficiency
UNC-93B Deficiency
TRIF Deficiency
TRAF3 Deficiency
TBK1 Deficiency
IRF3 Deficiency
IRF7 Deficiency
Genetic Disorders of NF-κB–Mediated Immunity
NEMO Deficiency
IκBα Deficiency
IL-1 Receptor–Associated Kinase-4 Deficiency
MYD88 Deficiency
HOIL1 Deficiency
HOIP Deficiency
Genetic Disorders of Th17-Mediated Immunity
Conclusions
Acknowledgments
Multiple-Choice Questions
References
Chapter 37: Infections in the Immunocompromised Host
Primary Immunodeficiencies
Phagocyte Defects (Chapter 22)
Chronic Granulomatous Disease
Leukocyte Adhesion Deficiencies
Quantitative Phagocyte Defects
Humoral Immunodeficiencies (Chapter 34)
Primary Cellular and Combined Immunodeficiencies (Chapter 35)
Severe Combined Immunodeficiency
DiGeorge Syndrome
Autosomal Dominant Hyper-IgE Syndrome (Job’s Syndrome)
DOCK8 Deficiency
Defects of the IL-12/IFN-γ Axis
Complement Deficiencies (Chapter 21)
Asplenia
Secondary Non–Medication-Associated Immunodeficiency
Cytokine Autoantibodies
Infections in Patients Receiving Immunosuppressive Medications
Cytotoxic Agents (e.g., Cyclophosphamide, Methotrexate, Azathioprine)
Glucocorticoids
Calcineurin Inhibitors and Mammalian Target of Rapamycin Inhibitors
Mycophenolate Mofetil
Antithymocyte Globulin
Monoclonal Antibodies and Small Molecules
Tumor Necrosis Factor-α Inhibitors
Rituximab
Alemtuzumab
Daclizumab and Basiliximab
Natalizumab
Bortezomib
Infections in Solid Organ Transplantation
Infections in the First Month After Transplantation
Infections 1–6 Months After Transplantation
Infections 6 Months After Transplantation
Infections in Hematopoietic Stem Cell Transplantation
Preengraftment Period
Early Postengraftment Period
Late Postengraftment Period
Infections of Particular Importance in Transplant Recipients
Cytomegalovirus Infection
Other Herpes Viruses
Invasive Filamentous Fungal Infections
Invasive Candidiasis
Translational Research
Conclusions
Multiple Choice Questions
References
Chapter 38: Immune Deficiencies at the Extremes of Age
Infancy and the Generation of an Immune System
Innate Immune Development
Dysfunction of Innate Immune Cells
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 and Senescence
Clinical Consequences of Immune Aging—Immunodeficiency, Autoimmunity, and Accelerated Degenerative Diseases
Strategies and Interventions on the Horizon
Multiple-Choice Questions
References
Chapter 39: Human Immunodeficiency Virus Infection and Acquired Immunodeficiency Syndrome
US Perspective
HIV Pathogenesis
HIV Lifecycle
HIV Entry Through Mucosal Surfaces
T-cell Depletion
HIV Latency and HIV Reservoirs
Anti-HIV Immunity
HIV Vaccines: Basic Concepts
Routes of Infection
Immunopathogenesis
Mucosal Dendritic Cells: Myeloid Versus Plasmacytoid
Gastrointestinal System: Early Target
Chronic Immune Activation and Progression to AIDS
Anti-HIV Cellular Immunity
Mechanisms of T-Cell Depletion
Apoptosis
Autophagy
Anti-HIV Humoral Immunity
Innate Immunity
NK Cells in HIV Infection
Cytokines in HIV Infection
Clinical Features
Acute HIV Infection
Asymptomatic HIV Infection
Symptomatic HIV Infection (pre-AIDS)
End-Stage HIV Infection: AIDS
Long-Term Nonprogressors/Elite Controllers
Diagnosis and Monitoring of HIV Infection
Diagnostic Tests
Enzyme Immunoassays
Rapid HIV EIA Tests
Nucleic Acid Amplification Tests
Monitoring Tests
HIV Viral Load
Drug Resistance: HIV Genotype Versus Phenotype
Testing for Viral Tropism and Abacavir Hypersensitivity
Treatment
Antiretroviral Therapy: Attacking HIV’s Lifecycle
When to Start Therapy
Antiretroviral Agents
Reverse Transcriptase Inhibitors, Protease Inhibitors, and Integrase Inhibitors
Fusion Inhibitors, CCR5 Blockers, and Low-Molecular-Weight 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
Preexposure Prophylaxis
Prophylactic Antiretroviral Therapy
Expanded Treatment With Antiretroviral Therapy
HIV Vaccines: Clinical Trials
Preventive Vaccines
Therapeutic Vaccines
Future for HIV Vaccines
Translational Research Needs and Conclusions
Acknowledgments
Multiple-Choice Questions
References
Chapter 40: 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 Recurrent Staphylococcal Skin Infection
Management
Conclusions
Acknowledgements
Multiple-Choice Questions
References
Part Five: Allergic Diseases
Chapter 41: Immunological Mechanisms of Airway Diseases and Pathways to Therapy
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
DRESS Syndrome
Allergic Bronchopulmonary Aspergillosis
Acute Eosinophilic Pneumonia
Intrinsic Eosinophilic Syndromes
Chronic Eosinophilic Pneumonia
Idiopathic Hypereosinophilic Syndrome
Churg-Strauss Syndrome
Immunological 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
Nonallergic Respiratory Tract Inflammatory Syndromes
Hypersensitivity Pneumonitis
Chronic Obstructive Pulmonary Disease
Novel Pathways to Therapy in Inflammatory Airway Disease
Multiple-Choice Questions
References
Chapter 42: Urticaria, Angioedema, and Anaphylaxis
Definition
Epidemiology
Genetics
Clinical Patterns
Etiopathogenesis and Etiological Classification
Mast Cell–Dependent Mechanisms
Allergic Urticaria
Autoimmune Urticaria
Immune Complex–Mediated Urticarial Rash
Nonimmunological Mast-Cell Activation
Mast-Cell and Basophil Releasability in Urticaria
Skin Response to Mast-Cell Activation in Chronic Urticaria
Mast Cell–Independent Mechanisms of Urticaria
Pseudoallergy (Intolerance)
NSAIDs
Food-Induced Pseudoallergic Reactions in CSU
Kinin-Mediated Angioedema
Clinical Classification
Spontaneous Urticaria
Acute Spontaneous Urticaria
Chronic Spontaneous Urticaria
Episodic Spontaneous Urticaria
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
Histaminergic angioedema (without wheals)
Idiopathic.
Drug-induced.
Bradykininergic angioedema
Hereditary.
Drug-induced.
Autoinflammatory Syndromes Presenting With Urticarial Rash
Acquired
Schnitzler syndrome.
Hereditary (Cryopyrin-Associated) Periodic Syndromes
Differential Diagnosis
Workup in Patients With Urticaria
Workup in Acute Urticaria
Workup in Physical Urticarias
Workup in Chronic and Episodic Spontaneous Urticarias
The Diagnosis of Autoimmune Chronic Urticaria
Management of Urticaria
General Measures
First-Line Therapy
Second-Line Therapy
Third-Line Therapy
Management of Hereditary Angioedema
Treatment of the Acute Attack
Short-Term Prophylaxis
Long-Term Prophylaxis
Anaphylaxis
Epidemiology of Anaphylaxis
Pathophysiology of Anaphylaxis
Etiology of Anaphylaxis
Food-Induced Anaphylaxis
Drug-Induced Anaphylaxis
Perioperative Anaphylaxis
Insect Sting–Induced Anaphylaxis
Latex-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
Multiple-Choice Questions
References
Chapter 43: Allergic Reactions to Stinging and Biting Insects
Entomological Aspects
Apidae
Vespidae
Ants (Myrmicinae, Formicinae)
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 Stings by Flying Hymenoptera
Risk Factors for Hymenoptera Allergy
Mortality Caused by Hymenoptera Stings
Natural History of Hymenoptera Sting Allergy (Table 43.3)
Epidemiological Aspects of Allergic Reactions to Ant Stings
Diagnosis
History
Skin Tests
Venom-Specific Serum IgE Antibodies
Sensitivity and Specificity of Skin Tests and sIgE
Cross-Reactivity
Cellular Tests
Allergen-Specific IgG
Baseline Serum Tryptase
Sting Challenge Tests
Prevention and Treatment
Prevention
Treatment of Large Local Reactions
Systemic Allergic Reactions
Emergency Medication Kit
Venom Immunotherapy
Indications
Dosage and Treatment Regimens
Adverse Reactions to VIT
Efficacy of VIT
Duration of VIT
Risk Factors for Recurrence of SRs After Stopping VIT
Allergic Reactions to Biting Insects
Clinical Symptoms
Allergens
Prevention and Treatment
Multiple-Choice Questions
References
Chapter 44: 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
Antiinfective Therapy
Antipruritic Agents
Recalcitrant Disease
Hospitalization
Wet Wrap Therapy
Systemic Immunosuppressive Agents
Phototherapy and Photochemotherapy
Allergen-Specific Immunotherapy
Biologics and Investigational Therapies
Intravenous Gammaglobulin
Omalizumab
Rituximab
Dupilumab
Anti–IL-12/IL-23
Other Biologics
Recombinant Human Interferon-γ
Phosphodiesterase-4 Inhibitors
Probiotics
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
Symptomatic Therapy
Perspectives in Atopic Dermatitis and Allergic Contact Dermatitis
Multiple-Choice Questions
References
Chapter 45: Food Allergy
Prevalence
Spectrum of Disease
IgE-Mediated Food Allergies
Mixed IgE/Non-IgE– and Non–IgE-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
Conclusions
Multiple-Choice Questions
References
Chapter 46: Eosinophil-Associated Gastrointestinal Disorders
Eosinophilic Esophagitis
Definition
Epidemiology
Demographic Cornerstones
Incidence and Prevalence of Eosinophilic Esophagitis
Pathophysiology
Eosinophils’ Natural Lifecycle
The Role of IgE in Eosinophilic Esophagitis
Th2-Mediated Immune Response
Esophageal Remodeling
Clinical Manifestation of Eosinophilic Esophagitis
Endoscopy and Histology
Treatment
Drugs
Diet
Dilatation
Idiopathic Eosinophilic Gastroenteritis
Definition and Classification
Epidemiology and Natural History
Clinical Presentation
Diagnostic Measures
Treatment
Hypereosinophilic Syndromes With Gastrointestinal Involvement
Definition and Classification
Epidemiology and Natural History
Clinical Presentation
Immunopathogenesis
Treatment
Summary
Multiple-Choice Questions
References
Chapter 47: Allergic Disorders of the Eye
Seasonal Allergic Conjunctivitis
Conjunctival Immunostaining in SAC
Therapy
Perennial Allergic Conjunctivitis
Immunohistological Studies in PAC
Therapy
Experimental Models of Allergic Conjunctivitis
Conjunctival Allergen Challenge
Experimental Allergic Conjunctivitis
Vernal Keratoconjunctivitis
Immunological Studies in VKC
Management of VKC
Experimental Model of VKC
Atopic Keratoconjunctivitis
Immunological Studies in AKC
Experimental Model of AKC
Therapy
Multiple-Choice Questions
References
Chapter 48: Drug Hypersensitivity
Epidemiology of Drug Hypersensitivity
Immune Drug Recognition and Genetic Basis of Drug Hypersensitivity
Risk Factor for Drug Allergy: Host, Pathogens, and Drug Response
Classification of Drug Hypersensitivity Reactions
Antibody-Mediated Drug Hypersensitivity Reactions
Type I IgE-Mediated Hypersensitivity
Non–IgE-Mediated Type I Hypersensitivity Reactions
Type II Reactions: IgG-Mediated Cytotoxic Reactions
Type III Reactions
Type IV Reactions
Diagnosis of Drug Hypersensitivity: Clinical Symptoms and History
Tryptase
Skin Testing, Specific IgE, and Challenges
Patch Testing, Delayed Intradermal Reading, and Lymphocyte Transformation Tests
Specific Drug Hypersensitivity
Beta-Lactams
Radio Contrast Media
Perioperative Anaphylaxis
Local Anesthetics
Sulfonamides
Aspirin
Biological Agents and Monoclonal Antibodies
Chemotherapy
Taxanes Hypersensitivity
Management of Drug Hypersensitivity and Desensitization
Multiple-Choice Questions
References
Chapter 49: Occupational Respiratory Allergies
Mechanisms of Occupational Sensitization
IgE-Mediated
Non–IgE-Mediated
Natural History of Occupational Asthma and Risk Factors
Natural History of the Development of the Disease
Risk Factors
Host Factors
Atopy
Clinical evidence.
Pathophysiology.
Rhinitis and airway hyperresponsiveness
Clinical evidence.
Pathophysiology.
Genetic predisposition
Clinical evidence.
Pathophysiology.
Environmental Factors
Level of exposure.
Tobacco smoke and irritants.
Pathophysiology.
Diagnosis and Management of Occupational Asthma
Diagnosis of Occupational Asthma
Management of Occupational Asthma
Multiple-Choice Questions
References
Part Six: Systemic Immune Diseases
Chapter 50: Mechanisms of Autoimmunity
The Distinct Phases in the Development of Autoimmunity
Phase I: Susceptibility
Incomplete Thymic Tolerance Induction Predisposes to Autoimmunity
Impaired Clearance and Tolerance Induction by Apoptotic Cells: Susceptibility Defect in Systemic Autoimmunity
Defective Production of Regulatory T Cells
Signaling Thresholds and Susceptibility to Autoimmunity
Phase 2: Initiation
Dominance and Crypticity
High-Affinity Binding of Antigen to Ligands or Antibodies
Tissue-Specific Protease Expression
Posttranslational Modification of Autoantigen Structure
Novel Antigen Cleavage During Cell Damage, Cell Death, or Inflammation
Autoantigen Alteration Caused by Mutation, Truncation, or Splicing
Antigen Mimicry
Phase III: 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
Multiple-Choice Questions
References
Chapter 51: Systemic Lupus Erythematosus
Epidemiology
Mortality
Damage
Immunopathogenesis
Autoantibodies
The Predisposed Host: Genetic Contributions
Genes Associated With Antigen Presentation
Genes Associated With Impaired Clearance of Apoptotic Debris
Genes Associated With Lymphocyte Activation, Proliferation, and Function
Genes Encoding Cytokines and Chemokines
Genes Associated With Cell Survival
Genes Regulating Target Organ Damage
Epigenetic Contributions
B Cells
B-Cell Selection
B-Cell Signaling
B-Cell Rescue
B-Cell Pathogenicity Unrelated to Antibody Production
Neutrophils
Dendritic Cells
T Cells
Hormonal Influences
Clinical Manifestations
Musculoskeletal Involvement
Arthritis and Arthralgia
Tendinitis
Myositis/Myalgia
Avascular Necrosis
Mucocutaneous Manifestations
Skin
Acute Cutaneous SLE
Subacute Cutaneous SLE
Chronic Cutaneous SLE
Hair and Nail
Oral Lesions
Gastrointestinal Manifestations
Esophagus
Abdominal Pain/Vasculitis
Intestinal Pseudoobstruction
Peritonitis
Pancreatitis
Liver
Protein-Losing Enteropathy (PLE)
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
Hematological
Anemia
Leukopenia
Thrombocytopenia
Central and Peripheral Nervous System
NPSLE Nomenclature
NPSLE Pathogenesis
NPSLE Assessment and Attribution
Drug-Induced Lupus
Treatment
Translational Research
Conclusions
Multiple-Choice Questions
References
Chapter 52: Rheumatoid Arthritis
Epidemiology
Etiology and Pathogenesis
Environmental and Nongenetic Factors
Immunogenetics
Synovial Pathology
Increased Vascularity and Cell Migration
Organization of Lymphoid Tertiary Microstructures
Gene Expression Signatures
Immunobiology of RA
Initiation of the Immune Response
Autoantigens in RA
The Discovery of Citrulline as a Key Target for Autoimmunity in RA
Lymphocyte Biology
Molecular Basis of Persistence
Immune Regulation
Impact of the Immune Response on Cartilage and Bone
Clinical Features
Disease Onset
Diagnosis
Classification Criteria
Laboratory Findings
Insights Into the Preclinical Phase of Disease
Treatment
Disease-Modifying Antirheumatic Drugs
Anticytokine Therapy
Anti-T-Cell Therapy
Anti-B-Cell Therapy
Future Prospects for Therapy
Multiple-Choice Questions
References
Chapter 53: Juvenile Idiopathic Arthritis
Etiology and Pathogenesis
Genetic Contribution
Polygenic Disorder
HLA Associations
Non-HLA Associations
Environmental Factors
Immune Abnormalities
Autoantibodies
T-Helper Cells
Cytokines
Macrophage Activation Syndrome
JIA Clinical Subtypes
Oligoarticular JIA
Polyarticular JIA
Psoriatic Arthritis
Enthesitis-Related Arthritis
Systemic JIA
Laboratory Evaluation
Differential Diagnosis
Clinically Silent Complications
Treatment
Overview
Nonsteroidal Antiinflammatory Drugs
Glucocorticoids
Nonbiological DMARDs
Biological DMARDs
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
Multiple-Choice Questions
References
Chapter 54: Sjögren Syndrome
Epidemiology
Immunopathogenesis
Immunogenetic Factors
Environmental Factors
Epithelial Cell Activation and Chronic Inflammation
Autoantibodies
Autonomic Nervous System Abnormalities
Clinical Manifestations
Constitutional Symptoms
Ocular Involvement
Oral Involvement
Musculoskeletal Involvement
Neuropsychiatric Manifestations
Dermatological Involvement
Gastrointestinal Involvement
Pulmonary Involvement
Cardiac Involvement
Genitourinary and Renal Involvement
Clinical Manifestations in Children
Associated Autoimmune Conditions
Lymphoma Associated With SS
Diagnosis and Classification Criteria
Novel Biomarkers for Diagnosis and Management of Sjӧgren Syndrome
Treatment
Symptomatic Treatment of Sicca Symptoms
Immune-Modulating Medications
Treatment for Lymphoma Associated With SS
Patient Education
Translational Research and Future Directions
Multiple-Choice Questions
References
Chapter 55: Scleroderma–Systemic Sclerosis
Prevalence and Epidemiology
Etiology and Pathogenesis
Genetic Factors
Environmental Factors
Pathology
Pathogenesis
Microangiopathy
Cellular and Humoral Immune Responses
Fibrosis: Cellular and Molecular Components
Clinical Features
Overview
Symptoms
Diffuse SSc
Limited Cutaneous SSc
Raynaud Phenomenon
Gastrointestinal Involvement
Pulmonary Involvement
Interstitial Lung Disease
Pulmonary Arterial Hypertension
Cardiac Involvement
Renal Involvement
Musculoskeletal Complications
Emotional Aspects
Treatment
Other Fibrosing Diseases
Multiple-Choice Questions
References
Chapter 56: 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
Multiple-Choice Questions
References
Chapter 57: Spondyloarthritis
Classification of Spondyloarthritis
Epidemiology
Pathogenesis
Genetics of Spondyloarthritis
Familial Aggregation
HLA-B27 and Spondyloarthritis
Other MHC Genes and SpA Susceptibility
Non-MHC 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
Laboratory Investigations
Diagnosis
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 Antiinflammatory Drugs
Disease-Modifying Antiinflammatory Drugs
Sulfasalazine.
Other DMARDs.
Corticosteroids.
Intraarticular/Intralesional Corticosteroids
Antibiotics
TNF-α Blockers
Interleukin-17 Blockers (Secukinumab)
Surgical Treatment of AS Complications
Conclusions and Research Opportunities
References
Chapter 58: Small- and Medium-Vessel Primary Vasculitis
Epidemiology
Pathogenesis of AAV
The Pathogenic Role of ANCA in GPA and MPA
Genetics
Epigenetics
Environmental and Infectious Triggers
Drug Induced AAV
Propylthiouracil
Hydralazine
Levamisole-Contaminated Cocaine
Loss of B- and T-Cell Tolerance in ANCA-Associated Vasculitis
Role of Neutrophils
Role of Complement
Pathogenesis of Kawasaki Disease
Pathogenesis of Polyarteritis Nodosa
Pathogenesis of Cryoglobulinemic Vasculitis
Pathogenesis of EGPA
Classification
Diagnosis
Individual Diseases
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
Acknowledgements
Multiple-Choice Questions
References
Chapter 59: 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
Multiple Choice Questions
References
Chapter 60: Systemic 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
Multiple-Choice Questions
References
Chapter 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 APS
Perioperative Management
Additional Therapeutic Considerations
Conclusions and Translational Research
Multiple-Choice Questions
References
Part Seven: Organ-Specific Inflammatory Disease
Chapter 62: Immunohematological Disorders
Immune-Mediated Hemolytic Anemia
Autoimmune Hemolysis Mediated by Warm Antibody
Drug-Induced Immune Hemolysis
Cold Agglutinin Diseases
Paroxysmal Cold Hemoglobinuria
Hemolytic Transfusion Reactions
Immune Hemolysis Associated With Transplantation
Immunopathogenesis
Diagnosis
Therapy
Immune-Mediated Neutropenia
Isoimmune Neonatal Neutropenia
Primary Autoimmune Neutropenia
Neutropenia Associated With Systemic Autoimmune or Lymphoproliferative Diseases
Felty Syndrome
T-Cell Large Granular Lymphocyte Leukemia
Clinical Overlap Between Felty Syndrome and T-LGL Leukemia
Drug-Induced Immune Neutropenia
Immunopathogenesis
Regulation of Antineutrophil Antibody Production
Antibody Specificity
Patterns of Autoantibody 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 Thrombocytpenias
Immune Thrombocytopenia
ITP During Pregnancy and the Neonatal Period
Neonatal Alloimmune Thrombocytopenia and Posttransfusion Purpura
Drug-Induced Thrombocytopenia
Pathogenesis
Laboratory Diagnosis
Therapy of ITP
Therapy of ITP During Pregnancy and the Neonatal Period
Multiple-Choice Questions
References
Chapter 63: Bullous Diseases of the Skin and Mucous Membranes
Pemphigus
Pemphigus Vulgaris
Pemphigus Foliaceus
Paraneoplastic Pemphigus
IgA Pemphigus
Pathogenesis
Therapy
Bullous Pemphigoid
Clinical Features
Pathogenesis
Therapy
Epidermolysis Bullosa Acquisita
Pathogenesis
Treatment
Pemphigoid Gestationis
Pathogenesis
Treatment
Mucous Membrane Pemphigoid
Pathogenesis
Therapy
Linear IgA Bullous Disease
Pathogenesis
Therapy
Dermatitis Herpetiformis
Clinical Features
Pathogenesis
Therapy
Translational Research
Multiple-Choice Questions
References
Chapter 64: Immunology of Psoriasis
Clinical and Histological Features of Psoriasis
Immune-Related Genetic Factors Predisposing to Psoriasis
Effector Cells and Immune Mechanisms Operating in Psoriasis
Plasmacytoid DCs as Inducers of Primary Immune Responses in Psoriasis
DC Driving of T-Cell Responses in Psoriatic Skin
Activation of T Lymphocytes and Establishment of the Cytokine Milieu Influencing Keratinocyte Proliferation and Immune Functions
Intrinsic Defects of Keratinocytes Are Fundamental for the Amplification of Psoriatic Processes
Conclusions
Multiple-Choice Questions
References
Chapter 65: Myasthenia Gravis
Classification
Diagnosis
AChR Structure
Neuromuscular Transmission
Immunopathogenesis of MG
Properties of Anti-AChR Antibodies and Characterization of B-Cell Epitopes
Anti-AChR Antibody Levels and Relationship to Disease Activity
Pathogenic Effects of Anti-AChR Antibodies
Complement-Mediated Damage
Acceleration of AChR Degradation
Receptor Blockade
Role of T Cells
Experimental Autoimmune Myasthenia Gravis
The Thymus in Myasthenia Gravis
Thymic Pathology
Intrathymic Factors Possibly Contributing to Local Anti-AChR Antibody Response
Etiological Factors
Genetic Factors
Exogenous Factors
Treatment of Myasthenia Gravis
Anticholinesterases
Thymectomy
Corticosteroids
Plasmapheresis
Intravenous Immunoglobulin
Immunosuppressive Agents
Possible Future Therapeutic Options
Conclusions
Acknowledgment
Multiple-Choice Questions
References
Chapter 66: Multiple Sclerosis
Clinical Subsets and Phenomenology
Relapsing-Remitting MS (RRMS)
Secondary Progressive MS (SPMS)
Primary Progressive MS (PPMS)
Diagnosis
Risk Factors
Genetic Risk Factors
Environmental Risk Factors
Geographic Prevalence Patterns
Vitamin D
Infection
Obesity
Modifiable Habits
Sex Hormones
Pathological Features of MS
White Matter Lesions
Gray Matter Lesions
Meningeal Inflammation
Immunopathogenesis
Animal Models of MS
Immune Dysregulation in Patients With MS
Disease-Modifying Therapies
Recombinant IFN-β
Glatiramer Acetate
Teriflunomide
Dimethyl Fumarate
Fingolimod
Natalizumab
Alemtuzumab
Daclizumab
B Cell–Depleting Monoclonal Antibodies
Future Directions
Multiple-Choice Questions
References
Chapter 67: Autoimmune Peripheral Neuropathies
Acute Inflammatory Polyneuropathy: Guillain-Barré Syndrome(s)
Diagnosis
Antecedent Illnesses or Events
Immunopathology of Guillain-Barré Syndrome
Cellular Factors
Humoral Factors and Antiganglioside Antibodies
Molecular Mimicry: Relationship Between Campylobacter jejuni and Gangliosides in Acute Motor Axonal Neuropathy
Nodal and Paranodal Alterations and Specific Antinodal Antibodies
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 in Patients With IgM M Monoclonal Gammopathies of Undetermined Significance Polyneuropathy (Anti-MAG Neuropathy)
Polyneuropathy, Organomegaly, Endocrinopathy, Myeloma, and Skin Changes
Cryoglobulinemic Neuropathy
Paraneoplastic Peripheral Neuropathies With Anti-Hu Antibodies
Autoimmune Autonomic Neuropathies
Mononeuropathy Multiplex and Localized, Isolated Vasculitis of the Peripheral Nerves
Neuropathy With Viruses and Human Immunodeficiency Virus
Treatment
Guillain-Barré Syndrome
Supportive Care
Plasmapheresis
High-Dose Intravenous Immunoglobulin
Chronic Inflammatory Demyelinating Polyneuropathy
Prednisone
Intravenous Immunoglobulin
Plasmapheresis
Polyneuropathy With Paraproteinemias
Multifocal Motor Neuropathy
Paraneoplastic Anti-Hu Neuropathy
Vasculitic Neuropathies
Human Immunodeficiency Virus Neuropathies
Acknowledgments
Multiple-Choice Questions
References
Chapter 68: Immunological Renal Diseases
Hematuria
Proteinuria
Nephrotic Syndrome
Acute Nephritic Syndrome
Chronic Glomerulonephritis
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
Hepatitis C
Human Immunodeficiency Virus
Bacterial Infections
Poststreptococcal Glomerulonephritis
Etiology and pathogenesis.
IgA Nephropathy
Pathology
Etiology and Pathogenesis
Natural History
Treatment
Renal Vasculitis Associated With Antineutrophil Cytoplasmic Antibodies
Pathology
Treatment and Prognosis
Anti-GBM Antibody-Mediated Nephritis: Goodpasture Disease
Lupus Nephritis
Pathogenesis
Clinical Features
Pathology
Treatment
Scleroderma (Systemic Sclerosis) Renal Disease
Renal Disease of Sjögren Syndrome
Multiple-Choice Questions
References
Chapter 69: Inflammation and Atherothrombosis
Atherosclerosis: a Chronic Inflammatory Disease
Role of Inflammation in the Pathogenesis of Acute Coronary Syndromes
Plaque Fissure With Systemic Inflammation
Plaque Fissure: Pathological and Clinical Findings
Widespread Coronary Inflammation
Activation of Innate Immunity
Activation of Adaptive Immunity
T-helper 1 (Th1) Cells
CD4+CD28null T Cells
Th17 Cells
Regulatory T Cells
B Cells
TCR Signaling Alteration in ACS
Plaque Fissure Without Systemic Inflammation
Plaque Erosion
Plaque Erosion: Pathological Findings
Mechanisms of Plaque Erosion
Functional Alterations of Coronary Circulation
Clinical Perspective
Plaque Fissure With Systemic Inflammation
Plaque Fissure Without Systemic Inflammation
Plaque Erosion
Functional Alterations of Coronary Circulation
Conclusion
Multiple-Choice Questions
References
Chapter 70: Autoimmune Thyroid Diseases
Graves Hyperthyroidism
Epidemiology
Etiology
Immunopathogenesis
Clinical Presentation
Investigation and Diagnosis of GD
Management of GD
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
Translational Research
Multiple-Choice Questions
References
Chapter 71: Type 1 Diabetes
Epidemiology and Natural History of T1DA
Pathogenesis: Nature and Nurture
Genes
β Cells
Environment—Outside and Inside
Treatment and Prevention
Multiple-Choice Questions
References
Chapter 72: Immunological Lung Diseases
Inflammation in the Pathogenesis of Interstitial Lung Disease
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
Drug-Induced Lung Disease
Systemic Sclerosis (Scleroderma)
Interstitial Lung Disease
Pulmonary Vascular Disease
Conclusions
Multiple-choice questions
References
Chapter 73: Sarcoidosis
Epidemiology
Genetics
Environmental Factors
Role of Infectious Agents
Autoimmunity
Immunology/Pathogenesis
Th1 Polarization in Sarcoidosis
Innate Immunity in Sarcoidosis
Serum Amyloid A Aggregation Hypothesis
Patient Evaluation and Differential Diagnosis
Pulmonary Sarcoidosis
Extrapulmonary Sarcoidosis
Sarcoidosis of the Upper Respiratory Tract
Ocular Sarcoidosis
Cutaneous Sarcoidosis
Cardiac Sarcoidosis
Hepatic Sarcoidosis
Joints and Bones
Neurosarcoidosis
Salivary, Parotid, and Lacrimal Gland Sarcoidosis
Hematological Sarcoidosis
Sarcoidosis Myopathy
Hypercalcemia, Hypercalciuria, and Renal Disease
Psychosocial Manifestations
Associated Conditions
Sarcoidosis and Pregnancy
Th1-Promoting Therapeutics
Common Variable Immunodeficiency
IgG4-Related Disease
Human Immunodeficiency Virus
Autoimmune Disorders
Cancer
Diagnosis
Other Diagnostic Studies
Clinical Course and Patient Management
Treatment
Alternative Cytotoxic Therapies
Specific Situations
Löfgren Syndrome
Mucocutaneous and Joint Sarcoidosis and Hypercalcemia
Ocular Sarcoidosis
Pulmonary Hypertension
Cardiac Sarcoidosis
Neurosarcoidosis
Depression/Fatigue/Pain
Role of Transplantation in Sarcoidosis
Opportunities for Progress in Sarcoidosis
Multiple-Choice Questions
References
Chapter 74: Immunological Ocular Disease
Ocular Immune Privilege
Fas Ligand
Cytokines, Neuropeptides, and Complement in the Promotion and Regulation of Ocular Inflammation
Anterior Chamber–Associated Immune Deviation
Immobility of Dendritic Cells Within the Anterior Chamber
Role of the Commensal Microbiota in Ocular Immunity
Uveitis
Uveitis as a Diagnostic Entity
Epidemiology
Prevention and Patient Management
Overview of the Most Common Uveitis Diagnoses
Ankylosing Spondylitis–Associated Uveitis
Inflammatory Bowel Disease–Associated Uveitis
Psoriatic Arthritis–Associated Uveitis
Sarcoidosis-Associated Uveitis
Behçet Uveitis
Multiple Sclerosis–Associated Uveitis
Juvenile Idiopathic Arthritis–Associated Uveitis
Advancements and New Treatments for Uveitis
Scleritis
Description and Natural History
Genetic and Environmental Factors
Immunology and Pathology
Prevention and Management
Evaluation and Differential Diagnosis
Pitfalls and Controversy
Keratitis
Corneal Transplantation and Transplant Rejection
Cancer-Associated Retinopathy
Immunologic Etiologic Factors in “Nonimmunologic” Ocular Disease
Multiple-Choice Questions
References
Chapter 75: Immunological Diseases of the Gastrointestinal Tract
Gastritis
Atrophic Gastritis/Pernicious Anemia
Helicobacter pylori Gastritis
Celiac Disease
Presentation
Immune Pathophysiology
Diagnosis
Treatment
Crohn Disease
Presentation
Immune Pathophysiology
Diagnosis
Treatment
Ulcerative Colitis
Presentation
Immune Pathophysiology
Diagnosis
Treatment
Other Idiopathic Inflammatory Bowel Diseases
Microscopic Colitis
Eosinophilic Esophagitis
Gastrointestinal Complications of Primary Immunodeficiencies
Common Variable Immunodeficiency
Presentation
Immune Pathophysiology
Diagnosis
Treatment
Chronic Granulomatous Disease
Presentation
Immune Pathophysiology
Diagnosis
Treatment
GI Complications Occurring in Other Primary Immunodeficiency States
Multiple-Choice Questions
References
Chapter 76: Inflammatory Hepatobiliary Diseases
Autoimmune Hepatitis
Epidemiology
Pathogenesis
Clinical Features and Diagnosis
Serum Autoantibodies
Histology
Therapy
Primary Biliary Cholangitis
Nomenclature
Epidemiology
Pathogenesis
Clinical Features and Diagnosis
Serum Autoantibodies
Histology
Therapy
Primary Sclerosing Cholangitis
Epidemiology
Pathogenesis
Clinical Features and Diagnosis
Histology
Therapy
Autoimmune Cholangitis
Overlap Syndromes
IgG4-Related Cholangitis
Multiple Choice Questions
References
Part Eight: Immunology of Neoplasia
Chapter 77: Immunotherapy of Cancer
Activation and Regulation of T-Cell Responses
Immune Checkpoint Therapy
Anti-CTLA-4 Therapy
Anti-PD-1/PD-L1 Therapy
T-Cell Immunoglobulin and Mucin Domain 3
Lymphocyte Activation Gene 3
V-Domain Ig Suppressor of T-Cell Activation
Immune Checkpoint Therapy With Clinical Benefit in Solid Tumors and Hematological Malignancies
Melanoma
Lung Cancer
Renal Cell Carcinoma
Bladder Cancer
Head and Neck Cancer
Hodgkin Lymphoma
Early and Late-Phase Trials With Checkpoint Therapy in Other Tumors
Pancreatic Cancer
Prostate Cancer
Immune Costimulatory Molecules
Inducible T-Cell Costimulator
4-1BB (CD137)
OX40 (CD134)
Adoptive Cell Transfer
Adoptive Transfer of Tumor-Specific Cytotoxic T Cells
Adoptive Immunotherapy With Genetically Modified Lymphocytes
Clinical Development of Chimeric Antigen Receptor T Cells
Adoptive Transfer of Viral-Specific T Cells
Monoclonal Antibodies
Naked mAbs
Conjugated/Tagged/Labeled/Loaded mAbs
Bispecific Monoclonal Antibodies
Cytokine Therapy
Cancer Vaccines
Oncolytic Virus Immunotherapy
Clinical Challenges in Immunotherapy
Resistance Mechanisms
Activation of Oncogenic Pathways
Loss of Interferon γ Signaling
Immunosuppressive Tumor Microenvironment
Gut Microbiome
Immune-Related Adverse Events
irAEs With Immune Checkpoint Immunotherapy
irAEs With Adoptive T-Cell Therapy
Perspectives on Future Developments
Biomarkers
Combination Therapy
Conclusions
Multiple-Choice Questions
References
Chapter 78: Lymphoid Leukemias
Acute Lymphoblastic Leukemia
Epidemiology and Etiology
Immunological and Molecular Classification of ALL
Immunological Classification
B-Cell Precursor Leukemias
T-Cell ALL
Genetic and Molecular Classification
Numerical Chromosomal Aberrations
Chromosomal Translocations
Amplifications and Deletions
Oncogenic-Activating Mutations
Genes Involved in Leukemogenesis Often Play Key Roles in Normal Development
Major, Clinically Relevant, Molecular Subtypes of ALL
B-Lineage ALL
T-Lineage ALL
Clinical Features
Special Diagnostic Tests
Principles of Therapy
Prognostic Factors
Where Immunology Meets Oncology—Minimal Residual Disease
Course and Prognosis
Treatment Sequelae
Current Controversies and Future Perspectives
Chronic Lymphocytic Leukemia
Epidemiology
Pathogenesis and the Biology of Leukemic Lymphocytes
Clinical Features of CLL
Treatment
Immunological Aspects of CLL
The Pathophysiological Rationale
Immunological Deficiencies
Autoimmune Phenomena
Other Malignancies
Conclusions
Multiple-Choice Questions
References
Chapter 79: Lymphomas
Mature B-Cell Neoplasms
Lymphoplasmacytic Lymphoma
Mantle-Cell Lymphoma
Follicular Lymphoma
Mucosa-Associated Lymphoid Tissue Lymphomas
Nodal Marginal Zone Lymphoma
Splenic Marginal Zone Lymphomas
Diffuse Large B-Cell Lymphoma, Not Otherwise Specified
Primary Mediastinal Large B-Cell Lymphoma
Burkitt Lymphoma
T-Cell and NK-Cell Neoplasms
Overview of the Classification of T-Cell Neoplasms
Extranodal NK/T-Cell Lymphoma, Nasal Type
Nodal T-Cell Lymphoma With TFH Phenotype: Angioimmunoblastic T-Cell Lymphoma
Peripheral T-Cell Lymphomas, Not Otherwise Specified
Anaplastic Large-Cell Lymphoma
Primary Cutaneous ALCL
Subcutaneous Panniculitis-Like T-Cell Lymphoma
Primary Cutaneous γ/δ T-Cell Lymphomas
Mycosis Fungoides and Sézary Syndrome
Enteropathy-Associated T-Cell Lymphoma
Hepatosplenic T-Cell Lymphoma
Adult T-Cell Leukemia/Lymphoma
Hodgkin Lymphomas
Nodular Lymphocyte-Predominant Hodgkin Lymphoma
Classic Hodgkin Lymphoma, Nodular Sclerosis
Classic Hodgkin Lymphoma, Mixed Cellularity
Classic Hodgkin Lymphoma, Lymphocyte Depletion
Classic Hodgkin Lymphoma, Lymphocyte-Rich
Multiple-Choice Questions
References
Chapter 80: Monoclonal Gammopathies
Monoclonal Gammopathy of Undetermined Significance
Epidemiology
Clinical Presentation and Laboratory Findings
Diagnosis
Clinical Course
Management and Prognosis
Multiple Myeloma
Epidemiology
Clinical Presentation
Laboratory Findings
Biochemical Tests
Hematology
Bone Marrow Evaluation
Radiography
Diagnosis
Management
Prognosis
Smoldering Multiple Myeloma
Prognosis and Management
Nonsecretory Myeloma
Oligosecretory Myeloma
Plasma Cell Leukemia
Clinical Presentation and Diagnosis
Management and Prognosis
Solitary Plasmacytoma of Bone
Clinical Presentation
Diagnosis
Management and Prognosis
Solitary Extramedullary Plasmacytoma
Clinical Presentation
Diagnosis
Management and Prognosis
POEMS Syndrome
Clinical Presentation
Diagnosis
Management and Prognosis
Waldenström Macroglobulinemia
Clinical Presentation
Laboratory Findings and Diagnosis
Management and Prognosis
Heavy Chain Diseases
Clinical Presentation
Diagnosis
Management and Prognosis
Light Chain Amyloidosis
Clinical Presentation
Laboratory Findings and Diagnosis
Management and Prognosis
Monoclonal Immunoglobulin Deposition Diseases
Clinical Presentation
Laboratory Findings
Management and Prognosis
Multiple-Choice Questions
References
Part Nine: Transplantation
Chapter 81: Concepts and Challenges in Organ Transplantation
Rejection
Innate Immunity and Ischemia-Reperfusion Injury
Initiation of the Adaptive Immune System
Signal 1: Recognition of Alloantigen
Signal 2: Costimulation
Signal 3: Proliferation and Differentiation of Effector T Cells
Memory T Cells
Cell Migration
The Effector Response and Graft Destruction
Acute Antibody-Mediated Rejection
Acute Cellular Rejection
Delayed Allograft Rejection and Dysfunction
Clinical Implications
Immunosuppression
Immunodepletion
Antithymocyte Globulin
Anti-CD52 Monoclonal Antibody (Alemtuzumab)
Signal 1: Blockade of Antigen Recognition
Anti-CD3 Monoclonal Antibody
Anti-CD20 Monoclonal Antibody (Rituximab)
Signal 2: Blockade of Costimulation
CD28:B7 (CD80/CD86) Blockade
Signal 3: Blockade of Proliferation/Differentiation
Anti-IL-2R Monoclonal Antibody (Basiliximab and Daclizumab)
Glucocorticoids
Antiproliferative Agents
Calcineurin Inhibitors
Mechanistic Target of Rapamycin Inhibitors
Tolerance
Molecule-Based Tolerogenic Protocols
Full Chimerism
Mixed Chimerism
Regulatory T Cells
Biomarkers of Rejection or Tolerance
Multiple-Choice Questions
References
Chapter 82: Immune Reconstitution Therapy for Immunodeficiency
Hematopoietic Stem Cell Transplantation: General Considerations
Sources of Hematopoietic Stem Cells for Transplantation
Donor Selection and Manipulation of the Graft
HSCT From a Related HLA-Identical Donor
HSCT From a Haploidentical Donor
In Utero Haploidentical HSCT
HSCT From Matched Unrelated Donors
HSCT Using Unmanipulated Cord Blood
Complications of Hematopoietic Stem Cell Transplantation
Graft Rejection
Acute Graft-Versus-Host Disease
Chronic Graft-Versus-Host Disease
Prevention of GvHD
Treatment of GvHD
Infections
Toxicity Related to Conditioning Regimen
HSCT for SCID
General Considerations
Survival Following HSCT for SCID
Complications Following HSCT for SCID
Quality and Kinetics of T-Cell Immune Reconstitution
Reconstitution of B- and NK-Cell Immunity
HSCT for Combined Immunodeficiencies Other Than SCID
Wiskott-Aldrich Syndrome
Cytotoxicity Defects
Phagocytic Cell Disorders
Other Primary Immune Deficiencies
Future Translational Research for HCST in the Treatment of PID
Multiple-Choice Questions
References
Chapter 83: Hematopoietic Stem Cell Transplantation for Malignant Diseases
Immune Mechanisms Related to Allo-HSCT
Histocompatibility
Graft-Versus-Host Disease
Clinical Aspects of aGvHD
Autologous GvHD
Clinical Aspects of cGvHD
GvT Responses
Adjuvant Therapy With HSCT
Clinical HSCT
Sources of HSCs
Purging of Cell Populations
Expansion of HSC Products
Hematological Recovery
Conditioning Regimens
Dose-Intensive and Reduced Intensity Chemotherapy
HSCT 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 NHL
Aggressive NHL
Hodgkin Lymphoma
Solid Tumors
Future Directions
Multiple-Choice Questions
References
Part Ten: Prevention and Therapy of Immunological Diseases
Chapter 84: Immunoglobulin Therapy
Replacement Therapy With IVIG
Adverse Events Associated With IVIG Therapy
Rate-Related Adverse Events
Central Nervous System–Related Adverse Events
Renal Adverse Events
Thromboembolic Events
Transfusion Reaction Caused by Antibodies Against IgA
Other Adverse Reactions
Summary: Ig Replacement in Treatment of Immune Deficiency
Mechanisms of Action of Ig Therapy in Autoimmune and Inflammatory Diseases
Blockade of Fc Receptors of the Reticuloendothelial System
Interactions of Idiotype and Antiidiotype as Immune Modulation
The Role of the FcRn Receptor on Immune Modulation
Modulation of Immunoregulatory Function Through the Fc Receptor
Neutralizing Antibody Activity in IVIG Against Bacterial Toxins
Modulation of Adhesion Molecules on Endothelial Cells and Antibodies in IVIG to Cell Surface Receptors
Modulation of Complement Effector Function
Effects of Ig on the Regulatory T-Cell Pathways
Summary: IVIG in Treatment of Autoimmune and Inflammatory Diseases
Multiple-Choice Questions
References
Chapter 85: Gene Therapy for Primary Immune Deficiency Diseases
Gene Transfer to Hematopoietic Stem Cells
Clinical Trials of Gene Therapy for Primary Immune Deficiencies
Role of Cytoreductive Conditioning to Facilitate Engraftment
Adenosine Deaminase (ADA)-Deficient Severe Combined Immune Deficiency (SCID; Chapter 35)
X-linked SCID (Chapter 35)
Leukocyte Adhesion Defect (LAD; Chapter 22)
Chronic Granulomatous Disease (CGD; Chapter 22)
Wiskott-Aldrich Syndrome (WAS; Chapter 35)
Gene Therapy Considerations for Other PID
Gene Correction (Editing) for Gene Therapy of PID
Use of Pluripotent Stem Cells as a Source of HSC for Gene Therapy of PID
Gene Therapy for PID Involving Serum Protein Deficiencies
Advancing Gene Therapy for PID From Experimental to Standard of Care
Conclusion
Multiple-Choice Questions
References
Chapter 86: Glucocorticoids
Mechanisms of Action
Genomic Actions of Glucocorticoids
Structure of the Cytosolic Glucocorticoid Receptor
Translocation Into the Nucleus
Interactions With Transcription Factors
The cGCRβ Isoform
Posttranscriptional and Posttranslational Mechanisms
Glucocorticoid Receptor Resistance
Nongenomic Actions of Glucocorticoids
cGCR-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
Glucocorticoid Treatment Regimens: General Aspects
Low Dose
Medium Dose
High Dose
Very High Dose
Pulse Therapy
Alternate-Day Regimens
Glucocorticoid Withdrawal Regimens
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
Importance of Timing of Glucocorticoid Administration
New Glucocorticoid Receptor Ligands on the Horizon
Selective Glucocorticoid Receptor Agonists
Nitrosteroids
Long-Circulating Liposomal Glucocorticoids
Combining Prednisolone and Dipyridamole
Conclusions
Acknowledgments
Multiple-Choice Questions
References
Chapter 87: Immunomodulating Pharmaceuticals
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
Multiple-Choice Questions
References
Chapter 88: Protein Kinase Antagonists in Therapy of Immunological and Inflammatory Diseases
Structure and Function of Protein Kinases
The Discovery of Kinase Inhibitors
Imatinib and Other First-Generation Protein Tyrosine Kinases Inhibitors
Targeting Cytokine Signaling by Inhibiting Janus Kinases: Tofacitinib, Ruxolitinib, and Related Compounds
Targeting Antigen Receptor Signaling
Protein Kinase C Family and NF-κB
Lipid Kinases and Downstream Signaling
MAPK Pathways
The ERK Cascade
The JNK Cascade
The p38 MAPK Cascade
Conclusions
Multiple-Choice Questions
References
Chapter 89: Biological Modifiers of Inflammatory Diseases
Immunomodulatory Cytokines
Recombinant Interleukin-2 (Aldesleukin)
Interferons
Interferon-α
Interferon-β
Interferon-γ
Inhibitors of Inflammatory Cytokines
Tumor Necrosis Factor-α Inhibitors
Interleukin-1β Inhibitors
Interleukin-6 Inhibitors
On the Horizon: Other Anti–IL-6R and Anti–IL-6 mAbs and Sgp130:Fc Reagents
Interleukin-12/-23 Inhibitors
On the Horizon: IL-23 Specific Inhibitors
Interleukin-17 Inhibitors
Secukinumab
Ixekizumab
On the Horizon: Il17 Receptor Antagonists
Other Immunomodulatory Cytokines and Cytokine Inhibitors
On the Horizon: Inhibitors of the Type 1 Interferon Pathway
On the Horizon: Recombinant Promoters of Treg Function
Complement Pathway Inhibitors
Adhesion Molecule Inhibitors
Inhibitors of B-Cell Activation
On the Horizon: Other Inhibitors of B-Cell Activation
Inhibitors of T-Cell Activation
Basiliximab
Abatacept
Inhibitors of Mast Cell Activation
Omalizumab
Inhibitors of Eosinophil Activation
On the Horizon: Anti-IL-5 Receptor Reagents
B Cell– and T Cell–Depleting Agents
Rituximab
Ofatumumab
Obinutuzumab
Alemtuzumab
Brentuximab Vedotin
Multiple-Choice Questions
References
Chapter 90: Vaccines
History of Vaccines
Accomplishments of Vaccination
Recent Changes in Vaccine Development Strategies
Current Recommendations
Some Present and Future Challenges
A Vaccine Against Human Immunodeficiency Virus
Improved Influenza Vaccines
Zika Virus
Other Needed Vaccines
Multiple-Choice Questions
References
Chapter 91: Immunotherapy of Allergic Disease
Mechanisms of SIT
SIT for Venom Anaphylaxis
Assessing Effectiveness in Clinical Trials of SIT for Asthma and Rhinitis
SIT for Allergic Rhinitis
SIT for Asthma
SIT for Food Allergy
Comparison of SIT With Other Therapies
Effects of SIT on the Natural History of Allergic Disease
Safety
Sublingual Immunotherapy
Future Directions
Conclusions
Multiple-Choice Questions
References
Part Eleven: Diagnostic Immunology
Chapter 92: 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–MHC Multimers
Conclusions
Multiple-Choice Questions
References
Chapter 93: 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
NK Cell Activation and Function
NK Cell Cytotoxicity
Evaluation of Regulatory T-Cell (Treg) Function
Assessment of Signaling and DNA Repair Pathways in Lymphocytes via Phosphoflow Cytometry
Assessment of B-Cell Function
Summary
Multiple-Choice Questions
References
Chapter 94: 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
Multiple-Choice Questions
References
Chapter 95: Assessment of Human Allergic Diseases
Biological Properties of IgE
Clinical Importance of Total Serum IgE
Clinical Importance of Allergen-Specific IgE
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 IgE
Total IgE Measurements After Therapeutic Anti-IgE Administration
Allergen-Specific IgE
Allergen
Calibration
Single-Plex, Multiallergen, and Multiplex Assays
Competitive IgE Antibody Inhibition Assay
Allergen-Specific IgG
Mast-Cell Tryptase
Basophil Mediator Release Assays
Histamine Release Assay
Leukotriene C4 (LTC4) Release Assay
Utility of Mediator Release Assays as Diagnostic Tests
Flow Cytometry Basophil Activation Assays
Diagnostic Utility of Basophil Activation Flow Cytometric Assays
Multiple-Choice Questions
References
Chapter 96: Molecular Methods
Basic Principles
Genome Structure and Gene Expression
Polymorphic Variation and Linkage
Physical Maps and DNA Copy Number Variation
Mutation and Pathogenic Variants
X-Chromosome Inactivation
Description and Principles of DNA Diagnostic Techniques
Detection of Disease-Causing Copy Number Variants: FISH and Microarrays
Fluorescence in situ Hybridization
Array-Based Copy Number Analysis
Gene Expression
Detection of Disease Causing Mutations—Point Mutations, Insertions/Deletions, and Structural Variants
Sanger Sequencing
Next-Generation DNA Sequencing
Sequencing by synthesis (Illumina).
Electrochemical sequencing.
Long read sequencing—single-molecule sequencing and nanopores.
Bioinformatics
Sample and Laboratory Process Management
Primary Data Analysis—Genotyping and Base Calling
Secondary Data Analysis—Demultiplexing, Alignment, and Variant Calling
Tertiary Data Analysis—Variant Annotation, Interpretation, and Reporting
Clinical Performance of Genomics Assays
Recommendations for Use
Clinically Important Applications of Next-Generation Sequencing
Targeted Panels
Whole Exome/Whole-Genome Sequencing
Cell-Free DNA and Liquid Biopsy
Laboratory Standards and Reporting
Future Directions
Translational Research and Clinical Application
Multiple-Choice Questions
References
Appendix 1: Selected CD Molecules and Their Characteristics
Appendix 2: Laboratory Reference Values