About the Authors
Contributors
Preface and Acknowledgments
1 OVERVIEW OF THE IMMUNE SYSTEMIntroduction
Innate and Acquired Immunity
Innate Immunity
Acquired Immunity
Active, Passive, and Adoptive Immunization
Clonal Selection Theory
Humoral and Cellular Immunity
Cell-Mediated Immunity
Generation of Diversity in the Immune Response
Benefits of Immunology
Damaging Effects of the Immune Response
The Future of Immunology
The Short Course Begins Here References
2 INNATE IMMUNITY
Introduction
Innate Immunity
Physical and Chemical Barriers of Innate Immunity
Intracellular and Extracellular Killing of Microorganisms
Cells Involved in the Innate Immune System
Inflammation
Fever
Biologically Active Substances
Receptors Involved in the Innate Immune System
Pattern Recognition Receptors
Acquired Immunity
Cells and Organs Involved in Acquired Immunity
The Lymphatic Organs
Lymphocyte Migration and Recirculation
Fate of Antigen After Penetration
Frequency of Antigen-Specific Naive Lymphocytes
Interrelationship Between Innate and Acquired Immunity
Summary
References
Review
Questions
Answers to Review Questions
3 ADAPTIVE IMMUNITY
4 IMMUNOGENS AND ANTIGENS
Introduction
Requirements for Immunogenicity
Foreignness
High Molecular Weight
Chemical Complexity
Degradability
Haptens
Further Requirements for Immunogenicity
Primary and Secondary Immune Responses
Antigenicity and Antigen-Binding Site
Epitopes Recognized by B and T Cells
Major Classes of Antigens
Binding of Antigen to Antigen-Specific Antibodies or T Cell Receptors
Cross-Reactivity
Adjuvants
Summary
References
Review Questions
Answers to Review Questions
5 ANTIBODY STRUCTURE AND FUNCTION
Introduction
Isolation and Characterization of Immunoglobulins
Structure of Light and Heavy Chains
Immunoglobulin Domains
Immunoglobulin Hinge Region
Immunoglobulin Variable Region
Immunoglobulin Variants
Isotypes
Allotypes
Idiotypes
Structural Features of IgG
Biologic Properties of IgG
Agglutination and Formation of Precipitate
Passage of Ig Through the Placenta and Absorption in Neonates
Opsonization
Antibody-Dependent, Cell-Mediated Cytotoxicity
Activation of Complement
Neutralization of Toxins
Immobilization of Bacteria
Neutralization of Viruses
Structural Features of IgM
Biologic Properties of IgM
Complement Fixation
First
Line of Humoral Defense
Agglutination
Isohemagglutinins
Structural and Biologic Properties of IgA
Biologic Properties of IgA
Role in Mucosal Infections
Bactericidal Activity
Antiviral Activity
Structural and Biologic Properties of IgD
Structural and Biologic Properties of IgE
Importance of IgE in Parasitic Infections and Hypersensitivity Reactions
Kinetics of Antibody Responses Following Immunization
Primary Response
Secondary Response
The Immunoglobulin Superfamily
Summary
References
Review Questions
Answers to Review Questions
6 ANTIGEN–ANTIBODY INTERACTIONS, IMMUNE ASSAYS, AND EXPERIMENTAL SYSTEMS
Introduction
Antigen–Antibody Interactions
Primary Interactions Between Antibody and Antigen
Association Constant
Affinity and Avidity
Secondary Interactions Between Antibody and Antigen
AgglutinationnReactions
PrecipitationnReactions
Immunoassays
Direct-Binding Immunoassays
Solid-Phase Immunoassays
Immunofluorescence
Direct Immunofluorescence
Indirect Immunofluorescence
Fluorescence-Activated Cell-Sorting Analysis
Immunoabsorption and Immunoadsorption
Cellular Assays
Assays to Assess Lymphocyte Function
B- and T-Cell Proliferation Assays
Assays that Assess Antibody Production by B Cells
Effector Cell Assays for T and NK Cells
Cell Culture
Primary Cell Cultures and Cloned Lymphoid Cell Lines
B-Cell Hybridomas and Monoclonal Antibodies
T-Cell Hybridomas
Genetically Engineered Molecules and Receptors
Experimental Animal Models
Inbred Strains
Adoptive Transfer
SCID Mice
Thymectomized and Congenically Athymic (Nude) Mice
Transgenic Mice and Gene Targeting
Transgenic Mice
Knockout Mice
Analysis of Gene Expression: Microarrays
Summary
References
Review Questions
Answers to Review Questions
7 THE GENETIC BASIS OF ANTIBODY STRUCTURE
Introduction
A Brief Review of Nonimmunoglobulin Gene Structure and Gene Expression
Genetic Events in Synthesis of Ig Chains
Organization and Rearrangement of Light-Chain Genes
Organization and Rearrangement of Heavy-Chain Genes
Regulation of Ig Gene Expression
Class or Isotype Switching
Generation of Antibody Diversity
Presence of Multiple V Genes in the Germline
VJ and VDJ Combinatorial Association
Random Assortment of H and L Chains
Junctional Diversity
Somatic Hypermutation
Somatic Gene Conversion
Receptor Editing
Role of Activation-Induced Cytidine Deaminase in Generating Antibody Diversity
Summary
References
Review Questions
Case Study
Answers to Review Questions
Answer to Case Study
8 BIOLOGY OF THE B LYMPHOCYTEIntroduction
Development of B Lymphocytes
Overview
Sites of Early B-Cell Differentiation
Early Stages of B-Cell Differentiation: Pro-B and Pre-B Cells
Immature B Cells
Mature B Cells
B-Lymphocyte Traffic: Anatomical Distribution of B-Cell Populations
Sites of Antibody Synthesis
Thymus-Dependent Antibody Synthesis in the Germinal Center
Antibody Synthesis in Mucosal Tissue
Thymus-Independent Antibody Responses at Different Sites
B-Cell Membrane Proteins
Stage-Specific Markers
Antigen-Binding Molecules: Membrane Immunoglobulin
Signal Transduction Molecules Associated with Membrane Immunoglobulin
Molecules Involved in T Cell–B Cell Interactions
Summary
References
Review Questions
Answers to Review Questions
9 HOW T CELLS RECOGNIZE ANTIGEN: THE ROLE OF THE MAJOR HISTOCOMPATIBILITY COMPLEX
Introduction
How the MHC Got Its Name
Different MHC Molecules Interact with Different Sets of T Cells
Variability of MHC Class I and MHC Class II Molecules
Structure of MHC Class I Molecules
Selectivity of Peptide Binding to MHC Class I Molecules
CD8 Binding to Invariant Region of MHC Class I Molecules
Structure of MHC Class II Molecule
Antigen Processing and Presentation: How MHC Molecules Bind Peptides and Create Ligands that Interact with T Cells
Exogenous Antigens and Generation of MHC Class II–Peptide Complexes
Endogenous Antigens: Generation of MHC Class I–Peptide Complexes
Decreased MHC Class I Expression in Virus-Infected and Tumor Cells
Cross-Presentation: Exogenous Antigens Presented in the MHC Class I Pathway
Which Antigens Trigger Which T-Cell Responses?
Binding of Peptides Derived from Self-Molecules by MHC Molecules
Inability to Respond to an Antigen
Other Types of Antigen that Activate T-Cell Responses
Lipids and Glycolipids Presented by CD1 to NKT Cells
Genes of the HLA Region
Polymorphic MHC Class I and II Genes
Nomenclature of Polymorphic MHC Molecules
Regulation of Expression of MHC Genes
Codominant Expression
Coordinate Regulation
Inheritance of MHC Genes
Other Genes Within HLA
MHC in Other Species
Diversity of MHC Molecules: MHC Association with Resistance and Susceptibility to Disease
Summary
References
Review Questions
Answers to Review Questions
10 BIOLOGY OF THE T LYMPHOCYTE
Introduction
The Antigen-Specific T-Cell Receptor
Molecules that Interact with Antigen
T-Cell Receptor Complex
Coreceptor Molecules
Other Important Molecules Expressed on the T-Cell Surface
Genes Coding for T-Cell Receptors
Generation of T-Cell Receptor Diversity
T-Cell Differentiation in Thymus
Interactions of Developing T Cells with Nonlymphoid Cells of Thymus
Early T-Cell Receptor Gene Rearrangements: Double-Negative Cells and Splitting Off of γδ T Cells
Pre-T Cells
Double-Positive Cells
Thymic Selection
Role of AIRE Gene Product in Negative Selection
Single-Positive Cells
Generation of the T-Cell Repertoire
Characteristics of αβ T Cells Emerging from Thymus
Further Differentiation of CD4+ and CD8+ T Cells Outside Thymus
Differentiation of Other Sets of Cells in Thymus
Summary
References
Review Questions
Answers to Review Questions
11 ACTIVATION AND FUNCTION OF T CELLS
Introduction
Activation of CD4+ T Cells
Specialized Cells Present Antigen to Naive CD4+ T Cells
Paired Interactions at the Surface of APC and CD4+ T Cells
Intracellular Events in CD4+ T-Cell Activation
Clonal Expansion, Differentiation to Effector Cells, and Migration Out of the Lymph Node
Other Ways to Activate CD4+ T Cells
Superantigens
Plant Proteins and Antibodies to T-Cell Surface Molecules
T-Cell Function
Subsets of CD4+ T Cells Defined by Cytokine Production and Effector Function
CD4+ T Cells
T-Helper-Cell Function: Interaction of CD4+ T Cells with B Cells to Synthesize Antibody
Activation and Function of CD8+ T Cells
Generation of Effector CD8+ T Cells
CD8+ T-Cell Killing of Target Cells
MHC Restriction and CD8+ T Cell Killer Function
Termination of the Response: Induction of Memory Cells
Function of NKT Cells and γδ T Cells
NKT Cells
γδ T Cells
B-Cell Function: Antibody Synthesis in the Absence of T-Cell Help
Conjugate Vaccines
Intracellular Pathways in B-Cell Activation
Modulation of BCR Signal
Summary
References
Review Questions
Answers to Review Questions
12 CYTOKINES
Introduction
The History of Cytokines
Pleiotropic and Redundant Properties of Cytokines
General Properties of Cytokines
Common Functional Properties
Common Systemic Activities
Common Cell Sources and Cascading Events
Functional Categories of Cytokines
Cytokines that Facilitate Innate Immune Responses
Cytokines that Regulate Adaptive Immune Responses
Cytokines that Induce Differentiation of Distinct T-Cell Lineages
Cytokines that Inhibit Lineage-Specific T-Cell Differentiation
Cytokines that Promote Inflammatory Responses
Cytokines that Affect Leukocyte Movement
Cytokines that Stimulate Hematopoiesis
Cytokine Receptors
Cytokine Receptor Families
Common Cytokine Receptor Chains
Cytokine Receptor-Mediated Signal Transduction
Role of Cytokines and Cytokine Receptors in Disease
Toxic-Shock Syndrome
Bacterial Septic Shock
Cancers
Autoimmunity and Other Immune-Based Diseases
Therapeutic Exploitation of Cytokines and Cytokine Receptors
Cytokine Inhibitors/Antagonists
Reversing Cellular Deficiencies
Treatment of Immunodeficiencies
Treatment of Cancer and Transplant Patients
Treatment of Allergies and Asthma
Summary
References
Review Questions
Answers to Review Questions
13 TOLERANCE AND AUTOIMMUNITY
Introduction
Central Tolerance
Anergy, Receptor Editing, Deletion, and Clonal Ignorance
Peripheral Tolerance
Anergy
Fas–FasL Interactions
Regulatory/Suppressor T Cells
Oral Tolerance
Immune Privilege
Autoimmunity and Disease
Genetic Susceptibility
Environmental Susceptibility
Drug and Hormonal Triggers of Autoimmunity
Autoimmune Diseases
Autoimmune Diseases in Which Antibodies Play a Predominant Role in Mediating Organ Damage
Autoimmune Diseases in Which T Cells Play a Predominant Role in Organ Damage
Therapeutic Strategies
Summary
References
Review
Questions
Answers to Review Questions
14 COMPLEMENT
Introduction
Overview of Complement Activation
Classical Pathway
Lectin Pathway
Alternative Pathway
Steps Shared by All Pathways: Activation of C3 and C5
Terminal Pathway
Regulation of Complement Activity
Biologic Activities of Complement
Production of Opsonins
Production of Anaphylatoxins
Lysis
Other Important Complement Functions
Complement Deficiencies
Summary
References
Review Questions
Answers to Review Questions
15 HYPERSENSITIVITY: TYPE I
Introduction
Coombs–Gell Hypersensitivity Designations
General Characteristics of Allergic Reactions
Sensitization Phase
Activation Phase
Effector Phase
Late-Phase Reaction
Clinical Aspects of Allergic Reactions
Allergic Rhinitis
Food Allergies
Atopic Dermatitis
Asthma
Clinical Tests for Allergies and Clinical Intervention
Detection
Intervention
Protective Role of IgE
Summary
References
Review Questions
Answers to Review Questions
16 HYPERSENSITIVITY: TYPES II AND III
Introduction
Type II Hypersensitivity
Complement-Mediated Reactions
Antibody-Dependent, Cell-Mediated Cytotoxicity
Antibody-Mediated Cellular Dysfunction
Examples of Type II Hypersensitivity Reactions
Transfusion Reactions
Drug-Induced Reactions
Rh Incompatibility Reactions
Reactions Involving Cell Membrane Receptors
Reactions Involving Other Cell Membrane Determinants
Type III Hypersensitivity
Systemic Immune Complex Disease
Localized Immune Complex Disease
Summary
References
Review Questions
Answers to Review Questions
17 HYPERSENSITIVITY: TYPE IV
Introduction
General Characteristics and Pathophysiology of DTH
Mechanisms Involved in DTH
Examples of DTH
Contact Sensitivity
Granulomatous Hypersensitivity
Tuberculin-Type Hypersensitivity
Allograft Rejection
Additional Examples of DTH
Treatment of DTH
Summary
References
Review Questions
Answers to Review Questions
18 IMMUNODEFICIENCY DISORDERS AND NEOPLASIAS OF THE LYMPHOID SYSTEM
Introduction
Immunodeficiency Syndromes
Primary Immunodeficiency Syndromes
Secondary Immunodeficiency Diseases
Acquired Immunodeficiency Syndrome
Initial Description and Epidemiology
Human Immunodeficiency Virus
Clinical Course
Prevention, Control, Diagnosis, and Therapy of HIV Infection
Neoplasms of Lymphoid System
B-Cell Neoplasms
T-Cell Neoplasms
Hodgkin Lymphoma
Immunotherapy
Summary
References
Review Questions
Answers to Review Questions
19 TRANSPLANTATION
Introduction
Relationship Between Donor and Recipient
Immune Mechanisms Responsible for Allograft Rejection
Categories of Allograft Rejection
Hyperacute Rejection
Acute Rejection
Chronic Rejection
Role of MHC Molecules in Allograft Rejection
Mechanisms of Alloantigen Recognition by T Cells
Role of T-Cell Lineages and Cytokines in Allograft Rejection
Laboratory Tests Used in Tissue Typing
Prolongation of Allograft Survival: Immunosuppresive Therapy
Anti-Inflammatory Agents
Cytotoxic Drugs
Agents that Interfere with Cytokine Production and Signaling
Immunosuppressive Antibody Therapy
New Immunosuppressive Strategies and Frontiers
Hematopoietic Stem Cell Transplantation
Graft-Versus-Host Disease
Xenogeneic Transplantation
The Fetus: A Tolerated Allograft
Summary
References
Review Questions
Answers to Review Questions
20 TUMOR IMMUNOLOGY
Introduction
Tumor Antigens
Categories of Tumor Antigens
Normal Cellular Gene Products
Mutant Cellular Gene Products
Tumor Antigens Encoded by Oncogenes
Immunologic Factors Influencing the Incidence of Cancer
Effector Mechanisms in Tumor Immunity
B-Cell Responses to Tumors
Cell-Mediated Responses to Tumor Cells
Cytokines
Limitations of the Effectiveness of Immune Responses Against Tumors
Immunodiagnosis
Detection of Myeloma Proteins Produced by Plasma Cell Tumors
Detection of α-Fetoprotein
Carcinoembryonic Antigen
Detection of Prostate-Specific Antigen
Cancer Antigen-125
Radiolabeled Monoclonal Antibody B72.3
Tumor Immunoprophylaxis
Immunotherapy
Summary
References
Review Questions
Answers to Review Questions
21 RESISTANCE AND IMMUNIZATION TO INFECTIOUS DISEASES
Introduction
Host Defense Against Various Classes of Microbial Pathogens
Immunity to Viruses
Immunity to Bacteria
Immunity to Parasites
Immunity to Fungi
Mechanisms by Which Pathogens Evade Immune Responses
Encapsulated Bacteria
Toxins
Superantigens
Antigenic Variation
Intracellular Survival
Suppression of the Immune System
Extracellular Enzymes
Expression of Antibody-Binding Proteins
Principles of Immunization
Objectives of Immunization
Active Immunizations
Recommended Immunizations
Use of Vaccines in Selected Populations
Basic Mechanisms of Protection
Significance of Primary and Secondary
Immune Responses
Age and Timing of Immunizations
Vaccine Precautions
Site of Administration of Antigen
Hazards
Recent Approaches to Production of Vaccines
Vaccines Produced by Recombinant DNA
Conjugated Polysaccharides
Synthetic Peptide Vaccines
Anti-Idiotype Vaccines
Virus-Carrier Vaccine
Bacterium-Carrier Vaccine
DNA Vaccines
Toxoids
Passive Immunization
Passive Immunization Through Placental Antibody
Transfer
Passive Immunization via Colostrum
Passive Antibody Therapy and Serum
Therapy
Monoclonal and Polyclonal Antibodies
Preparation and Properties of Human Immune Serum
Globulin
Indications for Use of Immune Globulin
Precautions About Uses of Human Immune Serum
Globulin Therapy
Colony-Stimulating Factors
Summary
References
Review Questions
Answers to Review Questions
Glossary
Appendix: Partial List of CD Antigens
Index