Contents

1. Chapter 1: Overview of the Immune System
   1. A Historical Perspective of Immunology
      1. Early Vaccination Studies Led the Way to Immunology
      2. Vaccination Is an Ongoing, Worldwide Enterprise
      3. Immunology Is about More than Just Vaccines and Infectious Disease
      4. Immunity Involves Both Humoral and Cellular Components
      5. How Are Foreign Substances Recognized by the Immune System?
   2. Important Concepts for Understanding the Mammalian Immune Response
      1. Pathogens Come in Many Forms and Must First Breach Natural Barriers
      2. The Immune Response Quickly Becomes Tailored to Suit the Assault
      3. Pathogen Recognition Molecules Can Be Encoded as Genes or Generated by DNA Rearrangement
      4. Tolerance Ensures That the Immune System Avoids Destroying the Host
      5. The Immune Response Is Composed of Two Interconnected Arms: Innate Immunity and Adaptive Immunity
      6. Immune Cells and Molecules Can Be Found in Many Places
      7. Adaptive Immune Responses Typically Generate Memory
   3. The Good, Bad, and Ugly of the Immune System
      1. Inappropriate or Dysfunctional Immune Responses Can Result in a Range of Disorders
      2. The Immune Response Renders Tissue Transplantation Challenging
      3. Cancer Presents a Unique Challenge to the Immune Response
   4. Conclusion
   5. References
   6. Study Questions
2. Chapter 2: Cells, Organs, and Microenvironments of the Immune System
   1. Hematopoiesis and Cells of the Immune System
      1. Hematopoietic Stem Cells Differentiate into All Red and White Blood Cells
      2. HSCs Differentiate into Myeloid and Lymphoid Blood Cell Lineages
      3. Cells of the Myeloid Lineage Are the First Responders to Infection
      4. Cells of the Lymphoid Lineage Regulate the Adaptive Immune Response
   2. Primary Lymphoid Organs: Where Immune Cells Develop
      1. The Site of Hematopoiesis Changes during Embryonic Development
      2. The Bone Marrow Is the Main Site of Hematopoiesis in the Adult
      3. The Thymus Is the Primary Lymphoid Organ Where T Cells Mature
   3. Secondary Lymphoid Organs: Where the Immune Response Is Initiated
      1. Secondary Lymphoid Organs Are Distributed throughout the Body and Share Some Anatomical Features
      2. Blood and Lymphatics Connect Lymphoid Organs and Infected Tissue
      3. The Lymph Node Is a Highly Specialized Secondary Lymphoid Organ
      4. The Spleen Organizes the Immune Response against Blood-Borne Pathogens
      5. Barrier Organs Also Have Secondary Lymphoid Tissue
      6. Tertiary Lymphoid Tissues Also Organize and Maintain an Immune Response
   4. Conclusion
   5. References
   6. Study Questions
3. Chapter 3: Recognition and Response
   1. General Properties of Immune Receptor-Ligand Interactions
      1. Receptor-Ligand Binding Occurs via Multiple Noncovalent Bonds
      2. How Do We Describe the Strength of Receptor-Ligand Interactions?
      3. Interactions between Receptors and Ligands Can Be Multivalent
      4. Combinatorial Expression of Protein Chains Can Increase Ligand-Binding Diversity
      5. Adaptive Immune Receptor Genes Undergo Rearrangement in Individual Lymphocytes
      6. Levels of Receptor and Ligand Expression Can Vary during an Immune Response
      7. Local Concentrations of Ligands May Be Extremely High during Cell-Cell Interactions
      8. Many Immune Receptors Include Immunoglobulin Domains
      9. Immune Antigen Receptors Can Be Transmembrane, Cytosolic, or Secreted
   2. Immune Antigen Receptor Systems
      1. The B-Cell Receptor Has the Same Antigen Specificity as Its Secreted Antibodies
      2. T-Cell Antigen Receptors Recognize Antigen in the Context of MHC Proteins
      3. Receptors of Innate Immunity Bind to Conserved Molecules on Pathogens
   3. Cytokines and Their Receptors
      1. Cytokines Are Described by Their Functions and the Distances at Which They Act
      2. Cytokines Exhibit the Attributes of Pleiotropy, Redundancy, Synergism, Antagonism, and Cascade Induction
      3. Cytokines of the IL-1 Family Promote Proinflammatory Signals
      4. Class 1 Cytokines Share a Common Structural Motif But Have Varied Functions
      5. Class 2 Cytokines Are Grouped into Three Families of Interferons
      6. TNF Family Cytokines May Be Soluble or Membrane-Bound
      7. The IL-17 Family of Cytokines and Receptors Is the Most Recently Identified
      8. Chemokines Induce the Directed Movement of Leukocytes
   4. A Conceptual Framework for Understanding Cell Signaling
      1. Ligand Binding Can Induce Dimerization or Multimerization of Receptors
      2. Ligand Binding Can Induce Phosphorylation of Tyrosine Residues in Receptors or Receptor-Associated Molecules
      3. Src-Family Kinases Play Important Early Roles in the Activation of Many Immune Cells
      4. Intracellular Adapter Proteins Gather Members of Signaling Pathways
      5. Common Sequences of Downstream Effector Relays Pass the Signal to the Nucleus
      6. Not All Ligand-Receptor Signals Result in Transcriptional Alterations
   5. Immune Responses: The Outcomes of Immune System Recognition
      1. Changes in Protein Expression Facilitate Migration of Leukocytes into Infected Tissues
      2. Activated Macrophages and Neutrophils May Clear Pathogens without Invoking Adaptive Immunity
      3. Antigen Activation Optimizes Antigen Presentation by Dendritic Cells
      4. Cytokine Secretion by Dendritic Cells and T Cells Can Direct the Subsequent Immune Response
      5. Antigen Stimulation by T and B Cells Promotes Their Longer-Term Survival
      6. Antigen Binding by T Cells Induces Their Division and Differentiation
      7. Antigen Binding by B Cells Induces Their Division and Differentiation
   6. Conclusion
   7. References
   8. Study Questions
4. Chapter 4: Innate Immunity
   1. Anatomical Barriers to Infection
      1. Epithelial Barriers Prevent Pathogen Entry into the Body’s Interior
      2. Antimicrobial Proteins and Peptides Kill Would-Be Invaders
   2. Cellular Innate Response Receptors and Signaling
      1. Toll-Like Receptors Initiate Responses to Many Types of Molecules from Extracellular Pathogens
      2. C-Type Lectin Receptors Bind Carbohydrates on the Surfaces of Extracellular Pathogens
      3. NOD-Like Receptors Bind PAMPs from Cytosolic Pathogens
      4. ALRs Bind Cytosolic DNA
      5. RLRs Bind Cytosolic Viral RNA
      6. cGAS and STING Are Activated by Cytosolic DNA and Dinucleotides
   3. Induced Innate Immunity Effector Mechanisms
      1. Expression of Innate Immunity Proteins Is Induced by PRR Signaling
      2. Phagocytosis Is an Important Mechanism for Eliminating Pathogens
      3. Regulated Cell Death Contributes to Pathogen Elimination
      4. Local Inflammation Is Triggered by Innate Immune Responses
   4. Innate Lymphoid Cells
      1. Natural Killer Cells Are ILCs with Cytotoxic Activity
      2. ILC Populations Produce Distinct Cytokines and Have Different Roles
   5. Regulation and Evasion of Innate and Inflammatory Responses
      1. Innate and Inflammatory Responses Can Be Harmful
      2. Innate and Inflammatory Responses Are Regulated Both Positively and Negatively
      3. Pathogens Have Evolved Mechanisms to Evade Innate and Inflammatory Responses
   6. Interactions between the Innate and Adaptive Immune Systems
      1. The Innate Immune System Activates Adaptive Immune Responses
      2. Recognition of Pathogens by Dendritic Cells Influences Helper T-Cell Differentiation
      3. Some Antigens Containing PAMPs Can Activate B Cells Independent of Helper T Cells
      4. Adjuvants Activate Innate Immune Responses That Increase the Effectiveness of Immunizations
      5. Some Pathogen Clearance Mechanisms Are Common to Both Innate and Adaptive Immune Responses
   7. Ubiquity of Innate Immunity
      1. Some Innate Immune System Components Occur across the Plant and Animal Kingdoms
      2. Invertebrate and Vertebrate Innate Immune Responses Show Both Similarities and Differences
   8. Conclusion
   9. References
   10. Study Questions
5. Chapter 5: The Complement System
   1. The Major Pathways of Complement Activation
      1. The Classical Pathway Is Initiated by Antibody Binding to Antigens
      2. The Lectin Pathway Is Initiated When Soluble Proteins Recognize Microbial Antigens
      3. The Alternative Pathway Is Initiated in Three Distinct Ways
      4. The Three Complement Pathways Converge at the Formation of C5 Convertase and Generation of the MAC
   2. The Diverse Functions of Complement
      1. Complement Receptors Connect Complement-Tagged Pathogens to Effector Cells
      2. Complement Enhances Host Defense against Infection
      3. Complement Acts at the Interface between Innate and Adaptive Immunities
      4. Complement Aids in the Contraction Phase of the Immune Response
   3. The Regulation of Complement Activity
      1. Complement Activity Is Passively Regulated by Short Protein Half-Lives and Host Cell Surface Composition
      2. The C1 Inhibitor, C1INH, Promotes Dissociation of C1 Components
      3. Decay-Accelerating Factor Promotes Decay of C3 Convertases
      4. Factor I Degrades C3b and C4b
      5. CD59 (Protectin) Inhibits the MAC Attack
      6. Carboxypeptidases Can Inactivate the Anaphylatoxins C3a and C5a
   4. Complement Deficiencies
   5. Microbial Complement Evasion Strategies
   6. The Evolutionary Origins of the Complement System
   7. Conclusion
   8. References
   9. Study Questions
6. Chapter 6: The Organization and Expression of Lymphocyte Receptor Genes
   1. The Puzzle of Immunoglobulin Gene Structure
      1. Investigators Proposed Two Early Theoretical Models of Antibody Genetics
      2. Breakthrough Experiments Revealed That Multiple Gene Segments Encode the Immunoglobulin Light Chain
   2. Multigene Organization of Immunoglobulin Genes
      1. κ Light-Chain Genes Include V, J, and C Segments
      2. λ Light-Chain Genes Include Paired J and C Segments
      3. Heavy-Chain Gene Organization Includes V_H, D, J_H, and C_H Segments
      4. The Antibody Genes Found in Mature B Cells Are the Product of DNA Recombination
   3. The Mechanism of V(D)J Recombination
      1. V(D)J Recombination in Lymphocytes Is a Highly Regulated Sequential Process
      2. Recombination Is Directed by Recombination Signal Sequences
      3. Gene Segments Are Joined by a Diverse Group of Proteins
      4. V(D)J Recombination Occurs in a Series of Well-Regulated Steps
      5. Five Mechanisms Generate Antibody Diversity in Naïve B Cells
      6. The Regulation of V(D)J Gene Recombination Involves Chromatin Alteration
   4. B-Cell Receptor Expression
      1. Each B Cell Synthesizes only one Heavy Chain and One Light Chain
      2. Receptor Editing of Potentially Autoreactive Receptors Occurs in Light Chains
      3. mRNA Splicing Regulates the Expression of Membrane-Bound versus Secreted Ig
   5. T-Cell Receptor Genes and Their Expression
      1. Understanding the Protein Structure of the TCR Was Critical to the Process of Discovering the Genes
      2. The β-Chain Gene Was Discovered Simultaneously in Two Different Laboratories
      3. A Search for the α-Chain Gene Led to the γ-Chain Gene Instead
      4. TCR Genes Are Arranged in V, D, and J Clusters of Gene Segments
      5. Recombination of TCR Gene Segments Proceeds at a Different Rate and Occurs at Different Stages of Development in αβ versus γδ T Cells
      6. The Process of TCR Gene Segment Rearrangement Is Very Similar to Immunoglobulin Gene Recombination
      7. TCR Expression Is Controlled by Allelic Exclusion
   6. Conclusion
   7. References
   8. Study Questions
7. Chapter 7: The Major Histocompatibility Complex and Antigen Presentation
   1. The Structure and Function of MHC Class I and II Molecules
      1. Class I Molecules Consist of One Large Glycoprotein Heavy Chain Plus a Small Protein Light Chain
      2. Class II Molecules Consist of Two Nonidentical Membrane-Bound Glycoprotein Chains
      3. Class I and II Molecules Exhibit Polymorphism in the Region That Binds to Peptides
   2. The Organization and Inheritance of MHC Genes
      1. The MHC Locus Encodes the Three Major Classes of MHC Molecules
      2. Allelic Forms of MHC Genes Are Inherited in Linked Groups Called Haplotypes
      3. MHC Molecules Are Codominantly Expressed
      4. Class I and Class II Molecules Exhibit Diversity at Both the Individual and Species Levels
      5. MHC Polymorphism Is Primarily Limited to the Antigen-Binding Groove
   3. The Role and Expression Pattern of MHC Molecules
      1. MHC Molecules Present Both Intracellular and Extracellular Antigens
      2. MHC Class I Expression Is Found Throughout the Body
      3. Expression of MHC Class II Molecules Is Primarily Restricted to Antigen-Presenting Cells
      4. MHC Expression Can Change with Changing Conditions
      5. MHC Alleles Play a Critical Role in Immune Responsiveness
      6. Seminal Studies Demonstrate That T Cells Recognize Peptide Presented in the Context of Self-MHC Alleles
      7. Evidence Suggests Distinct Antigen Processing and Presentation Pathways
   4. The Endogenous Pathway of Antigen Processing and Presentation
      1. Peptides Are Generated by Protease Complexes Called Proteasomes
      2. Peptides Are Transported from the Cytosol to the Rough Endoplasmic Reticulum
      3. Chaperones Aid Peptide Assembly with MHC Class I Molecules
   5. The Exogenous Pathway of Antigen Processing and Presentation
      1. Peptides Are Generated from Internalized Antigens in Endocytic Vesicles
      2. The Invariant Chain Guides Transport of MHC Class II Molecules to Endocytic Vesicles
      3. Peptides Assemble with MHC Class II Molecules by Displacing CLIP
   6. Unconventional Antigen Processing and Presentation
      1. Dendritic Cells Can Cross-Present Exogenous Antigen via MHC Class I Molecules
      2. Cross-Presentation by APCs Is Essential for the Activation of Naïve CD8⁺ T Cells
   7. Presentation of Nonpeptide Antigens
   8. Conclusion
   9. References
   10. Study Questions
8. Chapter 8: T-Cell Development
   1. Early Thymocyte Development
      1. Thymocytes Progress through Four Double-Negative Stages
      2. Thymocytes Express Either αβ or γδ T Cell Receptors
      3. DN Thymocytes Undergo β-Selection, Which Results in Proliferation and Differentiation
   2. Positive and Negative Selection
      1. Thymocytes “Learn” MHC Restriction in the Thymus
      2. T Cells Undergo Positive and Negative Selection
      3. Positive Selection Ensures MHC Restriction
      4. Negative Selection (Central Tolerance) Ensures Self-Tolerance
      5. The Selection Paradox: Why Don’t We Delete All Cells We Positively Select?
      6. An Alternative Model Can Explain the Thymic Selection Paradox
      7. Do Positive and Negative Selection Occur at the Same Stage of Development, or in Sequence?
   3. Lineage Commitment
      1. Several Models Have Been Proposed to Explain Lineage Commitment
      2. Transcription Factors Th-POK and Runx3 Regulate Lineage Commitment
      3. Double-Positive Thymocytes May Commit to Other Types of Lymphocytes
   4. Exit from the Thymus and Final Maturation
   5. Other Mechanisms That Maintain Self-Tolerance
      1. T_REG Cells Negatively Regulate Immune Responses
      2. Peripheral Mechanisms of Tolerance Also Protect against Autoreactive Thymocytes
   6. Conclusion
   7. References
   8. Study Questions
9. Chapter 9: B-Cell Development
   1. B-Cell Development in the Bone Marrow
      1. Changes in Cell-Surface Markers, Gene Expression, and Immunoglobulin Gene Rearrangements Define the Stages of B-Cell Development
      2. The Earliest Steps in Lymphocyte Differentiation Culminate in the Generation of a Common Lymphoid Progenitor
      3. The Later Stages of B-Cell Development Result in Commitment to the B-Cell Phenotype and the Stepwise Rearrangement of Immunoglobulin Genes
      4. Immature B Cells in the Bone Marrow Are Exquisitely Sensitive to Tolerance Induction through the Elimination of Self-Reactive Cells
   2. Completion of B-Cell Development in the Spleen
      1. T1 and T2 Transitional B Cells Form in the Spleen and Undergo Selection for Survival and against Self-Reactivity
      2. T2 B Cells Give Rise to Mature Follicular B-2 B Cells
      3. T3 B Cells Are Primarily Self-Reactive and Anergic
   3. The Properties and Development of B-1 and Marginal Zone B Cells
      1. B-1a, B-1b, and MZ B Cells Differ Phenotypically and Functionally from B-2 B Cells
      2. B-1a B Cells Are Derived from a Distinct Developmental Lineage
   4. Comparison of B- and T-Cell Development
   5. Conclusion
   6. References
   7. Study Questions
10. Chapter 10: T-Cell Activation, Helper Subset Differentiation, and Memory
    1. T-Cell Activation and the Two-Signal Hypothesis
       1. TCR Signaling Provides Signal 1 and Sets the Stage for T-Cell Activation
       2. Costimulatory Signals Are Required for Optimal T-Cell Activation Whereas Coinhibitory Signals Prevent T-Cell Activation
       3. Clonal Anergy Results If a Costimulatory Signal Is Absent
       4. Cytokines Provide Signal 3
       5. Antigen-Presenting Cells Provide Costimulatory Ligands and Cytokines to Naïve T Cells
       6. Superantigens Are a Special Class of T-Cell Activators
    2. Helper CD4⁺ T-Cell Differentiation
       1. Helper T Cells Can Be Divided into Distinct Subsets and Coordinate Type 1 and Type 2 Responses
       2. The Differentiation of Helper T-Cell Subsets Is Regulated by Polarizing Cytokines
       3. Each Effector Helper T-Cell Subset Has Unique Properties
       4. Helper T Cells May Not Be Irrevocably Committed to a Lineage
       5. Helper T-Cell Subsets Play Critical Roles in Immune Health and Disease
    3. T-Cell Memory
       1. Naïve, Effector, and Memory T Cells Can Be Distinguished by Differences in Surface Protein Expression
       2. Memory Cell Subpopulations Are Distinguished by Their Locale and Effector Activity
       3. Many Questions Remain Surrounding Memory T-Cell Origins and Functions
    4. Conclusion
    5. References
    6. Study Questions
11. Chapter 11: B-Cell Activation, Differentiation, and Memory Generation
    1. T-Dependent B-Cell Responses: Activation
       1. Naïve B Cells Encounter Antigen in the Lymph Nodes and Spleen
       2. B-Cell Recognition of Cell-Bound Antigen Culminates in the Formation of an Immunological Synapse
       3. Antigen Binding to the BCR Leads to Activation of a Signal Transduction Cascade within the B Cell
       4. B Cells Also Receive and Propagate Signals through Coreceptors
       5. B Cells Use More Than One Mechanism to Acquire Antigen from Antigen-Presenting Cells
       6. Antigen Receptor Binding Induces Internalization and Antigen Presentation
       7. The Early Phases of the T-Dependent Response Are Characterized by Chemokine-Directed B-Cell Migration
       8. Specification of the Stimulated B-Cell Fate Depends on Transcription Factor Expression
    2. T-Dependent B-Cell Responses: Differentiation and Memory Generation
       1. Some Activated B Cells Differentiate into Plasma Cells That Form the Primary Focus
       2. Other Activated B Cells Enter the Follicles and Initiate a Germinal Center Response
       3. The Mechanisms of Somatic Hypermutation and Class Switch Recombination
       4. Memory B Cells Recognizing T-Dependent Antigens Are Generated Both within and outside the Germinal Center
       5. Most Newly Generated B Cells Are Lost at the End of the Primary Immune Response
    3. T-Independent B-Cell Responses
       1. T-Independent Antigens Stimulate Antibody Production in the Absence of T-Cell Help
       2. Two Novel Subclasses of B Cells Mediate the Response to T-Independent Antigens
    4. Negative Regulation of B Cells
       1. Negative Signaling through CD22 Balances Positive BCR-Mediated Signaling
       2. Negative Signaling through the Receptor FcγRIIb Inhibits B-Cell Activation
       3. CD5 Acts as a Negative Regulator of B-Cell Signaling
       4. B-10 B Cells Act as Negative Regulators by Secreting IL-10
    5. Conclusion
    6. References
    7. Study Questions
12. Chapter 12: Effector Responses: Antibody- and Cell-Mediated Immunity
    1. Antibody-Mediated Effector Functions
       1. Antibodies Provide Protection against Pathogens, Toxins, and Harmful Cells in a Variety of Ways
       2. Different Antibody Classes Mediate Different Effector Functions
       3. Fc Receptors Mediate Many Effector Functions of Antibodies
       4. Protective Effector Functions Vary among Antibody Classes
       5. Antibodies Have Many Therapeutic Uses in Treating Diseases
    2. Cell-Mediated Effector Responses
       1. Cytotoxic T Lymphocytes Recognize and Kill Infected or Tumor Cells via T-Cell Receptor Activation
       2. Natural Killer Cell Activity Depends on the Balance of Activating and Inhibitory Signals
       3. NKT Cells Bridge the Innate and Adaptive Immune Systems
    3. Conclusion
    4. References
    5. Study Questions
13. Chapter 13: Barrier Immunity: The Immunology of Mucosa and Skin
    1. Common Themes in Barrier Immune Systems
       1. All Barrier Surfaces Are Lined by One or More Layers of Epithelial Cells
       2. Barrier Organs Are Populated by Innate and Adaptive Immune Cells That Interact with Epithelium and Secondary Lymphoid Tissue
       3. Barrier Immune Systems Initiate Both Tolerogenic and Inflammatory Responses to Microorganisms
    2. Intestinal Immunity
       1. The Gut Is Organized into Different Anatomical Sections and Tissue Layers
       2. Gut Epithelial Cells Vary in Phenotype and Function
    3. Setting the Stage: Maintaining Immune Homeostasis in the Intestine
       1. The Gut Immune System Maintains a Barrier between the Microbiome and the Epithelium
       2. Antigen Is Delivered from the Intestinal Lumen to Antigen-Presenting Cells in Multiple Ways
       3. Immune Homeostasis in the Intestine Is Promoted by Several Innate and Adaptive Cell Types
       4. The Immune Systems in the Small and Large Intestines Differ
       5. Commensal Microbes Help Maintain Tolerogenic Tone in the Intestine
    4. Springing into Action: Intestinal Immune System Response to Invasion
       1. The Gut Immune System Recognizes and Responds to Harmful Pathogens
       2. The Intestinal Immune System Can Mount Both Type 1 and Type 2 Responses
    5. Dysbiosis, Inflammatory Bowel Disease, and Celiac Disease
    6. Other Barrier Immune Systems
       1. The Respiratory Immune System Shares Many Features with the Intestinal Immune System
       2. The Skin Is a Unique Barrier Immune System
    7. Conclusion
    8. References
    9. Study Questions
14. Chapter 14: The Adaptive Immune Response in Space and Time
    1. Immune Cells in Healthy Tissue: Homeostasis
       1. Naïve Lymphocytes Circulate between Secondary and Tertiary Lymphoid Tissues
       2. Extravasation Is Driven by Sequential Activation of Surface Molecules
       3. Naïve Lymphocytes Browse for Antigen along the Reticular Network of Secondary Lymphoid Organs
    2. Immune Cell Response to Antigen: The Innate Immune Response
       1. Innate Immune Cells Are Activated by Antigen Binding to Pattern Recognition Receptors
       2. Antigen Travels in Two Different Forms to Secondary Lymphoid Tissue via Afferent Lymphatics
       3. Antigen-Presenting Cells Presenting Processed Antigen Travel to the T-Cell Zones of Secondary Lymphoid Tissue
       4. Unprocessed Antigen Travels to the B-Cell Zones
       5. Blood-Borne Antigen Is Captured by Specialized APCs at the Marginal Zone of the Spleen
    3. First Contact between Antigen and Lymphocytes
       1. Naïve CD4⁺ T Cells Arrest Their Movements after Engaging Antigens
       2. B Cells Seek Help from CD4⁺ T Cells at the Border between the Follicle and Paracortex of the Lymph Node
       3. Dynamic Imaging Adds New Perspectives on B- and T-Cell Behavior in Germinal Centers
       4. CD8⁺ T Cells Are Activated in the Lymph Node via a Multicellular Interaction
       5. A Summary of the Timing of a Primary Response
       6. Differentiation into Central Memory T Cells Begins Early in the Primary Response
       7. The Immune Response Contracts within 10 to 14 Days
    4. The Effector and Memory Cell Response
       1. Activated Lymphocytes Exit the Lymph Node and Recirculate through Various Tissues
       2. Chemokine Receptors and Adhesion Molecules Regulate Homing of Memory and Effector Lymphocytes to Peripheral Tissues
    5. The Immune Response: Case Studies
       1. CD8⁺ T-Cell Response to Infection with Toxoplasma gondii
       2. Resident Memory T-Cell Response to Herpes Simplex Virus Infection
       3. Host Immune Cell Response to a Tissue Graft
       4. Dendritic Cell Contribution to Listeria Infection
       5. T-Cell Response to Tumors
       6. Regulatory T Cells Inhibit the Immune Response in Multiple Ways
    6. Conclusion
    7. References
    8. Study Questions
15. Chapter 15: Allergy, Hypersensitivities, and Chronic Inflammation
    1. Allergies: Type I Hypersensitivity
       1. IgE Antibodies Are Responsible for Type I Hypersensitivity
       2. Many Allergens Can Elicit a Type I Response
       3. IgE Antibodies Act by Binding Antigen, Resulting in the Cross-Linking of Fcε Receptors
       4. IgE Receptor Signaling Is Tightly Regulated
       5. Granulocytes Produce Molecules Responsible for Type I Hypersensitivity Symptoms
       6. Type I Hypersensitivities Are Characterized by Both Early and Late Responses
       7. There Are Several Categories of Type I Hypersensitivity Reactions
       8. Susceptibility to Type I Hypersensitivity Reactions Is Influenced by Both Environmental Factors and Genetics
       9. Diagnostic Tests and Treatments Are Available for Allergic Reactions
       10. Why Did Allergic Responses Evolve?
    2. Antibody-Mediated (Type II) Hypersensitivity
       1. Transfusion Reactions Are an Example of Type II Hypersensitivity
       2. Hemolytic Disease of the Newborn Is Caused by Type II Reactions
       3. Hemolytic Anemia Can Be Drug Induced
    3. Immune Complex–Mediated (Type III) Hypersensitivity
       1. Immune Complexes Can Damage Various Tissues
       2. Immune Complex–Mediated Hypersensitivity Can Resolve Spontaneously
       3. Auto-Antigens Can Be Involved in Immune Complex–Mediated Reactions
       4. Arthus Reactions Are Localized Type III Hypersensitivity Reactions
    4. Delayed-Type (Type IV) Hypersensitivity
       1. The Initiation of a Type IV DTH Response Involves Sensitization by Antigen
       2. The Effector Phase of a Classical DTH Response Is Induced by Second Exposure to a Sensitizing Antigen
       3. The DTH Reaction Can Be Detected by a Skin Test
       4. Contact Dermatitis Is a Type IV Hypersensitivity Response
    5. Chronic Inflammation
       1. Infections Can Cause Chronic Inflammation
       2. There Are Noninfectious Causes of Chronic Inflammation
       3. Obesity Is Associated with Chronic Inflammation
       4. Chronic Inflammation Can Cause Systemic Disease
    6. Conclusion
    7. References
    8. Study Questions
16. Chapter 16: Tolerance, Autoimmunity, and Transplantation
    1. Establishment and Maintenance of Tolerance
       1. Antigen Sequestration, or Evasion, Is One Means to Protect Self Antigens from Attack
       2. Central Tolerance Processes Occur in Primary Lymphoid Organs
       3. Cells That Mediate Peripheral Tolerance Are Generated Outside Primary Lymphoid Organs
       4. Multiple Immune Cell Types Work in the Periphery to Inhibit Anti-Self Responses
    2. Autoimmunity
       1. Some Autoimmune Diseases Target Specific Organs
       2. Some Autoimmune Diseases Are Systemic
       3. Both Intrinsic and Extrinsic Factors Can Favor Susceptibility to Autoimmune Disease
       4. What Causes Autoimmunity?
       5. Treatments for Autoimmune Disease Range from General Immune Suppression to Targeted Immunotherapy
    3. Transplantation Immunology
       1. Demand for Transplants Is High, but Organ Supplies Remain Low
       2. Antigenic Similarity between Donor and Recipient Improves Transplant Success
       3. Some Organs Are More Amenable to Transplantation Than Others
       4. Matching Donor and Recipient Involves Prior Assessment of Histocompatibility
       5. Allograft Rejection Follows the Rules of Immune Specificity and Memory
       6. Graft Rejection Takes a Predictable Clinical Course
       7. Immunosuppressive Therapy Can Be Either General or Target-Specific
       8. Immune Tolerance to Allografts Is Favored in Certain Instances
    4. Conclusion
    5. References
    6. Study Questions
17. Chapter 17: Infectious Diseases and Vaccines
    1. The Importance of Barriers and Vectors in Infectious Disease
    2. The Link between Location and Immune Effector Mechanism
       1. Mucosal or Barrier Infections Are Typically Controlled by T_H2-Type Responses
       2. Extracellular Pathogens Must Be Recognized and Attacked Using Extracellular Tools
       3. Mechanisms That Recognize Infected Host Cells Are Required to Combat Intracellular Infections
    3. Viral Infections
       1. The Antiviral Innate Response Provides Key Instructions for the Later Adaptive Response
       2. Many Viruses Are Neutralized by Antibodies
       3. Cell-Mediated Immunity is Important for Viral Control and Clearance
       4. Viruses Employ Several Strategies to Evade Host Defense Mechanisms
       5. The Imprinting of a Memory Response Can Influence Susceptibility to Future Viral Infection
    4. Bacterial Infections
       1. Immune Responses to Extracellular and Intracellular Bacteria Differ
       2. Bacteria Can Evade Host Defense Mechanisms at Several Different Stages
    5. Parasitic Infections
       1. Protozoan Parasites Are a Diverse Set of Unicellular Eukaryotes
       2. Parasitic Worms (Helminths) Typically Generate Weak Immune Responses
    6. Fungal Infections
       1. Innate Immunity Controls Most Fungal Infections
       2. Immunity against Fungal Pathogens Can Be Acquired
    7. Emerging and Re-emerging Infectious Diseases
       1. Some Noteworthy New Infectious Diseases Have Appeared Recently
       2. Diseases May Re-emerge for Various Reasons
    8. Vaccines
       1. Basic Research and Rational Design Advance Vaccine Development
       2. Protective Immunity Can Be Achieved by Active or Passive Immunization
       3. There Are Several Vaccine Strategies, Each with Unique Advantages and Challenges
       4. Adding a Conjugate or Multivalent Component Can Improve Vaccine Immunogenicity
       5. Adjuvants Are Included to Enhance the Immune Response to a Vaccine
    9. Conclusion
    10. References
    11. Study Questions
18. Chapter 18: Immunodeficiency Diseases
    1. Primary Immunodeficiencies
       1. Primary Immunodeficiency Diseases Are Often Detected Early in Life
       2. Combined Immunodeficiencies Disrupt Adaptive Immunity
       3. B-Cell Immunodeficiencies Exhibit Depressed Production of One or More Antibody Isotypes
       4. Disruptions to Innate Immune Components May Also Impact Adaptive Responses
       5. Complement Deficiencies Are Relatively Common
       6. NK-Cell Deficiencies Increase Susceptibility to Viral Infections and Cancer
       7. Immunodeficiency Disorders That Disrupt Immune Regulation Can Manifest as Autoimmunity
       8. Immunodeficiency Disorders Are Treated by Replacement Therapy
       9. Animal Models of Immunodeficiency Have Been Used to Study Basic Immune Function
    2. Secondary Immunodeficiencies
       1. Secondary Immunodeficiencies May Be Caused by a Variety of Factors
       2. HIV/AIDS Has Claimed Millions of Lives Worldwide
       3. The Retrovirus HIV-1 Is the Causative Agent of AIDS
       4. HIV-1 is Spread by Intimate Contact with Infected Body Fluids
       5. In Vitro Studies Have Revealed the Structure and Life Cycle of HIV
       6. HIV Variants with Preference for CCR5 or CXCR4 Coreceptors Play Different Roles in Infection
       7. Infection with HIV Leads to Gradual Impairment of Immune Function
       8. Changes over Time Lead to Progression to AIDS
       9. Antiretroviral Therapy Inhibits HIV Replication, Disease Progression, and Infection of Others
       10. A Vaccine May Be the Only Way to Stop the HIV/AIDS Pandemic
    3. Conclusion
    4. References
    5. Study Questions
19. Chapter 19: Cancer and the Immune System
    1. Terminology and the Formation of Cancer
       1. Accumulated DNA Alterations or Translocation Can Induce Cancer
       2. Genes Associated with Cancer Control Cell Proliferation and Survival
       3. Malignant Transformation Involves Multiple Steps
    2. Tumor Antigens
       1. Tumor-Specific Antigens Contain Unique Sequences
       2. Tumor-Associated Antigens Are Normal Cellular Proteins with Unique Expression Patterns
    3. The Immune Response to Cancer
       1. Immunoediting Can Both Protect Against and Promote Tumor Growth
       2. Innate and Adaptive Pathways Participate in Cancer Detection and Eradication
       3. Some Immune Response Elements Can Promote Cancer Survival
       4. Tumor Cells Evolve to Evade Immune Recognition and Apoptosis
    4. Anticancer Immunotherapies
       1. Monoclonal Antibodies Can Be Used to Direct the Immune Response to Tumor Cells
       2. Tumor-Specific T Cells Can Be Expanded, or Even Created
       3. Therapeutic Vaccines May Enhance the Antitumor Immune Response
       4. Manipulation of Comodulatory Signals, Using Checkpoint Blockade
    5. Conclusion
    6. References
    7. Study Questions
20. Chapter 20: Experimental Systems and Methods
    1. Antibody Generation
       1. Polyclonal Antibodies Are Secreted by Multiple Clones of Antigen-Specific B Cells
       2. A Monoclonal Antibody Is the Product of a Single Stimulated B Cell
       3. Monoclonal Antibodies Can Be Modified for Use in the Laboratory or the Clinic
    2. Immunoprecipitation- and Agglutination-Based Techniques
       1. Immunoprecipitation Can Be Performed in Solution
       2. Immunoprecipitation of Soluble Antigens Can Be Performed in Gel Matrices
       3. Immunoprecipitation Enables Isolation of Specific Molecules from Cell and Tissue Extracts
       4. Hemagglutination Reactions Can Be Used to Detect Any Antigen Conjugated to the Surface of Red Blood Cells
       5. Hemagglutination Inhibition Reactions Are Used to Detect the Presence of Viruses and of Antiviral Antibodies
       6. Bacterial Agglutination Can Be Used to Detect Antibodies to Bacteria
    3. Antibody Assays Based on Molecules Bound to Solid-Phase Supports
       1. Radioimmunoassays Are Used to Measure the Concentrations of Biologically Relevant Proteins and Hormones in Body Fluids
       2. ELISAs Use Antibodies or Antigens Covalently Bound to Enzymes
       3. ELISPOT Assays Measure Molecules Secreted by Individual Cells
       4. Western Blotting Is an Assay That Can Identify a Specific Protein in a Complex Protein Mixture
    4. Methods to Determine the Affinity of Antigen-Antibody Interactions
       1. Equilibrium Dialysis Can Be Used to Measure Antibody Affinity for Antigen
       2. Surface Plasmon Resonance Is Now Commonly Used for Measurements of Antibody Affinity
    5. Antibody-Mediated Microscopic Visualization of Cells and Subcellular Structures
       1. Immunocytochemistry and Immunohistochemistry Use Enzyme-Conjugated Antibodies to Create Images of Fixed Tissues
       2. Immunoelectron Microscopy Uses Gold Beads to Visualize Antibody-Bound Antigens
    6. Immunofluorescence-Based Imaging Techniques
       1. Fluorescence Can Be Used to Visualize Cells and Molecules
       2. Confocal Fluorescence Microscopy Provides Three-Dimensional Images of Extraordinary Clarity
       3. Multiphoton Fluorescence Microscopy Is a Variation of Confocal Microscopy
       4. Intravital Imaging Allows Observation of Immune Responses in Vivo
       5. Visualization and Analysis of DNA Sequences in Intact Chromatin
    7. Flow Cytometry and Cell Sorting
       1. The Flow Cytometer Measures Scattered and Fluorescent Light from Cells Flowing Past a Laser Beam
       2. Sophisticated Software Allows the Investigator to Identify Individual Cell Populations within a Sample
       3. Flow Cytometers and Fluorescence-Activated Cell Sorters Have Important Clinical Applications
       4. The Analysis of Multicolor Fluorescence Data Has Required the Development of Increasingly Sophisticated Software
       5. CyTOF Uses Antibodies to Harness the Power of Mass Spectrometry
       6. Magnets Can Be Used in a Gentle, Sterile Method for Sorting Cells
    8. Cell Cycle Analysis
       1. Tritiated Thymidine Uptake Was One of the First Methods Used to Assess Cell Division
       2. Colorimetric Assays for Cell Division Are Rapid and Eliminate the Use of Radioactive Isotopes
       3. Bromodeoxyuridine-Based Assays for Cell Division Use Antibodies to Detect Newly Synthesized DNA
       4. Propidium Iodide Enables Analysis of the Cell Cycle Status of Cell Populations
       5. Carboxyfluorescein Succinimidyl Ester Can Be Used to Follow Cell Division
    9. Assays of Cell Death
       1. The ⁵¹Cr Release Assay Was the First Assay Used to Measure Cell Death
       2. Fluorescently Labeled Annexin A5 Measures Phosphatidylserine in the Outer Lipid Envelope of Apoptotic Cells
       3. The TUNEL Assay Measures Apoptotically Generated DNA Fragmentation
       4. Caspase Assays Measure the Activity of Enzymes Involved in Apoptosis
    10. Analysis of Chromatin Structure
        1. Chromatin Immunoprecipitation Experiments Characterize Protein-DNA Interactions
        2. Chromosome Conformation Capture Technologies Analyze Long-Range Chromosomal DNA Interactions
    11. CRISPR-Cas9
    12. Whole-Animal Experimental Systems
        1. Animal Research Is Subject to Federal Guidelines That Protect Nonhuman Research Species
        2. Inbred Strains Reduce Experimental Variation
        3. Congenic Strains Are Used to Study the Effects of Particular Gene Loci on Immune Responses
        4. Adoptive Transfer Experiments Allow in Vivo Examination of Isolated Cell Populations
        5. Transgenic Animals Carry Genes That Have Been Artificially Introduced
        6. Knock-in and Knockout Technologies Replace an Endogenous with a Nonfunctional or Engineered Gene Copy
        7. The Cre/lox System Enables Inducible Gene Deletion in Selected Tissues
    13. References
    14. Study Questions
21. Appendix I: CD Antigens
22. Appendix II: Cytokines and Associated JAK-STAT Signaling Molecules
23. Appendix III: Chemokines and Chemokine Receptors
24. Glossary
25. Answers to Study Questions
26. Index