About this Book
Cover Page
Accessibility
Halftitle Page
Icons Used in This Book
Title Page
Copyright Page
Dedication
About the Authors
Brief Contents
Feature Boxes in Kuby Immunology, Eighth Edition
Contents
Preface
Acknowledgments
Chapter 1: Overview of the Immune System
1.1 A Historical Perspective of Immunology
Early Vaccination Studies Led the Way to Immunology
Vaccination Is an Ongoing, Worldwide Enterprise
Immunology Is about More than Just Vaccines and Infectious Disease
Immunity Involves Both Humoral and Cellular Components
How Are Foreign Substances Recognized by the Immune System?
1.2 Important Concepts for Understanding the Mammalian Immune Response
Pathogens Come in Many Forms and Must First Breach Natural Barriers
The Immune Response Quickly Becomes Tailored to Suit the Assault
Pathogen Recognition Molecules Can Be Encoded as Genes or Generated by DNA Rearrangement
Tolerance Ensures That the Immune System Avoids Destroying the Host
The Immune Response Is Composed of Two Interconnected Arms: Innate Immunity and Adaptive Immunity
Immune Cells and Molecules Can Be Found in Many Places
Adaptive Immune Responses Typically Generate Memory
1.3 The Good, Bad, and Ugly of the Immune System
Inappropriate or Dysfunctional Immune Responses Can Result in a Range of Disorders
The Immune Response Renders Tissue Transplantation Challenging
Cancer Presents a Unique Challenge to the Immune Response
Conclusion
References
Study Questions
Chapter 2: Cells, Organs, and Microenvironments of the Immune System
2.1 Hematopoiesis and Cells of the Immune System
Hematopoietic Stem Cells Differentiate into All Red and White Blood Cells
HSCs Differentiate into Myeloid and Lymphoid Blood Cell Lineages
Cells of the Myeloid Lineage Are the First Responders to Infection
Cells of the Lymphoid Lineage Regulate the Adaptive Immune Response
2.2 Primary Lymphoid Organs: Where Immune Cells Develop
The Site of Hematopoiesis Changes during Embryonic Development
The Bone Marrow Is the Main Site of Hematopoiesis in the Adult
The Thymus Is the Primary Lymphoid Organ Where T Cells Mature
2.3 Secondary Lymphoid Organs: Where the Immune Response Is Initiated
Secondary Lymphoid Organs Are Distributed throughout the Body and Share Some Anatomical Features
Blood and Lymphatics Connect Lymphoid Organs and Infected Tissue
The Lymph Node Is a Highly Specialized Secondary Lymphoid Organ
The Spleen Organizes the Immune Response against Blood-Borne Pathogens
Barrier Organs Also Have Secondary Lymphoid Tissue
Tertiary Lymphoid Tissues Also Organize and Maintain an Immune Response
Conclusion
References
Study Questions
Chapter 3: Recognition and Response
3.1 General Properties of Immune Receptor-Ligand Interactions
Receptor-Ligand Binding Occurs via Multiple Noncovalent Bonds
How Do We Describe the Strength of Receptor-Ligand Interactions?
Interactions between Receptors and Ligands Can Be Multivalent
Combinatorial Expression of Protein Chains Can Increase Ligand-Binding Diversity
Adaptive Immune Receptor Genes Undergo Rearrangement in Individual Lymphocytes
Levels of Receptor and Ligand Expression Can Vary during an Immune Response
Local Concentrations of Ligands May Be Extremely High during Cell-Cell Interactions
Many Immune Receptors Include Immunoglobulin Domains
Immune Antigen Receptors Can Be Transmembrane, Cytosolic, or Secreted
3.2 Immune Antigen Receptor Systems
The B-Cell Receptor Has the Same Antigen Specificity as Its Secreted Antibodies
T-Cell Antigen Receptors Recognize Antigen in the Context of MHC Proteins
Receptors of Innate Immunity Bind to Conserved Molecules on Pathogens
3.3 Cytokines and Their Receptors
Cytokines Are Described by Their Functions and the Distances at Which They Act
Cytokines Exhibit the Attributes of Pleiotropy, Redundancy, Synergism, Antagonism, and Cascade Induction
Cytokines of the IL-1 Family Promote Proinflammatory Signals
Class 1 Cytokines Share a Common Structural Motif But Have Varied Functions
Class 2 Cytokines Are Grouped into Three Families of Interferons
TNF Family Cytokines May Be Soluble or Membrane-Bound
The IL-17 Family of Cytokines and Receptors Is the Most Recently Identified
Chemokines Induce the Directed Movement of Leukocytes
3.4 A Conceptual Framework for Understanding Cell Signaling
Ligand Binding Can Induce Dimerization or Multimerization of Receptors
Ligand Binding Can Induce Phosphorylation of Tyrosine Residues in Receptors or Receptor-Associated Molecules
Src-Family Kinases Play Important Early Roles in the Activation of Many Immune Cells
Intracellular Adapter Proteins Gather Members of Signaling Pathways
Common Sequences of Downstream Effector Relays Pass the Signal to the Nucleus
Not All Ligand-Receptor Signals Result in Transcriptional Alterations
3.5 Immune Responses: The Outcomes of Immune System Recognition
Changes in Protein Expression Facilitate Migration of Leukocytes into Infected Tissues
Activated Macrophages and Neutrophils May Clear Pathogens without Invoking Adaptive Immunity
Antigen Activation Optimizes Antigen Presentation by Dendritic Cells
Cytokine Secretion by Dendritic Cells and T Cells Can Direct the Subsequent Immune Response
Antigen Stimulation by T and B Cells Promotes Their Longer-Term Survival
Antigen Binding by T Cells Induces Their Division and Differentiation
Antigen Binding by B Cells Induces Their Division and Differentiation
Conclusion
References
Study Questions
Chapter 4 Innate Immunity
4.1 Physical and Chemical Barriers to Infection
Physical Barriers Prevent Pathogen Entry into the Body’s Interior
Antimicrobial Proteins and Peptides Kill Potential Microbial Invaders
4.2 The Cells of Innate Immunity
Myeloid Cells are Often the First to Respond
Innate Cells of the Lymphoid Lineage are also Early Responders
4.3 The Receptors of Innate Immunity
Toll-Like Receptors Are Expressed on the Endosomal and Plasma Membranes
C-Type Lectin Receptors Bind Carbohydrates on the Surfaces of Extracellular Pathogens
RLRs Bind Cytosolic Viral RNA
cGAS and STING Are Activated by Cytosolic DNA and Dinucleotides
NOD-Like Receptors Bind PAMPs from Cytosolic Pathogens
ALRs Bind Cytosolic DNA
4.4 The Effector Mechanisms of Induced Innate Immunity
Inflammation and Extravasation Focus Innate Immune Cells at the Site of Infection
Expression of Innate Immunity Proteins Is Induced by PRR Signaling
Phagocytosis is an Important Mechanism for Eliminating Pathogens
4.5 Modulation of Innate Responses
Innate and Inflammatory Responses Are Regulated Both Positively and Negatively
Trained Immunity Is a Manifestation of Innate Immune Memory
Pathogens Can Evade Innate and Inflammatory Responses
4.6 Interactions between the Innate and Adaptive Immune Systems
The Innate Immune System Activates Adaptive Immune Responses
Recognition of Pathogens by Dendritic Cells Customizes Helper T-Cell Differentiation
4.7 Ubiquity of Innate Immunity
Some Innate Immune System Components Occur across the Plant and Animal Kingdoms
Invertebrate and Vertebrate Innate Immune Responses Show Both Similarities and Differences
Conclusion
References
Study Questions
Chapter 5: The Complement System
5.1 The Major Pathways of Complement Activation
The Classical Pathway Is Initiated by Antibody Binding to Antigens
The Lectin Pathway Is Initiated When Soluble Proteins Recognize Microbial Antigens
The Alternative Pathway Is Initiated in Three Distinct Ways
The Three Complement Pathways Converge at the Formation of C5 Convertase and Generation of the MAC
5.2 The Diverse Functions of Complement
Complement Receptors Connect Complement-Tagged Pathogens to Effector Cells
Complement Enhances Host Defense against Infection
Complement Acts at the Interface between Innate and Adaptive Immunities
Complement Aids in the Contraction Phase of the Immune Response
5.3 The Regulation of Complement Activity
Complement Activity Is Passively Regulated by Short Protein Half-Lives and Host Cell Surface Composition
The C1 Inhibitor, C1INH, Promotes Dissociation of C1 Components
Decay-Accelerating Factor Promotes Decay of C3 Convertases
Factor I Degrades C3b and C4b
CD59 (Protectin) Inhibits the MAC Attack
Carboxypeptidases Can Inactivate the Anaphylatoxins C3a and C5a
5.4 Complement Deficiencies
5.5 Microbial Complement Evasion Strategies
5.6 The Evolutionary Origins of the Complement System
Conclusion
References
Study Questions
Chapter 6: The Organization and Expression of Lymphocyte Receptor Genes
6.1 The Puzzle of Immunoglobulin Gene Structure
Investigators Proposed Two Early Theoretical Models of Antibody Genetics
Breakthrough Experiments Revealed That Multiple Gene Segments Encode the Immunoglobulin Light Chain
6.2 Multigene Organization of Immunoglobulin Genes
κ Light-Chain Genes Include V, J, and C Segments
λ Light-Chain Genes Include Paired J and C Segments
Heavy-Chain Gene Organization Includes VH, D, JH, and CH Segments
The Antibody Genes Found in Mature B Cells Are the Product of DNA Recombination
6.3 The Mechanism of V(D)J Recombination
V(D)J Recombination in Lymphocytes Is a Highly Regulated Sequential Process
Recombination Is Directed by Recombination Signal Sequences
Gene Segments Are Joined by a Diverse Group of Proteins
V(D)J Recombination Occurs in a Series of Well-Regulated Steps
Five Mechanisms Generate Antibody Diversity in Naïve B Cells
The Regulation of V(D)J Gene Recombination Involves Chromatin Alteration
6.4 B-Cell Receptor Expression
Each B Cell Synthesizes only one Heavy Chain and One Light Chain
Receptor Editing of Potentially Autoreactive Receptors Occurs in Light Chains
mRNA Splicing Regulates the Expression of Membrane-Bound versus Secreted Ig
6.5 T-Cell Receptor Genes and Their Expression
Understanding the Protein Structure of the TCR Was Critical to the Process of Discovering the Genes
The β-Chain Gene Was Discovered Simultaneously in Two Different Laboratories
A Search for the α-Chain Gene Led to the γ-Chain Gene Instead
TCR Genes Are Arranged in V, D, and J Clusters of Gene Segments
Recombination of TCR Gene Segments Proceeds at a Different Rate and Occurs at Different Stages of Development in αβ versus γδ T Cells
The Process of TCR Gene Segment Rearrangement Is Very Similar to Immunoglobulin Gene Recombination
TCR Expression Is Controlled by Allelic Exclusion
Conclusion
References
Study Questions
Chapter 7: The Major Histocompatibility Complex and Antigen Presentation
7.1 The Structure and Function of MHC Class I and II Molecules
Class I Molecules Consist of One Large Glycoprotein Heavy Chain Plus a Small Protein Light Chain
Class II Molecules Consist of Two Nonidentical Membrane-Bound Glycoprotein Chains
Class I and II Molecules Exhibit Polymorphism in the Region That Binds to Peptides
7.2 The Organization and Inheritance of MHC Genes
The MHC Locus Encodes the Three Major Classes of MHC Molecules
Allelic Forms of MHC Genes Are Inherited in Linked Groups Called Haplotypes
MHC Molecules Are Codominantly Expressed
Class I and Class II Molecules Exhibit Diversity at Both the Individual and Species Levels
MHC Polymorphism Is Primarily Limited to the Antigen-Binding Groove
7.3 The Role and Expression Pattern of MHC Molecules
MHC Molecules Present Both Intracellular and Extracellular Antigens
MHC Class I Expression Is Found Throughout the Body
Expression of MHC Class II Molecules Is Primarily Restricted to Antigen-Presenting Cells
MHC Expression Can Change with Changing Conditions
MHC Alleles Play a Critical Role in Immune Responsiveness
Seminal Studies Demonstrate That T Cells Recognize Peptide Presented in the Context of Self-MHC Alleles
Evidence Suggests Distinct Antigen Processing and Presentation Pathways
7.4 The Endogenous Pathway of Antigen Processing and Presentation
Peptides Are Generated by Protease Complexes Called Proteasomes
Peptides Are Transported from the Cytosol to the Rough Endoplasmic Reticulum
Chaperones Aid Peptide Assembly with MHC Class I Molecules
7.5 The Exogenous Pathway of Antigen Processing and Presentation
Peptides Are Generated from Internalized Antigens in Endocytic Vesicles
The Invariant Chain Guides Transport of MHC Class II Molecules to Endocytic Vesicles
Peptides Assemble with MHC Class II Molecules by Displacing CLIP
7.6 Unconventional Antigen Processing and Presentation
Dendritic Cells Can Cross-Present Exogenous Antigen via MHC Class I Molecules
Cross-Presentation by APCs Is Essential for the Activation of Naïve CD8+ T Cells
7.7 Presentation of Nonpeptide Antigens
Conclusion
References
Study Questions
Chapter 8: T-Cell Development
8.1 Early Thymocyte Development
Thymocytes Progress through Four Double-Negative Stages
Thymocytes Express Either αβ or γδ T Cell Receptors
DN Thymocytes Undergo β-Selection, Which Results in Proliferation and Differentiation
8.2 Positive and Negative Selection
Thymocytes “Learn” MHC Restriction in the Thymus
T Cells Undergo Positive and Negative Selection
Positive Selection Ensures MHC Restriction
Negative Selection (Central Tolerance) Ensures Self-Tolerance
The Selection Paradox: Why Don’t We Delete All Cells We Positively Select?
An Alternative Model Can Explain the Thymic Selection Paradox
Do Positive and Negative Selection Occur at the Same Stage of Development, or in Sequence?
8.3 Lineage Commitment
Several Models Have Been Proposed to Explain Lineage Commitment
Transcription Factors Th-POK and Runx3 Regulate Lineage Commitment
Double-Positive Thymocytes May Commit to Other Types of Lymphocytes
8.4 Exit from the Thymus and Final Maturation
8.5 Other Mechanisms That Maintain Self-Tolerance
Regulatory T Cells Negatively Regulate Immune Responses
Peripheral Mechanisms of Tolerance Also Protect against Autoreactive Thymocytes
Conclusion
References
Study Questions
Chapter 9: B-Cell Development
9.1 B-Cell Development in the Bone Marrow
Changes in Cell-Surface Markers, Gene Expression, and Immunoglobulin Gene Rearrangements Define the Stages of B-Cell Development
The Earliest Steps in Lymphocyte Differentiation Culminate in the Generation of a Common Lymphoid Progenitor
The Later Stages of B-Cell Development Result in Commitment to the B-Cell Phenotype and the Stepwise Rearrangement of Immunoglobulin Genes
Immature B Cells in the Bone Marrow Are Exquisitely Sensitive to Tolerance Induction through the Elimination of Self-Reactive Cells
9.2 Completion of B-Cell Development in the Spleen
T1 and T2 Transitional B Cells Form in the Spleen and Undergo Selection for Survival and against Self-Reactivity
T2 B Cells Give Rise to Mature Follicular B-2 B Cells
T3 B Cells Are Primarily Self-Reactive and Anergic
9.3 The Properties and Development of B-1 and Marginal Zone B Cells
B-1a, B-1b, and MZ B Cells Differ Phenotypically and Functionally from B-2 B Cells
B-1a B Cells Are Derived from a Distinct Developmental Lineage
9.4 Comparison of B- and T-Cell Development
Conclusion
References
Study Questions
Chapter 10: T-Cell Activation, Helper Subset Differentiation, and Memory
10.1 T-Cell Activation and the Two-Signal Hypothesis
TCR Signaling Provides Signal 1 and Sets the Stage for T-Cell Activation
Costimulatory Signals Are Required for Optimal T-Cell Activation Whereas Coinhibitory Signals Prevent T-Cell Activation
Clonal Anergy Results If a Costimulatory Signal Is Absent
Cytokines Provide Signal 3
Antigen-Presenting Cells Provide Costimulatory Ligands and Cytokines to Naïve T Cells
Superantigens Are a Special Class of T-Cell Activators
10.2 Helper CD4+ T-Cell Differentiation
Helper T Cells Can Be Divided into Distinct Subsets and Coordinate Type 1 and Type 2 Responses
The Differentiation of Helper T-Cell Subsets Is Regulated by Polarizing Cytokines
Each Effector Helper T-Cell Subset Has Unique Properties
Helper T Cells May Not Be Irrevocably Committed to a Lineage
Helper T-Cell Subsets Play Critical Roles in Immune Health and Disease
10.3 T-Cell Memory
Naïve, Effector, and Memory T Cells Can Be Distinguished by Differences in Surface Protein Expression
Memory Cell Subpopulations Are Distinguished by Their Locale and Effector Activity
Many Questions Remain Surrounding Memory T-Cell Origins and Functions
Conclusion
References
Study Questions
Chapter 11: B-Cell Activation, Differentiation, and Memory Generation
11.1 T-Dependent B-Cell Responses: Activation
Naïve B Cells Encounter Antigen in the Lymph Nodes and Spleen
B-Cell Recognition of Cell-Bound Antigen Culminates in the Formation of an Immunological Synapse
Antigen Binding to the BCR Leads to Activation of a Signal Transduction Cascade within the B Cell
B Cells Also Receive and Propagate Signals through Coreceptors
B Cells Use More Than One Mechanism to Acquire Antigen from Antigen-Presenting Cells
Antigen Receptor Binding Induces Internalization and Antigen Presentation
The Early Phases of the T-Dependent Response Are Characterized by Chemokine-Directed B-Cell Migration
Specification of the Stimulated B-Cell Fate Depends on Transcription Factor Expression
11.2 T-Dependent B-Cell Responses: Differentiation and Memory Generation
Some Activated B Cells Differentiate into Plasma Cells That Form the Primary Focus
Other Activated B Cells Enter the Follicles and Initiate a Germinal Center Response
The Mechanisms of Somatic Hypermutation and Class Switch Recombination
Memory B Cells Recognizing T-Dependent Antigens Are Generated Both within and outside the Germinal Center
Most Newly Generated B Cells Are Lost at the End of the Primary Immune Response
11.3 T-Independent B-Cell Responses
T-Independent Antigens Stimulate Antibody Production in the Absence of T-Cell Help
Two Novel Subclasses of B Cells Mediate the Response to T-Independent Antigens
11.4 Negative Regulation of B Cells
Negative Signaling through CD22 Balances Positive BCR-Mediated Signaling
Negative Signaling through the Receptor FcγRIIb Inhibits B-Cell Activation
CD5 Acts as a Negative Regulator of B-Cell Signaling
B-10 B Cells Act as Negative Regulators by Secreting IL-10
Conclusion
References
Study Questions
Chapter 12: Effector Responses: Antibody- and Cell-Mediated Immunity
12.1 Antibody-Mediated Effector Functions
Antibodies Provide Protection against Pathogens, Toxins, and Harmful Cells in a Variety of Ways
Different Antibody Classes Mediate Different Effector Functions
Fc Receptors Mediate Many Effector Functions of Antibodies
Protective Effector Functions Vary among Antibody Classes
Antibodies Have Many Therapeutic Uses in Treating Diseases
12.2 Cell-Mediated Effector Responses
Cytotoxic T Lymphocytes Recognize and Kill Infected or Tumor Cells via T-Cell Receptor Activation
Natural Killer Cell Activity Depends on the Balance of Activating and Inhibitory Signals
NKT Cells Bridge the Innate and Adaptive Immune Systems
Conclusion
References
Study Questions
Chapter 13: Barrier Immunity: The Immunology of Mucosa and Skin
13.1 Common Themes in Barrier Immune Systems
Barrier Epithelial Cells Generate a Healthy Distance from Microbiota
Immune Cells Interact with the Barrier Epithelium and Lymphoid Tissue
Barrier Immune Systems Initiate Both Tolerogenic and Inflammatory Responses to Microorganisms
13.2 The Immune System of the Skin
The Skin and Its Epithelium Are Multilayered
Skin Immune Cells Are Present in Both the Epidermis and Dermis
The Interaction between Skin Immune System and Skin Microbes Generates Both Protective and Inflammatory Responses
13.3 The Immune System of the Intestine
The Gut Is Organized into Anatomical Sections and Tissue Layers
Gut Epithelial Cells Vary in Phenotype and Function
Immune Homeostasis in the Intestine Is Regulated by Both Innate and Adaptive Cells
Commensal Microbes Help Maintain Tolerance in the Intestine
The Gut Immune System Recognizes and Responds to Harmful Pathogens
13.4 The Immune System of the Respiratory Tract
The Respiratory Immune System Shares Many Features with the Intestinal Immune System
Conclusion
References
Study Questions
Chapter 14: The Immune Response in Space and Time
14.1 Immune Cells in Healthy Tissue: Homeostasis
Naïve Lymphocytes Circulate between Secondary and Tertiary Lymphoid Tissues
Naïve Lymphocytes Browse for Antigen along the Reticular Network of Secondary Lymphoid Organs
14.2 The Innate Immune Response to Antigen in Tissues
Innate Immune Cells Are Activated by Antigen Binding to Pattern Recognition Receptors
Antigen Travels in Two Different Forms to Secondary Lymphoid Tissue via Afferent Lymphatics
Antigen-Presenting Cells That Present Processed Antigen Travel to the T-Cell Zones of Secondary Lymphoid Tissue
Unprocessed Antigen Travels to the B-Cell Zones
14.3 First Contact between Antigen and Lymphocytes
Naïve CD4+ T Cells Arrest Their Movements after Engaging Antigens
B Cells Seek Help from CD4+ T Cells at the Border between the Follicle and Paracortex of the Lymph Node
B and T Cells Behave Differently in Germinal Centers
CD8+ T Cells Are Activated in the Lymph Node via a Multicellular Interaction
A Summary of the Timing of a Primary Response
Differentiation into Memory T Cells Begins Early in the Primary Response
14.4 The Effector and Memory Cell Responses in the Periphery
Chemokine Receptors and Adhesion Molecules Coordinate Lymphocyte Homing
Both Effector and Memory Lymphocytes Contribute to Clearing Infection in Tissues
The Immune Response Contracts after Two to Four Weeks
Memory Cells Position Themselves to Mount a Secondary Response to Re-Infection
Conclusion
References
Study Questions
Chapter 15: Allergy, Hypersensitivities, and Chronic Inflammation
15.1 Allergies: Type I Hypersensitivity
IgE Antibodies Are Responsible for Type I Hypersensitivity
Many Allergens Can Elicit a Type I Response
IgE Antibodies Act by Binding Antigen, Resulting in the Cross-Linking of Fcε Receptors
IgE Receptor Signaling Is Tightly Regulated
Granulocytes Produce Molecules Responsible for Type I Hypersensitivity Symptoms
Type I Hypersensitivities Are Characterized by Both Early and Late Responses
There Are Several Categories of Type I Hypersensitivity Reactions
Susceptibility to Type I Hypersensitivity Reactions Is Influenced by Both Environmental Factors and Genetics
Diagnostic Tests and Treatments Are Available for Allergic Reactions
Why Did Allergic Responses Evolve?
15.2 Antibody-Mediated (Type II) Hypersensitivity
Transfusion Reactions Are an Example of Type II Hypersensitivity
Hemolytic Disease of the Newborn Is Caused by Type II Reactions
Hemolytic Anemia Can Be Drug Induced
15.3 Immune Complex–Mediated (Type III) Hypersensitivity
Immune Complexes Can Damage Various Tissues
Immune Complex–Mediated Hypersensitivity Can Resolve Spontaneously
Auto-Antigens Can Be Involved in Immune Complex–Mediated Reactions
Arthus Reactions Are Localized Type III Hypersensitivity Reactions
15.4 Delayed-Type (Type IV) Hypersensitivity
The Initiation of a Type IV DTH Response Involves Sensitization by Antigen
The Effector Phase of a Classical DTH Response Is Induced by Second Exposure to a Sensitizing Antigen
The DTH Reaction Can Be Detected by a Skin Test
Contact Dermatitis Is a Type IV Hypersensitivity Response
15.5 Chronic Inflammation
Infections Can Cause Chronic Inflammation
There Are Noninfectious Causes of Chronic Inflammation
Obesity Is Associated with Chronic Inflammation
Chronic Inflammation Can Cause Systemic Disease
Conclusion
References
Study Questions
Chapter 16: Tolerance, Autoimmunity, and Transplantation
16.1 Establishment and Maintenance of Tolerance
Antigen Sequestration, or Evasion, Is One Means to Protect Self Antigens from Attack
Central Tolerance Processes Occur in Primary Lymphoid Organs
Cells That Mediate Peripheral Tolerance Are Generated Outside Primary Lymphoid Organs
Multiple Immune Cell Types Work in the Periphery to Inhibit Anti-Self Responses
16.2 Autoimmunity
Some Autoimmune Diseases Target Specific Organs
Some Autoimmune Diseases Are Systemic
Both Intrinsic and Extrinsic Factors Can Favor Susceptibility to Autoimmune Disease
What Causes Autoimmunity?
Treatments for Autoimmune Disease Range from General Immune Suppression to Targeted Immunotherapy
16.3 Transplantation Immunology
Demand for Transplants Is High, But Organ Supplies Remain Low
Antigenic Similarity between Donor and Recipient Improves Transplant Success
Some Organs Are More Amenable to Transplantation Than Others
Matching Donor and Recipient Involves Prior Assessment of Histocompatibility
Allograft Rejection Follows the Rules of Immune Specificity and Memory
Graft Rejection Takes a Predictable Clinical Course
Immunosuppressive Therapy Can Be Either General or Target-Specific
Immune Tolerance to Allografts Is Favored in Certain Instances
Conclusion
References
Study Questions
Chapter 17: Infectious Disease and Public Health
17.1 The Chain of Infection
Infectious Agents Reside in Reservoirs
Infection Can Occur via Various Modes of Transmission
Successful Infection Requires a Susceptible Host
17.2 Factors Contributing to Human Infectious Disease Patterns
Emerging and Re-Emerging Infectious Diseases Are on the Rise
Zoonotic Infections Arise from Contact with Animals
Anthropogenic Factors Contribute to the Emergence and Spread of Infectious Disease
Public Health Infrastructure Can Help Identify and Respond to Infectious Outbreaks
Human Nature, History, and Culture Also Play a Role
17.3 The Link Between Timing, Location, and Immune Effector Mechanisms
Earlier Infectious Exposures May Influence Innate Responses to Another Infectious Agent
Extracellular Infections at Barrier Surfaces Are Typically Controlled by Type 2 Responses
Extracellular Pathogens Are Targeted by Extracellular Tools and Type 3 Responses
Type 1 Responses Dominate During Intracellular Infections
Systemic Inflammatory Responses Can Be Life-Threatening
17.4 Viral Infections
The Antiviral Innate Response Provides Key Instructions for the Later Adaptive Response
Many Viruses Are Neutralized by Antibodies
Cell-Mediated Immunity Is Important for Viral Control and Clearance
Viruses Employ Several Strategies to Evade Host Defense Mechanisms
The Imprinting of a Memory Response Can Influence Susceptibility to Future Viral Infection
17.5 Bacterial Infections
Immune Responses to Extracellular and Intracellular Bacteria Differ
Bacteria Can Evade Host Defense Mechanisms at Several Stages
17.6 Parasitic Infections
Protozoan Parasites Are a Diverse Set of Unicellular Eukaryotes
Parasitic Worms (Helminths) Typically Generate Weak Immune Responses
17.7 Fungal Infections
Innate Immunity Controls Most Fungal Infections
Immunity against Fungal Pathogens Can Be Acquired
Conclusion
References
Study Questions
Chapter 18: Immunization and Vaccines
18.1 Passive Versus Active Immunity
Passive Immunity Is Temporary and Enacted by Preexisting Antibodies
Active Immunization Stimulates Immune Cells and Generates Memory Responses
18.2 Vaccine Research and Design Principles
Years of Basic Research Precede Each New Vaccine
Vaccine Design Begins with Defining the Immune Correlates of Protection
Vaccines Are Tightly Regulated and Monitored
Immunization Programs Must Consider the Human Context
18.3 Vaccine Formulations
Whole Pathogen Vaccines Contain Live or Killed Microbes
Subunit Vaccines Include Pieces of the Pathogen
Particle- or Membrane-Based Vaccines Include an Outer Envelope
Vectored Vaccines Replicate Without the Risk of Reversion
Nucleic Acid Vaccines Provide Instructions for Pathogen-Associated Proteins
18.4 Vaccine Adjuvants, Schedules, and Delivery Methods
Adjuvants Increase Vaccine Effectiveness by Activating Innate Response Elements
Full Immune Protection May Require Multiple Exposures or Boosters
Several Novel Vaccine Delivery Methods Are Under Investigation
Conclusion
References
Study Questions
Chapter 19: Immunodeficiency Diseases
19.1 Primary Immunodeficiencies
Primary Immunodeficiency Diseases Are Often Detected Early in Life
Combined Immunodeficiencies Disrupt Adaptive Immunity
B-Cell Immunodeficiencies Exhibit Depressed Production of One or More Antibody Isotypes
Disruptions to Innate Immune Components May Also Impact Adaptive Responses
Complement Deficiencies Are Relatively Common
NK-Cell Deficiencies Increase Susceptibility to Viral Infections and Cancer
Immunodeficiency Disorders That Disrupt Immune Regulation Can Manifest as Autoimmunity
Immunodeficiency Disorders Are Treated by Replacement Therapy
Animal Models of Immunodeficiency Have Been Used to Study Basic Immune Function
19.2 Secondary Immunodeficiencies
Secondary Immunodeficiencies May Be Caused by a Variety of Factors
HIV/AIDS Has Claimed Millions of Lives Worldwide
The Retrovirus HIV-1 Is the Causative Agent of AIDS
HIV-1 is Spread by Intimate Contact with Infected Body Fluids
In Vitro Studies Have Revealed the Structure and Life Cycle of HIV
HIV Variants with Preference for CCR5 or CXCR4 Coreceptors Play Different Roles in Infection
Infection with HIV Leads to Gradual Impairment of Immune Function
Changes over Time Lead to Progression to AIDS
Antiretroviral Therapy Inhibits HIV Replication, Disease Progression, and Infection of Others
A Vaccine May Be the Only Way to Stop the HIV/AIDS Pandemic
Conclusion
References
Study Questions
Chapter 20: Cancer and the Immune System
20.1 Cancer Development and Key Characteristics
Cancer Arises from Progressive DNA Changes in a Self Cell
Cancer-Associated Genes Regulate Cell Proliferation and Survival
Blood-Cell Cancers Arise from Various Stages of Hematopoietic Stem Cell Development
Several Key Characteristics Define All Cancers
Distinct Antigen Expression by Cancer Cells Can Aid Detection and Eradication
20.2 The Immune Response to Cancer
The Immune Response Has Pro-Tumor and Anti-Tumor Actions
Innate and Adaptive Mechanisms Detect and Eradicate Cancer
Some Immune Response Elements Promote Cancer Survival
Tumor Cells Evolve to Evade Immune Recognition and Apoptosis
20.3 Anticancer Immunotherapies
Early Physicians Observed the Immune Response to Cancer
Evaluating the Immune Microenvironment Provides Prognostic and Therapeutic Value
Antibodies Can Direct the Immune Response to Tumor Cells
Immune Checkpoint Blockades Can Manipulate Comodulatory Signals
Anti-Tumor Lymphocyte Populations Can Be Expanded or Enhanced to Treat Cancer
Prophylactic and Therapeutic Anticancer Vaccines May Enhance the Anti-Tumor Response
Oncolytic Viruses Can Treat Cancer
Conclusion
References
Study Questions
Appendix A: CD Antigens
Appendix B: Cytokines
Appendix C: Chemokines and Chemokine Receptors
Appendix D: Signal Transduction in the Immune System
Appendix E: Experimental Systems and Methods
Appendix F: An Extended List of CD Antigens
Glossary
Answers to Study Questions
Index
Notes
Extended Descriptions
Icons Used in This Book
Herd immunity threshold for five viruses
The rapid antigen tests for COVID-19 are based on a sandwich E L I S A
Immune response pathways
Engineered B i T E antibodies
Online assignment
Sample page of a PowerPoint presentation
Starting screen for an animation
LaunchPad
Figure 1-3 Drawing by Elie Metchnikoff of phagocytic cells surrounding a foreign particle
Passive Antibodies and the Iditarod
Figure 1-4 Representation of Paul Ehrlich’s side-chain theory to explain antibody formation
Figure 1-5 An Outline for the Humoral and Cell-Mediated (Cellular) Branches of the Immune System.
Figure 1-6 Generation of diversity and clonal selection in T and B lymphocytes
Figure 1-7 Collaboration between Innate and Adaptive Immunity in Resolving an Infection
Figure 1-8 Differences in the primary and secondary adaptive immune response to injected antigen reflect the phenomenon of immunologic memory
Figure 1-11 The proposed role of the microbiome in regulating immune, metabolic, and neurologic function
Figure 2-1 Hematopoiesis
Figure 1 Panning for stem cells
Figure 2 Current approaches for enrichment of pluripotent stem cells from bone marrow
Figure 2-2 Regulation of hematopoiesis by transcription factors
Figure 2-3 An example of lineage commitment during hematopoiesis: the development of B cells from HSCs
Figure 2-4 Examples of granulocytes
Figure 2-5 Examples of monocytes, macrophages, dendritic cells, and megakaryocytes
Figure 2-6 Examples of lymphocytes
Figure 2-7 Structure of the B-cell and T-cell antigen receptors
Figure 2-8 T-cell recognition of antigen
Figure 1 The general strategy used to correct a defective gene by autologous H S C transplantation
Figure 2-9 Sites of hematopoiesis during fetal development
Figure 2-10 The bone marrow microenvironment
Figure 2-11 Structure of the thymus
Figure 1 (b) the first page of the Lancet article (1961) describing his discovery of the function of the thymus
Figure 2-12 The human lymphatic system
Figure 2-13 Structure of a lymph node
Figure 2-14 Stromal cell networks in secondary lymphoid tissue
Figure 2-15 Structure of the spleen
Figure 2-16 Example of secondary lymphoid tissue in barrier organs: gut-associated lymphoid tissue (G A L T)
Figure 1 Evolutionary distribution of lymphoid tissues
Figure 2 Thymic tissue in the lamprey eel
Figure 3 The avian bursa
Recognition and response
Figure 3-1 Receptor-ligand binding obeys the rules of chemistry
Figure 3-2 Univalent and bivalent (or multivalent) binding
Figure 3-3 Cell surface receptors cluster on binding multivalent antigens
Figure 3-4 Combining one receptor chain with different partners allows increased receptor diversity and affinity while minimizing the need for new genetic information
Figure 3-5 Comparison of the three forms of the IL-2 receptor
Figure 3-6 Polarized secretion of I L-12 (pink) by dendritic cells (blue) in the direction of a bound T cell (green)
Figure 3-7 Some examples of proteins bearing immunoglobulin domains
Figure 3-8 The immunoglobulin domain is made up of amino acid residues arranged in beta sheets that are connected by variable loops
Figure 3-9 The B C R exists in both membrane-bound (a) and soluble (b) forms
Figure 1 Experimental demonstration that most antibodies are in the gamma-globulin fraction of serum proteins
Figure 2 Prototype structure of I g G, showing chain structure and interchain disulfide bonds
Figure 3-10 The structure of antibodies
Figure 3-11 The presence of hypervariable regions in the amino acid sequences of antibody V L and V H domain complementarity-determining regions (C D Rs)
Figure 3-12 General structures of the five major classes of antibodies
Figure 3-13 General structure of the four subclasses of human I g G
Figure 3-14 B-cell coreceptors require receptor-associated molecules and coreceptors for signal transduction
Figure 3-15 The three-dimensional structure of the alpha beta T C R
Figure 1 The generation of antibodies specific for the T C R
Figure 3-16 Structure of the C D 4 and C D 8 coreceptors
Figure 3-17 The T-cell receptor and coreceptor complex
Interleukin-1 family
Class 1 hematopoietin cytokine family
Class 2 (interferon) cytokine family
Tumor necrosis factor
Interleukin-17 family
Chemokines
Figure 3-18 Cytokine attributes of (a) pleiotropy, redundancy, synergism, antagonism, and (b) cascade induction
Figure 3-19 Ligands and receptors of the I L-1 family
Figure 3-21 Binding of T N F to T N F R-1 induces trimerization and activation of downstream events
Figure 3-22 The I L-17 family of cytokines and their associated receptors
Figure 3-23 Disulfide bridges in chemokine structures
Concepts in lymphocyte signaling
Figure 3-25 General model of signal transduction mediated by most class 1 and class 2 cytokine receptors
Figure 3-26 The role of lipid raft regions within membranes
Figure 3-27 Activation of S r c-family kinases
Figure 1 Fluorescence-activated cell-sorting (F A C S) profi les of a normal individual and a patient with X L A
Innate Immunity
Figure 4-2 The structure of the mucus layer varies along the length of the gastrointestinal tract
Figure 4-3 Psoriasin prevents colonization of the skin by Escherichia coli (E. coli)
Figure 4-4 Innate Lymphoid Cells
Pattern Recognition Receptors
Figure 4-6 Toll-like receptor (T L R) structure and binding of P A M P ligands
Figure 4-7 Cellular location of T L Rs
Figure 4-8 Cell wall components of gram-negative and gram-positive bacteria
Figure 4-9 L P S binding by T L R 4 complex on host cells
Figure 4-10 The R I G-I-like receptor family
Figure 4-11 The N L R P 3 inflammasome and its activators
Figure 4-12 Activation of inflammasomes
Effectors of innate immune response to infection
Figure 4-14 The steps of leukocyte extravasation
Figure 4-15 Inside-out signaling results in a high affinity form of L F A-1
Figure 4-16 Initiation of a local inflammatory response
Figure 4-17 Induction of antiviral activities by type Roman numeral 1 interferons
Figure 4-18 Phagocytosis
Figure 4-19 Generation of antimicrobial reactive oxygen and nitrogen species
Figure 1 Neutrophil extracellular traps (N E Ts) and N E Tosis
Figure 1 Evasion of type Roman numeral 1 interferon-mediated immunity by S A R S Co V-2
Figure 4-20 Pathogens induce differential signaling through D C P R Rs, influencing helper T-cell functions
Figure 1 Induced closure of leaf stomata following exposure to bacterial P A M Ps
Complement Proteins
Generation of C 3 and C 5 convertases by the three major pathways of complement activation
Figure 5-3 Structure of the C 1 macromolecular complex
Figure 5-4 Models of pentameric I g M and hexameric I g G derived from x-ray crystallographic data
Classical Pathway of Complement Activation
Figure 5-6 Binding of C 4 b to the microbial membrane surface occurs through a thioester bond via an exposed amino or hydroxyl group
Figure 5-7 Initiation of the lectin pathway relies on lectin receptor recognition of microbial cell surface carbohydrates
Figure 5-8 Initiation of the alternative tickover pathway of complement
Figure 2 Pillemer’s experiments
Figure 5-9 Initiation of the alternative pathway by specific, noncovalent binding of properdin to the target membrane
Figure 5-10 Formation of the membrane attack complex (M A C)
Complement and the Visual System
Figure 2 Fluorescence images of the lateral geniculate nucleus, analyzed by array tomography
Figure 5-11 Coligation of antigen to B cells
Figure 5-12 Anaphylatoxins and inflammatory response
Figure 5-13 Opsonization of microbial cells
Figure 5-14 C 1 q colocalizes with annexin A 5 on the surface of apoptotic cells
Figure 5-15 Clearance of circulating immune complexes
Figure 5-16 Regulation of complement activity
Figure 1 Treatment of P N H patients with eculizumab relieves hemoglobinuria
Figure 5-17 Evolution of complement components
Biochemistry of the membrane proteins
Flow cytometric histogram
Heavy chain locus and nuclear lamina
Figure 6-1 Sequencing studies of the variable and constant regions of immunoglobulin
Figure 6-2 Dreyer and Bennett hypothesis
Figure 6-3 The kappa light-chain gene is formed by D N A recombination between variable and constant region gene segments
Figure 6-4 The antibody kappa light-chain locus is composed of three families of D N A segments
Hozumi and Tonegawa’s classic experiment
Figure 6-5 Variable region of antibody heavy chains is encoded in three segments—V, D, and J
Figure 6-6 Organization of immunoglobulin germ-line gene segments in the mouse
Figure 6-7 Pre-B C R and B C R complexes
Figure 6-8 Two conserved sequences in light-chain and heavy-chain D N A function as recombination signal sequences (R S Ss)
Figure 6-9 Recombination between gene segments is required to generate complete variable region light- and heavy-chain genes
Figure 6-10 Structural features of the R A G 1/2 recombinase proteins
Recombnation of immunoglobulin variable region genes
Figure 6-12 Mechanism of V (D) J recombination, illustrated for V kappa-to-J kappa joining
Figure 1 Elements of the recombination substrate used by Carmona and colleagues
Figure 2 Evolution of the R A G 1/2 recombinase
Figure 6-13 Three-dimensional organization of chromosomal regions containing V, D, and J segments changes during B-cell development
Figure 6-14 Nuclear positioning of I g H and I g kappa loci alters during B-cell development
Figure 6-15 Generation of a functional immunoglobulin receptor requires productive rearrangement of heavy- and light-chain gene segments
Figure 6-16 Kappa light-chain receptor editing
Figure 6-17 Differential expression of the secreted and membrane-bound forms of immunoglobulin mu and delta chains is regulated by alternative R N A processing
Figure 6-18 Production and identification of a c D N A clone encoding the T-cell receptor beta gene
Figure 6-19 Germ-line organization of the mouse T C R alpha-, beta-, gamma-, and delta-chain gene segments
Figure 6-20 Locations R S S spacers in T C R genes
Figure 6-21 The pre-T C R: the T C R beta chain is expressed on the T-cell surface in combination with the pre-T alpha chain
D N A with V domain and D domain
Recombination of two gene segments
Position of genes in germ-line D N A and D N A from antibody-producing cells
Schematic diagrams of M H C class Roman numeral 1 (a) and M H C class Roman numeral 2 (b) molecules, showing the external domains, transmembrane segments, cytoplasmic tails, and peptide-binding groove
Figure 7-3 Peptide-binding groove of M H C class Roman numeral 1 and class Roman numeral 2 molecules, with bound peptides
Figure 7-4 Examples of anchor residues (blue) in nonameric peptides eluted from two different M H C class Roman numeral 1 molecules
Figure 7-5 Conformation of peptides bound to M H C class Roman numeral 1 molecules
Figure 7-6 Comparison of the organization of the major histocompatibility complex (M H C) in mice and humans
Figure 7-7 Simplified map of the mouse and human M H C loci
Figure 7-8 Illustration of inheritance of MHC haplotypes in inbred mouse strains and in humans
Figure 7-9 Diagram illustrating the various M H C molecules expressed on antigen-presenting cells of a heterozygous H 2 k/d mouse
Figure 7-10 Variability in the amino acid sequences of allelic H L A class Roman numeral 1 molecules
Figure 1 Experimental demonstration of self-M H C restriction in cells
Figure 2 Experimental demonstration that antigen recognition by T C cells exhibits M H C restriction
Figure 7-11 Experimental demonstration that antigen processing is necessary for
Figure 7-12 Overview of endogenous and exogenous pathways for processing antigen
Figure 7-13 Proteolytic system for degradation of intracellular proteins
Figure 7-14 T A P (transporter associated with antigen processing)
Figure 7-15 Assembly and stabilization of M H C class I molecules
Figure 7-16 Generation of antigenic peptides and assembly of M H C class Roman numeral 2 molecules in the exogenous processing pathway
Antigen-presenting pathways
Figure 7-18 Activation of naïve T c cells by exogenous antigen requires D C licensing and cross-presentation
Figure 7-19 Lipid antigen binding to the C D 1 molecule
Specificity of T cells against the M C M V and tum peptide
Development of T Cells in the Thymus
Figure 8-2 Development of T cells from hematopoietic stem cells on bone marrow stromal cells expressing the Notch ligand
T-cell receptor expression and function
Figure 8-4 Time course of appearance of gamma delta thymocytes and alpha beta thymocytes during mouse fetal development
Positive and negative selection of thymocytes in the mouse
Figure 8-6 Experimental demonstration that the thymus selects for maturation only those T cells whose T-cell receptors recognize antigen presented on target cells with the haplotype of the thymus
Figure 1 Experimental demonstration that negative selection of thymocytes requires both self antigen and self-M H C, and positive selection requires self-M H C
Figure 2 Primary data from experiments summarized in Figure 1
Figure 8-7 Relationship between T C R affinity and selection
Figure 8-8 Experimental support for the role of T C R affinity in thymic selection
Figure 8-9 A N D Accompanying Video 8-9v Imaging live d p thymocytes undergoing selection in the thymus
Figure 8-10 Proposed models of lineage commitment, the decision of double-positive thymocytes to become helper C D 4 plus or cytotoxic C D 8 plus T cells
Figure 8-11 How regulatory T cells (T R E G s) inactivate traditional T cells
Fluorescence activated cell sorting plots
Stages of B-cell development
B-Cell Development
Figure 9-2 H S Cs and B-cell progenitors
Figure 1 Factors regulating B-cell development
Figure 9-3 Transcription factors during early B-cell development
Figure 9-4 Immunoglobulin gene rearrangements and expression of marker proteins during B-cell development
Figure 1 Experimental approach for the isolation of Hardy’s fractions from bone marrow
Figure 2 Flow cytometric characterization of the stages of B-cell development in the bone marrow
Figure 9-5 The pre-B-cell receptor
Figure 9-6 Experimental evidence for negative selection (clonal deletion) and light-chain editing of self-reactive immature B cells in the bone marrow
Figure 9-7 T 2, but not T 1, transitional B cells can enter splenic B-cell follicles and recirculate
Figure 9-8 Transitional B cells undergo positive and negative selection in the spleen
Figure 9-9 Goodnow’s experimental system for demonstrating clonal anergy in mature peripheral B cells
Figure 9-10 The three major populations of mature B cells in the periphery
Levels of antigens in wild-type and Dicer knockout mice
Staining of Pro-B and Pre-B cells with Annexin V
Figure 10-1 T-Cell Activation and Differentiation
Figure 10-2 Three Signals Are Required for Activation of a Naïve T Cell
Figure 10-3 Surface interactions responsible for T-cell activation
Figure 10-4 Schematic of T-cell receptor signaling
Figure 1 Evidence that C D 28 is costimulatory ligand for T cell proliferation
Figure 1 How the checkpoint inhibitor ipilimumab works
Figure 10-5 Signals that lead to clonal anergy versus clonal expansion
Figure 10-6 Comparison of professional antigen-presenting cells that induce T-cell activation
Figure 10-7 Superantigen-mediated cross-linkage of T-cell receptor and M H C class Roman numeral 2 molecules
Figure 10-8 Activation and differentiation of naïve T cells into effector and memory T cells
Figure 10-9 T Helper Subset Differentiation
Figure 10-10 General events and factors that drive T H subset polarization
Figure 10-11 Initiation of T H 1 and T H 2 responses by pathogens
Figure 10-12 Cross-regulation of T helper cell subsets by transcriptional regulators
Figure 1 C D 4 + T cells from patients with hyper-I g E syndrome do not differentiate into T H 17 cells
Figure 1 The anatomy and cell biology of the human placenta
Figure 2 Genetic differences between the F o x P 3 enhancer in placental (eutherian) and nonplacental animals
Figure 10-13 Examples of how T F H and T H 1 T cells provide help in the immune response
Figure 10-14 Correlation between type of leprosy and relative T H 1 or T H 2 activity
Figure 10-15 One possible model for the development of memory T-cell subsets
Fluorescence-activated cell-sorting (F A C S) profiles
Figure 11-2 Maturation and clonal selection of B lymphocytes
Figure 11-3 Different types of antigens signal through different receptor units
Figure 11-4 Adoptive transfer experiments demonstrated the need for two cell populations during the generation of antibodies to T-dependent antigens
Figure 11-5 Alternative Fates of B Cells following T-Dependent Antigen Stimulation
Figure 11-6 Antigen presentation to follicular B cells in the lymph node
Figure 11-7 Antigen recognition by the B C R triggers membrane spreading
Figure 11- 8 The B- cell immunological synapse includes a central core of receptor, surrounded by adhesion molecules, and is corralled by an actin ring
Figure 11-9 Signal Transduction Pathways Emanating from the B C R
Figure 11-10 B cells extract antigen from the antigen-presenting cell membrane, using active contractions of the actomyosin skeleton
Figure 1 Visualization of antigen-specific B cell movements in the germinal center
Figure 11-11 Differential chemokine receptor expression controls B-cell migration during the T-dependent immune response
Figure 11-12 Movement of antigen-specific T and B cells within the lymph node after antigen encounter
Figure 11-13 Experiment showing that a single B cell can give rise to plasmablasts, germinal center B cells, or memory B cells
Figure 11-14 A regulatory network of transcription factors controls the germinal center B cell/plasma cell decision point
Figure 11-15 Terminology describing antibody-secreting cells
Figure 11-16 The germinal center
Figure 11-17 B-Cell Differentiation Events Occur in Different Anatomical Locations
Figure 11-18 Activation-induced cytidine deaminase (A I D) mediates the deamination of deoxycytidine and the formation of deoxyuridine
Figure 11-19 The generation of somatic cell mutations in I g genes by A I D. A I D deaminates a deoxycytidine residue, creating a uridine-guanosine (U-G) mismatch
Figure 11-20 Class switch recombination from a C mu to a C gamma 1 heavy-chain constant region gene
Figure 11-21 The bone marrow niche occupied by plasma cells is supported by eosinophils and megakaryocytes, as well as by mesenchymal stromal cells
Figure 11-22 Temporal separation of recall responses from I g G 1 and I g M 1 memory responses
Figure 11-24 The marginal zone of the mouse spleen
I g M levels
B cells and their flow cytometric data
Figure 12-1 The Six Broad Categories of Antibody Effector Functions
FIgure 12-3 Agglutination of Streptococcus pneumoniae by antibodies in nasal secretions
Figure 12-4 Structure of human F c receptors
Figure 12-5 Functions of F c receptors. F c receptors (F c Rs) come in a variety of types and are expressed by many different cell types
Figure 12-6 Generation of effector C T Ls
Figure 12-7 Localizing antigen-specific C D 8 plus T-cell populations in vivo
Figure 1 M H C-peptide tetramers
Figure 12-8 Stages in C T L-mediated killing of target cells
Figure 12-9 Effect of antigen activation on the ability of C T Ls to bind to the intercellular cell adhesion molecule I C A M-1
Figure 12-10 Formation of a conjugate between a C T L and a target cell and reorientation of C T L cytoplasmic granules as recorded by time-lapse photography
Figure 12-11 C T L-mediated pore formation in target cell membrane
Figure 12-12 Experimental demonstration that C T Ls use F a s and perforin pathways
Figure 12-13 Two pathways of C T L-activated target cell apoptosis
Figure 12-14 Time course of responses to viral infection
Figure 12-15 How N K cytotoxicity is restricted to altered self cells: missing self model and balanced signals model
Figure 12-16 Structures of N K inhibitory and activating receptors bound to their ligands
Figure 1 The investigators’ experimental approach
Figure 2 Experimental results
Figure 13.1 Barrier immune tissues
Figure 13.2 Major cell types in barrier immune systems
Figure 13.3 Major barrier tissue immune cells interact to produce type 1, type 2, and type 3 responses
Figure 13.4 Lymphoid tissues associated with barrier organs
Figure 13.5 Secondary lymphoid tissue associated with the small intestine
Figure 13.6 Common themes in barrier immune responses
Figure 13.7 Skin anatomy and associated immune cells
Figure 13.8 Developmental regulation of T R E G cells in the skin
Figure 13.9 Immune responses in the skin
Figure 13.10 Gross anatomy of the gastrointestinal (G I) tract
Figure 13.11 Cellular anatomy of the small and large intestines
Figure 13.12 How antigen is delivered from the lumen to antigen-presenting cells
Figure 13.13 Maintaining homeostasis and tolerance to the microbiome at the intestinal surface
Figure 13.14 Transcytosis of I g A to the lumen of the intestine
Figure 13.15 Effect of commensal bacteria on intestinal immune responses
Figure 13.16 Conditions that cause a switch from homeostatic (a) to inflammatory (b) immune responses
Figure 1 Maintaining germ-free mice
Figure 2 Mice from different laboratories harbor different microorganisms
S F B colonization affects I L-17 production by intestinal T H cells
Figure 1 Examples of the communication between the gut microbiota, immune system, and nervous system
Figure 13.17 Intestinal immune system response to Salmonella bacterial infection: an example of a type 1 response
Figure 13.18 Intestinal immune system response to worm infection: an example of a type 2 response
Figure 13.19 Gross and cellular anatomy of the respiratory tract
Figure 13.20 Immune responses in the respiratory tract
Figure 14-1 Lymphocyte recirculation routes
Figure 14-2 Lymphocyte migration through H E Vs
Figure 14-3 Lymphocyte migration in the spleen
Figure 1 The four families of cell-adhesion molecules
Figure 14-4 Lung associated lymphoid tissue
Cell traffic in a resting lymph node
Figure 14-6 Two-photon imaging of live T and B cells within a mouse lymph node
Figure 14-7 Antigen-presenting cells are present in all lymph-node microenvironments
Figure 14-8 Lymphocytes exit the lymph node through portals in the cortical and medullary sinuses
Figure 14-9 A successful immune response to a viral lung infection (S A R S-C o V-2)
Figure 14-10 How antigen travels into a lymph node
Figure 14-11 Migration of antigen-presenting cells from tissue to lymph node through efferent lymphatics
Figure 14-12 Antigen entry to lymph nodes and the spleen
Figure 14-13 Activation of C D 4 plus T cells and B cells in a lymph node during a primary immune response
Figure 14-14 B-cell activity in the germinal center
Figure 14-16 The formation of a tricellular complex in a lymph node during C D 8 plus T-cell activation
Figure 14-17 A summary of the nature and timing of events during T- and B-cell activation in a lymph node after the introduction of antigen
Figure 14-18 Effector and memory lymphocytes leave the lymph node via efferent lymphatics and circulate to infection sites
Figure 14-19 Examples of the homing receptors and addressins involved in trafficking naïve and effector T cells
Figure 14-20 The contraction of an immune response
Figure 14-21 Memory lymphocytes distribute themselves throughout the body, following cues provided by chemokines and cell adhesion molecules
Level of I g G against the spike protein
Level of I g M against the spike protein
Level of anti-spike I g G
Figure 15-1 The four types of hypersensitivity reactions
Figure 15-2 General mechanism underlying an immediate type 1 hypersensitivity reaction
Figure 15-3 Schematic diagrams of the high-affinity F c e R 1 and low-affinity F c e R 2 receptors that bind the F c region of I g E
Figure 15-4 Signaling pathways initiated by I g E allergen cross-linking of F c E R 1 receptors
Figure 15-5 Effects of mast cell activation
Figure 15-6 The early and late inflammatory responses in asthma
Figure 15-7 Environmental factors and genetics influence predisposition to allergies
Figure 15-8 Induction of I g E-mediated food allergy response
Figure 15-9 Skin testing for hypersensitivity
Figure 15-10 Mechanisms underlying immunotherapy-induced desensitization
Figure 15-11 A B O (A B H) blood groups
Figure 15-12 Destruction of R h-positive red blood cells during erythroblastosis fetalis
Figure 15-15 The D T H response
Figure 15-16 A prolonged D T H response can lead to formation of a granuloma, a nodule-like mass
Figure 15-17 Tuberculin skin test
Figure 15-18 Poison ivy causes contact dermatitis due to its toxin, urushiol
Figure 15-19 Induction of contact dermatitis by urushiol can be mediated by T H 1, T H 17, and C T L effector T cells
Figure 15-20 Causes and consequences of chronic inflammation
Figure 1 Signaling events that link obesity and inflammation to insulin resistance
Association between exposure to various bacterial species and the development of allergies
Figure 16-1 Central and peripheral tolerance
Figure 16-2 C T L A-4–mediated inhibition of A P Cs by T R E G cells
Figure 16-3 Linked suppression mediated by T R E G cells
Figure 16-5 Insulitis in Type 1 diabetes
Figure 16-6 Mechanism of myasthenia gravis induction
Figure 16-11 Schematic diagrams of the process of graft acceptance and rejection
Figure 16-12 Solid organ transplant numbers for 2020
Figure 16-13 Steps in the hyperacute rejection of a kidney graft
Figure 16-14 Direct versus indirect presentation of allogeneic M H C
Figure 16-15 Experimental demonstration that T cells can transfer allograft rejection
Figure 16-16 The role of C D 4 plus and C D 8 plus T cells in allograft rejection is demonstrated by the curves showing survival times of skin grafts between mice mismatched at the M H C
Figure 16-17 Effector mechanisms involved in allograft rejection
Figure 16-18 Blocking costimulatory signals at the time of transplantation can cause anergy instead of activation of T cells reactive against a graft
Figure 16-19 Site of action for various immunotherapy agents used in clinical transplantation
Figure 17-1 Causes of death worldwide, 2019
Figure 17-2 An increase in U.S. deaths in 2020 linked to COVID-19
Figure 17-3 Chain of infection
Figure 1 Characteristics of cytokine release syndrome (C R S) in COVID-19
Figure 1 A tubercle formed in pulmonary tuberculosis
Figure 1 Two mechanisms generate variations in influenza surface antigens
Figure 17-4 Transmission of respiratory infections
Figure 17-5 Vector-borne infectious diseases
Figure 17-6 Examples of global emerging and re-emerging infectious diseases
Figure 1 Structure of a typical coronavirus
Figure 2 Potential transmission route of the S A R S-Co V-2 precursor between hosts
Figure 1 Herd immunity explained
Figure 2 Herd immunity threshold as a function of R0
Figure 17-7 Progress with polio eradication
Figure 17-8 The five stages of infectious disease evolution from animals to humans
Figure 17-9 The Entry Points and in Vivo Microenvironments of Infectious Agents
Figure 17-10 The three major immune response pathways: type 1, 2, and 3
Figure 1 Two pathways to variation in influenza surface antigens
Figure 17-11 The presence of preformed antibody inhibits primary responses to a pathogen
Figure 17-12 Antibody-mediated mechanisms to combat infections by extracellular bacteria
Figure 17-14 Malarial life cycle
An advertisement for smallpox inoculation that was distributed in the early 1800s in Boston, M A
Figure 18-1 Return on investment from childhood immunizations in low- and middle-income countries, 2011 to 2020
Figure 18-2 Immune response pathways induced by vaccination
Recommended childhood immunization schedule in the United States, 2022
Figure 18-3 Pertussis cases in the United States, 1922 to 2019
Figure 1. Strategies used to design COVID-19 vaccines
Figure 18-5 Sequence of clinical trial phases in the United States
Figure 18-6 Vaccine formulations
Figure 18-8 Mucosal administration of a live, attenuated vaccine
Figure 18-9 Subunit vaccines
Figure 18-10 Multivalent subunit polysaccharide vaccines protect young children from bacterial pneumonia
Figure 18-11 Particle- and membrane-based vaccines
Figure 18-12 Viral- and bacterial-based vaccine vectors
Figure 18-13 Nucleic acid–based vaccines
Figure 18-14 A 2012 promotion for the pertussis booster
Figure 1 A prime-and-pull vaccine strategy protects mice against lethal challenge with H S V
Figure 18-15 Smallpox vaccination
A figure shows 9 graphs that depict E7-specific C D 8 plus T-cell response in mice
Two graphs show E7-specific CD8+ T lymphocyte response in wild type mice and C D 4 knockout mice
Primary immunodeficiencies resulting from inherited defects affect specific cell types
Figure 19-2 Primary immunodeficiency warning signs
Figure 19-3 Defects in lymphocyte development and signaling can lead to severe combined immunodeficiency (S C I D) in humans
Figure 19-4 Defects in C D 40 L on T cells or C D 40 on B cells and other A P Cs can give rise to the primary immunodeficiency known as hyper-I g M syndrome
Figure 19-5 Genetic defects resulting in Mendelian susceptibility to mycobacterial diseases (M S M Ds)
Figure 19- 7 Global AIDS epidemic
Figure 19-8 Trends in the H I V/ AIDS epidemic
Figure 19-9 Structure of H I V
Figure 19-11 Genetic organization of H I V-1 (a) and functions of encoded proteins (b)
H I V infection of target cells and virus replication
Figure 19-13 Budding of new virus particles from the surface of an infected T cell
Figure 19-14 C X C R 4 and C C R 5 serve as coreceptors for H I V infection of different cell types
Figure 19-15 Typical course of H I V infection in an untreated patient
Figure 19-16 Endoscopic and histologic evidence for depletion of C D 4 plus T cells in the G I tract of patients with A I D S
Figure 19-17 Stages in viral replication cycle that provide targets for therapeutic antiretroviral drugs
E 7-specific C D 8 plus T-cell response
Figure 1 New H I V infections worldwide among children with and without the provision of antiretroviral medicines to prevent mother-to-child transmission, from 1995 to 2020
Figure 2 Most countries are providing lifelong antiretroviral therapy to pregnant and breastfeeding women living with H I V
Figure 1 Neutralizing antibodies to H I V
Figure 2 Neutralizing antibodies to H I V
Figure 3 An immunization approach for stimulating production of broadly neutralizing antibodies to the H I V-1 E n v spike
Effect of C V I D on the immune response
Figure 19-2 Chromosomal translocations resulting in Burkitt’s lymphoma
Figure 19-3 Model of sequential genetic alterations leading to metastatic colon cancer
Figure 19-4 Hallmarks of cancer
Figure 19-5 Different mechanisms generate tumor-specific antigens (TSAs) and tumor-associated antigens (TAAs)
Figure 19-7 Down-regulation of MHC class I expression on tumor cells may allow for tumor escape mutants
Figure 19-9 Development of a monoclonal antibody specific for idiotypic determinants on B-lymphoma cells
Figure 1
Figure 2
Figure 19-10 Mechanism of action of sipuleucel-T, a prostate cancer vaccine
Figure 19-11 Use of CD80 (B7.1)-transfected tumor cells for cancer immunotherapy
Figure 19-12 Using checkpoint blockade therapy to treat cancer
Figure 20-1 Tumor growth and metastasis
Figure 20-2 Hallmarks of cancer
Figure 20-3 Mechanisms that generate tumor-specific antigens (T S As) and tumor-associated antigens (T A As)
Figure 1 Age of vaccination against H P V and the future risk of cervical cancer in women
Figure 20-4 The three stages of cancer immunoediting
Figure 20-5 The immunosuppressive, pro-tumor microenvironment
Figure 20-6 Immune contexture and immunoscores used in cancer staging and prognosis
Figure 20-7 Types of immunotherapy available to treat cancer
Figure 20-8 Bispecific T-cell engagers (B i T Es) used in cancer immunotherapy
Figure 20-9 Using checkpoint blockade therapy to treat cancer
Figure 20-10 The sipuleucel-T mechanism of action, a prostate cancer vaccine
Figure 1 Driving Cancer Away with CAR T Cells
Figure 2 Examples of the specialized accessories included in C A Rs
Figure 20-11 The NeoVax cancer vaccine platform
Figure 20-12 Using oncolytic viruses to treat cancer
Figure 1 Optical properties of the three types of filters
A photo shows an 8 by 8 micro-titre plate that is used for a hemagglutination inhibition assay
Stimulated and unstimulated T cells
C D 46 graph
Apoptotic and healthy cells
An illustration shows the formation of a recombined v j gene in a B cell from a germ-line light-chain (kappa) D N A
An illustration shows the formation of a recombined V D J gene from a germ-line heavy-chain (H) D N A in two steps
Recombined V D J B gene in T cell
Recombined V J gene
Comparing thymus and lymph nodes of normal and knockout mice
Different B cells
Activation-induced cytidine deaminase
Figure C-1 The chemokine system: an overview
Figure D-1 Icons used in this Appendix
Figure D-3 G protein activation
Figure D-4 The M A P kinase pathway
Figure D-5 Downstream components of the canonical and noncanonical pathways of N F-kappa B activation
Figure D-6 Upstream portion of the canonical N F-kappa B pathway
Figure D-7 Upstream portion of the noncanonical N F-kappa B pathway
Figure D-8 Integration of common signaling pathways
Figure D-9 Signaling through plasma membrane T L Rs
Figure D-10 Signaling through endosomal T L Rs
Figure D-11 Signaling through C L Rs
Figure D-12 Signaling through N L R and R L R receptors
Figure D-13 Signaling through c G A S and S T I N G
Figure D-14 The J A K-S T A T pathway of cytokine activation
Figure D-15 Signal transduction pathways from G protein–coupled receptors
Figure D-16 Signaling through T N F-R 1
Figure D-17 Pathways that regulate apoptosis
Figure D-18 Signaling through the Notch receptor
Figure D-19 Signaling through the T-cell receptor
Figure D-20 Signaling through the B-cell receptor
Figure D-21 Activation of S r c-family kinases
Figure E-1 The generation of polyclonal and monoclonal antibodies
Figure E-2 Immunoprecipitation in solution
Figure E-6 Competitive, solid-phase radioimmunoassay (R I A) to measure cytokine concentrations in serum
Figure E-7 Variations in the enzyme-linked immunosorbent assay (E L I S A) technique allow for the determination of antibody or antigen
Figure E-8 E L I S P O T measurements of interferon (I F N)- gamma secretion by N K T cells
Figure E-9 Western blotting uses antibodies to identify protein bands after gel electrophoresis
Figure E-10 Determining antibody affinity with equilibrium dialysis
Figure E-11 Surface plasmon resonance (S P R)
Figure E-14 Fluorescently labeled cells and the passage of light through a fluorescence microscope
Figure E-16 The principle of confocal microscopy
Figure E-17 Fluorescence excitation by one-photon versus two-photon laser excitation
Figure E-18 Three-dimensional fluorescence in situ hybridization (3-D F I S H)
Figure E-19 A simple flow cytometry setup
Figure E-20 Optical properties of the three types of filters
Figure E-21 Nature of the voltage pulse is determined by the shape of the emitting structure
Figure E-22 Typical dot plots of cytometric data
Figure E-23 Analysis of multicolor fluorescence data
Figure E-24 The emission spectra of commonly used dyes have considerable overlap
Figure E-25 Spectral cytometry collects the entire emission spectra of all fluorochromes
Figure E-26 C y T O F enables the measurement of up to 45 different parameters
Figure E-27 The M T T assay is used to measure the number of viable cells in a suspension
Figure E-28 Bromodeoxyuridine replaces deoxythymidine during D N A synthesis
Figure E-29 Propidium iodide intercalates into D N A and is a cell cycle and apoptosis indicator
Figure E-30 C F S E labeling can determine the frequency of cells that have divided a defined number of times
Figure E-31 Assessment of apoptosis, using a T U N E L assay
Figure E-32 D N A Hi-C detects regions of D N A that interact in three-dimensional space in situ
Figure E-33 Sanger dideoxy sequencing
Figure E-34 Next-generation sequencing
Figure E-35 The C R I S P R-Cas 9 system can be applied to problems that require targeted D N A manipulations
Figure E-36 Quantitative P C R detects the frequency of a viral sequence using fluorescence detection
Figure E-37 L A M P-P C R operates under isothermal conditions to amplify viral sequences
Figure E-38 C R I S P R-Cas 12 a can detect S A R S-Co V-2
Figure E-39 Antibody-based rapid detection test for viral antigens
Figure E-40 General procedure for generating transgenic mice
Figure E-41 Gene targeting with C r e / l o x
Back cover of the Kuby Immunology textbook
Back Cover

"It is our goal that students should complete an immunology course not only with a firm grasp of content, but also with a clear sense of how key discoveries were made, what interesting questions remain, and how they might best be answered"--