Excerpt

This book is intended as an introductory text for use in immunology courses for medical students, advanced undergraduate biology students, graduate students, and scientists in other fields who want to know more about the immune system. It attempts to present the field of immunology from a consistent viewpoint, that of the host’s interaction with an environment containing many species of potentially harmful microbes. The justification for this approach is that the absence of one or more components of the immune system is virtually always made clear by an increased susceptibility to one or more specific infections. Thus, first and foremost, the immune system exists to protect the host from infection, and its evolutionary history must have been shaped largely by this challenge. Other aspects of immunology, such as allergy, autoimmunity, graft rejection, and immunity to tumors, are treated as variations on this basic protective function. In these cases the nature of the antigen is the major variable.

Contents

• Preface to the Fifth Edition
• Acknowledgments
• Icons Used Throughout the Book
• Part I. An Introduction to Immunobiology and Innate Immunity
  • Chapter 1. Basic Concepts in Immunology
    • The components of the immune system
      • 1-1. The white blood cells of the immune system derive from precursors in the bone marrow
      • 1-2. Lymphocytes mature in the bone marrow or the thymus
      • 1-3. The peripheral lymphoid organs are specialized to trap antigen, to allow the initiation of adaptive immune responses, and to provide signals that sustain recirculating lymphocytes
      • 1-4. Lymphocytes circulate between blood and lymph
      • Summary
    • Principles of innate and adaptive immunity
      • 1-5. Most infectious agents induce inflammatory responses by activating innate immunity
      • 1-6. Activation of specialized antigen-presenting cells is a necessary first step for induction of adaptive immunity
      • 1-7. Lymphocytes activated by antigen give rise to clones of antigen-specific cells that mediate adaptive immunity
      • 1-8. Clonal selection of lymphocytes is the central principle of adaptive immunity
      • 1-9. The structure of the antibody molecule illustrates the central puzzle of adaptive immunity
      • 1-10. Each developing lymphocyte generates a unique antigen receptor by rearranging its receptor genes
      • 1-11. Lymphocyte development and survival are determined by signals received through their antigen receptors
      • 1-12. Lymphocytes proliferate in response to antigen in peripheral lymphoid organs, generating effector cells and immunological memory
      • 1-13. Interaction with other cells as well as with antigen is necessary for lymphocyte activation
      • Summary
    • The recognition and effector mechanisms of adaptive immunity
      • 1-14. Antibodies deal with extracellular forms of pathogens and their toxic products
      • 1-15. T cells are needed to control intracellular pathogens and to activate B-cell responses to most antigens
      • 1-16. T cells are specialized to recognize foreign antigens as peptide fragments bound to proteins of the major histocompatibility complex
      • 1-17. Two major types of T cell recognize peptides bound to proteins of two different classes of MHC molecule
      • 1-18. Defects in the immune system result in increased susceptibility to infection
      • 1-19. Understanding adaptive immune responses is important for the control of allergies, autoimmune disease, and organ graft rejection
      • 1-20. Vaccination is the most effective means of controlling infectious diseases
      • Summary
    • Summary to Chapter 1
    • General references
      • Historical background
      • Biological background
      • Primary journals devoted solely or primarily to immunology
      • Primary journals with frequent papers in immunology
      • Review journals in immunology
      • Advanced textbooks in immunology, compendia, etc
  • Chapter 2. Innate Immunity
    • The front line of host defense
      • 2-1. Infectious agents must overcome innate host defenses to establish a focus of infection
      • 2-2. The epithelial surfaces of the body are the first defenses against infection
      • 2-3. After entering tissues, many pathogens are recognized, ingested, and killed by phagocytes
      • 2-4. Pathogen recognition and tissue damage initiate an inflammatory response
      • Summary
    • The complement system and innate immunity
      • 2-5. Complement is a system of plasma proteins that interacts with pathogens to mark them for destruction by phagocytes
      • 2-6. The classical pathway is initiated by activation of the C1 complex
      • 2-7. The mannan-binding lectin pathway is homologous to the classical pathway
      • 2-8. Complement activation is largely confined to the surface on which it is initiated
      • 2-9. Hydrolysis of C3 causes initiation of the alternative pathway of complement
      • 2-10. Surface-bound C3 convertase deposits large numbers of C3b fragments on pathogen surfaces and generates C5 convertase activity
      • 2-11. Phagocyte ingestion of complement-tagged pathogens is mediated by receptors for the bound complement proteins
      • 2-12. Small fragments of some complement proteins can initiate a local inflammatory response
      • 2-13. The terminal complement proteins polymerize to form pores in membranes that can kill certain pathogens
      • 2-14. Complement control proteins regulate all three pathways of complement activation and protect the host from its destructive effects
      • Summary
    • Receptors of the innate immune system
      • 2-15. Receptors with specificity for pathogen surfaces recognize patterns of repeating structural motifs
      • 2-16. Receptors on phagocytes can signal the presence of pathogens
      • 2-17. The effects of bacterial lipopolysaccharide on macrophages are mediated by CD14 binding to Toll-like receptor 4
      • 2-18. Activation of Toll-like receptors triggers the production of pro-inflammatory cytokines and chemokines, and the expression of co-stimulatory molecules
      • Summary
    • Induced innate responses to infection
      • 2-19. Activated macrophages secrete a range of cytokines that have a variety of local and distant effects
      • 2-20. Chemokines released by phagocytes recruit cells to sites of infection
      • 2-21. Cell-adhesion molecules control interactions between leukocytes and endothelial cells during an inflammatory response
      • 2-22. Neutrophils make up the first wave of cells that cross the blood vessel wall to enter inflammatory sites
      • 2-23. Tumor necrosis factor-α is an important cytokine that triggers local containment of infection, but induces shock when released systemically
      • 2-24. Cytokines released by phagocytes activate the acute-phase response
      • 2-25. Interferons induced by viral infection make several contributions to host defense
      • 2-26. Natural killer cells are activated by interferons and macrophage-derived cytokines to serve as an early defense against certain intracellular infections
      • 2-27. NK cells possess receptors for self molecules that inhibit their activation against uninfected host cells
      • 2-28. Several lymphocyte subpopulations and ‘natural antibodies’ behave like intermediates between adaptive and innate immunity
      • Summary
    • Summary to Chapter 2
    • General references
    • Section references
      • 2-1 Infectious agents must overcome innate host defenses to establish a focus of infection
      • 2-2 The epithelial surfaces of the body are the first defenses against infection
      • 2-3 After entering tissues, many pathogens are recognized, ingested, and killed by phagocytes
      • 2-4 Pathogen recognition and tissue damage initiate an inflammatory response
      • 2-5 Complement is a system of plasma proteins that interacts with pathogens to mark them for destruction by phagocytes
      • 2-6 The classical pathway is initiated by activation of the C1 complex
      • 2-7 The mannan-binding lectin pathway is homologous to the classical pathway
      • 2-8 Complement activation is largely confined to the surface on which it is initiated
      • 2-9 Hydrolysis of C3 causes initiation of the alternative pathway of complement
      • 2-10 Surface-bound C3 convertase deposits large numbers of C3b fragments on pathogen surfaces and generates C5 convertase activity
      • 2-11 Phagocyte ingestion of complement-tagged pathogens is mediated by receptors for the bound complement proteins
      • 2-12 Small fragments of some complement proteins can initiate a local inflammatory response
      • 2-13 The terminal complement proteins polymerize to form pores in membranes that can kill certain pathogens
      • 2-14 Complement control proteins regulate all three pathways of complement activation and protect the host from its destructive effects
      • 2-15 Receptors with specificity for pathogen surfaces recognize patterns of repeating structural motifs
      • 2-16 Receptors on phagocytes can signal the presence of pathogens
      • 2-17 The effects of bacterial lipopolysaccharide on macrophages are mediated by CD14 binding to Toll-like receptor 4
      • 2-18 Activation of Toll-like receptors triggers the production of pro-inflammatory cytokines and chemokines, and the expression of co-stimulatory molecules
      • 2-19 Activated macrophages secrete a range of cytokines that have a variety of local and distant effects
      • 2-20 Chemokines released by phagocytes recruit cells to sites of infection
      • 2-21 Cell-adhesion molecules control interactions between leukocytes and endothelial cells during an inflammatory response
      • 2-22 Neutrophils make up the first wave of cells that cross the blood vessel wall to enter inflammatory sites
      • 2-23 Tumor necrosis factor-a is an important cytokine that triggers local containment of infection, but induces shock when released systemically
      • 2-24 Cytokines released by phagocytes activate the acute-phase response
      • 2-25 Interferons induced by viral infection make several contributions to host defense
      • 2-26 Natural killer cells are activated by interferons and macrophage-derived cytokines to serve as an early defense against certain intracellular infections
      • 2-27 NK cells possess receptors for self molecules that inhibit their activation against uninfected host cells
      • 2-28 Several lymphocyte subpopulations and ‘natural antibodies’ behave like intermediates between adaptive and innate immunity
• Part II. The Recognition of Antigen
  • Chapter 3. Antigen Recognition by B-cell and T-cell Receptors
    • The structure of a typical antibody molecule
      • 3-1. IgG antibodies consist of four polypeptide chains
      • 3-2. Immunoglobulin heavy and light chains are composed of constant and variable regions
      • 3-3. The antibody molecule can readily be cleaved into functionally distinct fragments
      • 3-4. The immunoglobulin molecule is flexible, especially at the hinge region
      • 3-5. The domains of an immunoglobulin molecule have similar structures
      • Summary
    • The interaction of the antibody molecule with specific antigen
      • 3-6. Localized regions of hypervariable sequence form the antigenbinding site
      • 3-7. Antibodies bind antigens via contacts with amino acids in CDRs, but the details of binding depend upon the size and shape of the antigen
      • 3-8. Antibodies bind to conformational shapes on the surfaces of antigens
      • 3-9. Antigen-antibody interactions involve a variety of forces
      • Summary
    • Antigen recognition by T cells
      • 3-10. The antigen receptor on T cells is very similar to a Fab fragment of immunoglobulin
      • 3-11. A T-cell receptor recognizes antigen in the form of a complex of a foreign peptide bound to an MHC molecule
      • 3-12. T cells with different functions are distinguished by CD4 and CD8 cell-surface proteins and recognize peptides bound to different classes of MHC molecule
      • 3-13. The two classes of MHC molecule are expressed differentially on cells
      • 3-14. The two classes of MHC molecule have distinct subunit structures but similar three-dimensional structures
      • 3-15. Peptides are stably bound to MHC molecules, and also serve to stabilize the MHC molecule on the cell surface
      • 3-16. MHC class I molecules bind short peptides of 8–10 amino acids by both ends
      • 3-17. The length of the peptides bound by MHC class II molecules is not constrained
      • 3-18. The crystal structures of several MHC:peptide:T-cell receptor complexes all show the same T-cell receptor orientation over the MHC:peptide complex
      • 3-19. A distinct subset of T cells bears an alternative receptor made up of γ and δ chains
      • Summary
    • Summary to Chapter 3
    • General references
    • Section references
      • 3-1 IgG antibodies consist of four polypeptide chains
      • 3-2 Immunoglobulin heavy and light chains are composed of constant and variable regions
      • 3-3 The antibody molecule can readily be cleaved into functionally distinct fragments
      • 3-4 The immunoglobulin molecule is flexible, especially at the hinge region
      • 3-5 The domains of an immunoglobulin molecule have similar structures
      • 3-6 Localized regions of hypervariable sequence form the antigen-binding site
      • 3-7 Antibodies bind antigens via contacts with amino acids in CDRs, but the details of binding depend upon the size and shape of the antigen. & 3-8 Antibodies bind to conformational shapes on the surfaces of antigens
      • 3-9 Antigen-antibody interactions involve a variety of forces
      • 3-10 The antigen receptor on T cells is very similar to a Fab fragment of immunoglobulin
      • 3-11 A T-cell receptor recognizes antigen in the form of a complex of a foreign peptide bound to an MHC molecule
      • 3-12 T cells with different functions are distinguished by CD4 and CD8 cell-surface proteins and recognize peptides bound to different classes of MHC molecule
      • 3-13 The two classes of MHC molecule are expressed differentially on cells
      • 3-14 The two classes of MHC molecule have distinct subunit structures but similar three-dimensional structures. / 3-15 Peptides are stably bound to MHC molecules, and also serve to stabilize the MHC molecule on the cell surface
      • 3-16 MHC class I molecules bind short peptides of 8–10 amino acids by both ends
      • 3-17 The length of the peptides bound by MHC class II molecules is not constrained
      • 3-18 The crystal structures of several MHC:peptide:T-cell receptor complexes all show the same T-cell receptor orientation over the MHC:peptide complex
      • 3-19 A distinct subset of T cells bears an alternative receptor made up of γ and δ chains
  • Chapter 4. The Generation of Lymphocyte Antigen Receptors
    • The generation of diversity in immunoglobulins
      • 4-1. Immunoglobulin genes are rearranged in antibody-producing cells
      • 4-2. The DNA sequence encoding a complete V region is generated by the somatic recombination of separate gene segments
      • 4-3. There are multiple different V-region gene segments
      • 4-4. Rearrangement of V, D, and J gene segments is guided by flanking DNA sequences
      • 4-5. The reaction that recombines V, D, and J gene segments involves both lymphocyte-specific and ubiquitous DNA-modifying enzymes
      • 4-6. The diversity of the immunoglobulin repertoire is generated by four main processes
      • 4-7. The multiple inherited gene segments are used in different combinations
      • 4-8. Variable addition and subtraction of nucleotides at the junctions between gene segments contributes to diversity in the third hypervariable region
      • 4-9. Rearranged V genes are further diversified by somatic hypermutation
      • 4-10. In some species most immunoglobulin gene diversification occurs after gene rearrangement
      • Summary
    • T-cell receptor gene rearrangement
      • 4-11. The T-cell receptor loci comprise sets of gene segments and are rearranged by the same enzymes as the immunoglobulin loci
      • 4-12. T-cell receptors concentrate diversity in the third hypervariable region
      • 4-13. γ:δ T-cell receptors are also generated by gene rearrangement
      • 4-14. Somatic hypermutation does not generate diversity in T-cell receptors
      • Summary
    • Structural variation in immunoglobulin constant regions
      • 4-15. The immunoglobulin heavy-chain isotypes are distinguished by the structure of their constant regions
      • 4-16. The same V_H exon can associate with different C_H genes in the course of an immune response
      • 4-17. Transmembrane and secreted forms of immunoglobulin are generated from alternative heavy-chain transcripts
      • 4-18. Antibody C regions confer functional specialization
      • 4-19. IgM and IgA can form polymers
      • 4-20. Various differences between immunoglobulins can be detected by antibodies
      • Summary
    • Summary to Chapter 4
    • General references
    • Section references
      • 4-1 Immunoglobulin genes are rearranged in antibody-producing cells
      • 4-2 The DNA sequence encoding a complete V region is generated by the somatic recombination of separate gene segments
      • 4-3 There are multiple different V-region gene segments
      • 4-4 Rearrangement of V, D, and J gene segments is guided by flanking DNA sequences
      • 4-5 The reaction that recombines V, D, and J gene segments involves both lymphocyte-specific and ubiquitous DNA-modifying enzymes
      • 4-6 The diversity of the immunoglobulin repertoire is generated by four main processes
      • 4-7 The multiple inherited gene segments are used in different combinations
      • 4-8 Variable addition and subtraction of nucleotides at the junctions between gene segments contributes to diversity in the third hypervariable region
      • 4-9 Rearranged V genes are further diversified by somatic hypermutation
      • 4-10 In some species most immunoglobulin gene diversification occurs after gene rearrangement
      • 4-11 The T-cell receptor loci comprise sets of gene segments and are rearranged by the same enzymes as the immunoglobulin loci
      • 4-12 T-cell receptors concentrate diversity in the third hypervariable region
      • 4-13 γ:δ T-cell receptors are also generated by gene rearrangement
      • 4-14 Somatic hypermutation does not generate diversity in T-cell receptors
      • 4-15 The immunoglobulin heavy-chain isotypes are distinguished by the structure of their constant regions
      • 4-16 The same V_H exon can associate with different C_H genes in the course of an immune response
      • 4-17 Transmembrane and secreted forms of immunoglobulin are generated from alternative heavy-chain transcripts
      • 4-18 Antibody C regions confer functional specialization
      • 4-19 IgM and IgA can form polymers
      • 4-20 Various differences between immunoglobulins can be detected by antibodies
  • Chapter 5. Antigen Presentation to T Lymphocytes
    • The generation of T-cell receptor ligands
      • 5-1. The MHC class I and class II molecules deliver peptides to the cell surface from two distinct intracellular compartments
      • 5-2. Peptides that bind to MHC class I molecules are actively transported from the cytosol to the endoplasmic reticulum
      • 5-3. Peptides for transport into the endoplasmic reticulum are generated in the cytosol
      • 5-4. Newly synthesized MHC class I molecules are retained in the endoplasmic reticulum until they bind peptide
      • 5-5. Peptides presented by MHC class II molecules are generated in acidified endocytic vesicles
      • 5-6. The invariant chain directs newly synthesized MHC class II molecules to acidified intracellular vesicles
      • 5-7. A specialized MHC class II-like molecule catalyzes loading of MHC class II molecules with peptides
      • 5-8. Stable binding of peptides by MHC molecules provides effective antigen presentation at the cell surface
      • Summary
    • The major histocompatibility complex and its functions
      • 5-9. Many proteins involved in antigen processing and presentation are encoded by genes within the major histocompatibility complex
      • 5-10. A variety of genes with specialized functions in immunity are also encoded in the MHC
      • 5-11. Specialized MHC class I molecules act as ligands for activation and inhibition of NK cells
      • 5-12. The protein products of MHC class I and class II genes are highly polymorphic
      • 5-13. MHC polymorphism affects antigen recognition by T cells by influencing both peptide binding and the contacts between T-cell receptor and MHC molecule
      • 5-14. Nonself MHC molecules are recognized by 1–10% of T cells
      • 5-15. Many T cells respond to superantigens
      • 5-16. MHC polymorphism extends the range of antigens to which the immune system can respond
      • 5-17. Multiple genetic processes generate MHC polymorphism
      • 5-18. Some peptides and lipids generated in the endocytic pathway can be bound by MHC class I-like molecules that are encoded outside the MHC
      • Summary
    • Summary to Chapter 5
    • General references
    • Section references
      • 5-1 The MHC class I and class II molecules deliver peptides to the cell surface from two distinct intracellular compartments
      • 5-2 Peptides that bind to MHC class I molecules are actively transported from the cytosol to the endoplasmic reticulum
      • 5-3 Peptides for transport into the endoplasmic reticulum are generated in the cytosol
      • 5-4 Newly synthesized MHC class I molecules are retained in the endoplasmic reticulum until they bind peptide
      • 5-5 Peptides presented by MHC class II molecules are generated in acidified endocytic vesicles
      • 5-6 The invariant chain directs newly synthesized MHC class II molecules to acidified intracellular vesicles
      • 5-7 A specialized MHC class II-like molecule catalyzes loading of MHC class II molecules with peptides
      • 5-8 Stable binding of peptides by MHC molecules provides effective antigen presentation at the cell surface
      • 5-9 Many proteins involved in antigen processing and presentation are encoded by genes within the major histocompatibility complex
      • 5-10 A variety of genes with specialized functions in immunity are also encoded in the MHC
      • 5-11 Specialized MHC class I molecules act as ligands for activation and inhibition of NK cells
      • 5-12 The protein products of MHC class I and class II genes are highly polymorphic
      • 5-13 MHC polymorphism affects antigen recognition by T cells by influencing both peptide binding and the contacts between T-cell receptor and MHC molecule
      • 5-14 Nonself MHC molecules are recognized by 1–10% of T cells
      • 5-15 Many T cells respond to superantigens
      • 5-16 MHC polymorphism extends the range of antigens to which the immune system can respond
      • 5-17 Multiple genetic processes generate MHC polymorphism
      • 5-18 Some peptides and lipids generated in the endocytic pathway can be bound by MHC class I-like molecules that are encoded outside the MHC
• Part III. The Development of Mature Lymphocyte Receptor Repertoires
  • Chapter 6. Signaling Through Immune System Receptors
    • General principles of transmembrane signaling
      • 6-1. Binding of antigen leads to clustering of antigen receptors on lymphocytes
      • 6-2. Clustering of antigen receptors leads to activation of intracellular signal molecules
      • 6-3. Phosphorylation of receptor cytoplasmic tails by tyrosine kinases concentrates intracellular signaling molecules around the receptors
      • 6-4. Intracellular signaling components recruited to activated receptors transmit the signal onward from the membrane and amplify it
      • 6-5. Small G proteins activate a protein kinase cascade that transmits the signal to the nucleus
      • Summary
    • Antigen receptor structure and signaling pathways
      • 6-6. The variable chains of lymphocyte antigen receptors are associated with invariant accessory chains that carry out the signaling function of the receptor
      • 6-7. The ITAMs associated with the B-cell and T-cell receptors are phosphorylated by protein tyrosine kinases of the Src family
      • 6-8. Antigen receptor signaling is enhanced by co-receptors that bind the same ligand
      • 6-9. Fully phosphorylated ITAMs bind the protein tyrosine kinases Syk and ZAP-70 and enable them to be activated
      • 6-10. Downstream events are mediated by proteins that associate with the phosphorylated tyrosines and bind to and activate other proteins
      • 6-11. Antigen recognition leads ultimately to the induction of new gene synthesis by activating transcription factors
      • 6-12. Not all ligands for the T-cell receptor produce a similar response
      • 6-13. Other receptors on leukocytes also use ITAMs to signal activation
      • 6-14. Antigen-receptor signaling can be inhibited by receptors associated with ITIMs
      • Summary
    • Other signaling pathways that contribute to lymphocyte behavior
      • 6-15. Microbes and their products release NFκB from its site in the cytosol through an ancient pathway of host defense against infection
      • 6-16. Bacterial peptides, mediators of inflammatory responses, and chemokines signal through members of the seven-transmembrane-domain, trimeric G protein-coupled receptor family
      • 6-17. Cytokines signal lymphocytes by binding to cytokine receptors and triggering Janus kinases to phosphorylate and activate STAT proteins
      • 6-18. Programmed cell death of activated lymphocytes is triggered mainly through the receptor Fas
      • 6-19. Lymphocyte survival is maintained by a balance between death-promoting and death-inhibiting members of the Bcl-2 family of proteins
      • 6-20. Homeostasis of lymphocyte populations is maintained by signals that lymphocytes are continually receiving through their antigen receptors
      • Summary
    • Summary to Chapter 6
    • General references
    • Section references
      • 6-1 Binding of antigen leads to clustering of antigen receptors on lymphocytes
      • 6-2 Clustering of antigen receptors leads to activation of intracellular signal molecules
      • 6-3 Phosphorylation of receptor cytoplasmic tails by tyrosine kinases concentrates intracellular signaling molecules around the receptors
      • 6-4 Intracellular signaling components recruited to activated receptors transmit the signal onward from the membrane and amplify it
      • 6-5 Small G proteins activate a protein kinase cascade that transmits the signal to the nucleus
      • 6-6 The variable chains of lymphocyte antigen receptors are associated with invariant accessory chains that carry out the signaling function of the receptor
      • 6-7 The ITAMs associated with the B-cell and T-cell receptors are phosphorylated by protein tyrosine kinases of the Src family
      • 6-8 Antigen receptor signaling is enhanced by co-receptors that bind the same ligand
      • 6-9 Fully phosphorylated ITAMs bind the protein tyrosine kinases Syk and ZAP-70 and enable them to be activated
      • 6-10 Downstream events are mediated by proteins that associate with the phosphorylated tyrosines and bind to and activate other proteins
      • 6-11 Antigen recognition leads ultimately to the induction of new gene synthesis by activating transcription factors
      • 6-12 Not all ligands for the T-cell receptor produce a similar response
      • 6-13 Other receptors on leukocytes also use ITAMs to signal activation
      • 6-14 Antigen-receptor signaling can be inhibited by receptors associated with ITIMs
      • 6-15 Microbes and their products release NFkB from its site in the cytosol through an ancient pathway of host defense against infection
      • 6-16 Bacterial peptides, mediators of inflammatory responses, and chemokines signal through members of the seven-transmembrane-domain, trimeric G protein-coupled receptor family
      • 6-17 Cytokines signal lymphocytes by binding to cytokine receptors and triggering Janus kinases to phosphorylate and activate STAT proteins
      • 6-18 Programmed cell death of activated lymphocytes is triggered mainly through the receptor Fas
      • 6-19 Lymphocyte survival is maintained by a balance between death-promoting and death-inhibiting members of the Bcl-2 family of proteins
      • 6-20 Homeostasis of lymphocyte populations is maintained by signals that lymphocytes are continually receiving through their antigen receptors
  • Chapter 7. The Development and Survival of Lymphocytes
    • Generation of lymphocytes in bone marrow and thymus
      • 7-1. Lymphocyte development occurs in specialized environments and is regulated by the somatic rearrangement of the antigen-receptor genes
      • 7-2. B cells develop in the bone marrow with the help of stromal cells and achieve maturity in peripheral lymphoid organs
      • 7-3. Stages in B-cell development are distinguished by the expression of immunoglobulin chains and particular cell-surface proteins
      • 7-4. T cells also originate in the bone marrow, but all the important events in their development occur in the thymus
      • 7-5. Most developing T cells die in the thymus
      • 7-6. Successive stages in the development of thymocytes are marked by changes in cell-surface molecules
      • 7-7. Thymocytes at different developmental stages are found in distinct parts of the thymus
      • Summary
    • The rearrangement of antigen-receptor gene segments controls lymphocyte development
      • 7-8. B cells undergo a strictly programmed series of gene rearrangements in the bone marrow
      • 7-9. Successful rearrangement of heavy-chain immunoglobulin gene segments leads to the formation of a pre-B-cell receptor that halts further V_H to DJ_H rearrangement and triggers the cell to divide
      • 7-10. Rearrangement at the immunoglobulin light-chain locus leads to cell-surface expression of the B-cell receptor
      • 7-11. The expression of proteins regulating immunoglobulin gene rearrangement and function is developmentally programmed
      • 7-12. T cells in the thymus undergo a series of gene segment rearrangements similar to those of B cells
      • 7-13. T cells with α:β or γ:δ receptors arise from a common progenitor
      • 7-14. T cells expressing particular γ- and δ-chain V regions arise in an ordered sequence early in life
      • 7-15. Rearrangement of the β-chain locus and production of a β chain trigger several events in developing thymocytes
      • 7-16. T-cell α-chain genes undergo successive rearrangements until positive selection or cell death intervenes
      • Summary
    • Interaction with self antigens selects some lymphocytes for survival but eliminates others
      • 7-17. Immature B cells that bind self antigens undergo further receptor rearrangement, or die, or are inactivated
      • 7-18. Mature B cells can also be rendered self-tolerant
      • 7-19. Only thymocytes whose receptors can interact with self MHC:self peptide complexes can survive and mature
      • 7-20. Most thymocytes express receptors that cannot interact with self MHC and these cells die in the thymus
      • 7-21. Positive selection acts on a repertoire of receptors with inherent specificity for MHC molecules
      • 7-22. Positive selection coordinates the expression of CD4 or CD8 with the specificity of the T-cell receptor and the potential effector functions of the cell
      • 7-23. Thymic cortical epithelial cells mediate positive selection of developing thymocytes
      • 7-24. T cells that react strongly with ubiquitous self antigens are deleted in the thymus
      • 7-25. Negative selection is driven most efficiently by bone marrow-derived antigen-presenting cells
      • 7-26. Endogenous superantigens mediate negative selection of T-cell receptors derived from particular V_β gene segments
      • 7-27. The specificity and strength of signals for negative and positive selection must differ
      • 7-28. The B-1 subset of B cells has a distinct developmental history and expresses a distinctive repertoire of receptors
      • Summary
    • Survival and maturation of lymphocytes in peripheral lymphoid tissues
      • 7-29. Newly formed lymphocytes home to particular locations in peripheral lymphoid tissues
      • 7-30. The development and organization of peripheral lymphoid tissues is controlled by cytokines and chemokines
      • 7-31. Only a small fraction of immature B cells mature and survive in peripheral lymphoid tissues
      • 7-32. The life-span of naive T cells in the periphery is determined by ongoing contact with self peptide:self MHC complexes similar to those that initially selected them
      • 7-33. B-cell tumors often occupy the same site as their normal counterparts
      • 7-34. A range of tumors of immune system cells throws light on different stages of T-cell development
      • 7-35. Malignant lymphocyte tumors frequently carry chromosomal translocations that join immunoglobulin loci to genes regulating cell growth
      • Summary
    • Summary to Chapter 7
    • General references
    • Section references
      • 7-1 Lymphocyte development occurs in specialized environments and is regulated by the somatic rearrangement of the antigen-receptor genes
      • 7-2 B cells develop in the bone marrow with the help of stromal cells and achieve maturity in peripheral lymphoid organs
      • 7-3 Stages in B-cell development are distinguished by the expression of immunoglobulin chains and particular cell-surface proteins
      • 7-4 T cells also originate in the bone marrow, but all the important events in their development occur in the thymus
      • 7-5 Most developing T cells die in the thymus
      • 7-6 Successive stages in the development of thymocytes are marked by changes in cell-surface molecules
      • 7-7 Thymocytes at different developmental stages are found in distinct parts of the thymus
      • 7-8 B cells undergo a strictly programmed series of gene rearrangements in the bone marrow
      • 7-9 Successful rearrangement of heavy-chain immunoglobulin gene segments leads to the formation of a pre-B-cell receptor that halts further V_H to DJ_H rearrangement and triggers the cell to divide
      • 7-10 Rearrangement at the immunoglobulin light-chain locus leads to cell-surface expression of the B-cell receptor
      • 7-11 The expression of proteins regulating immunoglobulin gene rearrangement and function is developmentally programmed
      • 7-12 T cells in the thymus undergo a series of gene segment rearrangements similar to those of B cells
      • 7-13 T cells with α:β or γ:δ receptors arise from a common progenitor
      • 7-14 T cells expressing particular γ- and δ-chain V regions arise in an ordered sequence early in life
      • 7-15 Rearrangement of the β-chain locus and production of a β chain trigger several events in developing thymocytes
      • 7-16 T-cell α-chain genes undergo successive rearrangements until positive selection or cell death intervenes
      • 7-17 Immature B cells that bind self antigens undergo further receptor rearrangement, or die, or are inactivated
      • 7-18 Mature B cells can also be rendered self-tolerant
      • 7-19 Only thymocytes whose receptors can interact with self MHC:self peptide complexes can survive and mature
      • 7-20 Most thymocytes express receptors that cannot interact with self MHC and these cells die in the thymus
      • 7-21 Positive selection acts on a repertoire of receptors with inherent specificity for MHC molecules
      • 7-22 Positive selection coordinates the expression of CD4 or CD8 with the specificity of the T-cell receptor and the potential effector functions of the cell
      • 7-23 Thymic cortical epithelial cells mediate positive selection of developing thymocytes
      • 7-24 T cells that react strongly with ubiquitous self antigens are deleted in the thymus
      • 7-25 Negative selection is driven most efficiently by bone marrow-derived antigen-presenting cells
      • 7-26 Endogenous superantigens mediate negative selection of T-cell receptors derived from particular V_β gene segments
      • 7-27 The specificity and strength of signals for negative and positive selection must differ
      • 7-28 The B-1 subset of B cells has a distinct developmental history and expresses a distinctive repertoire of receptors
      • 7-29 Newly formed lymphocytes home to particular locations in peripheral lymphoid tissues
      • 7-30 The development and organization of peripheral lymphoid tissues is controlled by cytokines and chemokines
      • 7-31 Only a small fraction of immature B cells mature and survive in peripheral lymphoid tissues
      • 7-32 The life-span of naive T cells in the periphery is determined by ongoing contact with self peptide:self MHC complexes similar to those that initially selected them
      • 7-33 B-cell tumors often occupy the same site as their normal counterparts
      • 7-34 A range of tumors of immune system cells throws light on different stages of T-cell development
      • 7-35 Malignant lymphocyte tumors frequently carry chromosomal translocations that join immunoglobulin loci to genes regulating cell growth
• Part IV. The Adaptive Immune Response
  • Chapter 8. T Cell-Mediated Immunity
    • The production of armed effector T cells
      • 8-1. T-cell responses are initiated in peripheral lymphoid organs by activated antigen-presenting cells
      • 8-2. Naive T cells sample the MHC:peptide complexes on the surface of antigen-presenting cells as they migrate through peripheral lymphoid tissue
      • 8-3. Lymphocyte migration, activation, and effector function depend on cell-cell interactions mediated by cell-adhesion molecules
      • 8-4. The initial interaction of T cells with antigen-presenting cells is mediated by cell-adhesion molecules
      • 8-5. Both specific ligand and co-stimulatory signals provided by an antigen-presenting cell are required for the clonal expansion of naive T cells
      • 8-6. Dendritic cells specialize in taking up antigen and activating naive T cells
      • 8-7. Macrophages are scavenger cells that can be induced by pathogens to present foreign antigens to naive T cells
      • 8-8. B cells are highly efficient at presenting antigens that bind to their surface immunoglobulin
      • 8-9. Activated T cells synthesize the T-cell growth factor interleukin-2 and its receptor
      • 8-10. The co-stimulatory signal is necessary for the synthesis and secretion of IL-2
      • 8-11. Antigen recognition in the absence of co-stimulation leads to T-cell tolerance
      • 8-12. Proliferating T cells differentiate into armed effector T cells that do not require co-stimulation to act
      • 8-13. The differentiation of CD4 T cells into T_H1 or T_H2 cells determines whether humoral or cell-mediated immunity will predominate.
      • 8-14. Naive CD8 T cells can be activated in different ways to become armed cytotoxic effector cells
      • Summary
    • General properties of armed effector T cells
      • 8-15. Effector T-cell interactions with target cells are initiated by antigen-nonspecific cell-adhesion molecules
      • 8-16. Binding of the T-cell receptor complex directs the release of effector molecules and focuses them on the target cell
      • 8-17. The effector functions of T cells are determined by the array of effector molecules they produce
      • 8-18. Cytokines can act locally or at a distance
      • 8-19. Cytokines and their receptors fall into distinct families of structurally related proteins
      • 8-20. The TNF family of cytokines are trimeric proteins that are often associated with the cell surface
      • Summary
    • T cell-mediated cytotoxicity
      • 8-21. Cytotoxic T cells can induce target cells to undergo programmed cell death
      • 8-22. Cytotoxic effector proteins that trigger apoptosis are contained in the granules of CD8 cytotoxic T cells
      • 8-23. Activated CD8 T cells and some CD4 effector T cells express Fas ligand, which can also activate apoptosis
      • 8-24. Cytotoxic T cells are selective and serial killers of targets expressing specific antigen
      • 8-25. Cytotoxic T cells also act by releasing cytokines
      • Summary
    • Macrophage activation by armed CD4 T_H1 cells
      • 8-26. Armed T_H1 cells have a central role in macrophage activation
      • 8-27. The production of cytokines and membrane-associated molecules by armed CD4 T_H1 cells requires new RNA and protein synthesis.
      • 8-28. Activation of macrophages by armed T_H1 cells promotes microbial killing and must be tightly regulated to avoid tissue damage.
      • 8-29. T_H1 cells coordinate the host response to intracellular pathogens.
      • Summary
    • Summary to Chapter 8
    • General references
    • Section references
      • 8-1 T-cell responses are initiated in peripheral lymphoid organs by activated antigen-presenting cells
      • 8-2 Naive T cells sample the MHC:peptide complexes on the surface of antigen-presenting cells as they migrate through peripheral lymphoid tissue
      • 8-3 Lymphocyte migration, activation, and effector function depend on cell-cell interactions mediated by cell-adhesion molecules
      • 8-4 The initial interaction of T cells with antigen-presenting cells is mediated by cell-adhesion molecules
      • 8-5 Both specific ligand and co-stimulatory signals provided by an antigen-presenting cell are required for the clonal expansion of naive T cells
      • 8-6 Dendritic cells specialize in taking up antigen and activating naive T cells
      • 8-7 Macrophages are scavenger cells that can be induced by pathogens to present foreign antigens to naive T cells
      • 8-8 B cells are highly efficient at presenting antigens that bind to their surface immunoglobulin
      • 8-9 Activated T cells synthesize the T-cell growth factor interleukin-2 and its receptor. & 8-10 The co-stimulatory signal is necessary for the synthesis and secretion of IL-2
      • 8-11 Antigen recognition in the absence of co-stimulation leads to T-cell tolerance
      • 8-12 Proliferating T cells differentiate into armed effector T cells that do not require co-stimulation to act
      • 8-13 The differentiation of CD4 T cells into T_H1 or T_H2 cells determines whether humoral or cell-mediated immunity will predominate
      • 8-14 Naive CD8 T cells can be activated in different ways to become armed cytotoxic effector cells
      • 8-15 Effector T-cell interactions with target cells are initiated by antigennonspecific cell-adhesion molecules
      • 8-16 Binding of the T-cell receptor complex directs the release of effector molecules and focuses them on the target cell
      • 8-17 The effector functions& of T cells are determined by the array of effector molecules they produce. 8-18 Cytokines can act locally or at a distance
      • 8-19 Cytokines and their receptors fall into distinct families of structurally related proteins
      • 8-20 The TNF family of cytokines are trimeric proteins that are often associated with the cell surface
      • 8-21 Cytotoxic T cells can induce target cells to undergo programmed cell death
      • 8-22 Cytotoxic effector proteins that trigger apoptosis are contained in the granules of CD8 cytotoxic T cells
      • 8-23 Activated CD8 T cells and some CD4 effector T cells express Fas ligand, which can also activate apoptosis
      • 8-24 Cytotoxic T cells are selective and serial killers of targets expressing specific antigen
      • 8-25 Cytotoxic T cells also act by releasing cytokines
      • 8-26 Armed T_H1 cells have a central role in macrophage activation
      • 8-27 The production of cytokines and membrane-associated molecules by armed CD4 T_H1 cells requires new RNA and protein synthesis
      • 8-28 Activation of macrophages by armed T_H1 cells promotes microbial killing and must be tightly regulated to avoid tissue damage
      • 8-29 T_H1 cells coordinate the host response to intracellular pathogens
  • Chapter 9. The Humoral Immune Response
    • B-cell activation by armed helper T cells
      • 9-1. The humoral immune response is initiated when B cells that bind antigen are signaled by helper T cells or by certain microbial antigens alone
      • 9-2. Armed helper T cells activate B cells that recognize the same antigen
      • 9-3. Antigenic peptides bound to self MHC class II molecules trigger armed helper T cells to make membrane-bound and secreted molecules that can activate a B cell
      • 9-4. Isotype switching requires expression of CD40L by the helper T cell and is directed by cytokines
      • 9-5. Antigen-binding B cells are trapped in the T-cell zone of secondary lymphoid tissues and are activated by encounter with armed helper T cells
      • 9-6. The second phase of the primary B-cell immune response occurs when activated B cells migrate to follicles and proliferate to form germinal centers
      • 9-7. Germinal center B cells undergo V-region somatic hypermutation and cells with mutations that improve affinity for antigen are selected
      • 9-8. Ligation of the B-cell receptor and CD40, together with direct contact with T cells, are all required to sustain germinal center B cells
      • 9-9. Surviving germinal center B cells differentiate into either plasma cells or memory cells
      • 9-10. B-cell responses to bacterial antigens with intrinsic ability to activate B cells do not require T-cell help
      • 9-11. B-cell responses to bacterial polysaccharides do not require peptide-specific T-cell help
      • Summary
    • The distribution and functions of immunoglobulin isotypes
      • 9-12. Antibodies of different isotype operate in distinct places and have distinct effector functions
      • 9-13. Transport proteins that bind to the Fc regions of antibodies carry particular isotypes across epithelial barriers
      • 9-14. High-affinity IgG and IgA antibodies can neutralize bacterial toxins
      • 9-15. High-affinity IgG and IgA antibodies can inhibit the infectivity of viruses
      • 9-16. Antibodies can block the adherence of bacteria to host cells
      • 9-17. Antibody:antigen complexes activate the classical pathway of complement by binding to C1q
      • 9-18. Complement receptors are important in the removal of immune complexes from the circulation
      • Summary
    • The destruction of antibody-coated pathogens via Fc receptors
      • 9-19. The Fc receptors of accessory cells are signaling receptors specific for immunoglobulins of different isotypes
      • 9-20. Fc receptors on phagocytes are activated by antibodies bound to the surface of pathogens and enable the phagocytes to ingest and destroy pathogens
      • 9-21. Fc receptors activate natural killer cells to destroy antibody-coated targets
      • 9-22. Mast cells, basophils, and activated eosinophils bind IgE antibody via the high-affinity Fcε receptor
      • 9-23. IgE-mediated activation of accessory cells has an important role in resistance to parasite infection
      • Summary
    • Summary to Chapter 9
    • General references
    • Section references
      • 9-1 The humoral immune response is initiated when B cells that bind antigen are signaled by helper T cells or by certain microbial antigens alone
      • 9-2 Armed helper T cells activate B cells that recognize the same antigen
      • 9-3 Antigenic peptides bound to self MHC class II molecules trigger armed helper T cells to make membrane-bound and secreted molecules that can activate a B cell
      • 9-4 Isotype switching requires expression of CD40L by the helper T cell and is directed by cytokines
      • 9-5 Antigen-binding B cells are trapped in the T-cell zone of secondary lymphoid tissues and are activated by encounter with armed helper T cells
      • 9-6 The second phase of the primary B-cell immune response occurs when activated B cells migrate to follicles and proliferate to form germinal centers
      • 9-7 Germinal center B cells undergo V-region somatic hypermutation and cells with mutations that improve affinity for antigen are selected
      • 9-8 Ligation of the B-cell receptor and CD40, together with direct contact with T cells, are all required to sustain germinal center B cells
      • 9-9 Surviving germinal center B cells differentiate into either plasma cells or memory cells
      • 9-10 B-cell responses to bacterial antigens with intrinsic ability to activate B cells do not require T-cell help
      • 9-11 B-cell responses to bacterial polysaccharides do not require peptide-specific T-cell help
      • 9-12 Antibodies of different isotype operate in distinct places and have distinct effector functions
      • 9-13 Transport proteins that bind to the Fc regions of antibodies carry particular isotypes across epithelial barriers
      • 9-14 High-affinity IgG and IgA antibodies can neutralize bacterial toxins
      • 9-15 High-affinity IgG and IgA antibodies can inhibit the infectivity of viruses
      • 9-16 Antibodies can block the adherence of bacteria to host cells
      • 9-17 Antibody:antigen complexes activate the classical pathway of complement by binding to C1q
      • 9-18 Complement receptors are important in the removal of immune complexes from the circulation
      • 9-19 The Fc receptors of accessory cells are signaling receptors specific for immunoglobulins of different isotypes
      • 9-20 Fc receptors on phagocytes are activated by antibodies bound to the surface of pathogens and enable the phagocytes to ingest and destroy pathogens
      • 9-21 Fc receptors activate natural killer cells to destroy antibody-coated targets
      • 9-22 Mast cells, basophils, and activated eosinophils bind IgE antibody via the high-affinity Fcε receptor
      • 9-23 IgE-mediated activation of accessory cells has an important role in resistance to parasite infection
  • Chapter 10. Adaptive Immunity to Infection
    • Infectious agents and how they cause disease
      • 10-1. The course of an infection can be divided into several distinct phases
      • 10-2. Infectious diseases are caused by diverse living agents that replicate in their hosts
      • Summary
    • The course of the adaptive response to infection
      • 10-3. The nonspecific responses of innate immunity are necessary for an adaptive immune response to be initiated
      • 10-4. An adaptive immune response is initiated when circulating T cells encounter their corresponding antigen in draining lymphoid tissues and become activated
      • 10-5. Cytokines made in the early phases of an infection influence the functional differentiation of CD4 T cells
      • 10-6. Distinct subsets of T cells can regulate the growth and effector functions of other T-cell subsets
      • 10-7. The nature and amount of antigenic peptide can also affect the differentiation of CD4 T cells
      • 10-8. Armed effector T cells are guided to sites of infection by chemokines and newly expressed adhesion molecules
      • 10-9. Antibody responses develop in lymphoid tissues under the direction of armed helper T cells
      • 10-10. Antibody responses are sustained in medullary cords and bone marrow
      • 10-11. The effector mechanisms used to clear an infection depend on the infectious agent
      • 10-12. Resolution of an infection is accompanied by the death of most of the effector cells and the generation of memory cells
      • Summary
    • The mucosal immune system
      • 10-13. Mucosa-associated lymphoid tissue is located in anatomically defined microcompartments throughout the gut
      • 10-14. The mucosal immune system contains a distinctive repertoire of lymphocytes
      • 10-15. Secretory IgA is the antibody isotype associated with the mucosal immune system
      • 10-16. Most antigens presented to the mucosal immune system induce tolerance
      • 10-17. The mucosal immune system can mount an immune response to the normal bacterial flora of the gut
      • 10-18. Enteric pathogens cause a local inflammatory response and the development of protective immunity
      • 10-19. Infection by Helicobacter pylori causes a chronic inflammatory response, which may cause peptic ulcers, carcinoma of the stomach, and unusual lymphoid tumors
      • 10-20. In the absence of inflammatory stimuli, the normal response of the mucosal immune system to foreign antigens is tolerance
      • Summary
    • Immunological memory
      • 10-21. Immunological memory is long-lived after infection or vaccination
      • 10-22. Both clonal expansion and clonal differentiation contribute to immunological memory in B cells
      • 10-23. Repeated immunizations lead to increasing affinity of antibody owing to somatic hypermutation and selection by antigen in germinal centers
      • 10-24. Memory T cells are increased in frequency and have distinct activation requirements and cell-surface proteins that distinguish them from armed effector T cells
      • 10-25. In immune individuals, secondary and subsequent responses are mediated solely by memory lymphocytes and not by naive lymphocytes
      • Summary
    • Summary to Chapter 10
    • General references
    • Section references
      • 10-1 The course of an infection can be divided into several distinct phases. & 10-2 Infectious diseases are caused by diverse living agents that replicate in their hosts
      • 10-3 The nonspecific responses of innate immunity are necessary for an adaptive immune response to be initiated
      • 10-4 An adaptive immune response is initiated when circulating T cells encounter their corresponding antigen in draining lymphoid tissues and become activated
      • 10-5 Cytokines made in the early phases of an infection influence the functional differentiation of CD4 T cells
      • 10-6 Distinct subsets of T cells can regulate the growth and effector functions of other T-cell subsets
      • 10-7 The nature and amount of antigenic peptide can also affect the differentiation of CD4 T cells
      • 10-8 Armed effector T cells are guided to sites of infection by chemokines and newly expressed adhesion molecules
      • 10-9 Antibody responses develop in lymphoid tissues under the direction of armed helper T cells
      • 10-10 Antibody responses are sustained in medullary cords and bone marrow
      • 10-11 The effector mechanisms used to clear an infection depend on the infectious agent
      • 10-12 Resolution of an infection is accompanied by the death of most of the effector cells and the generation of memory cells
      • 10-13 Mucosa-associated lymphoid tissue is located in anatomically defined microcompartments throughout the gut
      • 10-14 The mucosal immune system contains a distinctive repertoire of lymphocytes
      • 10-15 Secretory IgA is the antibody isotype associated with the mucosal immune system
      • 10-16 Most antigens presented to the mucosal immune system induce tolerance
      • 10-17 The mucosal immune system can mount an immune response to the normal bacterial flora of the gut
      • 10-18 Enteric pathogens cause a local inflammatory response and the development of protective immunity
      • 10-19 Infection by Helicobacter pylori causes a chronic inflammatory response, which may cause peptic ulcers, carcinoma of the stomach, and unusual lymphoid tumors
      • 10-20 In the absence of inflammatory stimuli, the normal response of the mucosal immune system to foreign antigens is tolerance
      • 10-21 Immunological memory is long-lived after infection or vaccination
      • 10-22 Both clonal expansion and clonal differentiation contribute to immunological memory in B cells
      • 10-23 Repeated immunizations lead to increasing affinity of antibody owing to somatic hypermutation and selection by antigen in germinal centers
      • 10-24 Memory T cells are increased in frequency and have distinct activation requirements and cell-surface proteins that distinguish them from armed effector T cells
      • 10-25 In immune individuals, secondary and subsequent responses are mediated solely by memory lymphocytes and not by naive lymphocytes
• Part V. The Immune System in Health and Disease
  • Chapter 11. Failures of Host Defense Mechanisms
    • Pathogens have evolved various means of evading or subverting normal host defenses
      • 11-1. Antigenic variation allows pathogens to escape from immunity
      • 11-2. Some viruses persist in vivo by ceasing to replicate until immunity wanes
      • 11-3. Some pathogens resist destruction by host defense mechanisms or exploit them for their own purposes
      • 11-4. Immunosuppression or inappropriate immune responses can contribute to persistent disease
      • 11-5. Immune responses can contribute directly to pathogenesis
      • Summary
    • Inherited immunodeficiency diseases
      • 11-6. A history of repeated infections suggests a diagnosis of immunodeficiency
      • 11-7. Inherited immunodeficiency diseases are caused by recessive gene defects
      • 11-8. The main effect of low levels of antibody is an inability to clear extracellular bacteria
      • 11-9. T-cell defects can result in low antibody levels
      • 11-10. Defects in complement components cause defective humoral immune function
      • 11-11. Defects in phagocytic cells permit widespread bacterial infections
      • 11-12. Defects in T-cell function result in severe combined immunodeficiencies
      • 11-13. Defective T-cell signaling, cytokine production, or cytokine action can cause immunodeficiency
      • 11-14. The normal pathways for host defense against intracellular bacteria are illustrated by genetic deficiencies of IFN-γ and IL-12 and their receptors
      • 11-15. X-linked lymphoproliferative syndrome is associated with fatal infection by Epstein-Barr virus and with the development of lymphomas
      • 11-16. Bone marrow transplantation or gene therapy can be useful to correct genetic defects
      • Summary
    • Acquired immune deficiency syndrome
      • 11-17. Most individuals infected with HIV progress over time to AIDS
      • 11-18. HIV is a retrovirus that infects CD4 T cells, dendritic cells, and macrophages
      • 11-19. Genetic deficiency of the macrophage chemokine co-receptor for HIV confers resistance to HIV infection in vivo
      • 11-20. HIV RNA is transcribed by viral reverse transcriptase into DNA that integrates into the host cell genome
      • 11-21. Transcription of the HIV provirus depends on host cell transcription factors induced upon the activation of infected T cells
      • 11-22. Drugs that block HIV replication lead to a rapid decrease in titer of infectious virus and an increase in CD4 T cells
      • 11-23. HIV accumulates many mutations in the course of infection in a single individual and drug treatment is soon followed by the outgrowth of drug-resistant variants of the virus
      • 11-24. Lymphoid tissue is the major reservoir of HIV infection
      • 11-25. An immune response controls but does not eliminate HIV
      • 11-26. HIV infection leads to low levels of CD4 T cells, increased susceptibility to opportunistic infection, and eventually to death
      • 11-27. Vaccination against HIV is an attractive solution but poses many difficulties
      • 11-28. Prevention and education are one way in which the spread of HIV and AIDS can be controlled
      • Summary
    • Summary to Chapter 11
    • General references
    • Section references
      • 11-1 Antigenic variation allows pathogens to escape from immunity
      • 11-2 Some viruses persist in vivo by ceasing to replicate until immunity wanes
      • 11-3 Some pathogens resist destruction by host defense mechanisms or exploit them for their own purposes
      • 11-4 Immunosuppression or inappropriate immune responses can contribute to persistent disease
      • 11-5 Immune responses can contribute directly to pathogenesis
      • 11-6 A history of repeated infections suggests a diagnosis of immunodeficiency
      • 11-7 Inherited immunodeficiency diseases are caused by recessive gene defects
      • 11-8 The main effect of low levels of antibody is an inability to clear extracellular bacteria
      • 11-9 T-cell defects can result in low antibody levels
      • 11-10 Defects in complement components cause defective humoral immune function
      • 11-11 Defects in phagocytic cells permit widespread bacterial infections
      • 11-12 Defects in T-cell function result in severe combined immunodeficiencies
      • 11-13 Defective T-cell signaling, cytokine production, or cytokine action can cause immunodeficiency
      • 11-14 The normal pathways for host defense against intracellular bacteria are illustrated by genetic deficiencies of IFN-γ and IL-12 and their receptors
      • 11-15 X-linked lymphoproliferative syndrome is associated with fatal infection by Epstein-Barr virus and with the development of lymphomas
      • 11-16 Bone marrow transplantation or gene therapy can be useful to correct genetic defects
      • 11-17 Most individuals infected with HIV progress over time to AIDS
      • 11-18 HIV is a retrovirus that infects CD4 T cells, dendritic cells, and macrophages
      • 11-19 Genetic deficiency of the macrophage chemokine co-receptor for HIV confers resistance to HIV infection in vivo
      • 11-20 HIV RNA is transcribed by viral reverse transcriptase into DNA that integrates into the host cell genome
      • 11-21 Transcription of the HIV provirus depends on host cell transcription factors induced upon the activation of infected T cells
      • 11-22 Drugs that block HIV replication lead to a rapid decrease in titer of infectious virus and an increase in CD4 T cells
      • 11-23 HIV accumulates many mutations in the course of infection in a single individual and drug treatment is soon followed by the outgrowth of drug-resistant variants of the virus
      • 11-24 Lymphoid tissue is the major reservoir of HIV infection
      • 11-25 An immune response controls but does not eliminate HIV
      • 11-26 HIV infection leads to low levels of CD4 T cells, increased susceptibility to opportunistic infection, and eventually to death
      • 11-27 Vaccination against HIV is an attractive solution but poses many difficulties
      • 11-28 Prevention and education are one way in which the spread of HIV and AIDS can be controlled
  • Chapter 12. Allergy and Hypersensitivity
    • The production of IgE
      • 12-1. Allergens are often delivered transmucosally at low dose, a route that favors IgE production
      • 12-2. Enzymes are frequent triggers of allergy
      • 12-3. Class switching to IgE in B lymphocytes is favored by specific signals
      • 12-4. Genetic factors contribute to the development of IgE-mediated allergy, but environmental factors may also be important
      • Summary
    • Effector mechanisms in allergic reactions
      • 12-5. Most IgE is cell-bound and engages effector mechanisms of the immune system by different pathways from other antibody isotypes
      • 12-6. Mast cells reside in tissues and orchestrate allergic reactions
      • 12-7. Eosinophils are normally under tight control to prevent inappropriate toxic responses
      • 12-8. Eosinophils and basophils cause inflammation and tissue damage in allergic reactions
      • 12-9. An allergic reaction is divided into an immediate response and a late-phase response
      • 12-10. The clinical effects of allergic reactions vary according to the site of mast-cell activation
      • 12-11. Allergen inhalation is associated with the development of rhinitis and asthma
      • 12-12. Skin allergy is manifest as urticaria or chronic eczema
      • 12-13. Allergy to foods causes symptoms limited to the gut and systemic reactions
      • 12-14. Allergy can be treated by inhibiting either IgE production or the effector pathways activated by cross-linking of cell-surface IgE
      • Summary
    • Hypersensitivity diseases
      • 12-15. Innocuous antigens can cause type II hypersensitivity reactions in susceptible individuals by binding to the surfaces of circulating blood cells
      • 12-16. Systemic disease caused by immune complex formation can follow the administration of large quantities of poorly catabolized antigens
      • 12-17. Delayed-type hypersensitivity reactions are mediated by T_H1 cells and CD8 cytotoxic T cells
      • Summary
    • Summary to Chapter 12
    • General references
    • Section references
      • 12-1 Allergens are often delivered transmucosally at low dose, a route that favors IgE production
      • 12-2 Enzymes are frequent triggers of allergy
      • 12-3 Class switching to IgE in B lymphocytes is favored by specific signals
      • 12-4 Genetic factors contribute to the development of IgE-mediated allergy, but environmental factors may also be important
      • 12-5 Most IgE is cell-bound and engages effector mechanisms of the immune system by different pathways from other antibody isotypes
      • 12-6 Mast cells reside in tissues and orchestrate allergic reactions
      • 12-7 Eosinophils are normally under tight control to prevent inappropriate toxic responses
      • 12-8 Eosinophils and basophils cause inflammation and tissue damage in allergic reactions
      • 12-9 An allergic reaction is divided into an immediate response and a late-phase response
      • 12-10 The clinical effects of allergic reactions vary according to the site of mast-cell activation
      • 12-11 Allergen inhalation is associated with the development of rhinitis and asthma
      • 12-12 Skin allergy is manifest as urticaria or chronic eczema
      • 12-13 Allergy to foods causes symptoms limited to the gut and systemic reactions
      • 12-14 Allergy can be treated by inhibiting either IgE production or the effector pathways activated by cross-linking of cell-surface IgE
      • 12-15 Innocuous antigens can cause type II hypersensitivity reactions in susceptible individuals by binding to the surfaces of circulating blood cells
      • 12-16 Systemic disease caused by immune complex formation can follow the administration of large quantities of poorly catabolized antigens
      • 12-17 Delayed-type hypersensitivity reactions are mediated by T_H1 cells and CD8 cytotoxic T cells
  • Chapter 13. Autoimmunity and Transplantation
    • Autoimmune responses are directed against self antigens
      • 13-1. Specific adaptive immune responses to self antigens can cause autoimmune disease
      • 13-2. Autoimmune diseases can be classified into clusters that are typically either organ-specific or systemic
      • 13-3. Susceptibility to autoimmune disease is controlled by environmental and genetic factors, especially MHC genes
      • 13-4. The genes that have been associated with the development of systemic lupus erythematosus provide important clues to the etiology of the disease
      • 13-5. Antibody and T cells can cause tissue damage in autoimmune disease
      • 13-6. Autoantibodies against blood cells promote their destruction
      • 13-7. The fixation of sublytic doses of complement to cells in tissues stimulates a powerful inflammatory response
      • 13-8. Autoantibodies against receptors cause disease by stimulating or blocking receptor function
      • 13-9. Autoantibodies against extracellular antigens cause inflammatory injury by mechanisms akin to type II and type III hypersensitivity reactions
      • 13-10. Environmental cofactors can influence the expression of autoimmune disease
      • 13-11. The pattern of inflammatory injury in autoimmunity can be modified by anatomical constraints
      • 13-12. The mechanism of autoimmune tissue damage can often be determined by adoptive transfer
      • 13-13. T cells specific for self antigens can cause direct tissue injury and have a role in sustained autoantibody responses
      • 13-14. Autoantibodies can be used to identify the target of the autoimmune process
      • 13-15. The target of T cell-mediated autoimmunity is difficult to identify owing to the nature of T-cell ligands
      • Summary
    • Responses to alloantigens and transplant rejection
      • 13-16. Graft rejection is an immunological response mediated primarily by T cells
      • 13-17. Matching donor and recipient at the MHC improves the outcome of transplantation
      • 13-18. In MHC-identical grafts, rejection is caused by peptides from other alloantigens bound to graft MHC molecules
      • 13-19. There are two ways of presenting alloantigens on the transplant to the recipient's T lymphocytes
      • 13-20. Antibodies reacting with endothelium cause hyperacute graft rejection
      • 13-21. The converse of graft rejection is graft-versus-host disease
      • 13-22. Chronic organ rejection is caused by inflammatory vascular injury to the graft
      • 13-23. A variety of organs are transplanted routinely in clinical medicine
      • 13-24. The fetus is an allograft that is tolerated repeatedly
      • Summary
    • Self-tolerance and its loss
      • 13-25. Many autoantigens are not so abundantly expressed that they induce clonal deletion or anergy but are not so rare as to escape recognition entirely
      • 13-26. The induction of a tissue-specific response requires the presentation of antigen by antigen-presenting cells with co-stimulatory activity
      • 13-27. In the absence of co-stimulation, tolerance is induced
      • 13-28. Dominant immune suppression can be demonstrated in models of tolerance and can affect the course of autoimmune disease
      • 13-29. Antigens in immunologically privileged sites do not induce immune attack but can serve as targets
      • 13-30. B cells with receptors specific for peripheral autoantigens are held in check by a variety of mechanisms
      • 13-31. Autoimmunity may sometimes be triggered by infection
      • Summary
    • Summary to Chapter 13
    • General references
    • Section references
      • 13-1 Specific adaptive immune responses to self antigens can cause autoimmune disease
      • 13-2 Autoimmune diseases can be classified into clusters that are typically either organ-specific or systemic
      • 13-3 Susceptibility to autoimmune disease is controlled by environmental and genetic factors, especially MHC genes
      • 13-4 The genes that have been associated with the development of systemic lupus erythematosus provide important clues to the etiology of the disease
      • 13-5 Antibody and T cells can cause tissue damage in autoimmune disease
      • 13-6 Autoantibodies against blood cells promote their destruction
      • 13-7 The fixation of sublytic doses of complement to cells in tissues stimulates a powerful inflammatory response
      • 13-8 Autoantibodies against receptors cause disease by stimulating or blocking receptor function
      • 13-9 Autoantibodies against extracellular antigens cause inflammatory injury by mechanisms akin to type II and type III hypersensitivity reactions
      • 13-10 Environmental cofactors can influence the expression of autoimmune disease
      • 13-11 The pattern of inflammatory injury in autoimmunity can be modified by anatomical constraints
      • 13-12 The mechanism of autoimmune tissue damage can often be determined by adoptive transfer
      • 13-13 T cells specific for self antigens can cause direct tissue injury and have a role in sustained autoantibody responses
      • 13-14 Autoantibodies can be used to identify the target of the autoimmune process
      • 13-15 The target of T cell-mediated autoimmunity is difficult to identify owing to the nature of T-cell ligands
      • 13-16 Graft rejection is an immunological response mediated primarily by T cells
      • 13-17 Matching donor and recipient at the MHC improves the outcome of transplantation
      • 13-18 In MHC-identical grafts, rejection is caused by peptides from other alloantigens bound to graft MHC molecules
      • 13-19 There are two ways of presenting alloantigens on the transplant to the recipient's T lymphocytes
      • 13-20 Antibodies reacting with endothelium cause hyperacute graft rejection
      • 13-21 The converse of graft rejection is graft-versus-host disease
      • 13-22 Chronic organ rejection is caused by inflammatory vascular injury to the graft
      • 13-23 A variety of organs are transplanted routinely in clinical medicine
      • 13-24 The fetus is an allograft that is tolerated repeatedly
      • 13-25 Many autoantigens are not so abundantly expressed that they induce clonal deletion or anergy but are not so rare as to escape recognition entirely
      • 13-26 The induction of a tissue-specific response requires the presentation of antigen by antigen-presenting cells with co-stimulatory activity
      • 13-27 In the absence of co-stimulation, tolerance is induced
      • 13-28 Dominant immune suppression can be demonstrated in models of tolerance and can affect the course of autoimmune disease
      • 13-29 Antigens in immunologically privileged sites do not induce immune attack but can serve as targets
      • 13-30 B cells with receptors specific for peripheral autoantigens are held in check by a variety of mechanisms
      • 13-31 Autoimmunity may sometimes be triggered by infection
  • Chapter 14. Manipulation of the Immune Response
    • Extrinsic regulation of unwanted immune responses
      • 14-1. Corticosteroids are powerful anti-inflammatory drugs that alter the transcription of many genes
      • 14-2. Cytotoxic drugs cause immunosuppression by killing dividing cells and have serious side-effects
      • 14-3. Cyclosporin A, FK506 (tacrolimus), and rapamycin (sirolimus) are powerful immunosuppressive agents that interfere with T-cell signaling
      • 14-4. Immunosuppressive drugs are valuable probes of intracellular signaling pathways in lymphocytes
      • 14-5. Antibodies against cell-surface molecules have been used to remove specific lymphocyte subsets or to inhibit cell function
      • 14-6. Antibodies can be engineered to reduce their immunogenicity in humans
      • 14-7. Monoclonal antibodies can be used to inhibit allograft rejection
      • 14-8. Antibodies can be used to alleviate and suppress autoimmune disease
      • 14-9. Modulation of the pattern of cytokine expression by T lymphocytes can inhibit autoimmune disease
      • 14-10. Controlled administration of antigen can be used to manipulate the nature of an antigen-specific response
      • Summary
    • Using the immune response to attack tumors
      • 14-11. The development of transplantable tumors in mice led to the discovery that mice could mount a protective immune response against tumors
      • 14-12. T lymphocytes can recognize specific antigens on human tumors
      • 14-13. Tumors can escape rejection in many ways
      • 14-14. Monoclonal antibodies against tumor antigens, alone or linked to toxins, can control tumor growth
      • 14-15. Enhancing the immunogenicity of tumors holds promise for cancer therapy
      • Summary
    • Manipulating the immune response to fight infection
      • 14-16. There are several requirements for an effective vaccine
      • 14-17. The history of vaccination against Bordetella pertussis illustrates the importance of developing an effective vaccine that is perceived to be safe
      • 14-18. Conjugate vaccines have been developed as a result of understanding how T and B cells collaborate in an immune response
      • 14-19. The use of adjuvants is another important approach to enhancing the immunogenicity of vaccines
      • 14-20. Live-attenuated viral vaccines are usually more potent than ‘killed’ vaccines and can be made safer by using recombinant DNA technology
      • 14-21. Live-attenuated bacterial vaccines can be developed by selecting nonpathogenic or disabled mutants
      • 14-22. Attenuated microorganisms can serve as vectors for vaccination against many pathogens
      • 14-23. Synthetic peptides of protective antigens can elicit protective immunity
      • 14-24. The route of vaccination is an important determinant of success
      • 14-25. Protective immunity can be induced by injecting DNA encoding microbial antigens and human cytokines into muscle
      • 14-26. The effectiveness of a vaccine can be enhanced by targeting it to sites of antigen presentation
      • 14-27. An important question is whether vaccination can be used therapeutically to control existing chronic infections
      • 14-28. Modulation of the immune system might be used to inhibit immunopathological responses to infectious agents
      • Summary
    • Summary to Chapter 14
    • General references
    • Section references
      • 14-1 Corticosteroids are powerful anti-inflammatory drugs that alter the transcription of many genes
      • 14-2 Cytotoxic drugs cause immunosuppression by killing dividing cells and have serious side-effects
      • 14-3 Cyclosporin A, FK506 (tacrolimus), and rapamycin (sirolimus) are powerful immunosuppressive agents that interfere with T-cell signaling
      • 14-4 Immunosuppressive drugs are valuable probes of intracellular signaling pathways in lymphocytes
      • 14-5 Antibodies against cell-surface molecules have been used to remove specific lymphocyte subsets or to inhibit cell function
      • 14-6 Antibodies can be engineered to reduce their immunogenicity in humans
      • 14-7 Monoclonal antibodies can be used to inhibit allograft rejection
      • 14-8 Antibodies can be used to alleviate and suppress autoimmune disease
      • 14-9 Modulation of the pattern of cytokine expression by T lymphocytes can inhibit autoimmune disease
      • 14-10 Controlled administration of antigen can be used to manipulate the nature of an antigen-specific response
      • 14-11 The development of transplantable tumors in mice led to the discovery that mice could mount a protective immune response against tumors
      • 14-12 T lymphocytes can recognize specific antigens on human tumors
      • 14-13 Tumors can escape rejection in many ways
      • 14-14 Monoclonal antibodies against tumor antigens, alone or linked to toxins, can control tumor growth
      • 14-15 Enhancing the immunogenicity of tumors holds promise for cancer therapy
      • 14-16 There are several requirements for an effective vaccine
      • 14-17 The history of vaccination against Bordetella pertussis illustrates the importance of developing an effective vaccine that is perceived to be safe
      • 14-18 Conjugate vaccines have been developed as a result of understanding how T and B cells collaborate in an immune response
      • 14-19 The use of adjuvants is another important approach to enhancing the immunogenicity of vaccines
      • 14-20 Live-attenuated viral vaccines are usually more potent than ‘killed’ vaccines and can be made safer by using recombinant DNA technology
      • 14-21 Live-attenuated bacterial vaccines can be developed by selecting nonpathogenic or disabled mutants
      • 14-22 Attenuated microorganisms can serve as vectors for vaccination against many pathogens
      • 14-23 Synthetic peptides of protective antigens can elicit protective immunity
      • 14-24 The route of vaccination is an important determinant of success
      • 14-25 Protective immunity can be induced by injecting DNA encoding microbial antigens and human cytokines into muscle
      • 14-26 The effectiveness of a vaccine can be enhanced by targeting it to sites of antigen presentation
      • 14-27 An important question is whether vaccination can be used therapeutically to control existing chronic infections
      • 14-28 Modulation of the immune system might be used to inhibit immunopathological responses to infectious agents
• Chapter 15. Afterword: Evolution of the Immune System: Past, Present, and Future, by Charles A. Janeway, Jr
  • Evolution of the innate immune system
    • Innate immunity has its origins in early eukaryotes such as the amoeba
    • Sophisticated means of host defense were hard-wired in the genome by the time organisms diverged into plants and animals
    • Fruit flies illustrate the virtues of a nonclonal system of host defense
    • Many genes that operate in fruit fly immunity also operate in humans and plants and appear to be universal components of host defense
    • Summary
  • Evolution of the adaptive immune response
    • Adaptive immunity appears abruptly in the cartilaginous fish
    • Gene rearrangement is used to control gene expression
    • Animals generate antigen receptor diversity in many different ways
    • Summary
  • The importance of immunological memory in fixing adaptive immunity in the genome
    • Immunological memory is the hallmark of adaptive immunity
    • Immunological memory allows survival in a world filled with pathogens
    • Immunological memory for self proteins leads to autoimmune disease
    • Summary
  • Future directions of research in immunobiology
    • Future studies should vastly expand our knowledge of innate immunity
    • Future studies should refine our knowledge of adaptive immunity
    • Future studies of tumor immunity hold great promise for an immunological cure for cancer
    • Future vaccine development should greatly increase our ability to prevent infectious disease
    • Future studies of autoimmunity and graft rejection should allow control of immune responses to one's own body or to a piece borrowed from someone else
    • Summary
  • Summary of the Afterword
• Appendices
  • Appendix I. Immunologists' Toolbox
  • Appendix II. CD Antigens
  • Appendix III. Cytokines and Their Receptors
  • Appendix IV. Chemokines and Their Receptors
  • Appendix V. Immunological Constants
• Biographies
• Glossary