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Cover of Immunobiology

Immunobiology , 5th edition

The Immune System in Health and Disease

Charles A Janeway, Jr , Paul Travers , Mark Walport , and Mark J Shlomchik .

Authors

Charles A Janeway, Jr , 1 Paul Travers , 2 Mark Walport , 3 and Mark J Shlomchik 1 .

Affiliations

1 Yale University School of Medicine 2 Anthony Nolan Research Institute, London 3 Imperial College School of Medicine, London New York: Garland Science ; 2001 . ISBN-10: 0-8153-3642-X Copyright © 2001, Garland Science. For more information, see the Bookshelf Copyright Notice.

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.

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
    - 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
    - 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
    - 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
    - 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
      - 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
      - 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
      - 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
      - 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
      - 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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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
        
        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 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
        
        Appendix I. Immunologists' Toolbox
        
        Appendix II. CD Antigens
        
        Appendix III. Cytokines and Their Receptors
        
        Appendix IV. Chemokines and Their Receptors
        
        Appendix V. Immunological Constants
        
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Immunobiology , 5th edition

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