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Book Details
Abstract
Immunology, 8th Edition makes it easy for you to learn all the basic and clinical concepts you need to know for your courses and USMLEs. This medical textbook’s highly visual, carefully structured approach makes immunology simple to understand and remember.
- Understand the building blocks of the immune system - cells, organs and major receptor molecules - as well as initiation and actions of the immune response, especially in a clinical context.
- Visually grasp and retain difficult concepts easily thanks to a user-friendly color-coded format, key concept boxes, explanatory diagrams, and over 190 photos to help you visualize tissues and diseases.
- Put concepts into practice. "Critical Thinking Boxes" and 25 online cases encourage you to "think immunologically" while anchoring your understanding of immunology through clinical application.
- Gauge your mastery of the material and build confidence with high-yield style chapter-opening summaries and case-based and USMLE-style questions that provide effective chapter review and quick practice for your exams.
- Access the full contents online at www.studentconsult.com where you'll find the complete text and illustrations, USMLE-style questions, clinical cases, and much more!
- Get the depth of coverage you need in a smaller, more manageably sized book. Through meticulous editing and reorganization, primary material remains in the book while more specialized and clinical material has been moved online.
- Master the most cutting-edge concepts in immunology. Thorough updates throughout provide the timely knowledge you need ace your exams.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Front Cover | Cover | ||
| Immunology | iii | ||
| Copyright | iv | ||
| Contents | v | ||
| Preface | vii | ||
| List of Contributors | ix | ||
| Section 1: Components of the Immune System | 1 | ||
| Chapter 1: Introduction to the Immune System | 3 | ||
| Cells and soluble mediators of the immune system | 4 | ||
| Cells of the immune system | 4 | ||
| Phagocytes internalize antigens and pathogens, and break them down | 4 | ||
| B cells and T cells are responsible for the specific recognition of antigens | 5 | ||
| Cytotoxic cells recognize and destroy other cells that have become infected | 6 | ||
| Auxiliary cells control inflammation | 6 | ||
| Soluble mediators of immunity | 6 | ||
| Complement proteins mediate phagocytosis, control inflammation and interact with antibodies in immune defense | 6 | ||
| Cytokines signal between lymphocytes, phagocytes and other cells of the body | 7 | ||
| Immune responses to pathogens | 8 | ||
| Effective immune responses vary depending on the pathogen | 8 | ||
| Innate immune responses are the same on each encounter with antigen | 8 | ||
| Adaptive immune responses display specificity and memory | 9 | ||
| Antigen recognition | 9 | ||
| Antigens initiate and direct adaptive immune responses | 9 | ||
| Antibody specifically binds to antigen | 9 | ||
| Each antibody binds to a restricted part of the antigen called an epitope | 9 | ||
| Fc regions of antibodies act as adapters to link phagocytes to pathogens | 10 | ||
| Peptides from intracellular pathogens are displayed on the surface of infected cells | 10 | ||
| Antigen activates specific clones of lymphocytes | 11 | ||
| Antigen elimination | 12 | ||
| Antigen elimination involves effector systems | 12 | ||
| Antibodies can directly neutralise some pathogens | 12 | ||
| Phagocytosis is promoted by opsonins | 12 | ||
| Cytotoxic cells kill infected target cells | 12 | ||
| Termination of immune responses limits damage to host tissues | 12 | ||
| Immune responses to extracellular and intracellular pathogens differ | 12 | ||
| Vaccination | 13 | ||
| Inflammation | 13 | ||
| Leukocytes enter inflamed tissue by crossing venular endothelium | 14 | ||
| Immunopathology | 14 | ||
| Inappropriate reaction to self antigens - autoimmunity | 14 | ||
| Ineffective immune response - immunodeficiency | 15 | ||
| Overactive immune response - hypersensitivity | 15 | ||
| Normal but inconvenient immune reactions | 15 | ||
| Chapter 2: Cells, Tissues, and Organs of the Immune System | 17 | ||
| Cells of the immune system | 17 | ||
| Cells of the innate immune system include monocytes/macrophages, polymorphonuclear granulocytes, NK cells, mast cells, and plat | 17 | ||
| Antigen-presenting cells (APCs) link the innate and adaptive immune systems | 18 | ||
| Adaptive immune system cells are lymphocytes | 18 | ||
| Myeloid cells | 19 | ||
| Mononuclear phagocytes and polymorphonuclear granulocytes are the two major phagocyte lineages | 19 | ||
| Mononuclear phagocytes are widely distributed throughout the body | 19 | ||
| There are three different types of polymorphonuclear granulocyte | 20 | ||
| Neutrophils comprise over 95% of the circulating granulocytes | 20 | ||
| Granulocytes and mononuclear phagocytes develop from a common precursor | 21 | ||
| Monocytes express CD14 and significant levels of MHC class II molecules | 22 | ||
| Neutrophils express adhesion molecules and receptors involved in phagocytosis | 22 | ||
| Eosinophils, basophils, mast cells and platelets in inflammation | 22 | ||
| Eosinophils are thought to play a role in immunity to parasitic worms | 22 | ||
| Basophils and mast cells play a role in immunity against parasites | 23 | ||
| Platelets have a role in clotting and inflammation | 23 | ||
| NK cells | 24 | ||
| CD16 and CD56 are important markers of NK cells | 24 | ||
| Antigen presenting cells | 25 | ||
| Dendritic cells are derived from several different lineages | 25 | ||
| Langerhans´ cells and interdigitating dendritic cells are rich in MHC class II molecules | 26 | ||
| FDCs lack class II MHC molecules and are found in B cell areas | 27 | ||
| Lymphocytes | 28 | ||
| Lymphocytes are phenotypically and functionally heterogeneous | 28 | ||
| Lymphocytes are morphologically heterogeneous | 28 | ||
| Lymphocytes express characteristic surface and cytoplasmic markers | 28 | ||
| Marker molecules allow lymphocytes to communicate with their environment | 30 | ||
| Marker molecules allow lymphocytes to be isolated from each other | 30 | ||
| T cells can be distinguished by their different antigen receptors | 30 | ||
| There are three major subpopulations of αβ T cells | 30 | ||
| T helper subsets are distinguished by their cytokine profiles | 30 | ||
| Other T cell subsets include γδ T cells and NKT cells | 31 | ||
| γδ T cells may protect the mucosal surfaces of the body | 31 | ||
| NKT cells may initiate T cell responses | 31 | ||
| B cells recognize antigen using the B cell receptor complex | 31 | ||
| Other B cell markers include MHC class II antigens and complement and Fc receptors | 32 | ||
| CD5+ B-1 cells and marginal zone B cells produce natural antibodies | 32 | ||
| CD5+ B-1 cells have a variety of roles | 32 | ||
| Marginal zone B cells are thought to protect against polysaccharide antigens | 32 | ||
| cells can differentiate into antibody-secreting plasma cells | 32 | ||
| Lymphocyte development | 32 | ||
| Lymphoid stem cells develop and mature within primary lymphoid organs | 33 | ||
| T cells develop in the thymus | 34 | ||
| Three types of thymic epithelial cell have important roles in T cell production | 34 | ||
| Stem cell migration to the thymus initiates T cell development | 36 | ||
| Stage III thymocytes become either CD4+ or CD8 | 37 | ||
| The T cell receptor is generated during development in the thymus | 37 | ||
| Positive and negative selection of developing T cells takes place in the thymus | 37 | ||
| Adhesion of maturing thymocytes to epithelial and accessory cells is crucial for T cell development | 38 | ||
| Negative selection may also occur outside the thymus in peripheral lymphoid tissues | 38 | ||
| Regulatory T cells are involved in peripheral tolerance | 38 | ||
| There is some evidence for extrathymic development of T cells | 38 | ||
| B cells develop mainly in the fetal liver and bone marrow | 38 | ||
| B cell production in the bone marrow does not occur in distinct domains | 39 | ||
| B cells are subject to selection processes | 39 | ||
| Immunoglobulins are the definitive B cell lineage markers | 40 | ||
| B cells migrate to and function in the secondary lymphoid tissues | 40 | ||
| Lymphoid organs | 40 | ||
| Lymphoid organs and tissues protect different body sites | 40 | ||
| The spleen is made up of white pulp, red pulp, and a marginal zone | 40 | ||
| The white pulp consists of lymphoid tissue | 41 | ||
| The red pulp consists of venous sinuses and cellular cords | 41 | ||
| The marginal zone contains B cells, macrophages, and dendritic cells | 41 | ||
| Lymph nodes filter antigens from the interstitial tissue fluid and lymph | 41 | ||
| Lymph nodes consist of B and T cell areas and a medulla | 42 | ||
| Secondary follicles are made up of a germinal center and a mantle zone | 44 | ||
| In the germinal centers B cells proliferate, are selected, and differentiate into memory cells plasma cell precursors | 44 | ||
| MALT includes all lymphoid tissues associated with mucosa | 45 | ||
| Follicle-associated epithelium is specialized to transport pathogens into the lymphoid tissue | 45 | ||
| Lamina propria and intraepithelial lymphocytes are found in mucosa | 45 | ||
| Lymphocyte recirculation | 47 | ||
| Lymphocytes leave the blood via high endothelial venules | 47 | ||
| Lymphocyte trafficking exposes antigen to a large number of lymphocytes | 47 | ||
| Antigen stimulation at one mucosal area elicits an antibody response largely restricted to MALT | 49 | ||
| Further reading | 50 | ||
| Chapter 3: Antibodies | 51 | ||
| Antibodies recognize and bind antigens | 51 | ||
| Antibodies function as membrane-bound antigen receptors on B cells and soluble circulating antibodies | 51 | ||
| Antibodies are a family of glycoproteins | 52 | ||
| All antibody isotypes except IgD are bifunctional | 52 | ||
| Antibody class and subclass is determined by the structure of the heavy chain | 53 | ||
| Different antibody isotypes activate different effector systems | 53 | ||
| IgG is the predominant antibody isotype in normal human serum | 53 | ||
| IgM accounts for about 10% of the serum antibody pool | 53 | ||
| IgA is the predominant antibody isotype present in seromucous secretions | 53 | ||
| IgD is an antigen-specific receptor (mIgD) on mature B cells | 53 | ||
| Basophils and mast cells are continuously saturated with IgE | 54 | ||
| Antibodies have a basic four chain structure | 54 | ||
| Antibodies are prototypes of the immunoglobulin superfamily | 54 | ||
| The overall structure of an antibody dependson its class and subclass | 54 | ||
| Light chains are of two types | 54e1 | ||
| Hypervariable regions of VH and VL domainsform the antigen-combining site | 54e1 | ||
| Assembled IgM molecules have a `star´ conformation | 55 | ||
| Secretory IgA is a complex of IgA, J chain and secretory component | 55 | ||
| Serum IgD has antigen specificity but not effector functions | 56 | ||
| The heavy chain of IgE is comprised of four constant region domains | 56 | ||
| Antigen-antibody interactions | 56 | ||
| The conformations of the epitope and the paratope are complementary | 56 | ||
| Antibody affinity is a measure of the strength of interaction between a paratope and its epitope | 56 | ||
| Antibodies form multiple non-covalent bonds with antigen | 56 | ||
| Antigen-antibody interactions are reversible | 57 | ||
| Avidity is likely to be more relevant than affinity | 57 | ||
| Cross-reactive antibodies recognize more than one antigen | 58 | ||
| Antibodies recognize the conformation of antigenic determinants | 58 | ||
| Antibody effector functions | 59 | ||
| IgM predominates in the primary immune response | 59 | ||
| IgG is the predominant isotype of secondary immune responses | 59 | ||
| Serum IgA is produced during a secondary immune response | 60 | ||
| IgD is a transmembrane antigen receptor on B cells | 61 | ||
| IgE may have evolved to protect against helminth parasites infecting the gut | 61 | ||
| Fc receptors | 61 | ||
| The three types of Fc receptor for IgG are FcγRI, FcγRII, and FcγRIII | 61 | ||
| FcγRI is involved in phagocytosis of immune complexes and mediator release | 62 | ||
| FcγRII is expressed in two forms | 62 | ||
| FcγRIII is expressed as FcγRIIIa and FcγRIIIb | 62 | ||
| Polymorphism in FcγRIIIa and FcγRIIIb may affect disease susceptibility | 62 | ||
| IgG Fc interaction sites for several ligands have been identified | 62 | ||
| Glycosylation is important for receptor binding to IgG | 63 | ||
| The FcR for IgA is FcαRI | 63 | ||
| The two types of Fc receptor for IgE are FcεRI and FcεRII | 63 | ||
| Cross-linking of IgE bound to FcεRI results in histamine release | 63 | ||
| FcεRII is a type 2 transmembrane molecule | 64 | ||
| IgE receptors bind to IgE by different mechanisms | 64 | ||
| Development of the antibody repertoire by gene recombination | 64 | ||
| Heavy chain gene recombination precedes light chain recombination | 65 | ||
| Antibody genes undergo rearrangement during B cell development | 65 | ||
| Rearrangement at the heavy chain Vh locus precedes rearrangement at light chain loci | 65 | ||
| The first event is recombination between a Jh gene segment and Dh segments, followed by recombination with a Vh gene segment | 65 | ||
| Rearrangement results in a Vk gene segment becoming contiguous with a Jk gene segment | 66 | ||
| Recombination results in a Vλ gene segment becoming contiguous with a functional Jλ gene segment | 66 | ||
| Recombination involves recognition of signal sequences by the V(D)J recombinase | 67 | ||
| Somatic hypermutation in antibody genes | 67 | ||
| Diversity is generated at several different levels | 68 | ||
| Different species have different strategies for generating diversity | 68e1 | ||
| Further reading | 70 | ||
| Internet references | 70 | ||
| Chapter 4: Complement | 71 | ||
| Complement and inflammation | 71 | ||
| Complement activation pathways | 72 | ||
| The classical pathway links to the adaptive immune system | 73 | ||
| The classical pathway is activated by antibody bound to antigen and requires Ca2 | 73 | ||
| C1 activation occurs only when several of the head groups of C1q are bound to antibody | 73 | ||
| C1s enzyme cleaves C4 and C2 | 73 | ||
| C4b2a is the classical pathway C3 convertase | 73 | ||
| C4b2a3b is the classical pathway C5 convertase | 74 | ||
| The ability of C4b and C3b to bind surfaces is fundamental to complement function | 75 | ||
| The alternative and lectin pathways provide antibody-independent `innate´ immunity | 75 | ||
| The lectin pathway is activated by microbial carbohydrates | 75 | ||
| Alternative pathway activation is accelerated by microbial surfaces and requires Mg2 | 76 | ||
| The C3bBb complex is the C3 convertase of the alternative pathway | 76 | ||
| The alternative pathway is linked to the classical pathway | 77 | ||
| Complement protection systems | 77 | ||
| C1 inhibitor controls the classical and lectin pathways | 77 | ||
| C3 and C5 convertase activity are controlled by decay and enzymatic degradation | 77 | ||
| Control of the convertases is mediated in two complementary ways | 77 | ||
| Decay acceleration - | 77 | ||
| Cofactor activity - | 78 | ||
| The membrane attack pathway | 78 | ||
| Activation of the pathway results in the formation of a transmembrane pore | 78 | ||
| Regulation of the membrane attack pathway reduces the risk of `bystander´ damage to adjacent cells | 78 | ||
| CD59 protects host cells from complement-mediated damage | 79 | ||
| Membrane receptors for complement products | 79 | ||
| Receptors for fragments of C3 are widely distributed on different leukocyte populations | 79 | ||
| CR1, CR2, CR3, and CR4 bind fragments of C3 attached to activating surfaces | 80 | ||
| Receptors for C3a and C5a mediate inflammation | 80 | ||
| Receptors for C1q are present on phagocytes, mast cells, and platelets | 81 | ||
| The plasma complement regulator fH binds cell surfaces | 81 | ||
| Complement functions | 81 | ||
| C5a is chemotactic for macrophages and polymorphs | 81 | ||
| C3a and C5a activate mast cells and basophils | 82 | ||
| C3b and iC3b are important opsonins | 82 | ||
| C3b disaggregates immune complexes and promotes their clearance | 82 | ||
| The MAC damages some bacteria and enveloped viruses | 83 | ||
| Immune complexes with bound C3b are very efficient in priming B cells | 83 | ||
| Complement deficiencies | 84 | ||
| Classical pathway deficiencies result in tissue inflammation | 85 | ||
| Deficiencies of MBL are associated with infection in infants | 85 | ||
| Alternative pathway and C3 deficiencies are associated with bacterial infections | 85 | ||
| Terminal pathway deficiencies predispose to Gram-negative bacterial infections | 85 | ||
| C1 inhibitor deficiency causes hereditary angioedema | 86 | ||
| Deficiencies in alternative pathway regulators cause a secondary loss of C3 | 86 | ||
| fH or fI deficiency predisposes to bacterial infections | 86 | ||
| Properdin deficiency causes severe meningococcal meningitis | 86 | ||
| Autoantibodies against complement components, regulators and complexes also cause disease | 86 | ||
| Complement polymorphisms and disease | 86 | ||
| C1inh deficiency is a dominant condition | 86e1 | ||
| Further reading | 87 | ||
| Chapter 5: T Cell Receptors and MHC Molecules | 89 | ||
| T cell receptors | 89 | ||
| TCRs recognize peptides displayed by MHC molecules | 90 | ||
| TCRs are similar to immunoglobulin molecules | 90 | ||
| The αβ heterodimer is the antigen recognition unit of the αβ TCR | 90 | ||
| The CD3 complex associates with the antigen-binding αβ or γδ heterodimers to form the complete TCR | 91 | ||
| The cytoplasmic portions of zeta and η chains contain ITAMs | 91 | ||
| The γδ TCR structurally resembles the αβ TCR but may function differently | 92 | ||
| Antigen recognition by γδ T cells is unlike that of their αβ counterparts | 92 | ||
| γδ T cells have a variety of biological roles | 93 | ||
| TCR variable region gene diversity is generated by V(D)J recombination | 93 | ||
| The mechanism of V(D)J recombination is the same in both T cells and B cells | 93 | ||
| Recombination yields great diversity | 93 | ||
| TCR V genes used in the responses against different antigens | 93 | ||
| MHC molecules | 93 | ||
| Recognition by the αβ TCR requires antigen to be bound to an MHC molecule | 93 | ||
| TCRs are encoded by several sets of genes | 93e1 | ||
| TCRA recombination entails joining of V to J gene segments | 93e1 | ||
| The TCRB locus includes two sets of D, J, and C genes | 93e1 | ||
| The arrangement of the TCRG locus differs in mice and in humans | 93e1 | ||
| The TCRD locus possesses only five Vδ, two Dδ, and six Jδ genes | 93e1 | ||
| In humans the MHC is known as the HLA | 94 | ||
| MHC molecules provide a sophisticated surveillance system for intracellular antigens | 94 | ||
| MHC class I molecules consist of an MHC-encoded heavy chain bound to β2-microglobulin | 95 | ||
| β2-Microglobulin is essential for expression of MHC class I molecules | 95 | ||
| Heavy chain α1, and α2 domains form the antigen-binding groove | 95 | ||
| Variations in amino acid sequence change the shape of the binding groove | 95 | ||
| MHC class II molecules resemble MHC class I molecules in their overall structure | 96 | ||
| Peptide binding properties of MHC molecules | 96 | ||
| The MHC class II binding groove accommodates longer peptides than MHC class I | 96 | ||
| Peptides are held in MHC molecule binding grooves by characteristic anchor residues | 97 | ||
| Interactions at the N and C termini confine peptides to the binding groove of MHC class I molecules | 98 | ||
| Peptides may extend beyond the ends of the binding groove of MHC class II molecules | 98 | ||
| Peptides binding MHC class II are less uniform in size than those binding MHC class I molecules | 98 | ||
| Antigen presentation by MHC molecules | 99 | ||
| Aggregation of TCRs initiates T cell activation | 100 | ||
| Antigenic peptides can induce or antagonize T cell activation | 100 | ||
| What constitutes T cell specificity? | 101 | ||
| Genetic organization of the MHC | 101 | ||
| The three principal human MHC class I loci are HLA-A, HLA-B, and HLA-C | 101 | ||
| HLA-E, HLA-F, HLA-G, and HLA-H are class Ib genes | 101 | ||
| Human MHC class II genes are located in the HLA-D region | 101 | ||
| Mice have two or three MHC class I loci | 101e1 | ||
| Qa, Tla, and M genes encode MHCclass Ib molecules | 101e1 | ||
| Mouse MHC class II genes are located in the H-2I region | 101e2 | ||
| MHC polymorphism is concentrated in and around the peptide-binding cleft | 102 | ||
| MHC haplotype and disease susceptibility | 102 | ||
| All nucleated cells of the body express MHC class I molecules | 103 | ||
| MHC molecules are co-dominantly expressed | 103 | ||
| The specificity of the TCR and MHC explains genetic restrictions in antigen presentation | 103 | ||
| Presentation of lipid antigens by CD1 | 104 | ||
| Further reading | 105 | ||
| Internet references | 106 | ||
| Section 2: Modes of Immune Response | 107 | ||
| Chapter 6: Mechanisms of Innate Immunity | 109 | ||
| Innate immune responses | 109 | ||
| Inflammation - a response to tissue damage | 110 | ||
| Inflammation brings leukocytes to sites of infection or tissue damage | 110 | ||
| Cytokines control the movement of leukocytes into tissues | 111 | ||
| Leukocytes migrate across the endothelium of microvessels | 111 | ||
| Leukocyte traffic into tissues is determined by adhesion molecules and signaling molecules | 112 | ||
| Selectins bind to carbohydrates to slow the circulating leukocytes | 113 | ||
| Chemokines and other chemotactic molecules trigger the tethered leukocytes | 114 | ||
| Chemokines receptors have promiscuous binding properties | 115 | ||
| Other molecules are also chemotactic for neutrophils and macrophages | 115 | ||
| Integrins on the leukocytes bind to CAMs on the endothelium | 116 | ||
| Integrins and CAMs - families of adhesion molecules | 116e1 | ||
| Leukocyte migration varies with the tissue and the inflammatory stimulus | 117 | ||
| Different chemokines cause different types of leukocyte to accumulate | 117 | ||
| Preventing leukocyte adhesion can be used therapeutically | 117 | ||
| Leukocyte migration to lymphoid tissues | 118 | ||
| Chemokines are important in controlling cell traffic to lymphoid tissues | 118 | ||
| Mediators of inflammation | 118 | ||
| The kinin system generates powerful vasoactive mediators | 119 | ||
| The plasmin system is important in tissue remodeling and regeneration | 119 | ||
| Mast cells, basophils and platelets release a variety of inflammatory mediators | 119 | ||
| Pain is associated with mediators released from damaged or activated cells | 119 | ||
| Lymphocytes and monocytes release mediators that control the accumulation and activation of other cells | 120 | ||
| Pathogen-associated molecular patterns | 120 | ||
| PRRs allow phagocytes to recognize pathogens | 121 | ||
| Phagocytes have receptors that recognize pathogens directly | 121 | ||
| Soluble pattern recognition molecules | 121e1 | ||
| Pentraxins | 121e1 | ||
| Collectins and ficolins opsonize pathogens and inhibit invasiveness | 121e1 | ||
| Toll-like receptors activate phagocytes and inflammatory reactions | 122 | ||
| Chapter 7: Mononuclear Phagocytes in Immune Defense | 125 | ||
| Macrophages: the `big eaters´ | 125 | ||
| Macrophages differentiate from blood monocytes | 125 | ||
| M-CSF is required for macrophage differentiation | 126 | ||
| Macrophage populations have distinctive phenotypes | 126e1 | ||
| The tissue environment controls differentiation of resident macrophages | 127 | ||
| Macrophages can act as antigen-presenting cells | 127 | ||
| Macrophages act as sentinels within the tissues | 127 | ||
| Phagocytosis and endocytosis | 128 | ||
| Soluble compounds are internalized by endocytosis | 128 | ||
| Large particles are internalized by phagocytosis | 129 | ||
| Macrophages sample their environment through opsonic and non-opsonic receptors | 129 | ||
| Opsonic receptors require antibody or complement to recognize the target | 130 | ||
| The best characterized non-opsonic receptors are the Toll-like receptors (TLRs) | 130 | ||
| TLRs activate macrophages through several different pathways | 131e1 | ||
| Lectin and scavenger receptors are non-opsonic receptors that recognize carbohydrates and modified proteins directly | 132 | ||
| Cytosolic receptors recognize intracellular pathogens | 132 | ||
| Functions of phagocytic cells | 133 | ||
| Clearance of apoptotic cells by macrophages produces anti-inflammatory signals | 133 | ||
| Mechanism of action of NLRs | 133e1 | ||
| Mechanisms of action of RLH receptors | 133e1 | ||
| Macrophages coordinate the inflammatory response | 135 | ||
| Recognition of necrotic cells and microbial compounds by macrophages initiates inflammation | 135 | ||
| Resident macrophages recruit neutrophils to inflammatory sites | 135 | ||
| Monocyte recruitment to sites of inflammation is promoted by activated neutrophils | 135 | ||
| Macrophages and neutrophils have complementary microbicidal actions | 136 | ||
| Phagocytes kill pathogens with reactive oxygen and nitrogen intermediates | 137 | ||
| Some pathogens avoid phagocytosis or escape damage | 138 | ||
| Resolution of inflammation by macrophages is an active process | 138 | ||
| Different pathways of macrophage activation | 138 | ||
| Functions of secreted molecules | 138e1 | ||
| Further reading - reviews | 141 | ||
| Selected references | 141 | ||
| Chapter 8: Antigen Presentation | 143 | ||
| Antigen presenting cells | 143 | ||
| Interactions with antigen-presenting cells direct T cell activation | 144 | ||
| Dendritic cells are crucial for priming T cells | 144 | ||
| Macrophages and B cells present antigen to primed T cells | 144 | ||
| Antigen processing | 146 | ||
| Antigens are partially degraded before binding to MHC molecules | 146 | ||
| MHC class I pathway | 146 | ||
| Proteasomes are cytoplasmic organelles that degrade cytoplasmic proteins | 147 | ||
| Transporters move peptides to the ER | 147 | ||
| A multi-component complex loads peptides onto MHC class-I molecules | 148 | ||
| Antigen processing affects which peptides are presented | 148 | ||
| Cross-presentation can occur if exogenous antigen is presented on class-I molecules | 148 | ||
| Some class I-like molecules can present limited sets of antigens | 148 | ||
| HLA-E-signal peptide complex interacts with the NKG2A inhibitory receptor on NK cells | 148 | ||
| CD1 molecules present lipids and glycolipids | 149 | ||
| Why are antigen-processing genes located in the MHC? | 150 | ||
| MHC class II pathway | 150 | ||
| Class II molecules are loaded with exogenous peptides | 150 | ||
| MHC-II peptide complexes recycle from the plasma membrane | 151 | ||
| T cell interaction with APCS | 151 | ||
| The immunological synapse is a highly ordered signaling structure | 151 | ||
| Costimulation by B7 binding to CD28 is essential for T cell activation | 152 | ||
| Ligation of CTLA-4 inhibits T cell activation | 152 | ||
| CTLA-4 is a member of a family of molecules that control lymphocyte activation | 152 | ||
| Intracellular signaling pathways activate transcription factors | 153 | ||
| Interleukin-2 drives T cell division | 153 | ||
| T-cell activation is initiated by Ca++ signaling | 153e1 | ||
| TCR-binding activates tyrosine kinases | 153e1 | ||
| Other cytokines contribute to activation and division | 154 | ||
| Types of immune response | 154 | ||
| Danger signals enhance antigen presentation | 154 | ||
| Further reading | 155 | ||
| Chapter 9: Cell Cooperation in the Antibody Response | 157 | ||
| B cell activation | 157 | ||
| T-independent antigens do not require T cell help to stimulate B cells | 157 | ||
| T-independent antigens induce poor memory | 158 | ||
| T-independent antigens tend to activate the CD5+ T-independent antigens tend to activate the CD5þ | 158 | ||
| Activation of B cells by T-dependent antigens | 158 | ||
| T cells and B cells recognize different parts of antigens | 158 | ||
| B-cell activation and T-cell activation follow similar patterns | 159 | ||
| Direct interaction of B cells and T cells involves costimulatory molecules | 160 | ||
| Cytokine secretion is important in B-cell proliferationand differentiation | 161 | ||
| Cytokine receptors guide B-cell growthand differentiation | 162 | ||
| B-cell–T-cell interaction may either activateor inactivate (anergize) | 162 | ||
| B cell differentiation and the antibody response | 163 | ||
| B cell affinity maturation occurs in germinal centers | 163 | ||
| Self-reactive B cells generated by somatic mutation are deleted | 164 | ||
| In-vivo antibody responses show isotype switching, affinity maturation and memory | 164 | ||
| Time course - | 165 | ||
| Antibody titre - | 165 | ||
| Antibody class - | 165 | ||
| Antibody affinity - | 165 | ||
| Affinity maturation depends on cell selection | 165 | ||
| B cell isotype switching and somatic hypermutation | 166 | ||
| B cells recombine their heavy chain genes to switch immunoglobulin isotype | 166 | ||
| Class switching occurs during maturation and proliferation | 166 | ||
| Class switching may be achieved by differential splicing of mRNA | 167 | ||
| Class switching is mostly achieved by gene recombination | 167 | ||
| Membrane and secreted immunoglobulins are produced by differential splicing of RNA transcripts of heavy chain genes | 168 | ||
| Immunoglobulin class expression is influenced by cytokines and type of antigenic stimulus | 168 | ||
| Further reading | 169 | ||
| Chapter 10: Cell-mediated Cytotoxicity | 171 | ||
| Cytotoxic lymphocytes | 171 | ||
| CTLs and NK cells mediate cytotoxicity | 171 | ||
| Effector CTLs home to peripheral organs and sites of inflammation | 172 | ||
| CTLs recognize antigen presented on MHC class I molecules | 172 | ||
| CTLs and NK cells are complementary in the defense against virally infected and cancerous cells | 172 | ||
| Not all NK cells mediate cytotoxicity | 173 | ||
| NK cell receptors | 173 | ||
| NK cells recognize cells that fail to express MHC class I | 173 | ||
| NK cell development | 173e1 | ||
| Killer immunoglobulin-like receptors recognize MHC class I | 174 | ||
| The lectin-like receptor CD94 recognizes HLA-E | 175 | ||
| LILRB1 recognizes all MHC class I molecules including HLA-G | 175 | ||
| NK cells are self-tolerant | 176 | ||
| Cancerous and virally-infected cells are recognized by NKG2D | 176 | ||
| NK cells can also recognize antibody on target cells using Fc receptors | 176 | ||
| The balance of inhibitory and activating signals determines whether an NK is activated | 177 | ||
| Cytoxicity | 177 | ||
| Cytotoxicity is effected by direct cellular interactions, granule exocytosis, and cytokines | 177 | ||
| Cytotoxicity may be signaled via TNF receptor family molecules on the target cell | 178 | ||
| CTL and NK cell granules contain perforin and granzymes | 178 | ||
| Some cell types are resistant to cell-mediated cytotoxicity | 180 | ||
| Non-lymphoid cytotoxic cells | 180 | ||
| Macrophages and neutrophils primarily kill target cells by phagocytosis | 180 | ||
| Eosinophils kill target cells by ADCC | 181 | ||
| Further reading | 182 | ||
| Chapter 11: Regulation of the Immune Response | 183 | ||
| Regulation by antigen | 183 | ||
| Different antigens elicit different kinds of immune response | 184 | ||
| Large doses of antigen can induce tolerance | 184 | ||
| Antigen route of administration can determine whether an immune response occurs | 184 | ||
| Regulation by the antigen presenting cell | 185 | ||
| Cytokine production by APCs influences T cell responses | 185 | ||
| T cell regulation of the immune response | 185 | ||
| Differentiation into CD4+ Th subsets is an important step in selecting effector functions | 185 | ||
| The cytokine balance controls T cell differentiation | 186 | ||
| T cell plasticity | 186 | ||
| Th cell subsets determine the type of immune response | 187 | ||
| CD8 T cells can be divided into subsets on the basis of cytokine expression | 188 | ||
| Regulatory T cells exert important suppressive functions | 188 | ||
| Treg differentiation is induced by Foxp3 | 188 | ||
| Tr1 regulatory cells | 188 | ||
| Mechanisms of Treg suppression | 188 | ||
| Reciprocal developmental relationship between induced Tregs and Th17 cells | 188e1 | ||
| Role of Tregs in infection | 189 | ||
| CD8+ T cells suppress secondary immune responses | 189 | ||
| NK and NKT cells produce immunoregulatory cytokines and chemokines | 190 | ||
| Regulation of the immune response by immunoglobulins | 190 | ||
| IgG antibody can regulate specific IgG synthesis | 191 | ||
| Immune complexes may enhance or suppress immune responses | 191 | ||
| Apoptosis in the immune system | 192 | ||
| Immune regulation by selective cell migration | 193 | ||
| T cell expression of different molecules can mediate tissue localization | 193 | ||
| Neuroendocrine regulation of immune responses | 194 | ||
| Genetic influences on the immune response | 195 | ||
| MHC haplotypes influence the ability to respond to an antigen | 195 | ||
| MHC-linked genes control the response to infections | 195 | ||
| Susceptibility to infection by Trichinella spiralis is affected by the I-E locus in mice | 195 | ||
| The I-E locus also influences susceptibility to Leishmania donovani | 195 | ||
| Certain HLA haplotypes confer protection from infection | 196 | ||
| Many non-MHC genes also modulate immune responses | 196 | ||
| Polymorphisms in cytokine and chemokine genes affect susceptibility to infections | 196 | ||
| Non-MHC-linked genes affect susceptibilityto infection | 198e1 | ||
| TLR4 polymorphisms, malaria and septic shock | 198e1 | ||
| Further reading | 198 | ||
| Chapter 12: Immune Responses in Tissues | 199 | ||
| Tissue-specific immune responses | 199 | ||
| Locally produced cytokine and chemokines influence tissue-specific immune responses | 200 | ||
| Endothelium controls which leukocytes enter a tissue | 200 | ||
| Some tissues are immunologically privileged | 201 | ||
| Immune reactions in the CNS | 202 | ||
| The blood-brain barrier excludes most antibodies from the CNS | 202 | ||
| Neurons suppress immune reactivity in neighboring glial cells | 203 | ||
| Immunosuppressive cytokines regulate immunity in the normal CNS | 203 | ||
| Immune reactions in CNS damage oligodendrocytes | 203 | ||
| Immune responses in the gut and lung | 205 | ||
| The gut immune system tolerates many antigens but reacts to pathogens | 205 | ||
| Immune reactions in the eye | 205e1 | ||
| The eye has powerful immunosuppressivemechanisms | 205e1 | ||
| Local immune privilege may extendsystemically | 205e2 | ||
| Gut enterocytes influence the localimmune response | 206 | ||
| IELs produce many immunomodulatorycytokines | 206 | ||
| Chronic inflammation in the gut | 207 | ||
| Immune reactions in the skin | 207 | ||
| Immune responses in the lung | 207e1 | ||
| Conclusions | 208 | ||
| Further reading | 208 | ||
| Section 3: Defense Against Infectious Agents | 209 | ||
| Chpater 13: Immunity to Viruses | 211 | ||
| Innate immune defenses against viruses | 211 | ||
| Microbicidal peptides have broad-spectrum antiviral effects | 211 | ||
| Type I interferons have critical antiviral and immunostimulatory roles | 212 | ||
| NK cells are cytotoxic for virally-infected cells | 213 | ||
| Macrophages act at three levels to destroy virus and virus-infected cells | 214 | ||
| Adaptive immune responses to viral infection | 214 | ||
| Antibodies and complement can limit viral spread or reinfection | 214 | ||
| Antibodies can neutralize the infectivity of viruses | 214 | ||
| NK cells are important in combating herpesvirus infections | 214e1 | ||
| Complement is involved in the neutralization of some free viruses | 215 | ||
| Antibodies mobilize complement and/or effector cells to destroy virus-infected cells | 215 | ||
| T cells mediate viral immunity in several ways | 215 | ||
| CD8+ T cells target virus-infected cells | 215 | ||
| CD4+ T cells are a major effector cell population in the response to some virus infections | 216 | ||
| Virus strategies to evade host immune responses | 217 | ||
| Viruses can impair the host immune response | 217 | ||
| Viral strategies for avoidance of recognition by host immune defenses | 218 | ||
| Viruses avoid recognition by T cells by reducing MHC expression on infected cells | 218 | ||
| Mutation of viral target antigen allows escape from recognition by antibodies or T cells | 219 | ||
| Viral strategies for resisting control by immune effector mechanisms | 219 | ||
| Pathological consequences of immune responses induced by viral infections | 221 | ||
| Excessive cytokine production and immune activation can be pathological | 221 | ||
| Pathological consequences of antiviral antibody production | 221 | ||
| Poorly-neutralizing antibodies can enhance viral infectivity | 221 | ||
| Antiviral antibodies can form immune complexes that cause tissue damage | 221 | ||
| Virus-specific T cell responses can cause severe tissue damage | 221 | ||
| Viral infection may provoke autoimmunity | 222 | ||
| Further reading | 222 | ||
| Chapter 14: Immunity to Bacteria and Fungi | 223 | ||
| Innate recognition of bacterial components | 223 | ||
| There are four main types of bacterial cell wall | 223 | ||
| Pathogenicity varies between two extreme patterns | 224 | ||
| The first lines of defense do not depend on antigen recognition | 224 | ||
| Commensals can limit pathogen invasion | 224 | ||
| The second line of defense is mediated by recognition of bacterial components | 225 | ||
| LPS is the dominant activator of innate immunity in Gram-negative bacterial infection | 226 | ||
| Other bacterial components are also potent immune activators | 226 | ||
| Bacterial PAMPs activate cells via Toll-like receptors | 226e1 | ||
| Lymphocyte-independent effector systems | 227 | ||
| Complement is activated via the alternative pathway | 227 | ||
| Release of proinflammatory cytokines increases the adhesive properties of the vascular endothelium | 228 | ||
| Pathogen recognition generates signals that regulate the lymphocyte-mediated response | 228 | ||
| Antibody dependent anti-bacterial defenses | 228 | ||
| Pathogenic bacteria may avoid the effects of antibody | 229 | ||
| Pathogenic bacteria can avoid the detrimental effects of complement | 230 | ||
| Bactericial killing by phagocytes | 230 | ||
| Bacterial components attract phagocytes by chemotaxis | 231 | ||
| The choice of receptors is critical | 231 | ||
| Uptake can be enhanced by macrophage-activating cytokines | 231 | ||
| Different membrane receptors vary in their efficiency at inducing a microbicidal response | 231 | ||
| Phagocytic cells have many killing methods | 231 | ||
| Some cationic proteins have antibiotic-like properties | 232 | ||
| Other antimicrobial mechanisms also play a role | 232 | ||
| Macrophage killing can be enhanced on activation | 233 | ||
| Optimal activation of macrophages is dependent on Th1 CD4 T cells | 233 | ||
| Persistent macrophage recruitment and activation can result in granuloma formation | 233 | ||
| Successful pathogens have evolved mechanisms to avoid phagocyte-mediated killing | 234 | ||
| Intracellular pathogens may `hide´ in cells | 234 | ||
| Direct anti-bacterial actions of T cells | 235 | ||
| Infected cells can be killed by CTLs | 235 | ||
| Other T cell populations can contribute to antibacterial immunity | 235 | ||
| Immunopathological reactions induced by bacteria | 236 | ||
| Excessive cytokine release can lead to endotoxin shock | 237 | ||
| The toxicity of superantigens results from massive cytokine release | 237 | ||
| The Schwartzman reaction is a form ofcytokine-dependent tissue damage | 237e1 | ||
| The Koch phenomenon is necrosis inT cell-mediated mycobacterial lesionsand skin test sites | 237e1 | ||
| Some individuals suffer from excessiveimmune responses | 237e1 | ||
| Excessive immune responses can occurduring treatment of severe bacterial infections | 237e2 | ||
| Heat-shock proteins are prominent targetsof immune responses | 237e2 | ||
| The `hygiene hypothesis´ | 238 | ||
| Fungal infections | 238 | ||
| There are four categories of fungal infection | 238 | ||
| Innate immune responses to fungi include defensins and phagocytes | 239 | ||
| T cell-mediated immunity is criticalfor resistance to fungi | 240 | ||
| Fungi possess many evasion strategies to promote their survival | 240 | ||
| New immunological approaches are being developed to prevent and treat fungal infections | 240 | ||
| Further reading | 241 | ||
| Chpater 15: Immunity to Protozoa and Worms | 243 | ||
| Parasite infections | 243 | ||
| Parasitic infections are often chronic and affect many people | 243e1 | ||
| Immune defenses against parasites | 244 | ||
| Host resistance to parasite infection may be genetic | 244 | ||
| Many parasitic infections are long-lived | 244 | ||
| Host defense depends upon a number of immunological mechanisms | 244 | ||
| Innate immune responses | 245 | ||
| Toll-like receptors recognize parasite molecules | 245 | ||
| Classical human PRRs also contribute to recognition of parasites | 246 | ||
| Complement receptors are archetypal PRRs | 246 | ||
| Adaptive immune responses to parasites | 247 | ||
| T and B cells are pivotal in the development of immunity | 247 | ||
| Both CD4 and CD8 T cells are needed for protection from some parasites | 248 | ||
| Cytokines, chemokines, and their receptors have important roles | 249 | ||
| T cell responses to protozoa depend on the species | 249 | ||
| The immune response to worms depends upon Th2-secreted cytokines | 250 | ||
| Some worm infections deviate the immune response | 250 | ||
| The host may isolate the parasite with inflammatory cells | 251 | ||
| Parasites induce non-specific and specific antibody production | 251 | ||
| Immune effector cells | 252 | ||
| Macrophages can kill extracellular parasites | 253 | ||
| Activation of macrophages is a feature of early infection | 253 | ||
| Neutrophils can kill large and small parasites | 254 | ||
| Eosinophils are characteristically associated with worm infections | 254 | ||
| Eosinophils can kill helminths by oxygen-dependent and independent mechanisms | 254 | ||
| Eosinophils and mast cells can act together | 255 | ||
| Mast cells control gastrointestinal helminths | 255 | ||
| Platelets can kill many types of parasite | 255 | ||
| Parasite escape mechanisms | 255 | ||
| Parasites can resist destruction by complement | 255 | ||
| Intracellular parasites can avoid being killed by oxygen metabolites and lysosomal enzymes | 256 | ||
| Parasites can disguise themselves | 256 | ||
| African trypanosomes and malaria undergo antigenic variation | 256 | ||
| Other parasites acquire a surface layer of host antigens | 257 | ||
| Some extracellular parasites hide from or resist immune attack | 257 | ||
| Most parasites interfere with immune responses for their benefit | 257 | ||
| Parasites produce molecules that interfere with host immune function | 257 | ||
| Some parasites suppress inflammation or immune responses | 260 | ||
| Immunopathological consequences of parasite infections | 260 | ||
| Vaccines against human parasites | 260e1 | ||
| Further reading | 261 | ||
| Websites | 261 | ||
| Chpater 16: Primary Immunodeficiencies | 263 | ||
| B lymphocyte deficiencies | 264 | ||
| Congenital agammaglobulinemia results from defects of early B cell development | 264 | ||
| Defects in terminal differentiation of B cells produces selective antibody deficiencies | 264 | ||
| Genetic defects in CVID | 264e1 | ||
| CVID is characterized by reduced levels of specific antibody isotypes | 265 | ||
| IgA deficiency is relatively common | 265 | ||
| Defects of class switch recombination (CSR) | 265 | ||
| T lymphocyte deficiencies | 267 | ||
| Severe combined immunodeficiency (SCID) can be caused by many different genetic defects | 267 | ||
| Th cell deficiency results from HLA class II deficiency | 268 | ||
| Treatment of SCID | 268e1 | ||
| The DiGeorge anomaly arises from a defect in thymus embryogenesis | 269 | ||
| Disorders of immune regulation | 270 | ||
| Defective function of regulatory T (Treg) cells causes severe autoimmunity | 270 | ||
| Impaired apoptosis of self-reactive lymphocytes causes autoimmune lymphoproliferative syndrome (ALPS) | 270 | ||
| Congenital defects of lymphocyte cytotoxicity result in persistent inflammation and severe tissue damage | 270 | ||
| Immunodeficiency syndromes | 271 | ||
| Chromosomal breaks occur in TCR and immunoglobulin genes in hereditary ataxia telangiectasia | 271 | ||
| T cell defects and abnormal immunoglobulin levels occur in Wiskott-Aldrich syndrome | 271 | ||
| Deficiency of STAT3 causes impaired development and function of Th17 cells in hyper-IgE syndrome | 271 | ||
| Genetic defects of phagocytes | 272 | ||
| Chronic granulomatous disease results from a defect in the oxygen reduction pathway | 272 | ||
| LAD is due to defects of leukocytes trafficking | 272 | ||
| Enzyme defects in CGD | 272 | ||
| Immunodeficiencies with selective susceptibility to infections | 272 | ||
| Enzyme defects in CGD | 272e1 | ||
| Macrophage microbicidal activity is impaired by defects in IFNγ signaling | 273 | ||
| Defects of TLR-signaling cause susceptibility to pyogenic infections | 273 | ||
| Genetic deficiencies of complement proteins | 273 | ||
| Immune complex clearance, inflammation, phagocytosis, and bacteriolysis can be affected by complement deficiencies | 273 | ||
| Hereditary angioneurotic edema (HAE) results from C1 inhibitor deficiency | 274 | ||
| Further reading | 275 | ||
| Chpater 17: AIDS, Secondary Immunodeficiency and Immunosuppression | 277 | ||
| Overview | 277 | ||
| Nutrient deficiencies | 277 | ||
| Infection and malnutrition can exacerbate each other | 278 | ||
| Protein-energy malnutrition and lymphocyte dysfunction | 278 | ||
| Nutrition also affects innate mechanisms of immunity | 279 | ||
| Deficiencies in trace elements impact immunity | 279 | ||
| Vitamin deficiencies and immune function | 279 | ||
| Obesity is associated with altered immune responses | 280 | ||
| Immunodeficiency secondary to drug therapies | 280 | ||
| Iatrogenic immune suppression post-organ transplantation | 280 | ||
| Glucocorticoids are powerful immune modulators | 280 | ||
| Functional effects of steroid treatment | 281 | ||
| Other causes of secondary immunodeficiencies | 281 | ||
| Human immunodeficieny virus causes AIDS | 281 | ||
| HIV life cycle | 282 | ||
| HIV targets CD4 T cells and mononuclear phagocytes | 283 | ||
| Acute symptoms occur 2-4weeks post infection | 283 | ||
| Viral latency is associated with chronic infection | 283 | ||
| HIV infection induces strong immune responses | 284 | ||
| HIV can evade the immune response | 284 | ||
| Immune dysfunction results from the direct effects of HIV and impairment of CD4 T cells | 284 | ||
| AIDS is the final stage of HIV infection and disease | 285 | ||
| An effective vaccine remains an elusive goal | 286 | ||
| Further reading | 288 | ||
| Chpater 18: Vaccination | 289 | ||
| Vaccination | 289 | ||
| Vaccines apply immunological principles to human health | 289 | ||
| Vaccines can protect populations as well as individuals | 290 | ||
| Antigen preparations used in vaccines | 290 | ||
| Live vaccines can be natural or attenuated organisms | 291 | ||
| Natural live vaccines have rarely been used | 291 | ||
| The new rotavirus vaccines should prevent many infants from dying in developing countries | 291 | ||
| Attenuated live vaccines have been highly successful | 291 | ||
| Attenuated microorganisms are less able to cause disease in their natural host | 291 | ||
| The new rotavirus vaccines should prevent manyinfants from dying in developing countries | 291e1 | ||
| Killed vaccines are intact but non-living organisms | 292 | ||
| Inactivated toxins and toxoids are the most successful bacterial vaccines | 292 | ||
| Subunit vaccines and carriers | 292 | ||
| Conjugate vaccines are effective at inducing antibodies to carbohydrate antigens | 293 | ||
| Antigens can be expressed from vectors | 293 | ||
| Adjuvants enhance antibody production | 293 | ||
| Conjugate meningitis vaccines | 293e1 | ||
| Adjuvants concentrate antigen at appropriate sites or induce cytokines | 294 | ||
| Vaccine administration | 295 | ||
| Most vaccines are delivered by injection | 295 | ||
| Mucosal immunization is a logical alternative approach | 295 | ||
| Vaccine efficacy and safety | 296 | ||
| Induction of appropriate immunity depends on the properties of the antigen | 296 | ||
| Vaccine safety is an overriding consideration | 297 | ||
| MMR controversy resulted in measles epidemics | 297 | ||
| New vaccines can be very expensive | 298 | ||
| Vaccines in general use have variable success rates | 299 | ||
| Some vaccines are reserved for special groups only | 299 | ||
| Vaccines for parasitic and some other infections are only experimental | 300 | ||
| For many diseases there is no vaccine available | 301 | ||
| Passive immunization can be life-saving | 301 | ||
| Future vaccines | 301 | ||
| Non-specific immunotherapy can boost immune activity | 301e2 | ||
| Immunization against a variety of non-infectious conditions is being investigated | 301e2 | ||
| Vaccinia is a convenient vector | 302 | ||
| ‘Naked’ DNA can be transfected intohost cells | 302 | ||
| Further reading | 303 | ||
| Section 4: Immune Responses Against Tissues | 305 | ||
| Chapter 19: Immunological Tolerance | 307 | ||
| Generation of autoreactive antigen receptors during lymphocyte development | 307 | ||
| T cell tolerance | 308 | ||
| Central T-cell tolerance develops in the thymus | 308 | ||
| Generation of their clonal TCR is the first step in T cell development | 308 | ||
| Thymocytes are positively selected for their ability to interact with self MHC molecules | 308 | ||
| Positive selection occurs predominantly in the thymic cortex | 309 | ||
| Lack of survival signals leads to death by neglect | 309 | ||
| Thymocytes are negatively selected if they bind strongly to self-peptides on MHC molecules | 310 | ||
| A library of self antigens is presented to developing T cells in the thymus | 310 | ||
| AIRE controls promiscuous expression of genes in the thymus | 310 | ||
| Peripheral T-cell tolerance | 311 | ||
| Immunological ignorance occurs if T cells do not encounter their cognate antigen | 311 | ||
| Some self antigens are sequestered in immunologically privileged tissues | 311 | ||
| Self-reactive T cells and experimental autoimmunity | 311e1 | ||
| Lymphocyte activation enhances their migration intonon-lymphoid tissues | 312 | ||
| Antigen presenting cells reinforce selftolerance | 312 | ||
| Dendritic cells can present antigen ina tolerogenic manner | 312 | ||
| Tolerogenic DCs mature under steady-state conditions | 312 | ||
| The amount of released self antigen critically affectssensitization | 312e1 | ||
| Regulatory T cells | 313 | ||
| Regulatory T cells suppress immuneresponses | 313 | ||
| Defects in FoxP3 result in multi-system autoimmunediseases | 313 | ||
| DC surface receptors involved in promoting tolerance | 313e1 | ||
| Natural Treg cells differentiate in the thymus | 314 | ||
| iTreg cells differentiate in the periphery | 315 | ||
| Treg effector functions | 315 | ||
| Tregs secrete immunosuppressive cytokines | 315 | ||
| Selection of nTregs is partly related to the affinityfor antigen/MHC | 315e1 | ||
| IL-2 is required for the development of Tregs | 315e1 | ||
| The phenotype of Treg cells | 315e2 | ||
| In vitro assays of Treg effector functions | 315e3 | ||
| In vivo analyses of Treg effector functions | 315e3 | ||
| Tregs can deplete IL-2 | 316 | ||
| Cytolysis | 316 | ||
| Modulation of DC maturation and function | 316 | ||
| Can loss of Treg function explain autoimmunedisease? | 317 | ||
| T cell anergy | 317 | ||
| The induction of anergy is an active process | 318 | ||
| T cells can be deleted in the periphery | 318 | ||
| T cells can be killed by ligation of Fas | 318 | ||
| B cell tolerance | 318 | ||
| B cells undergo negative selection in thebone marrow | 319 | ||
| Receptor editing allows potentiallyself-reactive B cells to avoid negativeselectio | 319 | ||
| B cell anergy can be induced by self antigens | 320 | ||
| Further reading | 321 | ||
| Chpater 20: Autoimmunity and Autoimmune Disease | 323 | ||
| Autoimmunity and autoimmune disease | 323 | ||
| Autoimmune conditions present a spectrum between organ-specific and systemic disease | 324 | ||
| Hashimoto's thyroiditis is highly organ-specific | 324 | ||
| SLE is a systemic autoimmune disease | 324 | ||
| The location of the antigen determines where a disease lies in the spectrum | 325 | ||
| An individual may have more than one autoimmune disease | 325 | ||
| Section 5: Hypersensitivity | 369 | ||
| Chapter 23: Immediate Hypersensitivity (Type I) | 371 | ||
| Classification of hypersensitivity reactions | 371 | ||
| Historical perspective on immediate hypersensitivity | 372 | ||
| Characteristics of type I reactions | 373 | ||
| Most allergens are proteins | 373 | ||
| IgE is distinct from the other dimeric immunoglobulins | 373 | ||
| The half-life of IgE is short compared with that of other immunoglobulins | 374 | ||
| IgG4 is transferred across the placenta, but IgE is not | 374 | ||
| T cells control the response to inhalant allergens | 375 | ||
| IgE production is dependent on Th2 cells | 375 | ||
| Cytokines regulate the production of IgE | 375 | ||
| Both IgE and IgG4 are dependent on IL-4 | 375 | ||
| Characteristics of allergens | 377 | ||
| Allergens have similar physical properties | 377 | ||
| The inhalant allergens cause hayfever, chronic rhinitis, and asthma | 378 | ||
| Small quantities of inhalant allergen cause immediate hypersensitivity | 378 | ||
| Only a small number of food proteins are common causes of allergic responses | 378 | ||
| IgE binding sites can be identified on the tertiary structure of allergens | 378e1 | ||
| Desensitization can be used to control type I hypersensitivity | 379 | ||
| Mediators released by mast cells and basophils | 379 | ||
| Mast cells in different tissues have distinct granule proteases | 379 | ||
| Cross-linking of FcεRI receptors results in degranulation | 380 | ||
| Genetic associations with asthma | 381 | ||
| In allergic individuals mast cells can berecruited to the skin and to the nose | 381e1 | ||
| Skin tests for diagnosis and to guide treatment | 382 | ||
| Positive skin tests are common | 383 | ||
| Late skin reactions probably include several different events | 384 | ||
| Pathways that contribute to the chronicity of allergic diseases | 384 | ||
| Atopic dermatitis and the atopy patch test | 384 | ||
| Epidermal spongiosis and a dermal infiltrate are features of a positive patch test | 384 | ||
| Allergens contribute to asthma | 384 | ||
| Late skin reactions probably includeseveral different events | 384e1 | ||
| BAL analysis after allergen challenge demonstrates mast cell and eosinophil products | 385 | ||
| Bronchial hyperreactivity is a major feature of asthma | 386 | ||
| Evidence for inflammation of the lungs of patients with asthma is indirect | 386 | ||
| Treatments for type I hypersensitivity | 387 | ||
| Immunotherapy is an effective treatment for hayfever and anaphylactic sensitivity to venom | 387 | ||
| Modified forms of allergen-specific immunotherapy | 388 | ||
| Peptides from the primary sequence of an allergen that can stimulate T cells in vitro | 388 | ||
| Modified recombinant allergens have decreased binding to IgE | 388 | ||
| Adjuvants can shift the immune response away from a simple Th2 response | 388 | ||
| DNA vaccines are being designed to change the immune response | 388 | ||
| Other forms of immune based non-specific therapy | 389 | ||
| Humanized monoclonal anti-IgE | 389 | ||
| Recombinant soluble IL-4R can block the biological activity of IL-4 | 389 | ||
| Humanized monoclonal anti-IL-5 decreases circulating eosinophils | 389 | ||
| Some new treatment approaches may not be practical | 389 | ||
| Further reading | 390 | ||
| Chapter 24: Hypersensitivity (Type II) | 393 | ||
| Mechanisms of tissue damage | 393 | ||
| Effector cells engage their targets using Fc and C3 receptors | 393 | ||
| Cells damage targets by releasing their normal immune effector molecules | 394 | ||
| Type II reactions against blood cells and platelets | 395 | ||
| Transfusion reactions occur when a recipient has antibodies against donor erythrocytes | 395 | ||
| The ABO blood group system is of primary importance | 395 | ||
| The Rhesus system is a major cause of hemolytic disease of the newborn | 396 | ||
| Transfusion reactions can be caused by minor blood groups | 396 | ||
| Cross-matching ensures that a recipient does not have antibodies against donor erythrocytes | 396 | ||
| Transfusion reactions involve extensive destruction of donor blood cells | 396 | ||
| Hyperacute graft rejection is related to the transfusion reaction | 396 | ||
| Transfusion reactions can be caused by minorblood groups | 396e1 | ||
| HDNB is due to maternal IgG reacting against the child's erythrocytes in utero | 397 | ||
| Autoimmune hemolytic anemias arise spontaneously or may be induced by drugs | 397 | ||
| Warm-reactive autoantibodies cause accelerated clearance of erythrocytes | 398 | ||
| Cold-reactive autoantibodies cause erythrocyte lysis by complement fixation | 398 | ||
| Drug-induced reactions to blood components occur in three different ways | 399 | ||
| Autoantibodies to platelets may cause thrombocytopenia | 399 | ||
| Reactions against neutrophils can occur in several autoimmune diseases | 399e1 | ||
| Type II hypersensitivity reactions in tissues | 400 | ||
| Antibodies against basement membranes produce nephritis in Goodpasture's syndrome | 400 | ||
| Pemphigus is caused by autoantibodies to an intercellular adhesion molecule | 400 | ||
| In myasthenia gravis autoantibodies to acetylcholine receptors cause muscle weakness | 400 | ||
| Autoantibodies and autoimmune disease | 401 | ||
| Further reading | 402 | ||
| Chpater 25: Hypersensitivity (Type III) | 405 | ||
| Immune complex diseases | 405 | ||
| Persistent infection with a weak antibody response can lead to immune complex disease | 406 | ||
| Immune complexes can be formed with inhaled antigens | 406 | ||
| Immune complex disease occurs in autoimmune rheumatic disorders | 406 | ||
| Cryoglobulins precipitate at low temperature | 406 | ||
| Immune complexes and inflammation | 406 | ||
| Complement is an important mediator of immune complex disease | 407 | ||
| Autoantibodies to complement components can modulate complement activity | 408 | ||
| Immune complexes clearance by themononuclear phagocyte system | 408 | ||
| Experimental models of immunecomplex diseases | 408e1 | ||
| Serum sickness can be induced with largeinjections of foreign antigen | 408e1 | ||
| Autoimmunity causes immune complexdisease in the NZB/NZW mouse | 408e1 | ||
| Injection of antigen into the skin ofpre-sensitized animals produces theArthus reaction | 408e1 | ||
| Complement solubilization of immunecomplexes | 409 | ||
| Complement deficiency impairs clearanceof complexes | 410 | ||
| The size of immune complexes affectstheir deposition | 410 | ||
| Immunoglobulin classes affect the rateof immune complex clearance | 411 | ||
| Phagocyte defects allow complexesto persist | 411 | ||
| Carbohydrate on antibodies affectscomplex clearance | 411 | ||
| Immune complex deposition in tissues | 411 | ||
| The most important trigger for immunecomplex deposition is probably an increasein vascular permeability | 411 | ||
| Immune complex deposition is mostlikely where there is high bloodpressure and turbulence | 412 | ||
| Affinity of antigens for specific tissues candirect complexes to particular sites | 412 | ||
| The site of immune complex depositiondepends partly on the size of the complex | 413 | ||
| The class of immunoglobulin in an immunecomplex can influence deposition | 413 | ||
| Diagnosis of immune complex disease | 413 | ||
| Further reading | 416 | ||
| Chpater 26: Hypersensitivity (Type IV) | 419 | ||
| Delayed hypersensitivity | 419 | ||
| There are three variants of type IV hypersensitivity reaction | 420 | ||
| Contact hypersensitivity | 420 | ||
| A contact hypersensitivity reaction has two stages - sensitization and elicitation | 420 | ||
| Dendritic cells and keratinocytes have key roles in the sensitization phase | 420 | ||
| Keratinocytes produce cytokines important to the contact hypersensitivity response | 421 | ||
| Sensitization stimulates a population of memory T cells | 421 | ||
| Elicitation involves recruitment of CD4+ and CD8+ lymphocytes and monocytes | 421 | ||
| Suppression of the inflammatory reaction is mediated by multiple mechanisms | 422 | ||
| Tuberculin-type hypersensitivity | 422 | ||
| The tuberculin skin test reaction involves monocytes and lymphocytes | 423 | ||
| Tuberculin-like DTH reactions are used practically in two ways | 423 | ||
| Granulomatous hypersensitivity | 424 | ||
| Epithelioid cells and giant cells are typical of granulomatous hypersensitivity | 425 | ||
| A granuloma contains epithelioid cells, macrophages, and lymphocytes | 426 | ||
| Cellular reactions in type IV hypersensitivity | 426 | ||
| T cells bearing αβ TCRs are essential | 426 | ||
| IFNγ is required for granuloma formation in humans | 426 | ||
| TNF and lymphotoxin-α are essential for granuloma formation during mycobacterial infections | 427 | ||
| Granulomatous reactions in chronic diseases | 427 | ||
| The immune response in leprosy varies greatly between individuals | 428 | ||
| Granulomatous reactions are necessary to control tuberculosis | 429 | ||
| Granulomas surround the parasite ova in schistosomiasis | 429 | ||
| The cause of sarcoidosis is unknown | 429 | ||
| The cause of Crohn's disease is unknown | 430 | ||
| Further reading | 430 | ||
| Websites | 431 | ||
| Critical thinking: Explanations | 433 | ||
| 1. Specificity andmemory in vaccination | 433 | ||
| 2. Development of the immune system | 433 | ||
| 3. The specificity of antibodies | 433 | ||
| 4. Complement deficiency | 434 | ||
| 5. Somatic hypermutation | 434 | ||
| 6. The role of adhesion moleculesin T cell migration | 434 | ||
| 7. The role of macrophages in toxicshock syndrome | 435 | ||
| Glossary | 445 | ||
| Index | 455 | ||
| Appendix 1: Major Histocompatibility Complex | e3 | ||
| Appendix 2: CD System | e1 | ||
| Appendix 3: The Major Cytokines | e1 | ||
| Appendix 4: Human Chemokines and Their Receptors | e1 |