| 13-May-2008 |
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Contents
Chapter 1: Overview of the Immune Response [PDF] 1-0 Overview: The Protective Mechanisms of Immunity [Full Text] [PDF] -The immune system protects us against infectious organisms -Immune mechanisms are divided into those of innate immunity and those of adaptive immunity -An antigen is operationally defined 1-1 Cells of the Immune System: Differentiation in the Bone Marrow [Full Text] [PDF] -The cells of the immune system originate in the bone marrow -Cytokines produced by bone marrow stromal cells drive the differentiation of immune cells from their common hematopoietic precursor -Reserves of hematopoietic cells are rapidly mobilized from the bone marrow during stress 1-2 Cells of the Immune System: Functional Characteristics [Full Text] [PDF] -Immune cells may differentiate in several stages -Neutrophils, macrophages and dendritic cells are phagocytic cells -Basophils, mast cells and eosinophils release inflammatory and cytotoxic mediators from intracellular stores -Lymphocytes detect antigen by means of variable receptors 1-3 Macrophage and Dendritic Cell Subsets [Full Text] [PDF] -Macrophages and dendritic cells are versatile cells of innate immunity -Macrophages have distinct specializations in different tissues -Dendritic cells can vary widely in form and function 1-4 Clonal Selection of Antigen-Specific Lymphocytes [Full Text] [PDF] -The versatility and selectivity of adaptive immunity are guaranteed by selective processes acting on a highly variable receptor repertoire -Variable receptors for antigen are generated by rearrangement of lymphocyte DNA during ontogeny -Selection by antigen leads to self tolerance and to the specific recognition of almost any foreign organism or particle 1-5 Major Histocompatibility Molecules and the Detection of Infection [Full Text] [PDF] -T lymphocytes recognize fragments of antigen carried to the cell surface by MHC molecules -MHC molecules are surface indicators of the proteins present in the interior compartments of cells -Cell-surface markers of different T cell classes reflect the differential recognition of MHC class I and class II molecules 1-6 The Lymphoid System and Lymphocyte Circulation [Full Text] [PDF] -There are two types of lymphoid tissues -Secondary lymphoid tissue brings antigen together with lymphocytes -Chemokines direct the migration of lymphocytes and determine the specialized microenvironments in which they are activated -Secondary lymphoid tissue is sustained and can be induced by signals from immune cells 1-7 Architecture of Secondary Lymphoid Tissues [Full Text] [PDF] -Dendritic cells and follicular dendritic cells collect antigen for recognition by T cells and B cells -The spleen is a critical filter for antigen in blood -Antigen enters mucosal lymphoid tissues through specialized cells 1-8 The Course of an Immune Response [Full Text] [PDF] -Innate immunity and specialized classes of lymphocytes provide front-line defense against invading microorganisms -T lymphocytes activated by dendritic cells differentiate and migrate to B cell follicles and sites of infection -Activated B lymphocytes differentiate into plasma cells and secrete antibody -At the end of an immune response, the vast majority of the antigen-specific cells die and surviving cells become resting memory cells Chapter 2: Signaling and Adhesive Molecules of the Immune System [PDF] Back to top 2-0 Overview: Immune Cell Surface and Signaling Molecules [Full Text] [PDF] -Immune cell migration and communication are controlled by specialized cell surface and signaling molecules -Adhesion molecules have important roles in promoting cell migration and cell–cell interaction -Large families of signaling molecules control nearly all aspects of immune system development and function 2-1 The Immunoglobulin Superfamily: Structural Features [Full Text] [PDF] -The Ig-like domain is an important element of structure for many proteins of the immune system -The Ig superfamily contains a diverse group of molecular recognition elements of the immune system 2-2 Signaling by Immunoglobulin Superfamily Receptors [Full Text] [PDF] -Ig superfamily members mediate antigen recognition and many functional effects of antibodies -Activating Ig superfamily receptors signal via intracellular tyrosine kinases -Immune cells express Ig superfamily inhibitory receptors that restrain immune responses 2-3 Adhesion Molecules of the Immunoglobulin Superfamily [Full Text] [PDF] -Ig superfamily members have important roles in cell–cell adhesion of immune cells -The CD2 subfamily participates in the adhesion and activation of immune system cells -Several Ig superfamily members serve as cell-bound ligands for integrins 2-4 Integrins in Immune Function [Full Text] [PDF] -Integrins mediate cell–cell and cell–matrix contacts -The adhesive properties of integrins are modulated by other signals coming into the cell -Integrin engagement regulates cell shape and also sends signals that support cell activation and survival -Integrins are differentially expressed to support specializations in immune cell function 2-5 C-Type Lectins and Carbohydrate Recognition [Full Text] [PDF] -Carbohydrate-recognizing molecules have diverse roles in the immune system 2-6 Cytokines and Cytokine Receptors [Full Text] [PDF] -Polypeptide mediators are a principal means of regulating immune responses -Cytokines act on many cell types in overlapping and coordinated ways -Cytokines can be grouped into structurally related families that act via homologous receptors 2-7 Cytokine Receptors that Signal via the Jak–STAT Pathway [Full Text] [PDF] -The family of type I cytokines is recognized by a conserved family of receptors -Interferons and IL-10 are related to type I cytokines and are also recognized by receptors signaling via the Jak–STAT pathway -Type I and type II cytokine receptors signal principally via the Jak–STAT signaling pathway -STATs are responsible for much of the specificity of cytokine receptor signaling -Jak–STAT signaling is negatively regulated by SOCS proteins 2-8 Shared Subunits in Subfamilies of Type I Cytokine Receptors [Full Text] [PDF] -Many cytokines and hematopoietins are recognized by structurally related receptors characterized by shared receptor subunits 2-9 The TNF Superfamily of Cell Regulators [Full Text] [PDF] -Members of the TNF superfamily regulate a variety of immune and developmental events -TNF-receptor superfamily members signal on oligomerization 2-10 NF-κB and Inflammatory Cytokine Action [Full Text] [PDF] -NF-κB activates inflammatory gene expression -NF-κB is regulated by inhibitory subunits -Some NF-κB heterodimers are self-inactivated 2-11 Molecular Control of Apoptosis [Full Text] [PDF] -Apoptosis has many important roles in immune function -Apoptosis is triggered by a proteolytic cascade involving caspases 2-12 Regulation of Apoptosis by Bcl-2 Family Members [Full Text] [PDF] -Increased mitochondrial outer-membrane permeability is the major trigger of the intrinsic apoptosis pathway 2-13 Chemokines and Chemokine Receptors [Full Text] [PDF] -Chemokines direct the migration of immune-system cells 2-14 Chemokines, Integrins and Selectins and Immune-Cell Homing [Full Text] [PDF] -Chemokines collaborate with other specialized molecules in directing the homing of lymphocytes and leukocytes to tissues -Selectins are C-type lectins that bind to carbohydrate structures usually on cell surfaces -Circulating lymphocytes express a regulatable receptor that directs their exit from lymphoid tissues Chapter 3: Innate Immunity [PDF] Back to top 3-0 Overview: Evolution and Function of Innate Immunity [Full Text] [PDF] -Multicellular organisms have conserved mechanisms of innate immune recognition -Innate immunity remains effective despite rapid evolution of microbes and viruses -Innate immune recognition mechanisms predate adaptive immunity and instruct it 3-1 Barriers to Infection at the Epithelium [Full Text] [PDF] -The epithelial cell layer provides the first barrier to most infections -Antimicrobial peptides are a widespread defense mechanism 3-2 Innate Recognition by Soluble Collectins and Ficolins [Full Text] [PDF] -Collectins and ficolins activate innate immune protective mechanisms at mucosal surfaces and in the bloodstream -Collectins and ficolins have a common architecture but distinct recognition domains -Two lung surfactants are mucosal collectins -Mannose-binding lectin provides innate immune protection against some bacterial infections 3-3 Overview of the Complement System [Full Text] [PDF] -The complement cascade links soluble factor recognition of microbes to mechanisms for their destruction -Inherited deficiencies in complement components lead to severe bacterial infections or to susceptibility to immune complex disease 3-4 Activation of the Complement Cascade [Full Text] [PDF] -Initiation of complement activation by the lectin and classical pathways has substantially common features -Complement activation is largely confined to cell surfaces -The alternative pathway of complement activation provides an amplification loop that is actived at cell surfaces 3-5 Complement Effector Actions and Receptors [Full Text] [PDF] -The complement cascade promotes inflammation, phagocytosis, membrane attack and antibody production -Complement receptors mediate many of the actions of complement 3-6 Regulation of Complement and Evasion by Microbes [Full Text] [PDF] -Complement activation is regulated by soluble factors and membrane-bound inhibitors -Many bacteria and viruses have evolved mechanisms for evading complement action 3-7 Recognition of Microbes by Phagocytes [Full Text] [PDF] -Phagocytosis is a major mechanism for the destruction of microbes -Phagocytes have receptors for recognizing and internalizing microbes 3-8 Mechanisms of Phagocytosis [Full Text] [PDF] -Phagocytosis proceeds by three distinct pathways -Phagocytosis of apoptotic cells is usually antiinflammatory -Inhibitory receptors can regulate phagocytosis 3-9 Destructive Mechanisms of Phagocytes [Full Text] [PDF] -Phagocytes have many mechanisms for killing internalized microbes -Reactive oxygen and nitrogen species are used to kill internalized microorganisms 3-10 The Toll-Like Receptor Family of Innate Immune Receptors [Full Text] [PDF] -Recognition of conserved microbial components by Toll-like receptors leads to inflammation and activation of sentinel immune cells -Accessory molecules aid Toll-like receptor recognition of some ligands -Mammalian Toll-like receptors recognize their ligands on the cell surface or intracellularly 3-11 Toll-Like Receptor Signaling to Cytokine Production [Full Text] [PDF] -Mammalian Toll-like receptors activate the production of proinflammatory cytokines and interferon -Mammalian Toll-like receptors signal via two major pathways 3-12 Intracellular Sensors of Bacterial Peptidoglycan Components [Full Text] [PDF] -NOD1, NOD2 and cryopyrin are intracellular sensors of peptidoglycan substructures -The NOD domain mediates ligand-induced signal generation 3-13 Inflammation: Initiation of an Inflammatory Response [Full Text] [PDF] -Innate immune recognition triggers an inflammatory response that focuses the immune system on the site of infection -Cytokines and lipid mediators are important inducers of inflammation 3-14 Inflammation: Recruitment of Immune Cells [Full Text] [PDF] -Leukocyte extravasation is a multi-step process -Chemokines and small-molecule chemoattractants direct phagocytes to the site of infection 3-15 Inflammation: Regulation and Systemic Effects [Full Text] [PDF] -Inflammatory responses can be divided into two phases: the acute phase and the chronic phase -Viruses have evolved devices for modulating inflammatory responses -Proinflammatory cytokines act systemically to promote immunity -Inflammation is normally downregulated by a series of feedback inhibitory mechanisms 3-16 Innate Defense Against Viruses: Interferon [Full Text] [PDF] -Interferon provides a critical defense against virus infection -Interferons are produced by innate immune cells and by infected cells 3-17 Inhibition of Virus Replication by Interferon [Full Text] [PDF] -Interferon primes cells to allow them to block virus replication -Viruses can evade the effects of interferon -Interferons are used to treat some diseases 3-18 Innate Defense Against Viruses: Induction of Apoptosis [Full Text] [PDF] -Viral replication triggers apoptotic mechanisms in the infected cell -Death domain receptors can induce death of virus-infected cells -Viruses have evolved many mechanisms to block apoptosis 3-19 Intracellular Defenses Targeting Viral Nucleic Acid [Full Text] [PDF] -Antiviral innate immune defenses include mechanisms directed at viral nucleic acid -APOBEC3G is a cytidine deaminase that mutates retroviral genomes -RNA interference is an antiviral defense mechanism in plants and probably in animals Chapter 4: Adaptive Immunity and the Detection of Infection by T Lymphocytes [PDF] Back to top 4-0 Overview: The Role of T Cells in the Adaptive Immune Response [Full Text] [PDF] -Adaptive immunity is distinct from innate immunity in three main ways -T lymphocytes kill cells infected with viruses and activate B cells and phagocytes -The major classes of T lymphocytes are defined by the class of MHC molecule they recognize -Dendritic cells provide a bridge between innate and adaptive immunity 4-1 Dendritic Cells in the Induction of Adaptive Immunity [Full Text] [PDF] -The function of dendritic cells is to present antigen to naïve T cells -Immature dendritic cells comprehensively sample their tissue environment -Recognition of infection licenses dendritic cells to activate the effector differentiation of naïve T cells 4-2 The Structure and Function of MHC Molecules [Full Text] [PDF] -The major histocompatibility molecules monitor the internal compartments of cells -The two classes of MHC molecules have a common architecture but distinct functions in immunity 4-3 The MHC and Polymorphism of MHC Molecules [Full Text] [PDF] -The major histocompatibility complex contains genes encoding many molecules with different functions in immunity -The classical MHC molecules are highly polymorphic 4-4 Non-Classical MHC Class I Molecules [Full Text] [PDF] -The non-classical MHC class I molecules are a diverse group of structural variants on the classical MHC class I molecules -The peptide-binding grooves of non-classical MHC class I molecules are adapted to different specialized functions 4-5 Peptide Binding by MHC Molecules [Full Text] [PDF] -Peptides bind in distinct ways to MHC class I and MHC class II molecules -Variable pockets in the peptide-binding groove anchor specific side chains of the peptide in the groove 4-6 Antigen Presentation by Classical MHC Class I Molecules [Full Text] [PDF] -Classical MHC class I molecules display peptides generated in the cytosol -Enzyme complexes in the cytosol process proteins into peptides -A machinery encoded mainly in the MHC exists in the endoplasmic reticulum to load peptides onto MHC class I molecules 4-7 Antigen Presentation by MHC Class II Molecules [Full Text] [PDF] -MHC class II molecules display peptides derived from pathogens internalized by specialized immune cells -Antigenic peptides loaded by MHC class II molecules are salvaged from endosomal pathways -Peptide loading onto MHC class II molecules is chaperoned 4-8 Regulation of Antigen Presentation [Full Text] [PDF] -MHC molecule expression and loading is upregulated by infection -MHC class I molecule expression and loading are upregulated by interferons -Immune cytokines modulate the presentation of peptides by MHC class II molecules 4-9 Specialized Features of Antigen Presentation by Dendritic Cells [Full Text] [PDF] -The endosomal pathway is highly regulated in dendritic cells -Dendritic cells present peptides derived from exogenous proteins on MHC class I molecules to activate naïve CD8 T cells Chapter 5: Activation and Effector Actions of T Cells [PDF] Back to top 5-0 Overview: T Cell-Mediated Immune Responses [Full Text] [PDF] -T lymphocytes are central to adaptive immune responses -T cells are activated by strong and sustained binding to their antigen receptors maintained by adhesive interactions -Most T cell responses depend upon the recruitment or activation of other effector cells -T cell actions and numbers are controlled by cytokines 5-1 Antigen Recognition by T Cells: Structure of the Receptor [Full Text] [PDF] -Antigen recognition is mediated by a heterodimeric molecule linked to signaling molecules -There are two kinds of variable receptors for antigen on T cells -The variability of T cell receptors is generated by DNA rearrangements during T cell ontogeny 5-2 Antigen Recognition by T Cells: TCR Specificity and Coreceptors [Full Text] [PDF] -The mature T cell receptor repertoire is determined by the germ-line pool of gene segments and thymic selection -Variable binding orientation and induced fit contribute to the versatility of peptide–MHC binding by αβ TCR -γδ TCRs bind invariant ligands -T cells bind to MHC molecules and signal with the help of coreceptors 5-3 Signaling from the T Cell Receptor [Full Text] [PDF] -T cells are sensitive to very small amounts of foreign peptide -TCR signaling is initiated by phosphorylation of receptor ITAM sequences -TCR signaling activates cytoskeletal remodeling and cytokine production 5-4 Regulation of TCR Signaling [Full Text] [PDF] -TCR signaling is dynamically regulated to support T cell activation -The contact between T cells and antigen-presenting cells can result in organized arrays of signaling molecules 5-5 T Cell Signaling to the Nucleus and the Role of CD28 [Full Text] [PDF] -TCR signaling leads to activation of proliferation and clonal expansion through induction of cytokine gene transcription -IL-2 gene transcription requires the activation of four transcriptional regulators by the TCR -The costimulatory receptor CD28 amplifies the signal from the TCR 5-6 Activation of Naïve T Cells in Secondary Lymphoid Tissue [Full Text] [PDF] -Activation of naïve T cells occurs when recirculating T cells recognize antigen at the surface of dendritic cells in secondary lymphoid tissues -Naïve T cells are directed into secondary lymphoid tissues by a characteristic combination of homing molecules -T cells that bind strongly to self-peptide–MHC complexes may be inactivated -T cell activation is initiated by lymph-node-resident dendritic cells and stabilized by recruited dendritic cells 5-7 Clonal Expansion of Naïve T Cells in Secondary Lymphoid Tissue [Full Text] [PDF] -Activation of T cells leads to proliferation accompanied by changes in their surface properties -Amplification of T cell numbers on activation is rapid and substantial -The engagement of the TCR and CD28 by peptide–MHC and B7 on the dendritic cell activates a positive feedback loop 5-8 Costimulatory Signals in T Cell Proliferation and Survival [Full Text] [PDF] -Induced modulators of T cell signaling regulate T cell survival and proliferation -Activation of CD8 T cell immunity sometimes requires help from CD4 T cells 5-9 Effector T Cell Differentiation [Full Text] [PDF] -CD4 T cells differentiate into subsets characterized by distinct patterns of cytokine expression -CD8 T cells most commonly differentiate into TC1 effector cells -T cell differentiation is driven by dendritic cells and cytokines -Most effector T cells disperse to peripheral tissues and accumulate at sites of infection 5-10 The Polarization of TH1 and TH2 Cells [Full Text] [PDF] -Polarization of T cell subsets is accompanied by changes in key transcriptional regulators -The differentiation of TH1 cells is mediated by induction of T-bet -The differentiation of TH2 cells is mediated by induction of GATA-3 5-11 The Functions of TH1 Cells [Full Text] [PDF] -TH1 cells coordinate the destruction and control of pathogens by cytolytic cells and activated phagocytes -The effects of TH1 cells are mediated by cytokines -TH1 cytokines induce B cells to make the types of antibodies that promote the destruction of pathogens by phagocytic cells -TH1 cells coordinate a system for antigen elimination but can cause immunopathology 5-12 The Functions of TH2 Cells [Full Text] [PDF] -TH2 cells coordinate barrier immunity against invading pathogens -TH2 cytokines induce alternatively activated macrophages and activate eosinophils, basophils and mast cells -TH2 cytokines induce B cells to produce antibodies involved in barrier immunity -Uncontrolled TH2 responses can cause immunopathology 5-13 The Functions of TFH Cells, TH17 Cells and Induced TREG Cells [Full Text] [PDF] -TFH cells provide help for germinal center B cells -TH17 cells recruit neutrophils to inflammatory sites -Induced TREG cells suppress activation of effector TH cells 5-14 Effector Functions of CD8 T Cells [Full Text] [PDF] -CD8 T cells are important for the clearance of viruses and bacteria that proliferate in the cytosol -There are two main mechanisms of CD8 T cell cytotoxicity -CD8 T cells are protected from their own cytotoxic products 5-15 T Cell Homeostasis and the Termination of Immune Responses [Full Text] [PDF] -T cell numbers are subject to dynamic control -Numbers of naïve T cells are maintained by cytokines and stimulation through the TCR -Effector T cells are programmed to undergo apoptosis -Inhibitory signals help to limit T cell responses in the periphery 5-16 T Cell Memory [Full Text] [PDF] -Two types of memory T cells are generated during immune responses -Memory T cells are maintained by cytokines and stimulation through the TCR, and possibly by antigen -T cell memory is particularly important for immunity to latent viruses Updates – 2007-2008 Back to top Tracking immune responses in vivo U5-1 Detecting and Analyzing T Cell Responses [Full Text] [PDF] -T cell responses can be tracked using transgenic mice and MHC tetramers -Mice carrying introduced genes are an important source of large numbers of T cells with defined specificity -MHC tetramers are important for tracking antigen-specific T cells U5-2 Real-Time Imaging of T Cell Signaling Events [Full Text] [PDF] -Imaging techniques allow lymphocyte interactions to be studied in whole cells and tissues -Molecular events in T cell activation can be followed in intact single cells -The molecular events at the immunological synapse can be inferred from model systems U5-3 Imaging Lymphocytes In Situ [Full Text] [PDF] -Localization of lymphocytes in organs can be determined by antibody staining -Lymphocyte interactions in vivo can be tracked by using fluorescent dyes and real-time two-photon microscopy Chapter 6: B Cells and Humoral Immunity [PDF] Back to top 6-0 B Cells and the Importance of Antibodies for Immune Defense [Full Text] [PDF] -Humoral immunity is complementary to cell-mediated immunity -Antibodies produced by distinct types of B cells are important in early protection from infection and in preventing reinfection 6-1 Structure of Antibodies [Full Text] [PDF] -Antibodies contain an antigen-binding region and a region that connects to effector mechanisms 6-2 Structural Properties of Antibodies [Full Text] [PDF] -There are five main kinds of antibodies with distinct functional properties -Specialized Fc receptors transport antibodies to their sites of action 6-3 Effector Functions of Antibodies [Full Text] [PDF] -Antibodies can act by neutralization and complement activation -Fc receptors mediate many of the effector functions of antibodies -FcγR effector function is regulated by the balance of activating and inhibitory receptor action 6-4 Monoclonal Antibodies [Full Text] [PDF] -Monoclonal antibodies can be produced to capture a single antibody specificity -Monoclonal antibodies have permitted the identification of most specialized surface molecules of lymphocytes -Human monoclonal antibodies can be made for therapeutic uses 6-5 Antibody-Based Methods: Radioimmunoassay and Hemagglutination [Full Text] [PDF] -Antibodies have many uses in diagnostic techniques and research -Immune complexes of antibodies and complex antigens can generate large insoluble aggregates -Use of antibodies in the analysis and measurement of biological molecules 6-6 Antibody-Based Methods: ELISA, Immunoblotting and FACS [Full Text] [PDF] -Antibodies bound to a solid substrate can be detected by the production of colored products -Antibodies can be used to characterize the properties of subsets of cells 6-7 Antigen Receptors of B Lymphocytes [Full Text] [PDF] -Membrane forms of immunoglobulin comprise the ligand-binding part of the B cell antigen receptor -The BCR binds native proteins, glycoproteins and polysaccharides -The type of Ig heavy chain produced is dependent on the differentiated state of the B cell 6-8 B Cell Antigen Receptor Signaling and B Cell Coreceptors [Full Text] [PDF] -The BCR signals via ITAM sequences in the Igα and Igβ subunits -BCR signaling is modulated by positive and negative coreceptors 6-9 Early and T Cell-Independent Antibody Responses by B Cells [Full Text] [PDF] -Protective antibodies are preexisting and induced -TI antibody responses are induced by two different mechanisms and are critical to the responses to some pathogens 6-10 Initiation of T Cell-Dependent Antibody Responses [Full Text] [PDF] -Antigen contact induces follicular B cells to migrate to the boundary between the B cell follicles and the T cell zone -Antigen bound to the BCR is taken up efficiently, processed and presented to helper T cells -Helper T cells induce rapid antibody production and the germinal center reaction 6-11 Hypermutation and Isotype Switching in the Germinal Center [Full Text] [PDF] -The germinal center is a transient structure that supports the production of high-affinity antibodies -Activation-induced cytidine deaminase mediates class switch recombination and hypermutation of Ig genes 6-12 Selection and Differentiation of B Cells in the Germinal Center [Full Text] [PDF] -Centrocytes are selected for the ability of their antigen receptors to bind effectively to antigen -Centrocytes give rise to long-lived plasma cells and memory B cells -Memory B cells can be rapidly activated to produce higher levels of antibodies Chapter 7: Development of Lymphocytes and Selection of the Receptor Repertoire [PDF] Back to top 7-0 Overview of Lymphocyte Development [Full Text] [PDF] -Lymphocyte development generates cells of many different specificities -Developing lymphocytes make multiple lineage choices -Lymphocytes undergo positive and negative selection during their development 7-1 Antigen Receptor Gene Structure and V(D)J Recombination [Full Text] [PDF] -Antigen receptor loci have multiple gene segments that are rearranged to generate functional genes -Antigen receptor genes are recombined by a site-specific recombinase that generates antigen receptors of great diversity 7-2 V(D)J Recombination: Mechanism of Recombination [Full Text] [PDF] -RAG-1 and RAG-2 proteins are lymphocyte-specific components of the V(D)J recombinase -Non-homologous end joining recombination components also participate in V(D)J recombination -Several mechanisms contribute to the generation of junctional diversity 7-3 V(D)J Recombination: Control of which Segments Recombine [Full Text] [PDF] -V(D)J recombination is regulated by modifications to chromatin structure affecting DNA accessibility -Often, only one allele of an Ig or TCR locus recombines productively 7-4 Phylogenetic Diversity in Antigen Receptor Genes [Full Text] [PDF] -The key elements of the adaptive immune system are found in all jawed vertebrates -Sharks have a tandem array of V/D/J/C IgH cassettes -Chickens and rabbits make extensive use of gene conversion to generate antibody diversity 7-5 B Cell Development in the Bone Marrow [Full Text] [PDF] -Commitment to the B cell lineage involves expression of transcriptional regulators and the RAG-1 and RAG-2 proteins -B cell developmental stages are defined primarily by Ig gene rearrangement and Ig chain expression -Expression of Ig heavy chain is responsible for driving B cell maturation in the bone marrow -Self-reactive immature B cells in the bone marrow arrest maturation and undergo receptor editing 7-6 Maturation of B Cells in the Periphery [Full Text] [PDF] -Transitional B cells are deleted or anergized by antigen contact in the periphery -Transitional B cells are positively selected into different types of mature B cells -BAFF is an important survival factor for transitional and mature B cells 7-7 Organization of the Thymus and Early T Cell Development [Full Text] [PDF] -The thymus provides a specialized environment for T cell development -Notch is important for commitment to the T cell lineage -Stages in T cell development are marked by expression of coreceptors -Lineage choice between αβ T cells and γδ T cells depends on functional TCR rearrangements -Pre-TCR signaling induces commitment to the αβ TCR lineage 7-8 Positive Selection of T Cells in the Thymus [Full Text] [PDF] -αβ TCR specificity determines cell fate and lineage choice between helper and cytotoxic T cells 7-9 Proposed Mechanisms of Positive Selection [Full Text] [PDF] -Double-positive thymocytes may mature by a stochastic/selection or by an instructive mechanism 7-10 Negative Selection [Full Text] [PDF] -Thymocytes encountering high-affinity peptide–MHC ligands in the thymus die rapidly -Special mechanisms exist to promote self-peptide presentation in the thymus -Thymocytes discriminate between positive selection and negative selection based in part on TCR off-rate -Some thymocytes encountering high-affinity ligands survive and become regulatory T cells 7-11 Diseases Related to Lymphocyte Development [Full Text] [PDF] -Defects or aberrations related to lymphocyte development can lead to immunodeficiency or cancers -Genetic defects in lymphocyte development lead to immunodeficiency -DNA breaks introduced by V(D)J recombination can lead to lymphomas and leukemias Chapter 8: Specialized Lymphocytes in Early Responses and Homeostasis [PDF] Back to top 8-0 Overview: Specialized Lymphocyte Populations [Full Text] [PDF] -Specialized types of lymphocytes can be grouped functionally by their capacity to mediate rapid immune responses -Activation of specialized lymphocytes can be mediated by self or foreign ligands 8-1 Natural Killer Cells and their Role in Immunity [Full Text] [PDF] -Natural killer cells provide early protection from intracellular pathogens, particularly viruses -NK cells are recruited and activated by cytokines released by other cells -NK cells express both activating and inhibitory receptors -NK cells express an array of polygenic and polymorphic receptors specific for host MHC class I 8-2 Natural Killer Cell Signaling Pathways [Full Text] [PDF] -Activating NK cell receptors recognize a variety of ligands -Activating receptors share conserved signaling pathways -Additional inhibitory signals regulate NK cell activation 8-3 NKT Cells [Full Text] [PDF] -NKT cells are specialized for detection of glycolipid antigens -NKT cells are selected in the thymus and populate the liver, spleen and bone marrow -NKT cells release cytokines rapidly after activation and can mediate defense against bacteria not detected by Toll-like receptors 8-4 γδ T Cells [Full Text] [PDF] -γδ T cells express antigen receptors of limited functional diversity -γδ T cells develop early in ontogeny and expand as oligoclonal populations in response to diverse environmental antigens -γδ T cells have immediate effector function -γδ T cells may have a role in tissue repair later in the immune response 8-5 Intraepithelial Lymphocytes and Other Specialized T Cells [Full Text] [PDF] -Intraepithelial lymphocytes populate the epithelia of bowel and lung -Intraepithelial lymphocytes are cytotoxic -Additional specialized lymphocyte populations exist that recognize non-classical MHC class I molecules that may present microbial components 8-6 B1 Cells [Full Text] [PDF] -B1 cells produce natural antibody, which is present before infection, and T-independent antibody that protects body cavities -Natural antibody is synthesized by B1 cells from a preprogrammed repertoire of immunoglobulin genes -B1 cells also participate in first-line IgM and IgA responses to bacteria in the peritoneal and pleural cavities -B1 cells require antigen recognition for their development and are restrained by the inhibitory receptor CD5 8-7 Marginal Zone B Cells [Full Text] [PDF] -Blood is filtered in the spleen via the specialized cells of the marginal zone -Marginal zone B cells make antibody responses to bloodborne infectious agents Chapter 9: The Immune Response to Bacterial Infection [PDF] Back to top 9-0 Overview: Bacterial Pathogens and Host Defenses [Full Text] [PDF] -Commensal bacteria colonize microenvironmental niches and contribute to a healthy epithelial interface -Disrupting the commensal bacterial flora creates an opportunity for pathogenic bacteria -Pathogenic bacteria exploit epithelial dysfunction and subvert innate immunity -Control of pathogenic organisms requires both innate and adaptive immune responses 9-1 Epithelial Barriers and Defenses Against Infection [Full Text] [PDF] -Epithelia present both a physical and an antimicrobial barrier -Specialized cell types in epithelia initiate and execute adaptive immune responses 9-2 Evasion of Epithelial Defenses by Pathogenic Bacteria [Full Text] [PDF] -Pathogenic bacteria have evolved to traverse epithelial barriers -Pathogenic bacteria evade innate defense mechanisms -Adaptive immunity is required for protection against pathogenic bacteria 9-3 Sepsis Syndrome: Bacterial Endotoxin [Full Text] [PDF] -Sepsis syndrome is a systemic response to invasive pathogens -Lipopolysaccharide recognition occurs via the innate immune system -Sepsis results from the activation of lipopolysaccharide-responsive cells in the bloodstream -Inflammation leads to widespread endothelial cell activation and organ dysfunction -Animal models have helped clarify mechanisms of sepsis 9-4 Sepsis Syndrome: Bacterial Superantigens [Full Text] [PDF] -Bacterial pyrogenic exotoxins can cause sepsis syndrome -Bacterial pyrogenic exotoxins are superantigens and activate T cells expressing unique Vβ T cell receptors -Mouse minor lymphocyte stimulating genes are endogenous retroviral superantigens derived from mouse mammary tumor viruses -Mice are susceptible to shock induced by superantigens binding to closely similar Vβ chains 9-5 The Immune Response to Streptococcus pneumoniae [Full Text] [PDF] -Streptococcus pneumoniae is a common cause of bacterial disease with significant mortality -Pneumococci disseminate widely in susceptible hosts -Control of pneumococci requires anti-capsular antibody and phagocytes 9-6 Listeria monocytogenes [Full Text] [PDF] -Listeria monocytogenes can be lethal to individuals with lowered cell-mediated immunity -Listeria is a facultative intracellular organism -Host immunity requires a type 1 response with TH1 cells and cytotoxic T cells -The importance of different components of the immune response to intracellular pathogens can be evaluated in mice infected with Listeria 9-7 Mycobacterium tuberculosis [Full Text] [PDF] -Tuberculosis is a major world health problem -Mycobacterium tuberculosis establishes chronic infection -Control of tuberculosis requires TH1-mediated immunity, and disease occurs when immunity is impaired -Tuberculosis antigens stimulate γδ T cells and T cells recognising CD1 -Inherited deficiencies in TH1 immunity predispose to mycobacteria Chapter 10: The Immune Response to Viral Infection [PDF] Back to top 10-0 Overview: Viral Infectious Strategies [Full Text] [PDF] -Viruses are ubiquitous and highly diverse -Tissue-specific receptors underlie viral tropism -Viruses evade immune responses by diverse mechanisms 10-1 Overview: Innate Strategies Against Viruses [Full Text] [PDF] -RNA and DNA sensors activate cells to achieve an antiviral state and to recruit host immune cells -Plasmacytoid dendritic cells are specialized producers of IFN-α -NK cells contribute to early antiviral immunity 10-2 Overview: Adaptive Immune Strategies Against Viruses [Full Text] [PDF] -Viral infections can activate massive oligoclonal expansion of CD8 T cells -Antibodies are critical for the control of many viruses 10-3 Subversion of Immune Mechanisms by Viruses [Full Text] [PDF] -Pathogenic viruses have captured genes that target cellular apoptosis, interferon and innate inflammation, and the display of peptide–MHC class I complexes 10-4 Origin and Structure of Human Immunodeficiency Virus [Full Text] [PDF] -AIDS originated as a zoonotic disease introduced into humans from primates -HIV is a retrovirus in the lentivirus subfamily 10-5 Tropism of Human Immunodeficiency Virus [Full Text] [PDF] -HIV crosses mucosal barriers, establishes early viremia, and targets CD4 T cells -Activated CD4 T cells drive viral replication while HIV subverts immune detection 10-6 AIDS Progression and Immune Control of HIV [Full Text] [PDF] -Progression to AIDS is determined by the viral set-point -Control of HIV is mediated by CD4 T cell-dependent cytotoxic CD8 T cells 10-7 Influenza Virus: Antigenic Shift and Drift [Full Text] [PDF] -Influenza viruses cause recurrent epidemics and occasional pandemics -Influenza A viruses are avian viruses that adapt to humans -Antigenic drift and shift in HA and NA underlie influenza A epidemics and pandemics 10-8 Influenza Virus: Innate and Adaptive Immunity [Full Text] [PDF] -Innate immunity to influenza depends on type 1 interferons -Influenza virus infection is cleared by cytotoxic CD8 T cells -Viral protection is mediated by neutralizing antibody 10-9 Lymphocytic Choriomeningitis Virus (LCMV) [Full Text] [PDF] -Lymphocytic choriomeningitis virus (LCMV) is extensively used in mouse models of immunity to viruses -LCMV is a noncytopathic virus that establishes persistent infection in mice -Acute infection, immune exhaustion and immune tolerance can be studied using LCMV in inbred mice Updates – 2007-2008 Back to top Epstein–Barr virus U10-1 Epstein–Barr Virus (EBV) [Full Text] [PDF] -EBV is a herpesvirus that causes lifelong infection of B cells -EBV induces B cell differentiation and establishes latency in memory B cells -Control of EBV is lost in immunodeficiency Chapter 11: The Immune Response to Fungal and Parasitic Infection [PDF] Back to top 11-0 Overview: The Scope of Fungal and Parasitic Infections [Full Text] [PDF] -Pathogenic fungi can be commensals, ubiquitous environmental molds, or geographically endemic species -Phagocytes and dendritic cells express receptors for fungal constituents -Host defense against fungi relies on epithelial barriers and phagocyte activation facilitated by TH1 and TH17 cells -Protozoa are a diverse group of systemic and intestinal pathogens -Protozoan pathogens induce disease-protective, but not sterile, immunity -Helminths constitute a diverse group of systemic and intestinal pathogens -Helminths cause chronic infections and incomplete immunity 11-1 Candida albicans [Full Text] [PDF] -Candida albicans is a commensal and opportunistic pathogen of humans -Candida albicans virulence is linked to the ability to grow vegetatively in morphologically distinct forms -Phagocyte oxidative killing is important in Candida host defense -Mouse models exist for both systemic and mucosal Candida infection 11-2 Pneumocystis [Full Text] [PDF] -Pneumocystis is an important cause of pneumonia in immunocompromised hosts -Pneumocystis comprises diverse host-specific strains of unusual fungi -Pneumocystis infection of mice comprises an experimental model for studying the immune response 11-3 Leishmania major [Full Text] [PDF] -Leishmania major is a protozoan pathogen transmitted by sandflies -Leishmania parasites invade macrophages without inducing inflammatory cytokines and reside in a phagolysosomal compartment -Immunity to Leishmania requires TH1 cells, and persistence is maintained by regulatory T cells -Some strains of mice develop an aberrant and fatal TH2 response to L. major 11-4 Nippostrongylus brasiliensis [Full Text] [PDF] -Nippostrongylus brasiliensis is a roundworm that matures during migration through the lung to the small intestines -Nippostrongylus induces a protective TH2-associated immune response -Recruitment of immune cells to tissue and activation of worm expulsion reflect compartmentalized signals via the IL-4Rα chain and STAT6 11-5 Schistosomiasis [Full Text] [PDF] -Schistosomes are a widespread human trematode infection of the abdominal vasculature -Host immune responses are modulated over the course of infection and culminate in a highly polarized type 2 granulomatous response to eggs -Type 2 granulomatous responses benefit the host and the parasite until fibrosis compromises the function of critical organs of the body -Mouse models for S. mansoni infection and for type 2 granulomatous responses reveal distinct roles for TH2 cytokines Updates – 2007-2008 Back to top Malaria U11-1 Malaria [Full Text] [PDF] -Malaria is an infection of red cells that is transmitted by mosquitoes -Plasmodium falciparum causes severe malaria through adherence of infected cells to the microvasculature and by induction of cytokines -Slow development of malaria immunity reflects antigenic variation Chapter 12: Tolerance and Autoimmunity [PDF] Back to top 12-0 Overview: Tolerance and Autoimmunity [Full Text] [PDF] -Immune tolerance is established and maintained by both central and peripheral mechanisms -Failures in self tolerance lead to autoimmune disease -Some autoimmune diseases are treated by blocking molecules of the immune system 12-1 Central Tolerance [Full Text] [PDF] -Highly self-reactive B cells and T cells are eliminated during their development -The thymus has specialized mechanisms for expressing self antigens 12-2 Peripheral Tolerance Mechanisms [Full Text] [PDF] -Central tolerance is insufficient to generate fully effective immune tolerance -B cells are anergized by antigen contact in the absence of T cell help -Dendritic cells constitutively present self antigen without costimulation or cytokines and induce abortive activation of self-reactive T cells 12-3 Regulatory T Cells [Full Text] [PDF] -Regulatory T cells are a distinct type of effector T cells that suppress T cell immune responses -Regulatory T cells are essential for avoiding pathological immune responses 12-4 Autoimmune Diseases: General Principles [Full Text] [PDF] -Many diseases result from immune attack on uninfected tissues -Autoimmunity is typically the result of genetic susceptibility and an environmental trigger -Molecular mimicry and epitope spreading may be important for autoimmunity 12-5 Organ-Specific Autoimmunity: Antibody-Mediated Diseases [Full Text] [PDF] -Antibodies against self components can cause disease -Autoantibodies can recognize cells or extracellular matrix and induce pathology -Autoantibodies can cause disease by affecting the function of the target autoantigen 12-6 Organ-Specific Autoimmunity: Cell-Mediated Diseases [Full Text] [PDF] -Cell-mediated autoimmune diseases attack a variety of organs -T cell costimulation is likely to be important for progression of cell-mediated autoimmune diseases 12-7 Organ-Specific Autoimmunity: Animal Models [Full Text] [PDF] -Animal models of cell-mediated autoimmune disease have been informative about the mechanisms of autoimmunity -NOD mice spontaneously develop type 1 diabetes -Experimental allergic encephalitis has many similarities to multiple sclerosis -Molecular mimicry is responsible for a virus-induced autoimmune eye disease 12-8 Systemic Autoimmunity: Lupus [Full Text] [PDF] -Systemic autoimmune diseases include SLE and rheumatoid arthritis -SLE is characterized by the production of high levels of antibodies against nuclear components -Mouse models provide insight into the genetic susceptibility of SLE 12-9 Systemic Autoimmunity: Rheumatoid Arthritis [Full Text] [PDF] -Rheumatoid arthritis is a common systemic autoimmune disease Chapter 13: Allergy and Hypersensitivity [PDF] Back to top 13-0 Overview: Causes and Nature of Hypersensitivity Reactions [Full Text] [PDF] -Hypersensitivity diseases result from excessive responses to non-infectious environmental antigens -Hypersensitive responses occur only after prior sensitization -Antigens that elicit hypersensitive responses can be haptens that modify host proteins -The time course of a hypersensitive reaction depends on the mechanism 13-1 Mast Cells and Allergic Reactions [Full Text] [PDF] -Immediate-type hypersensitivity reactions are initiated by binding of allergen to IgE on sensitized mast cells -Cytokines and lipid mediators are responsible for prolonged effects of mast cell triggering -Mast cells induce an inflammation rich in basophils, eosinophils and TH2 cells 13-2 Allergic Diseases [Full Text] [PDF] -Allergic diseases have both environmental and genetic causes -Manifestations of allergic diseases are site-dependent -Anaphylaxis is a systemic response to an allergen -Allergic rhinitis occurs in response to allergens in the nasal passages -Food allergy is commonest in young children -Allergies often manifest in skin 13-3 Asthma [Full Text] [PDF] -Asthma is a respiratory disease of increasing prevalence -Asthma reflects dysregulated TH2-associated immunity -Asthma represents an interaction of allergens and genetics -Mouse models mimic aspects of acute airway inflammation in human asthma 13-4 IgG-Mediated Immune Pathology [Full Text] [PDF] -A variety of hypersensitivities and autoimmune diseases exhibit immune pathology caused by IgG -Hemolytic anemias can be caused by Ig produced in response to infection or materno-fetal Rhesus incompatibility -Immune complexes can cause damage to joints, blood vessels and kidneys 13-5 Delayed-Type Hypersensitivity Reactions [Full Text] [PDF] -Delayed-type hypersensitivity reactions reflect the actions of TH1 and cytotoxic T cells -Contact sensitivity to urushiol is an inflammatory response to haptenated proteins -Celiac disease is a delayed-type hypersensitive response to gliadin peptides from dietary wheat -Delayed-type hypersensitive reactions are used to test for T cell function or for the presence of specific infections or hypersensitivities 13-6 Inflammatory Bowel Disease [Full Text] [PDF] -Crohn's disease and ulcerative colitis are chronic intestinal inflammatory diseases -Crohn's disease represents a dysregulated mucosal immune response -Ulcerative colitis represents a dysregulated TH2-associated mucosal immune response -Animal models for inflammatory bowel disease are diverse Chapter 14: Transplantation Immunology, Tumor Immunity and Vaccination [PDF] Back to top 14-0 Overview: Boosting and Suppressing Immune Responses [Full Text] [PDF] -Modulating the immune response is often important for improving human health -Vaccination is an important tool in the fight against infectious diseases -Immunosuppression is often required for the success of cell and organ therapies 14-1 Immunodeficiencies [Full Text] [PDF] -Genetic deficiencies in components of immunity often increase susceptibility to particular infections -Some immunodeficiencies are acquired 14-2 Features of Successful Vaccines [Full Text] [PDF] -Successful vaccines depend on the production of antibody -Adjuvants are required to potentiate and amplify immune responses to vaccines 14-3 Engineering Vaccines for Safety and Efficacy [Full Text] [PDF] -Declining incidence of infectious disease may encourage a decline in vaccination -The combined diphtheria/tetanus/pertussis vaccine is based on toxoids with added adjuvants -Conjugate vaccines activate T cell help for B cell responses to polysaccharides -The route of immunization is important in determining the type of protection elicited 14-4 Vaccines for Chronic Infections and Cancer [Full Text] [PDF] -Persistent pathogens present a special challenge for vaccine design -HIV escapes both neutralizing antibodies and cytotoxic T cells -Malaria is a complex target for recombinant vaccines -Cancer can be prevented by vaccines against tumorigenic pathogens 14-5 Tumor Immunity [Full Text] [PDF] -The immune system can eliminate many tumors before they become evident -Both innate and adaptive immune cells can detect cancer cells -Normal, mutant and foreign proteins can serve as tumor antigens -Cytokines, antibodies and T cells are all potentially useful for cancer immunotherapy 14-6 Transplants and Transplantation Antigens [Full Text] [PDF] -Immunological rejection is a major barrier to transplantation -Transplantation antigens include the blood group antigens, MHC and minor histocompatibility antigens 14-7 Transplant Recognition and Rejection [Full Text] [PDF] -Organ transplant rejection occurs by three different mechanisms -T cells can be stimulated by dendritic cells of the graft or of the host 14-8 Immunosuppression of Transplant Recipients [Full Text] [PDF] -Transplantation is successful because of immunosuppressive drugs and antibodies -Steroids, antiproliferative agents and calcineurin inhibitors are the mainstays of immunosuppression for transplantation -Anti-CD3 antibodies are used to combat rejection episodes Updated References [Full Text] [PDF]  | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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