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The Immune Wars Part I General types of immunity Innate (aka non-specific) inborn pattern recognition Adaptive (aka specific, acquired) “learned” through exposure exquisite specificity Chapter 15 Innate Immunity Preview • • • • • First line of defense Cells Sensor system Phagocytosis Inflammation First-line Defenses Physical barrier Antimicrobial chemicals Normal flora Physical Barriers Skin •Sheets of tightly packed cells •Outermost layers are embedded with keratin (dry) •Cells continually slough off •Perspiration (salty) •Normal flora Physical Barriers Mucous Membranes •Single layer of cells •Layer of mucus (traps particles, including microbes) •Often a mechanism to propel the mucus toward exit •(ex. mucociliary escalator, peristalsis) Antimicrobial Chemicals •Lysozyme •Transferrin, lactoferrin •Gastric acid The Cells of the Immune System Cell Communication Surface receptors - “eyes, ears” Cytokines - chemical messengers; proteins released by cells that affect the behavior of other cells; “voice” Cell Communication Surface receptors - “eyes, ears” Cytokines - chemical messengers; proteins released by cells that effect the behavior of other cells; “voice” Adhesion molecules - “hands” Sensor Systems Toll-like receptors - surface receptors that allow cells to “see” molecules that signify the presence of microorganisms or viruses pattern recognition Sensor Systems Toll-like receptors - surface receptors that allow cells to “see” molecules that signify the presence of microorganisms or viruses pattern recognition Sensor Systems The complement system - series of proteins that, when activated, result in destruction/removal of foreign material; cascade reaction C3 C3a + C3b C5 C5a + C5b “prepare for eating” Sensor Systems The complement system - series of proteins that, when activated, result in destruction/removal of foreign material; cascade reaction C3 C3a + C3b C5 C5a + C5b Alternative Complement Systems Sensor Systems The complement system - series of proteins that, when activated, result in destruction/removal of foreign material; cascade reaction C3 C3a + C3b C5 C5a + C5b Sensor Systems Recognition of long double-stranded RNA Signifies to a cell that it is infected with a virus infected cell produces interferon Apoptosis = programmed cell death Phagocytosis Macrophages Neutrophils (polymorphonuclear leukocytes, PMNs, polys) Process of phagocytosis Chemotaxis Recognition and attachment •opsonins Engulfment (ingestion) •phagosome Fusion of the phagosome with lysosomes (forms a phagolysosome) Destruction and digestion Exocytosis •Specialized attributes of macrophages Fixed in tissue or routinely wander Clean up infection Long-lived (months) Can become activated •Specialized attributes of neutrophils First to migrate to site of infection Short-lived (days) Always have tremendous killing power •Specialized attributes of macrophages Fixed in tissue or routinely wander Clean up infection Long-lived (months) Can become activated •Specialized attributes of neutrophils First to migrate to site of infection Short-lived (days) Always have tremendous killing power Inflammation Redness, pain, swelling, heat Purpose: Contain a site of damage Localize the response Restore tissue function Factors that initiate the inflammatory response Microbial cell products detected by toll-like receptors Microbial surfaces (trigger the complement cascade) Tissue damage The Inflammatory Process •Pro-inflammatory cytokines released •Dilation of small blood vessels increased blood flow to the area •Leakage of fluids from vessels •Adherence of phagocytic cells to endothelial cells •Diapedesis Apoptosis - programmed cell death; does not trigger inflammation Other responses Interferon Fever metabolic rate; response to invaders elevates temperature above optimum growth temperature of invader Immune Wars Adaptive Immunity Chapter16 Adaptive Immunity Preview • Characteristics of adaptive immunity • Lymphatic system • Humoral immunity – Antibody structure, function, classification, production (B cell activation) • Cellular immunity – T cell activation, function Strategy of the Adaptive Immune Response Characteristics of adaptive immunity •Memory •Specificity •“Self” vs. non-self …..or harmless vs. danger “self” vs. dangerous non-self Antigen - Material to which an immune system mounts a response Development of the Response Effect step 1 step 2 step 3 finale Strategy of the Adaptive Immune Response lymphocytes Strategy of the Adaptive Immune Response Extracellular antigens •Most bacteria •Toxins •Viral particles aka cell-mediated immunity (CMI) Intracellular antigens •Viruses (inside a cell) •Intracellular bacteria •(Cancer cells) Strategy of the Adaptive Immune Response Strategy of the Adaptive Immune Response Strategy of the Adaptive Immune Response Strategy of the Adaptive Immune Response Strategy of the Adaptive Immune Response Anatomy of the Lymphoid System Lymphatic vessels Secondary Collect fluids, lymphoid WBCs from organs the tissues Where lymphocytes “hang out” to encounter antigens •Lymph nodes Anatomy of the Lymphoid System Lymphatic vessels Secondary lymphoid organs Where lymphocytes “hang out” to encounter antigens •Lymph nodes •Spleen •Mucosal-associated lymphoid tissue •Peyer’s patches; M cells sample material in the intestine P M lumen Anatomy of the Lymphoid System Lymphatic vessels Secondary lymphoid organs Where lymphocytes “hang out” to encounter antigens •Lymph nodes •Spleen •Mucosal-associated lymphoid tissue •Peyer’s patches; M cells sample material in the intestine •Skin-associated lymphoid tissue Primary lymphoid organs Where lymphocytes develop •Bone marrow •Thymus The Nature of Antigens • Proteins • Molecules w/ repeating identical subunits (ex. polysaccharides) Epitopes/antigenic determinants 10-20 amino acids “antigenic” T helper cell dependent T helper cell independent The Nature of Antibodies Magic bullet: bind antigen with high specificity Basic structure: Y-shaped molecule •Fab regions - antigen-binding regions •Fc region - “red flag” region The Nature of Antibodies Structure and properties of antibodies Basic structure: Y-shaped molecule 200 a.a. 450 a.a. •Fab regions - antigen-binding regions •Fc region - “red flag” region •four protein chains - two heavy chains (H); two light chains (L) •variable region •constant region Immunoglobulin Classes (isotypes) Immunoglobulins = antibodies Protective outcomes of antigenantibody binding Protective outcomes of antigenantibody binding Protective outcomes of antigenantibody binding Clonal Selection and Expansion of Lymphocytes Basic principles are true for both B and T cells Clonal Selection and Expansion of Lymphocytes Basic principles are true for both B and T cells Naïve lymphocytes have a receptor, but have not “seen” antigen BCRs are membranebound antibodies ~1/2 billion naïve B cells, recognizing ~ 100 million different epitopes! Those that recognize “self” are eliminated during lymphocyte development Clonal Selection and Expansion of Lymphocytes Basic principles are true for both B and T cells Activated lymphocytes - able to proliferate; have received confirmatory signals Clonal Selection and Expansion of Lymphocytes Basic principles are true for both B and T cells Activated lymphocytes - able to proliferate; have received confirmatory signals Clonal Selection and Expansion of Lymphocytes Basic principles are true for both B and T cells Activated lymphocytes - able to proliferate; have received confirmatory signals Clonal Selection and Expansion of Lymphocytes Basic principles are true for both B and T cells Effector lymphocytes endowed with specific protective attributes (plasma cells = effector B cells) Clonal Selection and Expansion of Lymphocytes Basic principles are true for both B and T cells Effector lymphocytes endowed with specific protective attributes (plasma cells = effector B cells) Clonal Selection and Expansion of Lymphocytes Basic principles are true for both B and T cells Memory lymphocytes long-lived; ready to become effector cells Clonal Selection and Expansion of Lymphocytes Basic principles are true for both B and T cells •Naïve •Activated •Effector •Memory Requires confirmatory signals (“second opinion”) from another cell type B Lymphocytes and the Antibody Response (T-dependent antigens) •Most common type of response; primarily protein antigens •Requires assistance of T-helper cells (TH cells) B Cell Activation •B cell processes/presents antigen to TH cell for “inspection” in order to gain second opinion B Cell Activation •B cell processes/presents antigen to TH cell for “inspection” in order to gain second opinion B Cell Activation •B cell processes/presents antigen to TH cell for “inspection” in order to gain second opinion •If a TH cell recognizes a fragment being presented, it delivers cytokines that activate the B cell B Cell Activation •B cell processes/presents antigen to TH cell for “inspection” in order to gain second opinion •If a TH cell recognizes a fragment being presented, it delivers cytokines that activate the B cell •If no TH cell recognizes antigen, the B cell becomes unresponsive B Cell Activation •B cell processes/presents antigen to TH cell for “inspection” in order to gain second opinion Characteristics of the Primary Response Affinity maturation •Naïve •Activated •Effector •Memory Characteristics of the Primary Response Affinity maturation - mutation fine tunes the fit Characteristics of the Primary Response Affinity maturation - mutation fine tunes the fit Class switching - IgM IgG (or IgA or IgE) Characteristics of the Primary Response Affinity maturation - mutation fine tunes the fit Class switching - IgM IgG (or IgA or IgE) Formation of memory cells - cells have undergone affinity maturation and class switching Characteristics of the Primary Response Affinity maturation Class switching Formation of memory cells Secondary response Characteristics of the Secondary Response Swifter response, primarily IgG in blood/tissues (due to memory cells) (mucosal response is IgA) More effective response (due to affinity maturation) Continued fine-tuning Characteristics of the Secondary Response Swifter response, primarily IgG in blood/tissues (due to memory cells) (mucosal response is IgA) More effective response (due to affinity maturation) Continued fine-tuning General Characteristics of T Cells (regulatory T cells) Two general categories of T cells: General Characteristics of T Cells T-cell receptor - recognizes antigen “presented” by another cell Antigen is presented by major histocompatibility complex (MHC) molecules General Characteristics of T Cells T-cell receptor - recognizes antigen “presented” by another cell Antigen is presented by major histocompatibility complex (MHC) molecules Effector T cell delivers signals to the presenting cell General Characteristics of T Cells CD = cluster of differentiation •CD8+ T cell •CD4+ T cell Activation of T Cells The role of dendritic cells scouts Activation of T Cells The role of dendritic cells In the tissues: antigen-capturing Migrate to secondary lymphoid organs Co-stimulatory molecules expressed when “danger” is sensed In secondary lymphoid organs: antigenpresenting to naïve T cells; antigen presented by BOTH MHC Class I AND MHC Class II molecules Activation of T Cells The role of dendritic cells In the tissues: antigen-capturing Migrate to secondary lymphoid organs Co-stimulatory molecules expressed when “danger” is sensed In secondary lymphoid organs: antigenpresenting to naïve T cells; antigen presented by BOTH MHC Class I AND MHC Class II molecules Activation of T Cells The role of dendritic cells In secondary lymphoid organs: antigenpresenting to naïve T cells; antigen presented by BOTH MHC Class I AND MHC Class II molecules In the tissues: antigen-capturing Activates naïve T cell Migrate to secondary lymphoid organs Co-stimulatory molecules expressed when “danger” is sensed Activation of T Cells The role of dendritic cells In secondary lymphoid organs: antigenpresenting to naïve T cells; antigen presented by BOTH MHC Class I AND MHC Class II molecules In the tissues: antigen-capturing Naïve T cell becomes unresponsive Migrate to secondary lymphoid organs Co-stimulatory molecules expressed when “danger” is sensed Activation of T Cells The role of dendritic cells In secondary lymphoid organs: antigenpresenting to naïve T cells; antigen presented by BOTH MHC Class I AND MHC Class II molecules In the tissues: antigen-capturing Activates naïve T cell Migrate to secondary lymphoid organs Co-stimulatory molecules expressed when “danger” is sensed Functions of TC (CD8+) Cells •Recognizes antigen presented by Major Histocompatibility Complex (MHC) Class I •Found on all nucleated cells • Endogenous proteins (i.e. made by the cell) are presented •Induces apoptosis in “corrupt” self cells (ex. virallyinfected) • Secretes cytokines; some increase surveillance of neighboring cells (MHC Class I expression) Functions of TH (CD4+) Cells “Helps” other cells (operations commander); produces various cytokines that activate presenting cell and direct other cells Recognizes antigen presented by Major Histocompatibility Complex (MHC) Class II Exogenous proteins (i.e. those that have been taken up by the cell) are presented Found on antigen-presenting cells (macrophages, B cells….and dendritic cells) Functions of TH (CD4+) Cells Functions of TH (CD4+) Cells B cell activation (B cell as the APC) Antigen represents material that the B cell’s receptor has recognized Functions of TH (CD4+) Cells B cell activation (B cell as the APC) Antigen represents material that the B cell’s receptor has recognized TH cell directs cytokines to that B cell, activating it/enabling it to: •Multiply and differentiate to form antibody-secreting plasma cells •Produce memory cells •Undergo class switching Note: T-independent antigens (generally polysaccharides) can activate B cells without T cell help; IgM only, no memory Children < 2 yo have weak response Functions of TH (CD4+) Cells B cell activation ( B cell as the APC) Antigen represents material that the B cell’s receptor has recognized TH cell directs cytokines to that B cell, activating it/enabling it to: •Multiply and differentiate to form antibody-secreting plasma cells •Produce memory cells •Undergo class switching Note: T-independent antigens (generally polysaccharides) can activate B cells without T cell help; IgM only, no memory Children < 2 yo have weak response Functions of TH (CD4+) Cells Macrophage activation (macrophage as the APC) Presented peptides are parts of material that the phagocyte has engulfed TH cell: •directs cytokines to that macrophage (activating it) •secretes cytokines that stimulate activated T-cytotoxic cells B Lymphocytes and the Antibody Response (T-independent antigens) Primarily polysaccharide antigens; also LPS of Gram-negatives Multiple evenly-spaced identical epitopes No memory cells formed No class switching (therefore IgM only) Immature immune systems (children <2 years of age) respond poorly capsular polysaccharides - ex. Haemophilus influenzae The Big Picture Presented step-by-step Peripheral Tissues Primary Lymphoid Organs Immature T cells (thymus marrow) Immature B cells (bone marrow) Secondary lymphoid organs Peripheral Tissues Primary Lymphoid Organs Immature T cells (thymus marrow) Immature B cells (bone marrow) Secondary lymphoid organs Naive cytotoxic Naive-helper T cells (CD8) T cells (CD4) Naive B cells Peripheral Tissues Primary Lymphoid Organs After gathering antigen in periphery, dendritic cells bring it to naive T cells in the secondary lymphoid organs; co-stimulatory molecules are expressed if antigen represents microbial invasion or tissue damage. Antigens are presented by both MHC class I and MHC class II molecules, activating both cytotoxic T cells and helper T cells. Dendritic cells (gather antigen for presentation to naive T cells) Immature T cells (thymus marrow) Immature B cells (bone marrow) Secondary lymphoid organs Naive cytotoxic Naive-helper T cells (CD8) T cells (CD4) Activation, proliferation, differentiation to form effector cells and memory cells Naive B cells Virus Infected "self" cell (harbors antigen within the cell) Macrophage (engulf and destroy invaders; limited killing powers) Extracellular antigen Peripheral Tissues Primary Lymphoid Organs After gathering antigen in periphery, dendritic cells bring it to naive T cells in the secondary lymphoid organs; co-stimulatory molecules are expressed if antigen represents microbial invasion or tissue damage. Antigens are presented by both MHC class I and MHC class II molecules, activating both cytotoxic T cells and helper T cells. Dendritic cells (gather antigen for presentation to naive T cells) Immature T cells (thymus marrow) Immature B cells (bone marrow) Secondary lymphoid organs Naive cytotoxic Naive-helper T cells (CD8) T cells (CD4) Activation, proliferation, differentiation to form effector cells and memory cells TCcells Naive B cells TH cells Virus Memory helper T cells Infected "self" cell (harbors antigen within the cell) Memory cytotoxic T cells Macrophage (engulf and destroy invaders; limited killing powers) Extracellular antigen Peripheral Tissues Primary Lymphoid Organs After gathering antigen in periphery, dendritic cells bring it to naive T cells in the secondary lymphoid organs; co-stimulatory molecules are expressed if antigen represents microbial invasion or tissue damage. Antigens are presented by both MHC class I and MHC class II molecules, activating both cytotoxic T cells and helper T cells. Dendritic cells (gather antigen for presentation to naive T cells) Immature T cells (thymus marrow) Immature B cells (bone marrow) Secondary lymphoid organs Naive cytotoxic Naive-helper T cells (CD8) T cells (CD4) Activation, proliferation, differentiation to form effector cells and memory cells TCcells Naive B cells Activation, proliferation, differentiation to form effector cells and memory cells TH cells Virus Memory helper T cells Infected "self" cell (harbors antigen within the cell) Memory cytotoxic T cells Memory B cells Plasma cells secrete antibodies. Macrophage (engulf and destroy invaders; limited killing powers) Extracellular antigen Peripheral Tissues Primary Lymphoid Organs After gathering antigen in periphery, dendritic cells bring it to naive T cells in the secondary lymphoid organs; co-stimulatory molecules are expressed if antigen represents microbial invasion or tissue damage. Antigens are presented by both MHC class I and MHC class II molecules, activating both cytotoxic T cells and helper T cells. Dendritic cells (gather antigen for presentation to naive T cells) Immature T cells (thymus marrow) Immature B cells (bone marrow) Secondary lymphoid organs Naive cytotoxic Naive-helper T cells (CD8) T cells (CD4) Activation, proliferation, differentiation to form effector cells and memory cells TCcells Naive B cells Activation, proliferation, differentiation to form effector cells and memory cells TH cells Virus Memory helper T cells Infected "self" cell (harbors antigen within the cell) Memory cytotoxic T cells Memory B cells Plasma cells secrete antibodies. Macrophage (engulf and destroy invaders; limited killing powers) Extracellular antigen Peripheral Tissues Primary Lymphoid Organs After gathering antigen in periphery, dendritic cells bring it to naive T cells in the secondary lymphoid organs; co-stimulatory molecules are expressed if antigen represents microbial invasion or tissue damage. Antigens are presented by both MHC class I and MHC class II molecules, activating both cytotoxic T cells and helper T cells. Immature T cells (thymus marrow) Immature B cells (bone marrow) Secondary lymphoid organs Naive cytotoxic Naive-helper T cells (CD8) T cells (CD4) Activation, proliferation, differentiation to form effector cells and memory cells Dendritic cells (gather antigen for presentation to naive T cells) Naive B cells Activation, proliferation, differentiation to form effector cells and memory cells TCcells TH cells Virus Memory helper T cells Memory cytotoxic T cells Infected "self" cell (harbors antigen within the cell) Memory B cells Plasma cells secrete antibodies. TH cells activate macrophages that present antigen via MHC class II molecules; also produce cytokines that orchestrate other responses. Macrophage (engulf and destroy invaders; limited killing powers) Activated macrophage (engulf and destroy invaders; enhanced killing powers) Extracellular antigen Peripheral Tissues Primary Lymphoid Organs After gathering antigen in periphery, dendritic cells bring it to naive T cells in the secondary lymphoid organs; co-stimulatory molecules are expressed if antigen represents microbial invasion or tissue damage. Antigens are presented by both MHC class I and MHC class II molecules, activating both cytotoxic T cells and helper T cells. Immature T cells (thymus marrow) Immature B cells (bone marrow) Secondary lymphoid organs Naive cytotoxic Naive-helper T cells (CD8) T cells (CD4) Activation, proliferation, differentiation to form effector cells and memory cells Dendritic cells (gather antigen for presentation to naive T cells) Naive B cells Activation, proliferation, differentiation to form effector cells and memory cells TCcells TH cells Virus TC cells induce apoptosis in infected "self" cells; also produce cytokines that cause neighboring cells to become more vigilant against intracellular pathogens. Infected "self" cell (harbors antigen within the cell) Memory helper T cells Memory cytotoxic T cells Memory B cells Plasma cells secrete antibodies. TH cells activate macrophages that present antigen via MHC class II molecules; also produce cytokines that orchestrate other responses. Macrophage (engulf and destroy invaders; limited killing powers) Activated macrophage (engulf and destroy invaders; enhanced killing powers) Extracellular antigen Peripheral Tissues Primary Lymphoid Organs After gathering antigen in periphery, dendritic cells bring it to naive T cells in the secondary lymphoid organs; co-stimulatory molecules are expressed if antigen represents microbial invasion or tissue damage. Antigens are presented by both MHC class I and MHC class II molecules, activating both cytotoxic T cells and helper T cells. Immature T cells (thymus marrow) Immature B cells (bone marrow) Secondary lymphoid organs Naive cytotoxic Naive-helper T cells (CD8) T cells (CD4) Activation, proliferation, differentiation to form effector cells and memory cells Dendritic cells (gather antigen for presentation to naive T cells) Naive B cells Activation, proliferation, differentiation to form effector cells and memory cells TCcells TH cells Virus TC cells induce apoptosis in infected "self" cells; also produce cytokines that cause neighboring cells to become more vigilant against intracellular pathogens. Infected "self" cell (harbors antigen within the cell) Memory helper T cells Memory cytotoxic T cells Memory B cells Plasma cells secrete antibodies. TH cells activate macrophages that present antigen via MHC class II molecules; also produce cytokines that orchestrate other responses. Macrophage (engulf and destroy invaders; limited killing powers) Activated macrophage (engulf and destroy invaders; enhanced killing powers) Extracellular antigen Table 1 Non-specific Immunity Specific Immunity Response is antigenindependent Response is antigen-dependent There is immediate maximal response There is a lag time between exposure and maximal response Antigen-specific Not antigen-specific Exposure results in no immunologic memory Exposure results in immunologic memory