Touro Pa Microbiology Innate Immunity Lecture #12.ppt

Immunity: Nonspecific Defenses of the Host And Adaptive Immunity The Concept of Immunity To microbes, human body is nutrient-rich, but interior of body is generally sterile •Susceptibility: lack of resistance to a disease •Immunity: ability to ward off disease •Innate immunity: defenses against an...

Immunity: Nonspecific Defenses of the Host And Adaptive Immunity The Concept of Immunity To microbes, human body is nutrient-rich, but interior of body is generally sterile •Susceptibility: lack of resistance to a disease •Immunity: ability to ward off disease •Innate immunity: defenses against any pathogen •Adaptive immunity: immunity or resistance to a specific pathogen An Overview of the Body’s Defenses An overview of the body’s defenses. Adaptive Immunity First line of defense • Intact skin • Mucous membranes and their secretions • Normal microbiota Second line of defense Third line of defense • Phagocytes, such as neutrophils, eosinophils, dendritic cells, and macrophages • Inflammation • Fever • Antimicrobial substances • Specialized lymphocytes: T cells and B cells • Antibodies The Concept of Immunity • Host Toll-like receptors (TLRs) attach to pathogen-associated molecular patterns (PAMPs) • TLRs induce cytokines that regulate the intensity and duration of immune responses First Line of Defense: Skin and Mucous Membranes Physical Factors • Skin • Epidermis consists of tightly packed cells with • Keratin, a protective protein Skin Difficult for microbes to penetrate Dermis: tightly woven fibrous connective tissue Epidermis: many layers of epithelial cells • Outermost are dead, filled with keratin • Repels water, maintains dry environment • Continually flake off along with any attached microbes • Access the text alternative for slide images. 8 Physical Factors • Mucous membranes • Mucus: traps microbes • Ciliary escalator: transports microbes trapped in mucus away from the lungs Mucous Membranes • Digestive, respiratory, genitourinary tracts • Constantly bathed in secretions (for example, mucus) • Have mechanisms that move microbes toward areas where they can be eliminated • Peristalsis of intestines, mucociliary escalator of respiratory tract remove microbes 10 Ciliated cells of the respiratory system infected with Bordetella pertussis. B. pertussis Cilia © 2013 Pearson Education, Inc. The ciliary escalator. Trapped particles in mucus Cilia Goblet cells Insert Fig 16.4 Ciliated cells Computer-enhanced Physical Factors • Lacrimal apparatus: washes eye • Saliva: washes microbes off • Urine: flows out • Vaginal secretions: flow out The lacrimal apparatus. Lacrimal glands Upper eyelid Lacrimal canal Nasolacrimal duct Nose Chemical Factors • Fungistatic fatty acid in sebum • Low pH (3–5) of skin • Lysozyme in perspiration, tears, saliva, and urine • Low pH (1.2–3.0) of gastric juice • Low pH (3–5) of vaginal secretions Normal Microbiota and Innate Immunity • Microbial antagonism/competitive exclusion: normal microbiota compete with pathogens or alter the environment • Commensal microbiota: one organism (microbe) benefits, and the other (host) is unharmed • May be opportunistic pathogens Antimicrobial Substances Salt accumulates on skin from perspiration Lysozyme degrades peptidoglycan Peroxidases form antimicrobials; break down hydrogen peroxide Lactoferrin and transferrin bind iron Antimicrobial peptides (AMPs) • Defensins form pores in microbial membranes • Access the text alternative for slide images. 17 Second Line of Defense The Lymphatic System The lymphatic system. Right lymphatic duct Right subclavian vein Thoracic (left lymphatic) duct Left subclavian vein Tonsil Thymus Heart Thoracic duct Spleen Lymphatic vessel Small intestine Large intestine Red bone marrow (a) Components of lymphatic system Peyer’s patch Lymph node The lymphatic system. Venule Tissue cell Blood Interstitial fluid Blood capillary One-way opening Arteriole Blood Lymphatic capillary Interstitial fluid (between cells) Lymph Tissue cell Lymphatic capillary Relationship of lymphatic capillaries to tissue cells and blood capillaries Lymph Details of a lymphatic capillary Overview of the Innate Immune Defenses • First-line defenses are barriers blocking entry • If invaders breach, sensor systems detect • Sentinel cells use pattern recognition receptors (PRRs) to identify unique microbial components • Complement system found in blood and tissue fluid • Innate effector actions destroy invaders • Interferon (IFN) secreted with viral infection • Phagocytes engulf microbes or cell debris by phagocytosis • Inflammatory response is coordinated • Fever interferes with pathogen growth and enhances other immune responses 22 The Cells of the Immune System • Access the text alternative for slide images. 23 Granulocytes • Contain cytoplasmic granules; named based on staining properties • Release granule contents through degranulation • Neutrophils engulf and destroy bacteria; granules contain enzymes, antimicrobials; also called PMNs, increase in number during infection • Basophils involved in allergic reactions, inflammation; granules contain histamine • Mast cells similar; found in tissues • Eosinophils fight parasitic worms; involved in allergic reactions; granules contain antimicrobials and histaminase 24 Mononuclear Phagocytes Comprise mononuclear phagocyte system (MPS) Includes monocytes (circulate in blood) and cell types that develop as they leave bloodstream Macrophages differentiate from monocytes • Sentinel cells found in nearly all tissues • Access the text alternative for slide images. 25 Mononuclear Phagocytes • Dendritic Cells • Sentinel cells, function as “scouts” • Engulf material in tissues, bring it to cells of adaptive immune system for “inspection” • Usually develop from monocytes • Lymphocytes • Responsible for adaptive immunity • B cells, T cells highly specific in recognition of antigen • Generally reside in lymph nodes, lymphatic tissues • Innate lymphoid cells (ILCs) lack specificity • Can promote inflammatory response • Natural killer (NK) cells destroy certain types of cells 26 Differential White Cell Count • Percentage of each type of white cell in a sample of 100 white blood cells Neutrophils 60–70% Basophils 0.5–1% Eosinophils 2–4% Monocytes 3–8% Lymphocytes 20–25% Defense Second Line of Phagocytosis • Phago: from Greek, meaning eat • Cyte: from Greek, meaning cell • Ingestion of microbes or particles by a cell, performed by phagocytes A macrophage engulfing rod-shaped bacteria. Macrophage Bacterium Pseudopods Phagocytosis • Neutrophils • Fixed macrophages • Wandering macrophages Pattern Recognition Receptors (PRRs) • Allow body to “see” signs of microbial invasion; lead to cytokine secretion • PAMPs are pathogen-associated, but not exclusive to pathogens • Microbe-associated molecular patterns (MAMPs) detected by PRRs • Include cell wall components (peptidoglycan, lipoteichoic acid, lipopolysaccharide, lipoproteins), flagellin subunits, microbial nucleic acid • Damage-associated molecular patterns (DAMPs) indicate cell damage 32 Pattern Recognition Receptors (PRRs) • Found at three locations: • Cell surface • In endosomes and phagosomes • Free in cytoplasm • Access the text alternative for slide images. 33 The Phases of Phagocytosis. A phagocytic macrophage uses a pseudopod to engulf nearby bacteria. Pseudopods Phagocyte Cytoplasm 1 CHEMOTAXIS and ADHERENCE of phagocyte to microbe 2 INGESTION of microbe by phagocyte Microbe or other particle Details of adherence 3 Formation of phagosome (phagocytic vesicle) 4 Fusion of phagosome with a lysosome to form a phagolysosome Lysosome PAMP (peptidoglycan in cell wall) Digestive enzymes Partially digested microbe 5 DIGESTION of ingested microbes by enzymes in the phagolysosome Indigestible material 6 Formation of the residual body containing indigestible material TLR (Toll-like receptor) Plasma membrane 7 DISCHARGE of waste materials Oxidative Burst 4 Superoxide dismutase converts superoxide to hydrogen peroxide (H2O2) 5 H2O2 burst kills bacterium 3 NADPH oxidase 1 Bacterium adheres to membrane of neutrophil Insert art from Clinical Case on Superoxide p. 463 dismutase O2 • H2O2 Plasma membrane Neutrophil uses electron from NADPH to produce superoxide (O2 •) O2 If possible on this slide, include title: Oxidative Burst NADPH oxidase Pentose phosphate pathway NADP+ 2 NADPH is produced NADPH Microbial Evasion of Phagocytosis Inhibit adherence: M protein, capsules Streptococcus pyogenes, S. pneumoniae Kill phagocytes: Leukocidins Staphylococcus aureus Lyse phagocytes: Membrane attack complex Listeria monocytogenes Escape phagosome Shigella, Rickettsia Prevent phagosome– lysosome fusion HIV, Mycobacterium tuberculosis Survive in phagolysosome Coxiella burnettii Second Line of Defense Inflammation • Activation of acute-phase proteins (complement, cytokine, and kinins) • Vasodilation (histamine, kinins, prostaglandins, and leukotrienes) • Redness • Swelling (edema) • Pain • Heat Chemicals Released by Damaged Cells Histamine Kinins Vasodilation, increased permeability of blood vessels Vasodilation, increased permeability of blood vessels Prostaglandins Intensify histamine and kinin effect Leukotrienes Increased permeability of blood vessels, phagocytic attachment Phagocyte Migration and Phagocytosis The process of inflammation. Bacteria entering on knife Bacteria Epidermis Blood vessel Dermis Nerve Subcutaneous tissue (a) Tissue damage 1 Chemicals such as histamine, kinins, prostaglandins, leukotrienes, and cytokines (represented as blue dots) are released by damaged cells. 2 Blood clot forms. 3 Abscess starts to form (orange area). (b) Vasodilation and increased permeability of blood vessels The process of inflammation. Blood vessel endothelium Monocyte 4 Margination— phagocytes stick to endothelium. 5 Diapedesis— phagocytes squeeze between endothelial cells. Insert Fig 16.8c 6 Phagocytosis of invading bacteria occurs. Red blood cell Macrophage (c) Phagocyte migration and phagocytosis Bacterium Neutrophil The process of inflammation. Scab Blood clot Regenerated epidermis Insert Fig 16.8d (d) Tissue repair Regenerated dermis Fever • Abnormally high body temperature • Hypothalamus is normally set at 37°C • Gram-negative endotoxins cause phagocytes to release interleukin-1 (IL-1) • Hypothalamus releases prostaglandins that reset the hypothalamus to a high temperature • Body increases rate of metabolism, and shivering occurs, which raise temperature • Vasodilation and sweating: body temperature falls (crisis) Fever • Fever is indicator of infection, especially bacterial • Temperature-regulation center in brain normally holds at 37 degrees Celsius but raises during infection in response to fever-inducing cytokines called pyrogens • Pyrogens may be made by the body or by microbes • Oral temperature above 37.8 degrees Celsius regarded as fever • Growth rates of bacteria optimized for 37 degrees Celsius typically drop sharply above optimum, allows more time for defenses • Moderate temperature rise increases rates of enzymes • Enhances inflammatory response, phagocytic activity, multiplication of lymphocytes, release of attractants for neutrophils, production of interferons and antibodies, release of leukocytes from bone marrow 45 Antimicrobial Substances The Complement System • Serum proteins activated in a cascade • Activated by • Antigen–antibody reaction • Proteins C3, B, D, P and a pathogen The Complement System • C3b causes opsonization • C3a + C5a cause inflammation • C5b + C6 + C7 + C8 + C9 cause cell lysis Effects of Complement Activation • Opsonization, or immune adherence: enhanced phagocytosis • Membrane attack complex: cytolysis • Attract phagocytes Complement System Activation • Three pathways of activation: • Classical pathway: activated by antibodies bound to antigen, which interact with complement system • Alternative pathway triggered when C3 binds to foreign cell surfaces (C3 unstable, so some C3b always present) • Lectin pathway: pattern recognition molecules (mannose-binding lectins, or MBLs) bind to mannose of microbial cells, interact with complement system components 50 Outcomes of Complement Activation. 1 Inactivated C3 splits into activated C3 C3a and C3b. 2 C3b binds to microbe, resulting in opsonization. C3b C3a C3b proteins 3 C3b also splits C5 into C5a and C5b 5 C3a and C5a cause mast cells to release histamine, resulting in inflammation; C5a also attracts phagocytes. opsonization C5 Enhancement of phagocytosis by coating with C3b C5a C5b Histamine C5a Insert Fig 16.9 Mast cell 4 C5b, C6, C7, and C8 bind together sequentially and insert into the microbial plasma membrane, where they function as a receptor to attract a C9 fragment; additional C9 fragments are added to form a channel. Together, C5b through C8 and the multiple C9 fragments form the membrane attack complex, resulting in cytolysis. C5a receptor C6 C3a receptor C3a inflammation C7 C8 Increase of blood vessel permeability and chemotactic attraction of phagocytes C9 Microbial plasma membrane Channel C6 C7 C5b C8 C9 Formation of membrane attack complex (MAC) C6 C5b C7 C8 C9 Cytolysis cytolysis © 2013 Pearson Education, Inc. Bursting of microbe due to inflow of extracellular fluid through transmembrane channel formed by membrane attack complex Inflammation stimulated by complement. C5a C5a receptor Histamine Phagocytes Neutrophil Histaminecontaining granule Insert Fig 16.11 Histaminereleasing mast cell C3a C3a receptor C5a Macrophage Classical pathway of complement activation. Microbe Antigen C1 is activated by binding to antigen–antibody complexes. Antibody C1 Activated C1 splits C2 into C2a and C2b, and C4 into C4a and C4b. C4 C2 Insert Fig 16.12 C2b C2a C2a and C4b combine and activate C3, splitting it into C3a and C3b Opsonization C4b C4a C3 C3b Cytolysis C3a Inflammation Alternative pathway of complement activation. Lipid-carbohydrate complex Microbe C3 combines with factors B, D, and P on the surface of a microbe. B D P C3 Insert Fig 16.13 This causes C3 to split into fragments C3a and C3b. C3b C3a Inflammation Opsonization Cytolysis Key: B B factor D D factor P P factor The lectin pathway of complement activation. Microbe Carbohydrate containing mannose Lectin Lectin binds to an invading cell. Bound lectin splits C2 into C2b and C2a and C4 into C4b and C4a. C2 C2b C4 C2a and C4b combine and activate C3 (see also Figure 16.9). Opsonization C4b C2a C4a C3 C3b Cytolysis C3a Inflammation Some Bacteria Evade Complement • Capsules prevent C activation • Surface lipid–carbohydrate complexes prevent formation of membrane attack complex (MAC) • Enzymatic digestion of C5a Antimicrobial Substances Interferons (IFNs) • IFN- and IFN-: cause cells to produce antiviral proteins that inhibit viral replication • IFN-: causes neutrophils and macrophages to phagocytize bacteria Antiviral action of alpha and beta interferons (IFNs). 1 Viral RNA from an infecting virus enters the cell. 2 The infecting virus 5 New viruses released by replicates into new viruses. Viral RNA the virus-infected host cell infect neighboring host cells. 3 The infecting virus also induces the host cell to produce interferon mRNA (IFN-mRNA), which is translated into alpha and beta interferons. Infecting virus Viral RNA Nucleus Translation Insert Fig 16.15 Transcription Transcription IFN-mRNA 4 Interferons released by the virus-infected host cell bind to plasma membrane or nuclear membrane receptors on uninfected neighboring host cells, inducing them to synthesize antiviral proteins (AVPs). These include oligoadenylate synthetase and protein kinase. Alpha and beta interferons Translation Virus-infected host cell Neighboring host cell Antiviral proteins (AVPs) 6 AVPs degrade viral mRNA and inhibit protein synthesis—and thus interfere with viral replication. Innate Immunity • Transferrins • Bind serum iron • impedes bacterial survival • Antimicrobial peptides • Lyse bacterial cells Immunity • Innate immunity: defenses against any pathogen • Adaptive immunity: induced resistance to a specific pathogen • Antigens stimulate production of antibodies that bind and target them for destruction • Can also destroy infected host cells or “self” cells The Adaptive Immune System Dual Nature of Adaptive Immunity • T and B cells develop from stem cells in red bone marrow Differentiation of T cells and B cells. Stem cells develop in bone marrow or in fetal liver Stem cell (diverges into two cell lines) Red bone marrow of adults Thymus Differentiate to B cells in adult red bone marrow Differentiate to T cells in thymus B cell T cell Migrate to lymphoid tissue such as spleen, but especially lymph nodes Adaptive Immunity • Develops most effective means to eliminate invader • Lymphocytes recognize foreign material (antigen) and proliferate, leading to adaptive immunity • Takes a week or more to build following first exposure • Characteristics of adaptive immunity • Molecular specificity • Immunological Memory • Stronger response to re-exposure • Vaccination relies upon this ability • Immune Tolerance • Must distinguish between “healthy self” and “dangerous” • Science Photo Library/Getty Images 65 Overview of Adaptive Immune Response 1 1. • Cell-Mediated Immunity (CMI) • Deals with invaders residing in a “self” cell • Invaders include viruses and bacteria • Relies on T lymphocytes (T cells ); T indicates they mature in the thymus • Two types of T cells help eliminate antigens; differ in surface proteins, called CD markers • Cytotoxic T cell induce apoptosis in self cells infected with viruses or are otherwise “corrupt,” “corrupt” host cells • Helper T cell directs/assists the various immune responses Overview of Adaptive Immune Response 2 2. • Humoral Immunity • Eliminates microbial invaders and toxins in the blood or tissue fluids (humoral) • Involves B lymphocytes (B cells); B indicates Bursa of Fabricius in birds. • Programmed to produce Y-shaped proteins called antibodies • These bind to specific antigens, marking them as an invader to be eliminated Overview of Adaptive Immune Response • Access the text alternative for slide images. Antigen Receptors • T cells and B cells have thousands of copies of a receptor on their surfaces that allow them to recognize specific antigens • A region of the receptor called an antigen-binding site is responsible for that recognition • The antigen receptors on a single lymphocyte are identical; all recognize the same antigen • The body has hundreds of millions of different lymphocytes, the immune system can recognize a nearly infinite assortment of antigens T and B Cell Receptors • T-cell receptors (TCRs) only bind an antigen “presented” by one of the body’s own cell • Binding is guided by a surface molecule called a CD marker • Cytotoxic T cells have CD8 marker • Helper T cells have a CD4 marker • B-cell receptors (BCRs) are membrane-anchored antibodies • They bind free antigens • The two arms of the BCR are identical to each other, resulting in two antigen-binding sites T and B Cell Receptors • Access the text alternative for slide images. Immune Tolerance • Immune tolerance, prevents inappropriate adaptive immune responses from damaging the body’s own tissues • Provided by two sequential processes: • Central tolerance - as lymphocytes mature (T cells in the thymus and B cells in the bone marrow), immature T and B cells that recognize “self” molecules are eliminated • Peripheral tolerance - prevents mature T and B cells that were not eliminated during central tolerance from reacting against self or other harmless molecules Peripheral Tolerance • Naïve lymphocyte: never encountered antigen; cannot react until it receives confirming signals • Activated lymphocyte: has received confirming signals, proliferates, differentiates • Effector lymphocytes: short-lived, primary response • Memory lymphocytes: long-lived, activated more quickly to provide secondary response • The first adaptive immune response to a particular antigen is called the primary response • Additional encounters with the same antigen result in a faster and more effective reaction called the secondary response • Memory lymphocytes are responsible for the secondary response The dual nature of the adaptive immune system. Humoral (antibody-mediated) immune system Cellular (cell-mediated) immune system Control of freely circulating pathogens Control of intracellular pathogens Intracellular antigens are expressed on the surface of an APC, a cell infected by a virus, a bacterium, or a parasite. Extracellular antigens A B cell binds to the antigen for which it is specific. A Tdependent B cell requires cooperation with a T helper (TH) cell. T cell Cytokines activate T helper (TH) cell. Cytokines activate macrophage. Cytokines Cytokines B cell The B cell, often with stimulation by cytokines from a TH cell, differentiates into a plasma cell. Some B cells become memory cells. Cytokines from the TH cell transform B cells into antibody-producing plasma cells. Plasma cells proliferate and produce antibodies against the antigen. Activation of macrophage (enhanced phagocytic activity). TH cell Cytotoxic T lymphocyte Plasma cell A T cell binds to MHC–antigen complexes on the surface of the infected cell, activating the T cell (with its cytokine receptors). Memory cell Some T and B cells differentiate into memory cells that respond rapidly to any secondary encounter with an antigen. Lysed target cell The CD8+T cell becomes a cytotoxic T lymphocyte (CTL) able to induce apoptosis of the target cell. Dual Nature of Adaptive Immunity • Humoral immunity • Due to antibodies • B cells mature in the bone marrow • Chickens: bursa of Fabricius site of hematopoiesis Dual Nature of Adaptive Immunity • Cellular immunity • Due to T cells • T cells mature in the thymus Antigens and Antibodies The Nature of Antigens • Antigen (Ag): a substance that causes the body to produce specific antibodies or sensitized T cells • Antibodies (Ab) interact with epitopes, or antigenic determinants The Nature of Antibodies • Globular proteins called immunoglobulins • The number of antigen-binding sites determines valence Epitopes (antigenic determinants). Antibody A Epitopes (antigenic determinants) on antigen Antigens: components of cell wall Binding sites Bacterial cell Antibody B The structure of a typical antibody molecule. y n ai ch Li gh tc av He Antigenbinding site ha in Fc (stem) region Hinge region Antibody molecule Epitope (antigenic determinant) Antigen Antigenbinding site Enlarged antigen-binding site bound to an epitope IgG Antibodies • Monomer • 80% of serum antibodies • Fix complement • In blood, lymph, and intestine • Cross placenta • Enhance phagocytosis; neutralize toxins and viruses; protect fetus and newborn • Half-life = 23 days IgM Antibodies • Pentamer • 5–10% of serum antibodies • Fix complement • In blood, in lymph, and on B cells • Agglutinate microbes; first Ab produced in response to infection • Half-life = 5 days Disulfide bond J chain IgA Antibodies • Dimer • 10–15% of serum antibodies • In secretions • Mucosal protection • Half-life = 6 days J chain Secretory component IgD Antibodies • Monomer • 0.2% of serum antibodies • In blood, in lymph, and on B cells • On B cells, initiate immune response • Half-life = 3 days IgE Antibodies • Monomer • 0.002% of serum antibodies • On mast cells, on basophils, and in blood • Allergic reactions; lysis of parasitic worms • Half-life = 2 days B Cells and Humoral Immunity Activation of B Cells • Major histocompatibility complex (MHC) expressed on mammalian cells • T-dependent antigens • Ag presented with (self) MHC to TH cell • TH cell produces cytokines that activate the B cell • T-independent antigens • Antigen stimulate the B cell to make Abs T-independent antigens. Polysaccharide (T-independent antigen) Epitopes B cell receptors Activation of B cells to produce antibodies (T-cell dependent). Extracellular antigens Ag fragment MHC class II with Ag fragment MHC class II with Ag fragment displayed on surface Antibodies B cell B cell B cell Immunoglobulin receptors coating B cell surface Immunoglobulin receptors on B cell surface recognize and attach to antigen, which is then internalized and processed. Within the B cell a fragment of the antigen combines with MHC class II. TH cell Plasma cell Cytokines MHC class II–antigenfragment complex is displayed on B cell surface. Receptor on the T helper cell (TH) recognizes complex of MHC class II and antigen fragment and is activated— producing cytokines, which activate the B cell. The TH cell has been previously activated by an antigen displayed on a dendritic cell (see Figure 17.10). B cell is activated by cytokines and begins clonal expansion. Some of the progeny become antibody-producing plasma cells. Clonal Selection Clonal selection and differentiation of B cells. Stem cell Stem cells differentiate into mature B cells, each bearing surface immunoglobulins against a specific antigen. Antigen B cell III complexes with its specific antigen and proliferates. B cells I II III IV Memory cells Some B cells proliferate into longlived memory cells, which at a later date can be stimulated to become antibody-producing plasma cells. Other B cells proliferate into antibody-producing plasma cells. Plasma cells Plasma cells secrete antibodies into circulation. Antigens in circulation now attached to circulating antibodies Cardiovascular system Activation of B Cells • B cells differentiate into: • Antibody-producing plasma cells • Memory cells • Clonal deletion eliminates harmful B cells Antigen–Antibody Binding • Agglutination • Opsonization • Activation of complement • Antibody-dependent cell-mediated cytotoxicity • Neutralization The results of antigen–antibody binding. PROCTECTIVE Activation of complement MECHANISM OF BINDING ANTIBODIES Causes inflammation and Reduces number of infectious units TO ANTIGENS cell lysis to be dealt with Complement Agglutination Bacteria Bacterium Lysis Antibody-dependent cell-mediated cytotoxicity Opsonization Coating antigen with antibody enhances phagocytosis Phagocyte Antibodies attached to target cell cause destruction by macrophages, eosinophils, and NK cells Eosinophil Epitopes Large target cell (parasite) Neutralization Blocks adhesion of bacteria and viruses to mucosa Virus Bacterium Toxin Blocks attachment of toxin Perforin and lytic enzymes T Cells and Cellular Immunity T Cells and Cellular Immunity • T cells mature in the thymus • Thymic selection eliminates many immature T cells Cell-Mediated Immunity – T Cell Activation • Immune response cannot begin until a lymphocyte becomes activated • Dendritic cells help activate the naive T cells • Collect various antigens, including material from invading microbes • Travel to regions where naive T cells gather • Present pieces of the antigen • Producing surface proteins, called co-stimulatory molecules if the antigen being presented is microbial or otherwise represents “danger” • If a T cell TCR binds an antigen presented by a dendritic cell that also has co-stimulatory molecules, T-cell activation may result Principal Cells That Function in Cell-Mediated Immunity T Cells and Cellular Immunity • T cells respond to Ag by T-cell receptors (TCRs) • T cells require antigen-presenting cells (APCs) • Pathogens entering the gastrointestinal or respiratory tracts pass through: • M (microfold) cells • Peyer’s patches (small intestines), which contain APCs M cells. (a) M cell on Peyer’s patch. Note the tips of the closely packed microvilli on the surrounding epithelial cells. Antigen M cell Microvilli on epithelial cell TH cell Pocket B cells Macrophage Epithelial cell (b) M cells facilitate contact between the antigens passing through the intestinal tract and cells of the body’s immune system. T Helper Cells • CD4+ or TH cells • TCRs recognize Ags and MHC II on APC • TLRs are a costimulatory signal on APC and TH • TH cells produce cytokines and differentiate into: • • • • TH1cells TH2 cells TH17 cells Memory cells T Helper Cells • TH1 produce IFN-which activates cells related to cell-mediated immunity, macrophages, and Abs • TH2 activate eosinophils and B cells to produce IgE • TH17 stimulate the innate immune system Lineage of effector T helper cell classes and pathogens targeted. Antibodies B cell TH1 cells TH2 cells Recruits neutrophils; provides protection against extracellular bacteria and fungi TH cell TH17 cells IL-17 IL-4 TH17 cells Cell-mediated immunity; control of intracellular pathogens, delayed hypersensitivity reactions stimulates macrophages. IFN- TH1 cells TH2 cells Fungi Extracellular bacteria Neutrophil Macrophage Mast cell Basophil Eosinophil Intracellular bacteria and protozoa Important in allergic responses, especially by production of IgE Stimulates activity of eosinophils to control extracellular parasites such as helminths Helminth Activation of CD4+ T Helper Cells Activation of CD4+T helper cells. An APC encounters and ingests a microorganism. The antigen is enzymatically processed into short peptides, which combine with MHC class II molecules and are displayed on the surface of the APC. A receptor (TCR) on the surface of the CD4+T helper cell (TH cell) binds to the MHC–antigen complex. If this includes a Toll-like receptor, the APC is stimulated to secrete a costimulatory molecule. These two signals activate the TH cell, which produces cytokines. TH cell receptor (TCR) APC (dendritic cell) The cytokines cause the TH cell (which recognizes a dendritic cell that is producing costimulatory molecules) to become activated. T helper cell Antigen Antigen fragment Microorganism carrying antigens Complex of MHC class II molecule and antigen fragment Cytokines (short peptides) Costimulatory molecule, (required to activate T cells that have not previously encountered antigen) T Cytotoxic Cells • CD8+ or TC cells • Target cells: these are self-cells carrying endogenous antigens • Activated into cytotoxic T lymphocytes (CTLs) • CTLs recognize Ag + MHC I • Induce apoptosis in target cell • CTL releases perforin and granzymes • Apoptosis Killing of virus-infected target cell by cytotoxic T lymphocyte. Processed antigen presented with MHC class I Processed antigen T cell receptors Infected target cell is lysed MHC class I Virus-infected cell (example of endogenous antigen) A normal cell will not trigger a response by a cytotoxic T lymphocyte (CTL), but a virusinfected cell (shown here) or a cancer cell produces abnormal endogenous antigens. CTL Virus-infected cell Cytotoxic T lymphocyte (CTL) The abnormal antigen is presented on the cell surface in association with MHC class I molecules. CD8+T cells with receptors for the antigen are transformed into CTLs. The CTL induces destruction of the virus-infected cell by apoptosis. Apoptosis. T Regulatory Cells • Treg cells  CD4 and CD25 on surface • Suppress T cells against self by regulating their activities. T Cells and Cellular Immunity Antigen-Presenting Cells • Digest antigen • Ag fragments on APC surface with MHC • B cells • Dendritic cells • Activated macrophages Natural Killer (NK) Cells • Granular leukocytes destroy cells that don’t express MHC I • Kill virus-infected and tumor cells • Attack parasites ADCC • Antibody-dependent cell-mediated cytotoxicity Antibody-dependent cell-mediated cytotoxicity (ADCC). KEY Macrophage Cytotoxic cytokines Lytic enzymes Perforin enzymes Eosinophil Extracellular damage Fc region Large parasite Epitope Antibody (a) Organisms, such as many parasites, that are too large for ingestion by phagocytic cells must be attacked externally. Antibody-dependent cell-mediated cytotoxicity (ADCC). Eosinophils Fluke Eosinophils adhering to the larval stage of a parasitic fluke. Cytokines • Chemical messengers • Overproduction leads to cytokine storm Cells Communicate via Cytokines Cytokine Representative Activity Interleukin-1 (IL-1) Stimulates TH cells in presence of antigens; attracts phagocytes Interleukin-2 (IL-2) Proliferation of antigen-stimulated CD4+ T helper cells, proliferation and differentiation of B cells; activation of CD8+ T cells and NK cells Interleukin-12 (IL-12) Inhibits humoral immunity; activates TH1 cellular immunity Cells Communicate via Cytokines Cytokine Representative Activity Chemokines Induce the migration of leukocytes TNF-α Promotes inflammation Hematopoietic cytokines Influence differentiation of blood stem cells IFN- and IFN- Response to viral infection; interfere with protein synthesis IFN- Stimulates macrophage activity Immunological Memory • Antibody titer is the amount of Ab in serum • Primary response occurs after initial contact with Ag • Secondary (memory or anamnestic) response occurs after second exposure The primary and secondary immune responses to an antigen. Antibody titer in serum IgG IgM Initial exposure to antigen Time (days) Second exposure to antigen Types of Adaptive Immunity • Naturally acquired active immunity • Resulting from infection • Naturally acquired passive immunity • Transplacental or via colostrum • Artificially acquired active immunity • Injection of Ag (vaccination) • Artificially acquired passive immunity • Injection of Ab