Presentation on theme: "Lecture 19 Host Defense Against Infection"— Presentation transcript:
1 Lecture 19 Host Defense Against Infection Innate immunityAdaptive ImmunityIn this lecture you should develop a sense of how innate and adaptive immunity are interrelated.How does the nature of the innate response influence the subsequent adaptive response?
5 Innate Host Defense Mechanisms Anatomic FactorsMechanical FactorsBiochemical FactorsThe material on anatomical and mechanical factors will not be covered in class due to time limitations. You are responsible for the concepts.
6 Skin Stratified and cornified epithelium provides a mechanical barrier Indigenous microbiota competes with pathogensAcid pH inhibits growth of disease producing bacteriaBactericidal long chain fatty acids in sebaceous gland secretions
7 Respiratory Tract Upper Respiratory Tract Lower Respiratory Tract Nasal hairs induce turbulenceMucous secretions trap particlesMucous stream to the base of tongue where material is swallowedNasal secretions contain antimicrobial substancesUpper respiratory tract contains large resident floraLower Respiratory TractParticles trapped on mucous membranes of bronchi and bronchiolesBeating action of cilia causes mucociliary stream to flow up into the pharynx where it is swallowed90% of particles removed this way. Only smallest particles (<10µ in diameter) reach alveoliAlveoliAlveolar macrophage rapidly phagocytize small particles
8 Alimentary Tract General defense mechanisms Stomach Small Intestine Mucous secretionsIntegrity of of mucosal epitheliumPeristaltic motions of the gut propel contents downwardSecretory antibody and phagocytic cellsStomachGenerally sterile due to low pHSmall IntestineUpper portion contains few bacteriaAs distal end of ilieum is reached flora increasesColonEnormous numbers of microorganisms50-60% of fecal dry weight is bacteria
9 Genitourinary Tract Male Female (Vagina) No bacteria above urethrovesicular junctionFrequent flushing action of urineBactericidal substances from prostatic fluidpH of urineBladder mucosal cells may be phagocyticUrinary sIgAFemale (Vagina)Large microbial population (lactobacilli)Microorganisms produce low pH due to breakdown of glycogen produced by mucosal cells
10 EyeFlushing action of tears which drain through the lacrimal duct and deposit bacteria in nasopharynxTears contain a high concentration of lysozyme (effective against gram positive microorganisms
11 Innate Immune Recognition All multicellular organisms are able to recognize and eliminate pathogensDespite their extreme heterogeneity, pathogens share highly conserved molecules, called “pathogen-associated molecular patterns” (PAMPs)Host cells do not share PAMPs with pathogensPAMPs are recognized by innate immune recognition receptors called pattern-recognition molecules/receptors (PRMs/PRRs)
12 Three Functional Classes of PRRs/PRMs Endocytic receptorsMacrophage mannose receptorMacrophage scavenger receptor (SR)Integrin CD11b:CD18Secreted proteinsMannose-binding protein/lectinPulmonary surfactant proteins A and DC-reactive protein (CRP)Signaling receptorsToll receptor family
13 Endogenous Signals Induced by PAMPs Mediate inflammatory cytokinesInterleukin-1 (IL-1)IL-6Tumor necrosis factor (TNF-a)Type 1 interferon (INF-I)Major effector cytokinesChemokinesAntigen-presenting cells recognize PAMPsSame APC processes pathogens into specific pathogen-derived antigens and presents them with MHC encoded receptors to T-cellsT-cell responds only when presented with both signalsDifferent Effector Cytokines in Response to Different Pathogens (Th1 vs. Th2)
14 Antimicrobial Peptides/Defensins Four hundred peptides described to dateDefensins (3- 5-kD, four families in eukaryotes)a-defensins (neutrophils and intestinal Paneth cells)b-defensins (epithelial cells)Insect defensinsPlant defensinsDefensins appear to act by binding to outer membrane of bacteria, resulting in increased membrane permeability.May also play a role in inflammation and wound repair
15 Complement System Three pathways now known ClassicalAlternativeLectin or MBL pathway (binding to mannose-containing carbohydrates)Host cells have complement regulatory proteins on their surface that protect them from spontaneous activation of C3 molecules
16 Inflammatory Mediators in Innate Immunity Cytokines secreted by phagocytes in response to infection include:IL-1activates vascular endothelium and lymphocytesIncreases adhesiveness of leukocytesIL-6Induces B-cell terminal maturation into Ig-producing plasma cellsIL-8Induces expression of b2 integrin adhesion molecules on neutrophils, leading to neutrophil migration to infection siteIL-12Activates NK cells and induces Th1-cell differentiationIL-18TNF-aActivates vascular endothelium and increases vascular permeability, leading to accumulation of Ig and complement in infected tissues
17 Other Mediators and Molecules PhagocytesToxic oxygen radicalsPeroxidesNitric oxide (NO)Lipid mediators of inflammationProstaglandinsLTB4Platelet activating factorComplement component C5aStimulates mast cells to release histamine, serotonin and LTB4IL-1, IL-6 and TNF-aInduce acute-phase response in liverInduce feverIL-1 and IL-18 signaling pathways activate NF-kB, important in innate immunity
18 Immune Cells and Innate Immunity PhagocytesNeutrophilsMoncyte/macrophageEosinophils (to a lesser extent)NK cells (large granular lymphocytes)Antibody-dependent cell-mediated cytotoxicity (ADCC)Have two major functionsLysis of target cellsProduction of cytokines (IFN-g and TNF-a)Act against intracellular pathogensHerpesvirusesLeishmaniaListeria monocytogenesAct against protozoaToxoplasmaTrypanasoma
19 Immune Cells and Innate Immunity (cont’d) g/d T cellsTwo types of T cell receptorsOne composed of a and b chains (basic T cell antigen receptor)One composed of g and d chains (minor population of T cells)Two groups of g/d T cellsOne group found in lymphoid tissuesOne group located in paracellular space between epithelial cellsRecognizes unprocessed target antigen in absence of APC helpB-1 cells (minor fraction of B cells, do not require T-cell help)Mast cellsLocated in serosa, under epithelial surfaces and adjacent to blood vessels, nerves and glandsCapable of phagocytosisProcess and present antigen using MHC class I or II receptorsLPS can directly induce release of mast cell mediatorsComplement (C3a and C5a) induce mast cells to release mediatorsChemotaxis, complement activation, inflammationTNF-a secreted by mast cells results in neutrophil influx into infected site
20 Summary of Innate Immunity External and mechanical barriersReceptors for pathogen motifsSoluble antimicrobial proteinsPattern of cytokines produced influences adaptive response
22 Protective Role of Antibodies Against Pathogens Toxin neutralizationOpsonization/enhancement of phagocytosisSensitization for killing by NK cellsSensitization of mast cellsActivation of complement system
27 Activation of the Complement Cascade Cell Activation (anaphylatoxins)Activate inflammatory cellsInduce smooth muscle contraction and blood vessel permeabilityCytolysis ("membrane attack complexes“)Loss of cell membrane integrityOpsonizationComplement receptors on phagocytic cellsRenders cells vulnerable to phagocytosisStudy GuideWhat are immune adherence and opsonization?Why would a chemotactic factor be important in inflammation?What is the basis for chemotaxis?
29 Opsonization and Immune Adherence C3B (C4B)Facilitates adherence of bacteria, viruses and neutrophils to monocytes and macrophagesFacilitates ingestion of certain bacteria by neutrophils and monocytesFacilitates ingestion by activated macrophagesAugments mediated phagocytosis and IgG-mediated cell cytotoxicity (ADCC)Antibodyantibody may opsonize by itself, or bridge phagocyte and target cell, enhancing complement immune adherenceStudy GuideWhat is the immune adherence receptor? On what cell type is it found?
30 Chemotaxis Site of inflammation, tissue damage and immune reactions capillary blood vesselphagocyteendotheliumbasement membraneSite of inflammation, tissue damage and immune reactionsPAVEMENTINGC5aDIAPEDESISStudy GuideWhy does the granulocyte migrate out of the vessel?CHEMOTAXIS
33 Natural Killer Cells and Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)
34 Inflammation Increased blood supply to the infected area The four cardinal signs of inflammation (Cornelius Celsus, 30 BC to AD 38):rubor et tumor cum calore et doloreredness and swelling with heat and painIncreased blood supply to the infected areaIncreased capillary permeabilityMigration of leukocytes into tissues (Chemotaxis)What are the characteristic signs of inflammation?What is responsible for them?