WhatWhat youyou needneed toto knowknow aboutabout innateinnate immunityimmunity JenniferJennifer KoKo MD,MD, PhDPhD ClevelandCleveland ClinicClinic Immunology/PathologyImmunology/Pathology andand LaboratoryLaboratory MedicineMedicine InnateInnate ImmunityImmunity FirstFirst lineline ofof defense,defense, immediateimmediate defensedefense DayDay toto dayday protectionprotection OnlyOnly whenwhen innateinnate defensedefense bypassed,bypassed, evadedevaded oror overwhelmedoverwhelmed isis adaptiveadaptive immunityimmunity requiredrequired NonNon--specificspecific RecognizeRecognize pathogenspathogens inin aa genericgeneric wayway DoesDoes notnot conferconfer longlong lastinglasting oror protectiveprotective immunityimmunity toto hosthost EvolutionarilyEvolutionarily older,older, foundfound inin primitiveprimitive organismsorganisms InnateInnate ImmunityImmunity andand InflammationInflammation 1)1) RespondRespond rapidlyrapidly toto tissuetissue damagedamage physicalphysical andand chemicalchemical barrierbarrier recruitmentrecruitment ofof immuneimmune cellscells toto sitesite ofof injuryinjury 2)2) LimitLimit spreadspread ofof infectioninfection identificationidentification andand removalremoval ofof foreignforeign substancessubstances activationactivation ofof thethe complementcomplement cascadecascade activationactivation ofof coagulationcoagulation cascadecascade 3)3) InitiateInitiate adaptiveadaptive immuneimmune responseresponse antigenantigen presentationpresentation andand cytokinecytokine productionproduction 4)4) InitiateInitiate tissuetissue repairrepair InnateInnate ImmunityImmunity –– Physical/ChemicalPhysical/Chemical BarriersBarriers Breach of physical barrier -“resting” innate immune cells become activated to kill microbes, secrete cytokines to recruit and activate additional leukocytes, and to promote systemic killing and removal of microbes. InnateInnate ImmunityImmunity-- 11stst respondersresponders InnateInnate ImmunityImmunity-- Monocytes/MacrophagesMonocytes/Macrophages - MonocyteMonocyte --derivedderived macrophagesmacrophages ““largelarge eaterseaters ”” oror histiocytes,histiocytes, areare presentpresent inin allall tissuestissues - ““SentinelsSentinels ”” ofof immuneimmune systemsystem -- surveysurvey forfor ““foreignforeign ”” invadersinvaders - ForeignForeign microbesmicrobes areare recognizedrecognized viavia variousvarious cellcell surfacesurface andand intracellularintracellular receptorsreceptors - ReceptorReceptor ligationligation andand cytokinescytokines causescauses macrophagemacrophage activationactivation - ActivatedActivated macrophagesmacrophages - Digest and present antigens from microbes - Produce chemokines, cytokines, other molecules to recruit other immune cells MacrophageMacrophage PhagocytosisPhagocytosis Microbe killing= •Phagosome + lysosome = phagolysosome •Nitric oxide (nitric oxide synthase, iNOS2) •Superoxide anion (NADPH oxidase, -Macrophages kill respiratory internalized microbes burst) via reactive oxygen and •Hydrogen nitrogen species peroxide (superoxide dismutase) Phagocyte Toll receptors are stimulated by Pathogen Associated Molecular Patterns (PAMPs) NOD-like receptor (NLR) proteins are intracellular pattern recognition receptors (PRRs) Induced Innate Responses mediated by cytokines secreted by stimulated sentinel cells Chemokines secreted by stimulated sentinel cells recruit additional immune cells InnateInnate ImmunityImmunity--MacrophageMacrophage Systemic Complement Inflammatory •MBL Cascade Response •TNF α •IL-6 •IL-1 •Pattern Recognition Receptors •Toll-like receptors •NLRs •Macrophage Phagocytosis mannose receptor (clearance of •Macrophage •Scavenger chemokines/cytokines receptors microbes) •Co-stimulatory molecules •CD80/86 •Neutrophils •TNF α •IL-8 Recruitment of other cells Cytokine mediated vascular dilation and vascular permeability facilitate neutrophil extravasation into infected tissues -Macrophage activation causes degradation of membrane phospholipids and rapid production of prostaglandins, leukotrienes and platelet-activating factor which act with cytokines directly on smooth muscle and endothelial cells Cytokine induced adhesion cytokines and chemokines mediate neutrophil weak and firm adhesion to vascular endothelium InnateInnate ImmunityImmunity-- 11stst respondersresponders Neutrophils Essential to innate immunity, hallmark of acute inflammation Most prevalent WBC in blood with 50-100 billion produced per day 55% bone marrow weight dedicated Migrate in response to IL-8, C5a, leukotrienes, fMLP via chemotaxis Circulate 5.4 days, live in tissue 1-2 days Limit propagation of certain pathogens Limit host damage due to inflammation Phagocytosed by macrophages after pathogen digestion Neutrophil NET formation InnateInnate ImmunityImmunity--MacrophageMacrophage Systemic Complement Inflammatory •MBL Cascade Response •TNF α •IL-6 •IL-1 •Pattern Recognition Receptors •Toll-like receptors •NLRs •Macrophage Phagocytosis mannose receptor (clearance of •Macrophage •Scavenger chemokines/cytokines receptors microbes) •Co-stimulatory molecules •CD80/86 •Neutrophils •TNF α •IL-8 Recruitment NETosis of other cells Cytokines from PAMP-stimulated sentinel cells stimulate the production of acute phase proteins, which opsonize a large spectrum of pathogens bearing common pathogen associated molecular patterns There are two innate mechanisms by which complement can be activated: the lectin pathway and the alternative pathway Complement feeds forward to activate and increase macrophage and neutrophil phagocytosis Complement can form the membrane attack complex, which leads to the lysis of target pathogens The spread of viruses is limited by the interferon response Viral nucleic acids stimulate the production of interferon by the infected cell, which mediates both autocrine and paracrine protective responses InnateInnate ImmunityImmunity-- 11stst respondersresponders NK cells •Overlap innate and adaptive immunity •Stimulated by Type I interferons •Kill cells with down-regulated MHC I expression •Down-regulated by viruses and tumors trying to avoid CD8+ T-cell killing •Kill “non-self” via mostly shared mechanisms with cytotoxic T-cells •TRAIL •GranzymeB •Perforin InnateInnate ImmunityImmunity andand InflammationInflammation 1)1) RespondRespond rapidlyrapidly toto tissuetissue damagedamage physicalphysical andand chemicalchemical barrierbarrier recruitmentrecruitment ofof immuneimmune cellscells toto sitesite ofof injuryinjury 2)2) LimitLimit spreadspread ofof infectioninfection identificationidentification andand removalremoval ofof foreignforeign substancessubstances activationactivation ofof thethe complementcomplement cascadecascade activationactivation ofof coagulationcoagulation cascadecascade 3)3) InitiateInitiate adaptiveadaptive immuneimmune responseresponse antigenantigen presentationpresentation andand cytokinecytokine productionproduction 4)4) InitiateInitiate tissuetissue repairrepair Adaptive response initiation: Antigen presentation to T cells The context in which macrophage-derived dendritic cells present antigen to T-cells determines the type of adaptive T cell response that follows ImmuneImmune surveillancesurveillance inin cancercancer CarcinogenCarcinogen--inducedinduced tumorstumors arisearise moremore frequentlyfrequently andand quicklyquickly inin immunodeficientimmunodeficient micemice CancerCancer cellscells thatthat arisearise inin immunodeficientimmunodeficient micemice areare inefficientinefficient atat initiatinginitiating secondarysecondary tumorstumors inin syngeneicsyngeneic immunocompetentimmunocompetent micemice ImmuneImmune surveillancesurveillance inin cancercancer HeavyHeavy CTLCTL andand NKNK cellcell infiltrationinfiltration predictspredicts improvedimproved outcomeoutcome inin severalseveral humanhuman tumorstumors ImmunosuppressedImmunosuppressed organorgan transplanttransplant recipientsrecipients developdevelop donordonor --derivedderived cancercancer fromfrom ostensiblyostensibly tumortumor --freefree donorsdonors ImmuneImmune escapeescape inin cancercancer ClinicallyClinically apparentapparent tumorstumors variablyvariably suppresssuppress thethe antianti --tumortumor immuneimmune responseresponse TumorTumor --associatedassociated inflammationinflammation cancan enhanceenhance tumortumor progressionprogression Immunoediting Normal Cells •Inflammation/radiation/carcinogens/viruses Transformed Cells Protection •Tumor antigens/peptide-MHC I/ MHCII cross-presentation/NKG2D 3) Escape/Tumor Progression 1) Elimination/Immunosurveillance •T regulatory cells – IL-10 and TGF β •IFN γ and •Tumor-derived cytokines, growth IFN α/β factors, chemokines •Perforin •Trail •Myeloid-derived suppressor •Th1 and T c T cells, NKT, NK, cells (MDSC) γδT cells 2) Equilibrium/Tumor Persistence •Genetic instability and immune selection •Tumor variants •Immune exhaustion/inhibition •Tumors may remain dormant Adapted from Dunn G et al, Nat Rev Immunol 6, 836-48 (2006). ChronicChronic InflammationInflammation hashas aa knownknown rolerole inin cancercancer initiationinitiation Tobacco,Tobacco, asbestosasbestos BronchialBronchial CACA AlcoholAlcohol HepatocellularHepatocellular CA,CA, GastricGastric CA,CA, PancreaticPancreatic CACA HelicobacterHelicobacter pyloripylori MALTMALT lymphomalymphoma ShistosomaShistosoma bladderbladder CACA HCVHCV HepatocellularHepatocellular CACA HPVHPV CervicalCervical CACA EndogenousEndogenous inflammationinflammation inin inflammatoryinflammatory bowelbowel diseadiseasese