Lecture 13: Elements of the Immune System

Review Chapter 1 Elements of the Immune System and their Roles in Defense Numerous commensal microorganisms inhabit healthy human bodies Pathogens are infectious organisms that cause disease The skin and mucosal surfaces form barriers...

Review Chapter 1 Elements of the Immune System and their Roles in Defense Numerous commensal microorganisms inhabit healthy human bodies Pathogens are infectious organisms that cause disease The skin and mucosal surfaces form barriers against infection © Garland Science 2009 Chapter 1 Elements of the Immune System and their Roles in Defense The innate immune response causes inflammation at sites of infection The adaptive immune response adds to an ongoing innate immune response © Garland Science 2009 Chapter 1 Elements of the Immune System and their Roles in Defense Immune system cells with different functions all derive from hematopoietic stem cells Most lymphocytes are present in specialized lymphoid tissues Adaptive immunity is initiated in secondary lymphoid tissues © Garland Science 2009 Chapter 1 Elements of the Immune System and their Roles in Defense The spleen provides adaptive immunity to blood infections Many secondary lymphoid tissues are associated with the gut Adaptive immune responses generally give rise to long-lived immunological memory and protective immunity © Garland Science 2009 Chapter 1 Elements of the Immune System and their Roles in Defense The immune system can be compromised by inherited immunodeficiencies or by the actions of certain pathogens © Garland Science 2009 Chapters 2 and 3 Innate Immunity  We have various defense mechanisms against pathogens Defense is based on where pathogens reside 1) on intact epithelial surfaces 2) in tissues underneath penetrated epithelial surfaces types of infections : i) extracellular(e g.. bacteria , Viruses *most spend at least some time here ii) intracellular Le g.. bacteria , viruses Intact epithelia: In tissues, underneath penetrated epithelia: Objectives: Understand the differences between innate immunity to extracellular versus intracellular pathogens. innate immunity to extracellular pathogens: - complement - macrophages, neutrophils - innate immune receptors and adhesion molecules - cell homing and extravasation - receptor signaling, gene expression, inflammatory cytokine production and their effects - acute-phase proteins innate immunity to intracellular pathogens - receptor signaling, gene expression, interferon production and their effects - NK cells Understand how the timing of the immediate innate and induced innate arms of the immune system corresponds to their distinct roles in attacking the pathogen. 1. Immediate Innate: 0 - 4 hrs 2. Induced Innate: 4hrs – 4 days 3. Adaptive: ≥ 4 days  1. Immediate Innate: 0 - 4 hrs Immediate Innate Immune Response 0-4 hrs. after infection preformed effector molecules > start working immediately remain present throughout , but can also the immune - complement (alternative pathway) response - defensins - pentraxins resident effector cells in infected tissue - macrophages - dendritic cells  Breach of epithelium (skin or mucosal surface ) à activation of innate immunity Major consequence of innate immunity : *inflammation * One of first weapons : complement - soluble proteins made by liver - present in blood, lymph, extracellular fluids - coats surface of bacteria or extracellular viruses v process à pathogen is more easily phagocytosed ** in absence of complement, many bacteria are called opsonization resistant to phagocytosis (they have thick polysaccharide capsules)  Complement Made up of over 30 proteins > def. enzymes proteins that break Many components are inactive proteases down Infection triggers complement activation cascade Most important component : C3 - absence of C3 : severe infections - infections always lead to cleavage of C3 into C3a (small) and C3b (large)  (attachment of C3b to bacterial surface) (by a protease) covalent bond (irreversible) V (chemoattractant) 3 pathways of complement activation : 1) alternative (first to act) 2) lectin need to be induced (part of induced innate immune response) 3) classical **all lead to : 1) C3 cleavage 2) deposition of C3b on bacterial surface Lopsonization ( 3) recruitment of similar effector mechanisms to destroy pathogen (phagocytosis)  · there thinga in appe 2 ↓  Alternative Pathway of Complement Activation formation of C3 convertases : proteases that cleave and activate C3 a. soluble : iC3Bb > produce enzyme from C3 complement molecules - attaches to pathogen surface iC3Bb : soluble C3 convertase > breaks down/cuts other 3 molecules * intial hydrolysis of C3 is catalyzed by environment near bacterial surface b. alternative : C3bBb - These can also become convertases I signal is thus amplified) C3bBb : alternative C3 convertase positive feedback à amplification, coating of surface (opsonization)  Regulation of Complement Activation Complement control proteins > control activity of complement cascade 1. plasma proteins a. properdin (factor P) : stabilizes C3bBb b. factor H + factor I : inactivate C3b MEMORIZE - importance of regulation revealed by genetic deficiency of factor I à leads to depletion of C3 reservoirs à less efficient bacterial clearance 2.membrane proteins > kick off C3D molecule HUMAN Self , prevents them from sticking to surface of a. decay accelerating factor (DAF) b. membrane co-factor protein (MCP) - both disrupt C3 convertase C3bBb on human cell surface Regulation of Complement Activation  Regulation of Complement Activation Combined effect of promoting and regulating C3 activation : deposit C3b on pathogen surface, not human cells àdiscrimination of human cells (“self”) from invading microbes (“non-self”) > major mechanism of tolerance àdestruction of pathogen, not healthy tissue  How is complement used by innate immune cells ? First effector cells encountered : macrophages (MØ) -mature form of monocytes - phagocytose many pathogens using MØ receptors e.g.: CR1, CR2, CR3, CR4 (complement receptors): bind C3b fragments deposited on microbes from alternative pathway - opsonization : coating of pathogen with 7 I protein that facilitates phagocytosis èopsonization + phagocytosis : recognition and destruction of Fun fact : antibodies can pathogen at start of infection also opsonize How is complement used by innate immune cells ?  Terminal Complement Proteins 1) C5 : similar to C3 (small)(large) - cleaved by C5 convertase into C5a, C5b - C5b initiates formation of membrane attack complex (MAC) à makes holes in cell membranes alternative C5 convertase > chemoattractant  Terminal Complement Proteins 2) C6, C7 : recruited by C5 - hydrophobic site in C7 inserts into membrane 3) C8 : binds C5b and exposes hydrophobic site, inserts into membrane to start polymerization of C9 4) C9 : forms transmembrane holes ring perforates the membrane of the pathogen z  Terminal Complement Proteins Deficiency in C5-C9 : not dramatic - inherited deficiency may cause more susceptibility to certain bacterial infections - not uncommon (Japan : 1/40 heterozygous) (for mutation) SERIOUS ! - inherited deficiency in C3 is more severe - results in frequent bouts of infection; presents at childhood  Regulation of Terminal Complement Don't need to Proteins know the names , just the types (soluble proteins + membrane proteins) 1) soluble proteins : S protein, clusterin, factor J - prevent C5b/C6/C7 from binding human cell membranes 2) membrane proteins : - HRF : homologous restriction factor - CD59 : protectin à prevent C9 recruitment ** paroxysmal nocturnal hemoglobinuria : complement- mediated lysis of RBC (attack of “self”) - caused by imparied synthesis of GPI tail that links CD59, DAF, & HRF to human cell membrane  C3a and C5a : anaphylatoxins caused effects on blood vessels > by making them leaky and larger increase inflammation at site of complement activation - bind receptors on several cells (phagocytes, mast, endo’s) - attract neutrophils and monocytes - trigger release of histamine and other A D substances : increase vascular perm. à facilitates plasma protein and cell transport to infection * if systemic, they can induce * > characterized by drop in BP anaphylactic shock : acute inflammatory response > rather than occurring simultaneously in tissues throughout body just at the site of the pathogen Other Plasma Proteins Inhibit Infection > closes off where the pathogen can go lipids ( 1) coagulation system : clots (clot formation facilitated by - activated by blood vessel damage 2) kinin system (bradykinin) : ↑ vasodilation - triggered by tissue damage 3) protease inhibitors - proteases break down tissues, disseminate pathogen, inactivate antimicrobials 7 a K a IgE. - a2-macroglobulins inhibit these proteases.. * * Protease Inhibitors resembles protein substrate of protease bound by receptor on hepatocytes, MØ, fibroblasts and cleared from circulation > inactivates mechanism for tissues pathogen to propagate to other  Antimicrobial peptides - have both hydrophilic and hydrophobic parts Defensins : the major human family of antimicrobials - amphipathic, penetrate microbial membr. a : expressed by neutrophils, Paneth cells - cryptdins (HD5, HD6) (Paneth cells also secrete lysozyme) b : epithelial cells of skin, respiratory tract, urogenital tract  Antimicrobial peptides Defensins (cont’d): - for human cell protection : - produced in inactive form that needs to be cleaved - function poorly in physiological conditions, but are active in tears, sweat, phagosome, etc. - in neutrophils : defensins kill phagocytosed pathogens - in Paneth cells : secreted defensins maintain normal gut flora Chelp kill pathogenic bacterial  Defensins: 6a’s, 4b’s differ in aa sequence à different specificities for microbes (e.g. Gram + vs. Gram – bacteria) differ in area protected (respiratory tract vs. intestine) Defensins denature microbial toxins  immediate innate (Also part of Pentraxins response immune plasma proteins that bind microbes and deliver them to phagocytes function similarly to antibodies of adaptive immune system 2 classes: 1 end of pentraxin binds to microbe, other binds to receptor on immune cell > same as receptor on antibodies Fornai et al., Immunity and Ageing 13: Article number 25 (2016) 1. Immediate Innate: 0 - 4 hrs 2. Induced Innate: 4hrs – 4 days 3. Adaptive: ≥ 4 days  2. Induced Innate: 4hrs – 4 days Induced Innate Immune Response after immediate innate immune response effective completely eliminating > was not at the pathogen 4 hrs. – 4 days after infection new DNA transcription and protein synthesis recruitment of soluble effector molecules and effector cells to infected tissue Induced Innate Immune Response resident effector cells in infected tissue - macrophages, dendritic cells internal signaling : gene expression changes - TLR receptor signaling Le macrophages. g. in > general function : cytokines are proteins external signaling: cytokine production produced by one cell and sent to another cell - inflammatory cytokines: all pathogens - interferons: intracellular pathogens recruited effector cells - neutrophils, NK cells induced complement pathways - lectin and classical pathways  Innate Immune Receptors differentiate between self, non-self, and altered self Major Types of Innate Immune Cells: macrophages, neutrophils, dendritic cells, NK cells Pathogen-Associated Molecular Pattern (PAMP): - structural feature on microbe surface > recognized by receptors on human cells Pattern-recognition receptor (PRR): - molecule on immune cell surface that recognizes and binds PAMPs common to many types of pathogen à need to distinguish between self, non-self, and altered self seg , cancer cells , virus-infecteda  Innate Immune Receptors Work with complement receptors to remove pathogen Many microbial ligands are carbohydrates and lipids not present on eukaryotic cells Receptors for these ligands: 1) lectins : receptors that recognize carbohydrates - mannose receptor, glucan receptor on MØ (macrophages) 2) scavenger receptor on MØ : binds (-) charged ligands (polysaccharides, bacterial cell wall components, nucleic acids), apoptotic human cells > develop negative charge on external side of the cell (flipped membrane ) 3) CR3, CR4: bind complement and microbial antigens  Innate Immune Receptors (cont’d) -simultaneous engagement of many molecules à irreversible attachment to MØ -binding triggers receptor-mediated endocytosis: pathogen-bound receptor à phagosome à phagolysosome 4) other MØ receptors : trigger cytokine release MEMORIZE L -Toll-like receptor (TLR), NOD-like receptors, RLR receptors  Toll-Like Receptors (TLRs) Structure similar to Toll receptor in Drosophila Several types, each specific for common elements of different microbial products (LPS, DNA, RNA) Expressed by different cell types MØ : TLR4, recognizes LPS and other molecules on Gram (-) bacteria - causes gene expression that triggers induced innate immune responses & inflammation à inflammatory cytokines essential for induced innate response and for setting up adaptive response  Toll-Like Receptors (TLRs) 2 major types : i. Plasma membrane-bound : sense molecules on microbial surface (direct contact made with extracellular pathogen) ii. Endosomal membrane-bound : sense mostly viral DNA & RNA released in extracellular environment and taken up by cells intracellular pathogens > also recognize  MOST IMPORTANT (MEMORIZE ~  Toll-Like Receptors (TLRs) > found extracellularly Most studied : TLR4 - binds LPS on microbe surface - generates intracellular signals through cytoplasmic domain, results in synthesis and release of inflammatory cytokines  TLR signaling 2 responses : TLR4 unbound: 1) NFkB pathway (most TLRs) * major role in innate & adaptive responses i. activation of nuclear factor kB (NFkB) nucleus - normally held inactive by inhibitor of kB (IkB) in cytoplasm - antigen binding Antigen to TLR binding causes to TLT activation causes activation after TLR4 binds andand nuclear translocation of NFkB nuclear translocation of NFκB bacterial antigen: ii. nuclear NFkB activates expression of intracellular signaling genes that create a state of inflammation  TLR signaling receptor adaptor ** kinase : adds phosphate group to specific site in another protein ; critical to signaling  TLR signaling Importance of NFkB signaling - genetic lack of IKK subunit called NEMO (NF-kB Essential MOdifier) results in X-linked hypohydrotic extodermal dysplasia and immunodeficiency (NEMO deficiency) à impaired activation of NFkB ; susceptible to bacterial infections because of inefficient MØ activation  TLR signaling 2) interferon pathway (TLR3,TLR7) - response to viral infections, intracellular bacteria > IRF = Interferon response factor - IRF7 or IRF3 translocates into nucleus, results in synthesis and > IFNX + IFNB secretion of type I interferons à result: infected cell will be killed  TLR signaling * With TLR signaling, cells of innate immune response can tailor response to different type of pathogen à extracellular bacteria : inflammatory cytokines (via TLR4 receptor and NF-kB) à viral : interferons (via TLR3,7 receptors and IRF3,7) Mutant TLR signaling can cause autoimmunity > - receptor on endosome recognizes parts of virules and intracellular pathogens - -causes it to recognize human DNA Nature 605: 349-356 (2022)  Cytoplasmic Receptors also recognize bacteria vs. viruses NOD-like Receptors (NLR) RIG-1-like receptors (RLR) - recognize parts - recognize viral RNA of cell wall from - kinase cascade activates phagocytosed IRF3 and IRF7 bacteria à type I interferons are - kinase cascade produced activates NF-kB à inflammatory cytokines are produced  Consequences of MØ Activation (inflammatory ( ànuclear translocation of NFkB induces↑cytokine gene expression àcytokines and other MØ secretions cause inflammation and recruit other cells (mostly neutrophils) because of changes in local capillaries recruits complement > also * cytokines : small signaling proteins made in response to external stimuli ; influence other cells by binding to specific receptors Pro-inflammatory cytokines secreted by MØ IL-1b (interleukin-1b) change adhesion properties of blood *master regulator of inflammation vessels; allow effector cells to enter TNF-a tissue from blood IL-6 (interleukin-6) IL-12: induces NK lymphocyte proliferation (innate antiviral response) CXCL8 (IL-8) and CCL2 & *chemokines : small proteins that attract specific leukocytes - differ in cell of origin and cell recruited - bind to specific receptors > HIGH LOW To - cells follow concentration gradient à recruit neutrophils (CXCL8), monocytes (CCL2) i. alter cell adhesive properties (à leave blood, enter tissue) ii. guide neutrophils, monocytes along gradient of chemokine (Other inflammatory mediators : C3a, C5a, prostaglandins, nitric oxide, peroxides) Pro-inflammatory cytokines secreted by MØ used in covid by Covid caused T macrophages in the lungs to be overactivated IL-1 inhibitors now approved for clinical use: anakinra: IL-1 receptor antagonist canakinumab: neutralizes IL-1b rilonacept: neutralizes IL-1a and IL-1b > pyrogen ~ cause fever  TNF-a : release must be controlled Stimulates vascular endothelial cells to make platelet activating factor (PAF) à triggers blood clotting, helps block local blood vessels and restricts infection Systemic infection : pathogen is disseminated throughout the body via bloodstream à widespread TNF-a production by liver, spleen à dilation of blood vessels, massive systemic edema à septic shock CHUGE drop 39) in - widespread clotting in capillaries, organ failure because of lack of blood supply *people with a defective TLR : - increased risk of septic shock - weaker response to LPS - pathogen cannot be eliminated from site of infection - bacteria may enter the blood à leads to widespread TNFa production Fun fact also : dendritic cells cells are Phagocytic Cells phagocytic Principal means to destroy pathogens 2 major types in innate immune system: 1) macrophage (MØ) - long-lived, reside in tissues - immediate response to infection - phagocytosis, signal to activate other cells 2) neutrophils - short-lived, circulate in blood - recruited by MØ  Neutrophils Granulocytes (granules in cytoplasm) Polymorphonuclear leukocytes (many lobes) Smaller than MØ (“microphages”) Most abundant WBC in blood (~50 billion circulating!) Short life span ( Ans : Using chemokines ! Neutrophils have surface receptors for inflammatory mediators (e.g. CXCL8, C5a) à ligand/receptor interactions induce : i. expression of adhesion molecules on neutrophil ii. expression of ligands for adhesion molecules on vascular endothelial cells (VEC) in capillaries near infection ~ expression of chemokines (green) is highest at site of infection à neutrophils bind to blood vessel and squeeze into tissue  How do neutrophils arrive at infection ? Extravasation : migration from vessel to tissue 1) neutrophil is slowed down by VEC (only > inflammation) when there chemokines is are released - neutrophil adhesion molecules bind upregulated ligands for these molecules on VEC - reversible “adhere and roll”  How do neutrophils arrive at infection ? Extravasation (cont’d) 2) tight binding - mediated by adhesion molecules on neutrophil and VEC - normally weak interactions, chemokines induce stronger ones è neutrophil stops rolling 3) diapedesis : neutrophil squeezes between adjacent VEC and reaches basement membrane of ECM - neutrophil secretes proteases to break down membrane  How do neutrophils arrive at infection ? Extravasation (cont’d) 4) migration to center of infection in tissue> CXC18 : ILS neutrophil * à driven by gradient of chemokine (CXCL8) Lattracts - Neutrophils sense chemokines - chemokines are most concentrated at the site of infection (low to high All white blood cells leave the blood, migrate to infected tissue at some point : homing ** where & when determined by cytokines & chemokines  Leukocyte rolling & extravasation Nature Immunology 15:45 (2014) Extravasation  How do neutrophils kill pathogens? 1) Target identification : - many phagocytic receptors for microbial products - complement receptors for L opsonized microbes distinguishing feature of neutrophils is their toxins - range of engulfed material > that of MØ  How do neutrophils kill pathogens? > function : holds toxins 2) Fusion of phagosomes with neutrophil granules - 3 major types : i. azurophilic (primary) - lysozymes, defensins, proteases, others - acidic environment keeps them inactive ii. gelatinase - gelatinase enzyme: restricts bacterial growth iii. specific (secondary)> after bacterium has been phagocytosed - lactoferrin (competes for iron and copper), lysozyme, NADPH oxidase - NADPH oxidase produces superoxide radicals by consuming O2 (respiratory burst) à removes H+ ions and produces hydrogen peroxide (toxic!) à raises pH of phagosome à antimicrobial peptides are activated (why have a separate compartment for each type of granule ?) 3) Fusion of phagosome with lysosomes à acid hydrolases finish the job  Importance of respiratory burst Chronic granulomatous disease - genetic defect in NADPH oxidase subunits à no respiratory burst after phagocytosis, so pH of phagosome cannot be raised to activate antimicrobials à leads to chronic bacterial and fungal infections that are localized in nodules (granulomas)  Death of neutrophils because they cannot replenish granules, neutrophils die quickly by apoptosis àphagocytosed by MØ also lyse by netosis (nucleus swells and bursts) and form neutrophil extracellular traps (NETs) to trap and kill pathogens V sticky parts of neutrophils NET : matrix of neutrophil histones, antimicrobials that get glued together Salmonella if neutrophils terminate infection, > stop production and chemokines of inflammation MØ stop neutrophil recruitment and begin repair  Systemic effects of inflammatory cytokines in innate immunity IL-1/IL-6/TNF-a 1) induce fever (systemic) - act on hypothalamus and muscle, fat cells to generate heat - molecules that induce fever : pyrogens - helps fight infection : à some pathogens grow & replicate faster at T< 37o à helps prevent energy use on other body activities à helps human cells resist the effects of TNFa  Systemic effects of inflammatory cytokines in innate immunity IL-1/IL-6/TNF-a (cont’d) > induced during acutely induced innate Immu 2) produce acute-phase response (systemic) - change spectrum of soluble plasma proteins made by liver cells : acute phase proteins (~1000 fold ↑) i. mannose binding lectin (MBL) ↑↑ - binds carbohydrates (CHOs) of bacteria, viruses, fungi, protozoans MBL-associated serine protease à geometry allows multipoint attachment to repetitive structures on pathogens but not human cells - MBL bound to pathogen : - triggers lectin pathway of complement > by 23b - opsonizes bacteria, facilitates phagocytosis  Systemic effects of inflammatory cytokines in innate immunity acute-phase proteins (cont’d) ii. C-reactive protein (CRP)> part of classical pathway - binds phosphocholine of bacterial and fungal cell walls, but not human cells - opsonizes bacteria, triggers classical pathway of complement in absence of antibody haven't antibody because iii. serum amyloid A protein absent we > triggered adaptive immune response - induces inflammatory cytokine production in MØ’s iv. fibrinogen: blood clotting - localizes pathogen and prevents spread  Lectin pathway of complement activation binding of MBL to bacterial surface à cleaves C4 (similar to C3), and C2 (similar to factor B) anaphylatoxin (recruits) active enzyme “classical” C3 convertase then, C3b activates factor B fixation to pathogen à C3bBb (alternative C3 convertase) Lectin pathway of complement activation contributes more to complement fixation because C3 >> C4 in blood  Lectin pathway of complement activation genetic deficiencies in MBL are common (> 10% in humans) à can result in severe meningitis  Classical Pathway of complement activation (triggered by C-reactive protein) C1 binding of C1 to C-reactive protein on pathogen activates protease à cleaves C4 and C2 C4bC2a (classical C3 convertase) fixation to pathogen  (review) 3 pathways of complement activation : 10-th ; immediate innate immune response) 1) alternative : main pathway at start of infection 2) lectin increased complement activation later; 3) classical induced by acute-phase proteins all lead to : 1) C3 activation 2) deposition of C3b on bacterial surface Copsonization 3) recruitment of similar effector mechanisms to destroy pathogen (phagocytosis macrophages) (e g..  Defense against intracellular viruses (NK cells) type I interferons : made by any > RBCs can't be infected human cell infected with virus virus , by a SO INF not found there - interfere with viral replication - signal neighboring cells to prepare for virus - alert immune cells of viral infection - make virus-infected cells targets for NK cells almost all human cells can make interferons and their receptors (exception : R& x) - expression stimulated by infection  Type I Interferons many forms : IFN-b, IFN-a > MEMORIZE THESE ONLY (others : IFN-d, -k, -l, -t, -w) synthesis is induced by viral infection or binding to signaling receptor (ds RNA binding to TLR3) - ds RNA not found in healthy human cells, but forms some viral genomes can act in both > def activates itself (same all that autocrine and. Produced INF) paracrine fashions > def. activates nearby cells  Type I Interferons interferon response positive feedback loop: amplification infected cell will stop making A proteins (including -degrade viral RNA -prevent protein synthesis  Type I Interferons boost immune response : investigating uses as therapies for cancer, hepatitis, MS plasmacytoid dendritic cell (different from conventional dendritic cell) - produce huge amts. of type I IFN - rare cell found in blood and lymphoid tissues - also called IPC (interferon producing cell)  NK (natural killer) cells 5-25% of lymphocytes larger than B and T cells, cytoplasmic granules provide innate immunity against intracellular infections migrate from blood to tissues in response to inflammatory cytokines  NK (natural killer) cells respond quickly to infection (already partially activated in circulation) 2 functions : i. kill infected cells (stimulated by IFN-a,b) > pro-inflammatory cytokines produced by ii. produce cytokines (stimulated by IL-12) macrophage - IFN-g (type II IFN): further activates MØ would activate adaptive immune response M sufficient innate resp. insufficient innate resp. interact with dendritic cells (suppress/activate)  NK (natural killer) cells Viral infection of human cell triggers IFN response Immune response to virus: infected cells produce type I IFN (IFNa, IFNb) (start at 4 days - induces proliferation and differentiation of NK cells NK cells recognize and kill infected human cells by inducing them to die by apoptosis mechanism for cell > Major death (why ? prevents cell from releasing cell contents when it dies , inducing additional inflammation which other cell death mechanisms would do , 1e g.. necrosis)  NK (natural killer) cells many receptors: (mostly bind proteins) varied ligands : expression on target cell is altered because of infection or malignancy (cancer) > inactivating NK cells - on healthy cell : inhibitory ligands >> activating - producing antigen signaling NK cell to kill infected cell - on infected cell: inhibitory ligands kill dendritic cells (no adaptive immune response) NK cells Low > signal - activation of dendritic cell (activate adaptive immune response SUMMARY Chapter 2 Innate Immunity A variety of defense mechanisms have evolved to eliminate the different types of pathogen Complement is a system of plasma proteins that marks pathogens for destruction At the start of an infection, complement activation proceeds by the alternative pathway © Garland Science 2009 Chapter 2 Innate Immunity Regulatory proteins determine the extent and site of C3b deposition Phagocytosis by macrophages provides a first line of cellular defense against invading microorganisms The terminal complement proteins lyse pathogens by forming a membrane pore © Garland Science 2009 Chapter 2 Innate Immunity Small peptides released during complement activation induce local inflammation Several classes of plasma protein limit the spread of infection Defensins are a family of variable antimicrobial peptides © Garland Science 2009 Chapter 2 Innate Immunity Innate immune receptors distinguish features of microbial structure Toll-like receptors sense the presence of infection Signaling through Toll-like receptors leads to two different cytokine responses © Garland Science 2009 Chapter 2 Innate Immunity Activation of resident macrophages induces inflammation at sites of infection Neutrophils are dedicated phagocytes that are summoned to sites of infection The homing of neutrophils to inflamed tissues involves altered interactions with vascular endothelium © Garland Science 2009 Chapter 2 Innate Immunity Neutrophils are potent killers of pathogens and are themselves programmed to die Inflammatory cytokines raise body temperature and activate hepatocytes to make the acute- phase response The lectin pathway of complement activation is initiated by mannose-binding lectin © Garland Science 2009 Chapter 2 Innate Immunity C-reactive protein triggers the classical pathway of complement activation Type I interferons inhibit viral replication and activate host defenses NK cells provide an early defense against intracellular infections © Garland Science 2009 Chapter 2 Innate Immunity NK-cell receptors differ in the ligands they bind and the signals they generate © Garland Science 2009 High energy thioester bond is key to C3 function