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Innate Immunity -M261 Spring 2005 May 6, 2005 Kathleen A. Kelly Reading: Immunobiology (6 th Edition) Janeway, Travers, Walpert & Capra Chapter 2 (p. 37-100),

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Presentation on theme: "Innate Immunity -M261 Spring 2005 May 6, 2005 Kathleen A. Kelly Reading: Immunobiology (6 th Edition) Janeway, Travers, Walpert & Capra Chapter 2 (p. 37-100),"— Presentation transcript:

1 Innate Immunity -M261 Spring 2005 May 6, 2005 Kathleen A. Kelly Reading: Immunobiology (6 th Edition) Janeway, Travers, Walpert & Capra Chapter 2 (p. 37-100), and Chapter 6 (p. 209-212) Fundamental Immunology (5 th Edition) Lippincott, Williams & Wilkins Chapter 17 (p.497-517) Janeway, CA, et al. Innate Immune Recognition. Annu. Rev. Immunol. 20:197-252, 2002

2 Innate Immunity -M261 Spring 2004 Kathleen A. Kelly Innate immunity predates development of adaptive immunity Does not produce protective immunity ●No memory response ●Prerequisite for developing adaptive immunity Non-antigen-specific immunity ●Found in plants, invertebrates and vertebrates

3 Innate Immunity 1. Provides a barrier to prevent the spread of infection ●Mechanical (tight junctions, movement) ●Chemical (fatty acids, enzymes, pH, antimicrobial peptides) ●Microbiological (normal flora) ●Mucosal surfaces oNasopharyngeal, Oral, Respiratory, Intestinal tract Urogenital tract ●Skin (epithelial cells) oWounds, burns, insect bites

4 Innate Immunity 2. Identifies and eliminates pathogens ●Non-adaptive recognition systems ●Activates molecules that target the microbe and aid in it’s identification. oThese factors may be expressed at the surface or within cells, released from immune cells or are secreted and present within circulatory system

5 Innate Immunity 3. Initiates an inflammatory response ●Reaction to injury or infection oTrauma to tissues or cells oPresence of foreign matter (self vs. non-self) oInfectious agents (viruses, bacteria, fungi) ●Delivers effector molecules & immune cells to the site of infection ●Components oLeukocytes & secreted factors oBlood vessels oPlasma proteins

6 Innate Immunity 4. Provides signals to activate and regulate the type of adaptive immune response generated ●Stimulation of co-stimulatory molecules oB7 family (CD80/86, PD-L, ICOSL) oTNFR family (OX40L) ●Induction of a cytokine/chemokine response oCytokines: IL-12, IL-23, IL-4 oChemokines: CXCR1, CXCR2, CCL20 a variety and depends on stimulus

7 The Phases of Immunity

8 Identification of Microbes Recognition ●Receptors – Pattern Recognition Receptors (PRRs) oFixed in the genome, ie gene rearrangement is not needed ●Distribution oNon-clonal, ie all cells of a class are identical Differentiation ●Pathogen vs. Commensal

9 Identification of Microbes PRR ●Recognize conserved molecular patterns on microbes called microbe associated molecular patterns (MAMPs) which are not present on the host oNot limited to pathogens ●Identify a class of microbes oLPS, LTA, peptidoglycan, lipoarabinomannan, dsRNA, mannans, b-glycans ●MAMPs are often essential for microbe survival Action Time ●Immediate activation of effectors ●Delays need for adaptive immunity

10 Pattern Recognition Receptors (PRRs) Three broad classes of PRRs based on expression profile, localization, function ●1) PRRs that signal an infection oInclude the Toll Receptor Family oExpressed external or internally oActivation of “pro-inflammatory” signaling pathways  NF  B and MAP kinase signaling pathways Antimicrobial peptides (Defensins) / lysozyme, Inflammatory cytokines (TNF , IL-8, IL-1) oRegulate activation of adaptive immune response co-stimulatory molecules

11 ●2) Phagocytic (endocytic) PRRs oExpressed on the surface of phagocytic cells  (MQs, PMNs, DCs) oMediate uptake of microbe into phagocytes ●3) Secreted PRRs oSecreted by MQs, epithelial cells, liver oActivate C’, opsonize microbial cells, function as accessory proteins for MAMP recognition Pattern Recognition Receptors (PRRs)

12 Toll-like Receptor Family Curr. Opin. Hematology 9:2-10, 2002 PPR receptor ●Found both on the surface and within cells ●First discovered in Drosophila ●Currently 13 receptors o1-9 mouse & human o10 human o11-13 mouse Toll-like Receptor family

13 Intracellular PRRs: Present in the Cytosol of Host Cells 1. Protein kinase receptor (PKR) ●Activated upon binding to dsRNA (viruses) oBlocks viral & cellular protein synthesis (eIF2  ) oActivates NF  B, MAP kinase STATs & IRF signaling pathways oInduces apoptosis & IFN  production of infected cells 2. 2’-5’ Oligoadenylate Synthase & RNaseL ●Family of IFN-inducible enzymes odsRNA activates OAS oRNaseL degrades viral and host RNA oInduces apoptosis

14 Intracellular PRRs: Present in the Cytosol of Host Cells 3. NOD proteins or nucleotide-binding oligomerization domain ●Recognize intracellular peptidoglycan-derived MAMPs and transduce signals ●three distinct functional domains ocarboxy-terminal ligand-recognition domain (LRD) ocentrally located NOD oamino-terminal effector-binding domain (EBD)  CARD domains in mammals  Interacts and activates RIP2 inducing NF  B and MAP- kinase pathways

15 Structure of NOD Proteins Inohara N, & Nunez G. Nat Rev Immunol. 2003 3:371

16 NOD Proteins Inohara N, & Nunez G. Nat Rev Immunol. 2003 3:371

17 Phagocytic (endocytic) PRRs Bind Carbohydrates 1. Macrophage Mannose Receptor (C-type lectin) ●Type 1 transmembrane receptor ●Recognizes patterns of mannose residues in a certain spatial orientation unique to microbes (CRD) ●Only found on macrophages (not monocytes or PMNs) 2. Glucan Receptor (Dectin-1) ●Type 2 transmembrane receptor ●Recognizes  -1,3 &  -1,6 linked glycans ●Present on all phagocytes

18 Phagocytic (endocytic) PRRs: Cont. 3. Scavenger Receptors ●Recognize charged ligands oPolyanionic ligands (ds-RNA, LPS, LTA) oAcetylated low-density lipoproteins (LDL) ●Found on all phagocytes ●MARCO (macrophage receptor with collagenous struction) obinds bacterial cell walls but not yeast ●Phagocytose apoptotic cells onew factor MFG-E8 (released from activated macrophages and binds to apoptotic cells via phosphatidylserine)

19 Secreted PRRs activate the Complement (C’) System Complement system is activated by innate immunity Recognition by Complement receptors (CR) oCR1, CR2, CR3, CR4, C5a, C3a Comprised of plasma proteins that when activated forms a triggered enzyme cascade ●Zymogens – activated by the cleavage of other proteases oPrecursor enzymes Function ●Facilitates the uptake & destruction of pathogens by phagocytes ●Induces an inflammatory responses

20 b C4b + C2b C3b + Bb Activation of C’ System

21 Secreted Pattern Recognition Molecules Acute Phase Proteins Activation of Complement Opsonization of microbial cells Primarily produced by the liver but can be produced by phagocytes

22 Secreted Pattern Recognition Molecules 1. Collectins ●Recognizes microbial carbohydrates (CRD domain) ●Effector function mediated by collagenous domain ●Mannan-binding lectin (MBL) oRecognizes patterns of mannose & fucose residues in a certain spatial orientation unique to microbes oInitiates the lectin pathway of C’ cleaving C2 & C4 oCan function as an opsonin  Binds a receptor on phagocytes (C1qRp) ●Surfactant proteins (SP-A / SP-D) olung

23 Collectins Structure is conserved and similar to other proteins with similar function: oSome Complement proteins & Mannose Binding Protein oBinds to bacteria, fungi & viruses Function by binding microbes and are important for mediating phagocytosis of alveolar macrophages Microbe C-type Lectin domain Collagen helix  -coiled helix

24 Secreted Pattern Recognition Molecules – Cont. 2. Pentraxin ●Members include oSerum amyloid protein (SAP) oC-reactive protein (CRP) ●Recognize phosphorylcholines on microbes ●Functions as an opsonins ●Binds to C1q & activate classical C’ pathway

25 Secreted Pattern Recognition Molecules – Cont. 3. Lipid Transferases ●LPS binding protein (LBP) oOpsonin ●Bactericidal permeability increasing protein (BPI) oBactericidal protein 4. Peptidoglycan recognition proteins (PGRS) ●Recognizes peptidoglycans in evolutionarily distant organisms ●4 human PGRS ●Function is unknown oOne has bactericidal effects oTriggers a serine protease cascade in insects  ? Complement cascade ?

26 Inflammatory Response

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28 Leukocyte Adhesion

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30 Naïve and Memory T Cells Travel in Different Paths  Naïve (have not seen their antigen) T cells travel in the blood and lymphatics  Memory T cells (have been activated by their antigen) can also travel through tissues

31 Lymphocyte Trafficking Patterns of Naïve T Cells Peripheral Blood Peripheral lymph nodes Lymphatic system HEV GlyCAM-1 CD62L:selectin Chemokines CCL21 / SLC CCL19 / ELC (MIP-3  ) CCR7:chemokine receptor ICAM-1

32 Lymphocyte Trafficking Patterns of Naïve T Cells Peripheral Blood Peripheral lymph nodes Lymphatic system HEV GlyCAM-1 CD62L:selectin Chemokines CCL21 / SLC CCL19 / ELC (MIP-3  ) CCR7:chemokine receptor ICAM-1

33 Lymphocyte Trafficking Patterns of Effector/Memory T Cells Lymphatic system Any Tissue Peripheral lymph nodes Inflammation PSGL-1:selectin  4  1:Integrin CXCR3: chemokine receptor Chemokines CXCL9 / MIG CXCL10 / IP-10 CXCL11 / I-TAC HEV CD44 ICAM-1

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35 Endothelial Cell 1. Tethering 3. Firm adhesion 2. Triggering 4. Diapedesis Lymphocyte Pathogens Macrophage Cytokines Chemokines Stromal cells Blood Vessel Steps in Lymphocyte Trafficking

36 Phagocytosis ●Definition: uptake of large particles (>0.5  m) ●Actin-dependent, clathrin-independent ●High rate & efficiency of internalization Professional phagocytic cells ●Macrophages ●Neutrophils These cells have phagocytic receptors oExternal receptors  FcR, CR3, Mannose receptor oInternal receptors  TLRs

37 Macrophages (MQ) Blood - Called monocytes (1-6% WBC) Tissues - Called macrophages ●mature form of monocytes ●normally found in tissues such as gastrointestinal tract, lung, liver and spleen Functions: ●Phagocytose and kills after bactericidal mechanisms are activated (T cells) ●Produce cytokines/chemokines (initiates inflammation) ●Is an antigen presenting cell (co-stim. Molecules)

38 Neutrophils (PMN) Present in blood (55-60% of WBC) Not normally present in tissues Short lifespan - 12 hours Functions: ●First at the site of infection/injury Ingest and kill microbes after bactericidal mechanisms are activated (binding to pathogen)

39 Phagocytosis (MQ & PMN) Active process initiated by binding to pathogen Pathogen is surrounded and then internalized

40 Signaling Interactions during Phagocytosis Ann. Rev. Immunol. 20:825-852, 2002

41 Killing Mechanisms Phagosome - membrane bounded vesicle that becomes acidified Lysozome - granules that contain products that damage or kill pathogens ●Enzymes oLysozyme - dissolves cell walls of some bacteria oAcid hydrolases - digests bacteria ●Proteins oLactoferrin - binds Fe ++ needed for bacterial growth oVitamin B12-binding protein ●Peptides oDefensins and cationic proteins - direct antimicrobials

42 Killing Mechanisms - cont. Respiratory Burst ●Activated following phagocytosis ●Stimulated by PRR ●Requires increased oxygen consumption ●Produces substances that are directly toxic to the bacteria oOxygen-derived products  O 2 -, H 2 O 2 & Myeloperoxidase oNitrogen-derived products  NO (nitrogen oxide)  Produced by inducible NO synthase (iNOS) enzyme  Enzyme is induced by cytokines (LT, TNF  )

43 NADPH Oxidase Mitochondrial-independent respiratory burst P47phox & p67phox normally resides in the cytoplasma. P47phox becomes hyperhposphorylated following phagocytosis and binds to p67phox. These components move to the membrane and bind the NADPH complex resulting in an active complex.

44 Enzyme Reactions of Respiratory Burst Respiratory Burst NADPH NADP+Superoxide + dismutase 2 O 2 2 O - H 2 O 2 Myeloperoxidase ●Enzyme which is stored in primary granules of PMN & MQ and uses the products of the respiratory burst. ●H 2 O 2 + C1 - Chloramines

45 Professional APC

46 Regulation of Adaptive Response Veterinary Immunology & Immunopathology 91: 1, 2003

47 T cells Recirculate to “Find” Antigen-loaded Dendritic cells Germinal Center Efferent lymphatics Afferent lymphatics Paracortical Area Follicular Area HEV

48 Mucosal Immunity – Reading Assignment Immunobiology (6 th Edition) Janeway, Travers, Walpert and Capra Chapter 10 (p. 432-445). Neutra, MR et al Antigen sampling across epithelial barriers and induction of mucosal immune responses. Annu. Rev. Immunol. 14:275-300, 1996 Wright, JR. Immunoregulatory Functions of Surfactant Proteins. Nature Review Immunol. 5:58-68, 2005. Cheroutre, H. Start at the beginning: new perspectives on the biology of mucosal T cells. Annu. Rev. Immunol. 22:217-46, 2004. Weiner, H. Oral tolerance: immune mechanism and the generation of Th3- type TGF-beta-secreting regulatory cells. Microbes & Infection 3:947- 954, 2001. May 10, Spring 2004


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