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RECOGNITION BY SOLUBLE MOLECULES MANNOSE BINDING LECTIN

RECOGNITION BY SOLUBLE MOLECULES MANNOSE BINDING LECTIN. PHAGOCYTES ARE ABLE TO RECOGNIZE PATHOGENS. MANNOSE RECEPTOR MANNOSE BINDING LECTIN. Toll receptor. CR3. Toll receptor. OTHER PATTERN RECOGNITION MOLECULES. E ukariotic cells. Mannose.

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RECOGNITION BY SOLUBLE MOLECULES MANNOSE BINDING LECTIN

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  1. RECOGNITION BY SOLUBLE MOLECULES MANNOSE BINDING LECTIN

  2. PHAGOCYTES ARE ABLE TO RECOGNIZE PATHOGENS MANNOSE RECEPTOR MANNOSE BINDING LECTIN Toll receptor CR3 Toll receptor OTHER PATTERN RECOGNITION MOLECULES

  3. Eukariotic cells Mannose GLYCOSYLATION OF PROTEINS IS DIFFERENT IN VARIOUS SPECIES Prokariotic cells Galactose Glucoseamin Neuraminidase Mannose

  4. Mannose Bacterium Mannose Receptor MANNOSE RECEPTORS ON PHAGOCYTES Macrophage/dendritic cells

  5. PATTERN RECOGNITION BY MANNAN BINDING LECTIN Bacterium lysis Complement activation LECTIN PATHWAY CR3 Macrophage Phagocytosis Strong binding No binding

  6. COLLABORATION OF EFFECTOR MECHANISMS

  7. COMPLEMENT ACTIVATION COMPLEMENT Lysis of bacteria Complement-proteins Inflammation Chemotaxis Bacterium Lectin pathway Alternative pathway Complement-dependent phagocytosis MECHANISMS OF INNATE IMMUNITY Antigen + Antibody ACQUIRED IMMUNITY Few minutes – 1 hour Enzymes get fragmented, complement activity can be exhausted

  8. Degradation PRR ACTIVATION Bacterium Intracellular killing Phagocyte Uptake Antigen + Antibody ACQUIRED IMMUNITY Antigen presentation T cell ACQUIRED IMMUNITY MECHANISMS OF INNATE IMMUNITY PHAGOCYTOSIS 0.5 - 1 hours The amount of internalized particles is limited

  9. Failure of phagocytes to produce reactive oxigen species in chronic granulomatous didease PROTECTION against bacteria and fungi is down regulated

  10. INFLAMMATION – ACUTE PHASE RESPONSE PRR TNF- neutrophil LPS IL-12 NK-cell TNF- IL-1 IL-6 Bacterium IFN macrophage cytokines Few hours ACUTE PHASE RESPONSE LPS (endotoxin) (Gram(-) bacteria) DANGER SIGNAL ACTIVATION TNF- IL-1 IL-6 Kinetics of the release of pro-inflammatory citokines in bacterial infection Plasma level hrs MECHANISMS OF INNATE IMMUNITY

  11. Cytokines/chemokines produced by activated macrophages - local and systemic effects Szisztémás hatás

  12. RECOGNITION CYTOPLASMIC SENSORS

  13. CONSERVED RECEPTORS SENSING DANGER SIGNALS NLR Nucleotide binding domain Leucin rich repeats TLR NOD1/2, IPAF/NLRC4 CARD IPAF BIR TLR3 RLH CARD-CARD-helicase MEMBRAN NBD N C PYR NLRP1 – ASC NLRP3 – ASC – CARDINAL NBD NBD Fibroblast Epithelial cell DC CYTOPLASM

  14. INTERFERON RESPONSE

  15. VÍRUS INDUCED TYPE I INTERFERON PRODUCTION Type I IFN receptor IFN response Virus IFN- IRF-3 NFB AP-1 IRF-3 IFN- paracrine IFN- IRF-7 autocrine Infected cell IFN response IFN- subtypes IRF: interferon regulatory factor

  16. JAK2 JAK2 TYK2 JAK1 TYK2 JAK1 JAK1 JAK1 STAT1 STAT1 STAT1 STAT2 P P P P STAT1 STAT1 P STAT1 STAT2 P P P Type I. IFN receptor Type III. IFN receptor (IFNλ) Type II. IFN receptor IFNAR1/2 IFNLR1 IL-10R2 IFNG1/2 Plasma membrane Cytoplasm STAT1 STAT1 STAT2 ISGF-3 IRF9 Interferon-stimulated genes Nucleus GAS: Gamma Activating sequence ISG15, Mx, OAS and PKR ISRE GAS – promoter elements Interferon-stimulated Regulatory elements Antiviral immunity Antimycobacterial immunity

  17. EFFECTS OF TYPE I INTERFERONS vírus Plasmacytoid dendritic cells produce 1000x more type I interferon than other cells NATURAL INTERFERON PRODUCING CELLS – IPC After viral infection they are accumulated at the T cell zone of the lymph nodes

  18. INTERFERON EFFECTOR PATHWAYSinduction of the „antiviral state • 1. Mx GTPase pathway • block viral transcription • 2. 2',5'-oligoadenylate-synthetase (OAS)-directed Ribonuclease L pathway • degrade viral RNA • 3. Protein kinase R (PKR) pathway (Ser/Thr kinase, dsRNA-dependent) • inhibit translation • 4. ISG15 ubiquitin-like pathway • modify protein function CONTROL ALL STEPS OF VIRAL REPLICATION

  19. Oligomer accumulation in cytoplasmic membranes (e.g. ER) MxA oligomer MxA monomer (Cytoplasm) Trapped viral components MxA (Nucleus) ISRE Inhibition of translation P eIF2a eIF2a synthetized pppA(2’p5’A)n inactive RNaseL monomer Active PKR dimer Active OAS1 tetramer active RNaseL dimer Induction by viral RNAs Induction by viral dsRNA Inactive PKR monomer Inactive OAS1 monomer cleaved RNA (Cytoplasm) (Cytoplasm) OAS1 (Nucleus) PKR (Nucleus) ISRE ISRE Mechanism of action of MxA, OAS1 and PKR

  20. MULTIPLE EFFECTS OF TYPE I INTERFERONS Increased citotoxicity and proliferation of NK-cells TLR4 TRAM TRIF TLR7 TLR8 TLR9 TLR3 TRIF MyD88 TANK IRAK-1 Activation of - and γδ T-cells TRAF-6 RIG-1 IKKε TBK1 IRF-7 IRF-3 IRF-5 Increased antigen presentation in myeloid dendritic cells IFN-β, IFN-α1 IRF-7 Stimulation of Ig-production in B-cells Type I interferon receptor

  21. Mechanisms that induced optimal production of IFN-γ by NK cells: Requirement of concomitant engagement of TLR3 and RIG-I-like receptors (RLRs) on mDCs, and RLRs on NK cells by dsRNA. Perrot I et al. (2010) J Immunol 185(4): 2080–2088.

  22. ACTIVATION OF NATURAL KILLER CELLS NK-CELLS PRR Virus-infected cell RECOGNITION ACTIVATION Lysis of infected cell IFN IL-12 RECOGNITION OF ALTERED HOST CELLS NK-cells Relatív szint/aktivitás Kinetics of the activity of the complement system and NK cells in virus infection Complement system days MECHANISMS OF INNATE IMMUNITY

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