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INNATE IMMUNITY II

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

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INNATE IMMUNITY II

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  1. INNATE IMMUNITY II

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

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

  4. 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 cytokines in bacterial infection Plasma level hrs Reminder

  5. NK cells

  6. 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

  7. Adaptive components are also able to activate NK cells ADCC-Antibody Dependent Cell Cytotoxicity Activating NK cells through FcR on NK cells recognizing pathogen-bound Antibodies

  8. INTERFERON RESPONSE

  9. 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

  10. VIRUS 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

  11. 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 Signal Transducers and Activators of Transcription 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

  12. 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

  13. 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

  14. MULTIPLE EFFECTS OF TYPE I INTERFERONS on immune cells Increased cytotoxicity 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 dendriticcells IFN-β, IFN-α1 IRF-7 Stimulation of Ig-production in B-cells Type I interferon receptor

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