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ASPECTS OF INNATE IMMUNITY EVOLUTION OF THE IMMUNE SYSTEM Fujita T (2002) Nat Rev Immunol 2:346-353. EVOLUTION OF THE IMMUNE SYSTEM Sun JC et al. (2014) EMBO J - in press (DOI 10.1002/embj.201387651 ) INNATE/NATURAL IMMUNITY RECOGNIZING RECEPTORS PROTECTIVE MECHANISMS Enzyme systems Multicellular (Metazoa) Sea urchin 600 million years Toll-like receptors C. elegans Drosophila 700 million years complement PRINCIPLES OF INNATE IMMUNE RECOGNITION PRRs Source: http://www.m.kanazawa-u.ac.jp/eng/gaiyou/dep03/dep3-01.html CLASSES OF PRRs TLRs: Toll-like receptors NLRs: NOD-like receptors RLHs: RIG-I-like helicases CLRs: C-type lectin receptors ALRs: AIM2-like receptors Thomas CJ and Schroder K (2013) Trends Immunol 34:317-328. CONSERVED RECEPTORS/SENSORS THAT DETECT DANGER SIGNALS TLR3 Fibroblast Epithelial cell DC TLR LRR MEMBRANE TIR domain TIR: Toll-Interleukin Receptor signaling domain CELL MEMBRANE Bacteria MEMBRANES OF INTRACELLULAR VESICLES virus TOLL RECEPTORS ACTIVATE PHYLOGENETICALLY CONSERVED SIGNAL TRANSDUCTION PATHWAYS Fungus Bacterium Protease LPB LPS Toll Tube Spätzel CD14 Cactus Relish Pelle TLR4 MyD88 CD14 NFkB Drosophila TRIF IRAK IL-1R associated Kinase Peptide TLR3 TLR4 Inflammation Acute phase response Danger signal IL-6 Mammals IRF3 IFN TLR4 activation can lead to the production of either inflammatory cytokines or antiviral type I interferons (IFNs). Source: http://www.sabiosciences.com/images/pathway7/7/tlr_figure_1.jpg TLR SIGNALING – THE BASICS A Szabo and E Rajnavolgyi (2013) Am J Clin Exp Immunol 2:195-207. RLH SIGNALING PATHWAYS NLR ACTIVATION AND SIGNALING Valiante N et al. (2008) Nat Med 14:1318-1319. Cytokines/chemokines produced by activated macrophages local and systemic effects Szisztémás hatás THE ACUTE PHASE RESPONSE C-reactive protein (CRP) COMPLEMENT IL- 6 Mannose binding lectin/protein MBL/MBP COMPLEMENT Liver Serum Amyloid Protein (SAP) Mannose/galactose binding Fibrinogen Chromatin, DNA, Influenza IL-6 induces the production of acute phase protiens THE INTERFERON RESPONSE VIRUS-INDUCED TYPE I INTERFERON PRODUCTION Type I IFN receptor IFN response Virus IFN- IRF-3 NFB AP-1 IRF-3 IFN- paracrine IFN- IRF-7 autocrine Infected cell IFN response IFN- subtypes IRF: interferon regulatory factor Type I. IFN receptor Type III. IFN receptor (IFNλ) IFNAR1/2 IFNLR1 IL-10R2 Type II. IFN receptor IFNG1/2 JAK2 TYK2 JAK1 TYK2 STAT1 STAT1 JAK1 JAK2 JAK1 JAK1 Cytoplasm STAT1 STAT2 P Plasma membrane ISGF-3 P STAT2 STAT1 IRF9 P P STAT1 Interferon-stimulated genes STAT1 P STAT1 P STAT2 ISRE ISG15, Mx, OAS and PKR Antiviral immunity Interferon-stimulated regulatory elements P Nucleus P STAT1 GAS: Gamma Activating sequence GAS – promoter elements Antimycobacterial immunity EFFECTS OF TYPE I INTERFERONS 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 Establishment of the „antiviral state” Mechanism of action of MxA, OAS1 and PKR Oligomer accumulation in cytoplasmic membranes (e.g. ER) MxA oligomer MxA monomer (Cytoplasm) ISRE MxA Trapped viral components (Nucleus) P synthetized pppA(2’p5’A)n inactive RNaseL monomer eIF2 eIF2 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 ISRE (Cytoplasm) OAS1 (Nucleus) Inhibition of translation (Cytoplasm) ISRE PKR (Nucleus) MECHANISMS OF INNATE IMMUNITY COMPLEMENT ACTIVATION COMPLEMENT Complement-proteins Lysis of bacteria Inflammation Chemotaxis Bacterium Lectin pathway Alternative pathway Complement-dependent phagocytosis Antigen + Antibody Few minutes – 1 hour ACQUIRED IMMUNITY Enzymes get fragmented, complement activity can be exhausted MECHANISMS OF INNATE IMMUNITY PHAGOCYTOSIS PRR Degradation ACTIVATION Bacterium Phagocyte Uptake Intracellular killing 0.5 - 1 hours Antigen + Antibody The amount of internalized particles is limited ACQUIRED IMMUNITY Antigen presentation T cell ACQUIRED IMMUNITY MECHANISMS OF INNATE IMMUNITY INFLAMMATION – ACUTE PHASE RESPONSE PRR TNF- neutrophil LPS IL-12 DANGER SIGNAL ACTIVATION IFN Few hours LPS (endotoxin) (Gram(-) bacteria) ACUTE PHASE RESPONSE Kinetics of the release of proinflammatory citokines in bacterial infection macrophage cytokines TNF- IL-1 Plasma level Bacterium NK-cell TNF- IL-1 IL-6 IL-6 1 2 3 4 5 hrs Source: https://www1.uni-frankfurt.de/fb/fb16/institut/imm/Research/index.html Source: https://restoreimmunehealthdotcom2.files.wordpress.com/2012/08/natural-killer-cell.png MECHANISMS OF INNATE IMMUNITY ACTIVATION OF NATURAL KILLER CELLS NK-CELLS PRR Virus-infected cell RECOGNITION ACTIVATION Lysis of infected cell RECOGNITION OF ALTERED HOST CELLS Kinetics of the activity of the complement system and NK cells in virus infection Relative level/activity IFN IL-12 NK-cells Complement system 1 2 3 4 5 6 7 8 9 10 11 12 13 days
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