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TWO ARMS OF THE IMMUNE SYSTEM

TWO ARMS OF THE IMMUNE SYSTEM. INNATE/NATURAL IMMUNITY ACQUIRED IMMUNITY. INNATE/NATURAL IMMUNITY RECOGNITION. INNATE (NATURAL) IMMUNITY. RECOGNIZING RECEPTORS. PROTECTIVE MECHANISMS Enzyme systems. Multicellular (Metazoa). Sea urchin 600 million years. Toll- r e ceptors. C. elegans.

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TWO ARMS OF THE IMMUNE SYSTEM

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  1. TWO ARMS OF THE IMMUNE SYSTEM • INNATE/NATURAL IMMUNITY • ACQUIRED IMMUNITY

  2. INNATE/NATURAL IMMUNITY RECOGNITION

  3. INNATE (NATURAL) IMMUNITY RECOGNIZING RECEPTORS PROTECTIVE MECHANISMS Enzyme systems Multicellular (Metazoa) Sea urchin 600 million years Toll-receptors C. elegans Drosophila 700 million years complement IN PLANTS

  4. PHAGOCYTES ARE ABLE TO RECOGNIZE PATHOGENS Toll receptor-mediated signaling Toll receptor PHAGOCYTES (macrophages, dendritic cells, neutrophil granulocytes) RECOGNIZE PATHOGENS BY PATTERN RECOGNITION RECEPTORS RECOGNITION IS ESSENTIAL Macrophage, dendritic cell – ACT AS TISSUE SENSORS (GATE KEEPERS) Neutrophil granulocytes – MIGRATE FROM THE BLOOD TO THE SITE OF INFLAMMATION

  5. TOLL RECEPTORS RECOGNIZE VARIOUS MICROBIAL STRUCTURES Virus Bacteria ssRNS dsRNA CpG DNA Gram- Flagellin Peptidoglycane LPS Gram+ TLR9 TLR7 TLR8 TLR3 TLR2 TLR6 TLR5 TLR4 Interferon producing cell PC/DC IFN Macrophage/Dendritic cell ALL STRUCTURES ARE ESSENTIAL FOR THE SURVIVAL OR REPLICATION OF THE PATHOGEN

  6. Myeloid DC Plazmacytoid DC (IFNα production) 5 4 6 6 2 1 10 1 7 9 7 3 8 TLR1 – bacterial lipoprotein (together with TLR2) TLR2 – bacterial lipoprotein, peptidoglycane (Gram+), lipoteicolic acid zymosan, (fungy), lipoarabidomannan (mycobacteria) TLR3 – viral dsRNA TLR4 – bacterial LPS, Hsp60, Hsp70 (host) TLR5 – bacterial flagellin TLR6 – bacterial diacil lipopeptides (mycoplasma) TLR7 – viral ssRNS TLR8 – GU rich viral ssRNS, imidazoquinolin (antiviral drug) TLR9 – unmethylated CpG DNA

  7. TOLL RECEPTORS ACTIVATE PHYLOGENETICALLY CONSERVED SIGNAL TRANSDUCTION PATHWAYS TLR3 TLR4 Fungus CD14 Protease Spätzel Toll TRIF Tube IRF3 STAT1 RelX Pelle Kaktus NFkB IFN Peptid Bacterium LPB LPS TLR4 CD14 MyD88 IRAK IL-1R associated Kinase Inflammation Acute phase response Danger signal IL-6 Drosophyla Macrophage

  8. TOLL RECEPTOR MEDIATED SIGNALLING NEW THERAPEUTIC TARGET Figure 3 The 'hourglass' shape of the innate immune response. Although microbial stimuli are chemically complex and although the innate immune response ultimately involves the activation of thousands of host genes, innate immune signals traverse a channel of low complexity. Ten Toll-like receptors (TLRs), four TIR (Toll/interleukin-1 receptor homologous region) adaptors and two protein kinases are required for most microbial perception. This circumstance lends itself to effective pharmacotherapeutic intervention. NF-B, nuclear factor-B; STAT1, signal transducer and activator of transcription 1.

  9. THE ACUTE PHASE RESPONSE IL- 6 Mannose binding lectin/protein MBL/MBP COMPLEMENT C-reactive protein COMPLEMENT Fibrinogen Serum Amyloid Protein (SAP) Mannose/galactose binding Chromatin, DNA, Influenza Liver IL-6 induces the production of acute phase protiens

  10. PHAGOCYTES ARE ABLE TO RECOGNIZE PATHOGENS MANNOSE RECEPTOR Toll receptor CR3 Toll receptor OTHER PATTERN RECOGNITION RECEPTORS

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

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

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

  14. 9-13various Toll-receptors TLR family Innate immunity Ancient WHAT IS RECOGNIZED BY INNATE AND ACQUIRED IMMUNITY?HOW DO THEY RECOGNIZE PATHOGENS? RECEPTORS Common pattern of groups of pathogens Pathogen Associated Molecular Pattern PAMP Recognition by receptors Pattern Recognition Receptor PRR

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