Innate Immunity. Chapter 3. Connection Between Innate and Adaptive Immunity. Know Differences and Provide Examples. Antimicrobial peptide psoriasin
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1 Chapter Know Differences and Provide Examples Innate Immunity kin and Epithelial Barriers Antimicrobial peptide psoriasin -Activity against Gram (-) E. coli Connection Between Innate and Adaptive Immunity
2 PRRs Pattern Recognition Receptors on HOT CELL INFLAMMATION 0 Tissue Repair 6 PAMPs Pathogen- Associated Molecular Patterns on MICROBE Activation Inflammation Tissue damage Acute ) Release of Vasoactive and chemotactic Mediators histamine, serotonin, etc. ) Action on Blood Vessels cell adhesion molecules (CAMs) ) Vasodilation: diameter of capillaries, blood flow ) Increased Vascular Permeability: leakiness from blood vessels recruitment of cells and fluid edema ) Extravasation of Phagocytes recruitment of leukocytes Chemotaxis (chemokines; Ca/Ca, N-formyl peptides) 6) Phagocyte activation chemokine and cytokine production 6) Tissue Repair fibrin (clotting) and fibroblasts teps in Cell Recruitment from Blood Vessels CAMs cell adhesion molecules oluble Molecules and Membrane- Blood vessel endothelial cells 0 Inflammatory Mediators ) Antimicrobial Peptides defensins, interferons Defensins α-defensins, β-defensins Cationic (+) peptides (9- aa) Antibacterial and anti-fungal Disrupt microbial membranes and synthesis of RNA, DNA, and proteins Produced among others by neutrophils and epithelial cells (paneth cells) Interferons (Type I) -IFN-α and IFN-β Block viral replication (RNA viruses)
3 oluble Molecules and Membrane- ) Acute Phase Response Proteins C Reactive Proteins (CRP), Mannose Binding Protein (MBP), etc Increased in blood after tissue injury ynthesized by liver and macrophages Phagocytosis IL-β, IL-6, TNF-α Liver CRP binds polysaccharides and phosphorylcholine on microbial membranes phagocytosis and complement activation MBL - binds mannose residues on molecules found on microbial membranes Activates complement M M soluble, M membrane Nucleotide-binding oligomerization domain oluble Molecules and Membrane- NOD Nucleotide-Binding Oligomerization Domain - Cytosolic receptors - Two types: NOD and NOD - Recognize products derived from peptidoglycan degradation. - Both Gram (+) and (-) Pattern-Recognition Receptors - Receptors of the innate immune system - Recognize unique antigens (motifs) in microorganisms (Danger ignals!!!) - These antigens are absent in the host (nonself) oluble Molecules and Membrane- TLRs Toll-Like Receptors - found in humans and in mice - tructure: Exterior Leucine-rich repeats; Interior TIR (Toll-IL- Receptor) domain - Can form (HETERO or HOMO)DIMER affect their binding specificity - Membrane and cytoplasmic localization Interact with Ligand Interact with Adaptor Proteins
4 TLR- Triacyl lipopeptides (Mycobacterium) TLR- - Lipoarabinomannan), Lipoproteins, Peptidoglycans, and Fungi zymosan TLR- dsrna TLR- (MD, CD) - LP TLR- - Flagellin TLR-6 Diacyl lipopeptides (Mycobacterium) TLR-/6, TLR-/ - Lipoproteins TLR-7 - ssrna TLR-8 ssrna TLR-9 unmethylated CpG DNA Location: Outer membrane: TLR-,,,,6. urface of endosomes: TLR-,7,8,9. Pathways: ) Nuclear factor-κb (NF-κB) and mitogenactivated protein kinase (MAPK) p8 and JNK, and ) NFκB and interferon regulatory factor- and 7 (IRF-, IRF-7) ) MyD88 inflammatory cytokines & type I IFN genes ) TRIF inflammatory cytokines & type I IFN genes PAMP Microbial cell wall components Mannosecontaining carbohydrates Polyanions PRR Complement components Mannose-binding protein Biological Consequence of Interaction Opsonization; Complement activation Opsonization; Complement activation cavenger receptors Phagocytosis Cell Types of Innate Immunity Lipoproteins of Myocobacterium TLR-, 6 (Toll-like receptor) Macrophage recruitment & activation; ecretion of inflammatory cytokines
5 Neutrophils Phagocytosis Express PRRs on surface (TLRs, Complement, Antibodies, etc) Oxidative and Non-oxidative Killing Oxidative: RO (reactive oxygen species) and RN (reactive nitrogen species) triggered by NADPH Phagosome Oxidase (phox) Respiratory Burst oxygen uptake Non-oxidative Killing lysozyme, acidic cathepsins, proteases, defensins, etc 6 Activated Macrophages TLRs, Cytokines, etc phagocytic activity killing activity MHC-II expression cytokine production APR proteins and complement synthesis ino (inducible nitric oxide synthase) L-arginine + O + NADPH NO + L-citruline + NADP NK Cells Protect against viral infections Produce cytokines: IFN-γ and TNF-α These cytokines activate Macrophages, and differentiation of Th cells (Th) Dendritic Cells Immature Antigen Mature Interact with both Th and Tc cells (Crosspresentation) Activation TLRs leads to MHC-II and co-stimulatory molecules Produce cytokines: type I IFNs and IL-, TNF-α, IL-6. Killing by oxygen-dependent mechanisms P 6 7 P IRAK- IL-R-associated kinase TRAF6- tumor necrosis factor receptor associated factor 6 TAK- Transforming growth factor β- activated kinase
6 TLR Pathways IKK IĸB Kinase P IkB-P MAP mitogen activated protein NF-kB IL-, IL-β, IL-6, TNF-α/ Tc cells (MyD88) MAPK Type I IFNs/ / Tc cells (TRIF) Two major pathways: IRF /7 and NF-kB IRF /7 activation can result in the production of type I interferons NF-kB activation results in production of type I interferons and pro-inflammatory cytokines Most TLRs signal through MyD88, except TLR. TLR signals through both!!! The End!!! 6
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