Innate Immunity. Connection Between Innate and Adaptive Immunity. Know Differences and Provide Examples Chapter 3. Antimicrobial peptide psoriasin

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1 Know Differences and Provide Examples Chapter * Innate Immunity * kin and Epithelial Barriers * Antimicrobial peptide psoriasin -Activity against Gram (-) E. coli Connection Between Innate and Adaptive Immunity

2 s Pattern Recognition Receptors on HOT CELL INFLAMMATION 0 Tissue Repair s PathogenAssociated Molecular Patterns on MICROBE Inflammation teps in Cell Recruitment from Blood Vessels Tissue damage Acute ) Release of Vasoactive and chemotactic Mediators histamine, serotonin, etc ) 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) ) Action on Blood Vessels cell adhesion molecules (CAMs) ) Tissue Repair fibrin (clotting) and fibroblasts CAMs cell adhesion molecules oluble Molecules and MembraneAssociated Receptors ) Antimicrobial Peptides defensins, interferons Blood vessel endothelial cells 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 Interferons IFN-α and IFN-β 0 Block viral replication (RNA viruses)

3 oluble Molecules and MembraneAssociated Receptors ) Acute Phase Response Proteins C Reactive Proteins (CRP), Mannose Binding Protein (MBP) Increased in blood after tissue injury ynthesized by liver and macrophages Phagocytosis IL-β, IL-, 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 oluble Molecules and MembraneAssociated Receptors M M 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) - everal Patter-Recognition Receptors (s) identified NOD Nucleotide-Binding Oligomerization Domain - Cytosolic receptors - Two types: NOD and NOD - Recognize products derived from peptidoglycan degradation. oluble Molecules and MembraneAssociated Receptors 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

4 Biological Consequence of Microbial cell wall Complement components Opsonization; Complement activation Mannosecontaining carbohydrates Mannose-binding protein Opsonization; Complement activation Polyanions cavenger receptors Phagocytosis Lipoproteins of Myocobacterium TLR- (Toll-like receptor ) Flagellin (bacterial TLR- flagella) Lipopeptides Zymosan (yeast) TLR- ssrna viruses TLR-7 activation; ecretion of inflammatory Biological Consequence of Type I interferons Biological Consequence of Lipoteichoic acid TLR- (Toll-like of Gram + bacteria receptor ) Yeast cell wall components Double stranded TLR- RNA LP TLR- (lipopolysaccharide of Gram bacteria Viral proteins Production of interferon (antiviral) ssrna TLR-8 CpG unmethylated dinucleotides TLR-9 Toxoplasma profilin; uropathogenic bacteria components Biological Consequence of Type I IFNs TLR-0 Unknown TLR- Unknown NF-kB IL-, IL-β, IL-, TNF-α/ Tc cells (MyD88) MAPK Type I IFNs/ / Tc cells (TRIF)

5 Cell Types of Innate Immunity Neutrophils Phagocytosis Express s 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 Activated s TLRs, Cytokines 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 : IFN-γ and TNF-α These activate s, and differentiation of Th cells Dendritic Cells Immature Antigen Mature Interact with both Th and Tc cells Activation TLRs leads to MHC-II and co-stimulatory molecules Produce : type I IFNs and IL-, TNF-α, IL-. Killing by oxygen-dependent mechanisms

6 TLR ignaling 7 IKK IĸB Kinase IRAK- IL-R-associated kinase TRAF- tumor necrosis factor receptor associated factor TAK- Transforming growth factor βactivated kinase MAP mitogen activated protein NF-kB IL-, IL-β, IL-, TNF-α/ Tc cells (MyD88) MAPK Type I IFNs/ / Tc cells (TRIF)