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INNATE IMMUNITY

INNATE IMMUNITY. Signal Transduction Effector Mechanisms. Innate Immunity:definition. no need for prolonged induction no clonal expansion of Ag specificity act quickly immediate direct response 0-4 hrs rapid induced 4-96 hrs failure ==> adaptive immune response

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INNATE IMMUNITY

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  1. INNATE IMMUNITY Signal Transduction Effector Mechanisms

  2. Innate Immunity:definition • no need for prolonged induction • no clonal expansion of Ag specificity • act quickly • immediate direct response 0-4 hrs • rapid induced 4-96 hrs • failure ==> adaptive immune response • dependence on germ line encoded receptors • high discrimination of host and pathogen

  3. First Line of Defense -- Epithelia • Mechanical • tight junctions, air/fluid flow, ciliary rejection • Chemical • lysozyme, pH, defensins, surfactant opsonins, TOX(ROX) • Microbiolgical • normal protective flora competition, antimicrobial colicin • Inductive • receptors that recognize pathogens and signal other innate and adaptive immune response

  4. Cells of Innate Immunity • Neutrophils • Eosinophils • Basophils/Mast Cells • Monocytes • Macrophages • Natural Killer Cells • Platelets

  5. LEUKOCYTE TERMINOLOGYTwo Systems • Nuclear Morphology • Mononuclear Cells • Monocytes/Macrophages • Lymphocytes • Polymorphonuclear Cells • Polymorphonuclear Leukocytes, PMNLs, PMNs • Granule Morphlogy • Granulocytes • Neutrophils (neutral), Eosinophils (orange), Basophils (blue) • Agranulocytes • Lymphocytes, Macrophages,

  6. COMPARATIVE MORPHOLOGY OF GRANULOCYTES

  7. Human Neutrophil • Granulocytic Leukocyte • Most Abundant White Blood Cell • 2-6 x 103 cells/μL • 40 –75 % of leukocytes • Very Short Lifetime • t1/2 = 6 hours • 55 % of Bone Marrow Weight Devoted to Neutrophil Production

  8. Human Neutrophil Size • In Peripheral Blood Smear: • 12 – 15 µm diameter

  9. Human Neutrophil Size • In blood: • Volume = 300 μm3 sphere (300 fl vs. 90 fl for RBC) • Diameter = 8.3 μm

  10. NEUTROPHIL EM MORPHOLOGY

  11. EOSINOPHIL EM MORPHOLOGY

  12. BASOPHIL/MAST CELL EM MORPHOLOGY

  13. Signal Transduction • Receptors • recognition of pathogens • chemical signals • Transduction pathways • G proteins, Kinases • Effector activation • gene induction • motility, secretion • adherence, phagocytosis

  14. Three Types of Receptors ACh receptor Chemotaxis receptor Growth factor receptor

  15. G protein-coupled receptors • Largest receptor family appx ~1000 types • Bind proteins, peptides, absorb light • Highly homologous in structure • G protein exchange factors • G protein splitters ==> G-GTP & G • Primary transducers are G-GTP & G • Activate membrane phospholipases and cyclases

  16. FPR mutations affecting ligand binding rendered in CPK HII - L78A HIII - D106A(N), L109A HIV - T157A HV - R201A, I204A, R205A HVI - W254A, Y257A HVII - F291A

  17. FPR and G Protein: Functional Interaction

  18. G Protein Cycle

  19. L Receptor - G protein Coupling L L L L L L L L R R R        GDP GTP GDP L L L L R R PIP2 PIP3     PLC   GDP  P110 GTP GDP GTP GDP INTERNALIZED

  20. GPCR OF INNATE IMMUNITY • Peptide receptors • fMLF receptor-- chemotaxis toward bacteria • Complement receptors C5a, C3a -- chemotaxis toward sites of complement activation • Lipid receptors • Leukotriene (LTB4), Eiosanoid (LPXA4), PAF, PG • Chemokine receptors • CXC (IL-8), CC (MCP), CXXXC(Fractalkine) • nomenclature from amino terminal cysteines • IL-8, MCP induce extravasation of neuts, M • Fractalkine - monocyte /endothelial adhesion

  21. Enzyme Associated Receptors • Growth factor-like receptors • Cytokine receptors • Adherence/Phagocytosis receptors • Integrins • Selectins • FcR • Pattern/Pathogen recognition receptors • Mannose/Glucan receptors • LPS receptor • Scavenger • Complement • Toll receptors

  22. Enzyme-associated Receptors

  23. Mechanism of TK Receptors

  24. Primary Transduction by TK Receptors

  25. Mechanisms of Cytokine Receptors

  26. Primary Transducers of Cytokine Pathways • Non-receptor protein tyrosine kinases • Janus Kinase (JAK) family

  27. Primary Transducers of Pattern Recognition Receptor Pathways • Non-receptor protein tyrosine kinases • Src family; Fc-mediated Phagocytosis • Igene familyTyrActivation Motif phosphorylation (YXXL) • p72SykSyk kinase • MyD88; IL-1R-like Toll receptors • Serine threonine Immunity Kinase • P130cas;FocalAdhesionKinase;vinculin, talin; integrin-mediated

  28. Adhesin Mechanism

  29. Phagocytosis

  30. FcR-mediated PhagocytosisThree types of FcR • FcRI(CD64) • monocytes, M. IF-stim neutrophils • high affinity binds monomeric IgG • FcRII (CD32) A&B forms • low affinity binds to multimeric IgG • A - phagocytic and NK cells • B - B/T cells • FcRIII (CD16) • monocytes, M, neutrophils • GPI anchored Garcia-Garcia et al JLB 72:1092,2002

  31. FcR-mediated Phagocytosisearly events • Receptors clustered by geometry of binding • ITAMs phosphorylated by Src Y kinases • Small fraction of active Src kinases associated w/cytoplasmic domains • Fgr,Fyn, Hck, Lyn,Yes, Src • Pi ITAM dock SH2 domain of Syk(Y-Kin) • Syk maybe need for actin cup formation

  32. Syk Downstream SignalingCalcium? PKC-S/|T Kinases - 11types ? PLA  AA release (Ca dep/ind) PLC Ca++ release PLD Activ PKC via DAG PI-3K PIP2, PIP3 PHs(Vavs)  Pseudopod extension ERK S/T Knse; MAPK1(aka) (nucl. transcription factor activation) PKC@PM w/Raf1 SMGsCDC42, Rac, Rho? 50 GEFs(Vav w/PHs) WASPs/Arps PAK LIMK Cofilin

  33. Midterm Questions • 1. Choose a receptor that mediates directed motility. Trace the events that may lead to formation of pseudopods that extend in the appropriate directions. Make sure that you cover the SMGs and how they participate and what regulates their participation. Describe key points of evidence? Do innate immune cells differ from B & T cells in this function? • 2. Compare and contrast inflammatory and apoptotic phagocytosis. Name names, identify key regulatory points, be clear about SMG participation

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