Chapter 2

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LT24
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5041
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Chapter 2
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2010-01-25 00:37:39
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Innate Immunity
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Innate Immunity
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  1. Serum Proteins
    • Bind to microbes to increase visibility by the immune system
    • Recognize foreign presence
    • Soluble pattern recognition receptors - bind to pathogen assoicated molecular patterns (PAMPS)
    • Complement proteins
    • Mannose-binding lectins
    • C-reactive proteins
  2. Complement mechanisms
    • Lysis of microbes
    • Inflammation
    • Phagocytosis of complement-coated microbes
  3. C-reactive protein
    • Binds microbial phospholipids (membranes), opsonin
    • Increase phagocytosis
  4. Mannon-binding Lectins
    Binds microbial carbohydrates, opsonin
  5. 3 ways to activate complement
    • Alternative pathway - pathogen surface creates local environment conducive to complement activation (first to act)
    • Lectin pathway - mannose-bidning lectin binds to pathogen surface
    • Classical pathway - C-reactive protein or antibody binds to specific antigen on pathogen surface
  6. Cell surface Receptors
    • Toll-like receptors
    • Mannose receptors
    • Scavenger receptors
  7. Cytoplasmic Receptors
    • CARD-family sensors
    • Nod-like sensors
  8. Cells that express pattern recognition receptors
    • Neutrophils
    • Macrophages
    • Dendritic cells
    • Natural killer cells
    • Eosinophls, basophils, mast cells
  9. Monocytes
    • Circulate in the blood
    • Precursors to Macrophages and some dendritic cells
    • Can get recruited to the site of infection
  10. Macrophages
    • Found in the tissues
    • Highly phagocytic
    • Take up residence and become part of the tissue
    • Antigen presentation
  11. Macrophage Receptors
    • LPS receptor and Toll-like receptor 4: bind LPS a cell wall component of gram negative bacteria
    • CR3,4 complement: bind complement coated bacteria
    • Scavenger receptor: bind to negatively charged polymers
    • Mannose receptor: bind sugars unique to bacteria, activates C'
    • Glucan receptor: bacteria carbohydrates
    • Other TLRs
    • Chemokine receptors: mediate macrophage migration
    • Cytokine receptors
  12. Neutrophils
    • Most common WBC
    • Granulocytes
    • Short lived
    • Same receptors as macrophages
    • Engulf and digest bacteria
    • Do not live in tissues! Have to be recruited to site
  13. Receptor mediated phagocytosis
  14. Types cytokines secreted by macrophages
    • IL-1beta
    • TNF-alpha
    • IL-6
    • CXCL8
    • IL-12
  15. IL-1beta
    • Activates vascular endothelium
    • Activates lymphocytes
    • Local tissue destruction
    • Increases access of effector cells
  16. TNF-alpha
    Activates vascular endothelium and increases vascular permeability, which leads to increased entry of IgG, complement, and cells to tissues and increased fluid drainage to lymph nodes
  17. IL-6
    • Lymphocyte activation
    • Increased antibody production
  18. CXCL8
    Chemotactic (chemical sensing) factor recruits neutrophils, basophils, and T cells to site of infection
  19. IL-12
    • Activates NK cells
    • Induces the differentiation of CD4 T cells into TH1 cells
  20. Systemic effects of cytokines
    IL-1/IL-6/TNF-alpha
    • Liver - acute-phase proteins > activation of complement opsonization
    • Bone marrow endothelium - neutrophil mobilization > phagocytosis
    • Hypothalamus - increased body temp > decreased viral and bacterial replication
    • Fat, muscle - protein and energy mobilization to generate increased body temp > decreased viral and bacterial replication
  21. Toll-like receptors
    • Detect pathogen-specific molecular patterns
    • Extracellular domain: recognize pathogen (contains Leucine Rich Region-LRR)
    • Cytoplasmic signaling domain: conveys that info to inside of cell (Toll-interleukin receptor)
    • TLR binding leads to activation of NFkB mediated transcription
  22. Sepsis
    Infections of the blood
  23. Septic Shock
    • Dilation of blood vessels and massive leakage of fluid into tissues throughout the body (decreased BP)
    • Widespread blood clotting in capillaries > vital organs lack blood supply
    • Caused by too much production of TNF-alpha
  24. TLR-4
    Recognize LPS (lipopolysaccharide) on gram negative bacteria
  25. TLR-5
    • Recognize flagellin
  26. TLR-1:TLR-2
    • Heterodimer
    • Recognizes triacyl lypopeptides
  27. TLR-2:TLR-6
    Recognize diacyl lipopeptides
  28. TLRs in plasma membrane
    • 5
    • 4
    • 1:2
    • 2:6
  29. TLRs in cytoplasm
    • 3
    • 7
    • 8
    • 9
  30. Signaling Pathway of NFkB
  31. Steps in NFkB activation
    (Extracellular bacteria)
    • 1. LPS binds to TLR-4, MD2, CD14 complex
    • 2. TIR domain of TLR4 binds to MyD88
    • 3. MyD88 recruits IRAK4 (protein kinase)
    • 4. IRAK4 phosphorylates TRAF6
    • 5. Lead to activation of IKK
    • 6. IkB dissociates from NFkB
    • 7. NFkB goes into nucleus > txn of genes for cytokines
  32. Alternate TLR4 pathway
    (Viral infection)
    • 1. TRIF, TRAM forms complex with TLR4
    • 2. Phosphorylate TRAF3
    • 3. Lead to phosphorylation of IFR3
    • 4. IFR3 goes into nucleus
    • 5. Secretion of type I interferons
  33. Cytoplasmic Pathogen Recognition Receptors
    • NOD
    • RIG
  34. NOD2
    • Recognize bacterial proteoglycans in cytoplasm (intracellular)
    • Activates NFkB through RICK protein
  35. RIG-I
    • Cytoplasmic receptor for viral DNA
    • Activate IRF3
    • Leads to expression of interferons
  36. Dendritic Cell
    • Phagocytic and pinocytic
    • Found in tissues and in secondary lymphoid organs
    • When they encounter a pathogen, they are activated to travel to the local secondary lymphoid organs and become good antigen presenters
    • Upon activation, they secrete cytokins, mature, and travel to local lymph node to activate T cells
  37. Natural Killer Cells
    • Detect intracelluar pathogens
    • Contain cytolytic graules
    • Monitor cells for identification oas self
    • Kills cells infected with certain viruses or stressed cells
  38. NK Receptors
    • 1. Inhibitory receptors: tell them NOT to kill a target cell
    • 2. Activating receptors: tell them to kill a target
    • When they lose inhibitory signals or receive high levels of activating signals, they kill infected cell
    • Always ready to kill but can be better stimulated by cytokines
  39. Who is making the cytokines that activate NK cells?
    Macrophages
    • NK cells activate macrophages by releasing inteferon
    • Macrophages secreted IL-12 that activate NK cells
    • Positive feed back loop
  40. Type I Interferons
    • IFN-alpha and IFN-beta
    • 1. Induce resistnace to viral replication in all cells
    • 2. Increase expression of ligands for receptors on NK cells
    • 3. Activate NK cells to kill virus-infected cells

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