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Host Defense Against Infection Immune Evasion

Host Defense Against Infection Immune Evasion. Mar 5, 12, 19, 2007. References. IMMUNOBIOLOGY 6th ed. Janeway, Travers, Walport & Shlomchik (2005) Chapter 2 Innate Immunity Chapter 10 Adaptive Immunity to Infection. Outline. 1. The diversity of pathogens

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Host Defense Against Infection Immune Evasion

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  1. Host Defense Against InfectionImmune Evasion Mar 5, 12, 19, 2007

  2. References IMMUNOBIOLOGY 6th ed. Janeway, Travers, Walport & Shlomchik (2005) Chapter 2 Innate Immunity Chapter 10 Adaptive Immunity to Infection

  3. Outline 1. The diversity of pathogens 2. The general course of infection 3. The front line of host defense 4. Receptors of the innate immune system 5. Induced innate responses to infection 6. The course of the adaptive response to infection 7. The mucosal immune system 8. Immunological memory

  4. 1. The Diversity of Pathogens

  5. A Variety of Microorganisms Can Cause Disease 5 main types of pathogens: Viruses DNA viruses, RNA viruses Bacteria Gram+/Gram-, Cocci/Bacilli, Spirochetes, Mycobacteria, Richettsiae, Chlamydias, Mycoplasmas Fungi Protozoa Worms (Fig. 10.3)

  6. Pathogens Infect the Body through A Variety of Routes External epithelia: External surface Wounds & abrasions Insect bites Mucosal surfaces: Airway Gastrointestinal tract Reproductive tract (Fig. 2.2)

  7. Pathogens Can Be Found in Various Compartments of the Body

  8. Pathogens Can Damage Tissues in A Variety of Ways Direct mechanisms of tissue damage: Exotoxin production Endotoxin Direct cytopathic effect Indirect mechanisms of tissue damage: Anti-host antibody Immune complexes Cell-mediated immunity (Fig. 10.5)

  9. 2. The General Course of Infections

  10. Figure 2-1 The Response to An Initial Infection Occurs in 3 Phases

  11. Infection - A Series of Stages 1 2 3 4 5

  12. The Course of A Typical Acute Infection

  13. 3. The Front Line of Host Defense

  14. Figure 2-4 part 2 of 2 Surface Epithelia Provide Barriers to Infection Lysozymes

  15. Figure 2-5 Phagocytes Recognize Microbial Components LPS receptors (CD14) Toll-like receptor-4 (TLR-4) Scavenger receptor Mannose receptor Glucan receptor

  16. Figure 2-6 Phagocytes Produce Bactericidal Agents on the Ingestion of Microorganisms

  17. The Complement System Complement is a system of plasma proteins that interacts with pathogens to mark them for destruction. 1. Alternative pathway : pathogen surfaces 2. Mannan binding-lectin pathway : lectin binding to pathogen surfaces 3. Classical pathway : Ag:Ab complexes Functions: phagocytosis inflammation lysis

  18. 4. Receptors of the Innate Immune System

  19. Pattern Recognition Molecules 1. Soluble Molecules: Collectin family : e.g., Mannan-binding lectin (MBL), C1q LPS-binding protein (LBP) C-reactive protein (CRP) : binds phosphocholine portion of LPS 2. Cell-bound chemotactic receptors: f-Met-Leu-Phe receptor : binds the N-formylated peptide fMLP

  20. 3. Cell-bound phagocytic receptors: Mannose receptor : binds certain sugar molecules on microbes Scavenger receptor : recognizes certain anionic polymers, sialic acids & acetylated LDL 4. Signaling receptors : Toll-like receptor 4 (TLR-4): associated with LPS-LBP-CD14 Toll-like receptor 2 (TLR-2): recognizes proteoglycans of G(+)  Activation of NFkB  Production ofcytokines & chemokines  Expression of co-stimulatory molecules, e.g., B7.1, B7.2

  21. LPS Signals through the Toll-like Receptor 4 (TLR-4)

  22. Innate Immune Recognition by Toll-like Receptors

  23. LPS Induces the Migration of Langerhans’ CellsLangerhans’ cells: immature dendritic cells resident in the skin

  24. Structure of a Toll-like Receptor (TLR) (XLXXLXLXX) highly conserved among all members of the TIR family Toll/IL-1R

  25. 5. Induced Innate Responses to Infection

  26. Macrophages Release lipid mediators of Inflammation Prostaglandins Leukotrienes Platelet-activating facor (PAF)

  27. Macrophages Secret Pro-inflammatory Cytokine IL-1  Activates vascular endothelium Activates lymphocytes Local tissue destruction Increases access of effector cells  Fever, production of IL-6 (Fig. 2.39)

  28. Macrophages Secret Pro-inflammatory Cytokine TNF-  Activates vascular endothelium Increases vascular permeability  Increased entry of IgG, complement, and cells to tissues Increased fluid drainage to lymph nodes  Fever Mobilization of metabolites Shock (Fig. 2.39)

  29. Macrophages Secret Pro-inflammatory Cytokine IL-6  Lymphocyte activation Increased antibody production  Fever Induces acute-phase protein production (Fig. 2.39)

  30. Macrophages Secret Pro-inflammatory Cytokine IL-8 (CXCL8)  Chemotactic factor recruits neutrophils, basophils, and T cells to site of infection (Fig. 2.39)

  31. Macrophages Secret Pro-inflammatory Cytokine IL-12  Activates NK cells Induces the differentiation of CD4 T cells into TH1 cells (Fig. 2.39)

  32. IL-1/IL-6/TNF- Have a Wide Spectrum of Biological Activities That Help Coordinate the Body’s Responses to Infection Liver acute-phase proteins  increase of opsonization Bone marrow endothelium neutrophil mobilization  phagocytosis Dendritic cells TNF-a stimulates migration to lymph nodes & maturation  initiation of adaptive immune response (Fig 2.46)

  33. Hypothalamusincreased body temperature Fat, muscleprotein & energy mobilization to allow increased body temperature  decreased viral & bacterial replication & increased antigen processing & specific immune response (Fig 2.46)

  34. Chemokines • - Small polypeptides • - Produced by phagocytes, endothelial cells, • keratinocytes, fibroblasts & smooth muscle cells • - All chemokines are related in a.a. sequence & • functions • Chemoattractants for immune cells • - CXC, CC, C & CXXXC (CX3C) chemokines

  35. CXC : CXCL8 (IL-8), CXCL7 (PBP, -TG, NAP-2), CXCL1 (GRO), CXCL2 (GRO), CXCL3 (GRO), CXCL10 (IP-10), CXC12 (SDF-1), CXCL13 (BLC) CC : CCL3 (MIP-1), CCL4 (MIP-1), CCL2 (MCP-1), CCL5 (RANTES), CCL11 (Eotaxin), CCL18 (DC-CK) C : XCL1 (Lymphotactin) CXXXC : CX3CL1 (Fractalkine) (CX3C) (Fig. 2.41)

  36. Adhesion Molecules in Leukocyte Interaction Selectins Bind carbohydrates, P-selectin (CD62P) Initiate leukocyte- E-selectin (CD62E) endothelial interaction Integrins Bind to cell-adhesion molecules LFA-1 (CD11a/CD18) & extracellular matrix CR3 (CD11b/CD18) Strong adhesion CR4 (CD11c/CD18) Ig superfamily Various roles in cell adhesion ICAM-1 (CD54) Ligand for integrins ICAM-2 (CD102) VCAM-1 (CD106) PECAM (CD31) (Fig. 2.42)

  37. Integrins Mediate Adhesion

  38. Neutrophils Cross the Blood Vessel Wall to Enter Inflammatory Sites

  39. Acute-phase Response Produces Molecules That Bind Pathogens But Not Host Cells

  40. Interferons Are Antiviral Proteins Producedby Cells in Response to Viral Infection

  41. NK Cells Are An Early Component of the Host Response to Viral Infection

  42. NK Cells Distinguish Infected from Uninfected Cells

  43. NK Cells Distinguish Infected from Uninfected Cells

  44. 6. The Course of the Adaptive Response to Infection

  45. In vertebrates, the immune system can be divided into two branches: “innate immunity” and “adaptive immunity”.

  46. Innate Immunity • Innate immune system is phylogenetically • conserved and is present in almost all • multicellular organisms. • - Recently-identified Toll-like receptors • recognize specific patterns of microbial • components and regulates the activation • of innate immunity.

  47. Adaptive Immunity • Adaptive immunity detects non-self • through recognition of peptide antigens • using antigen receptors expressed on • the surface of B and T cells. • In order to respond to a wide range of • potential antigens, B and T cells • rearrange their immunoglobulin (Ig) • and T cell receptor (TCR) genes to • generate over 1011 different species of • antigen receptors.

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