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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 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 1. The Diversity of Pathogens 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) 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) Pathogens Can Be Found in Various Compartments of the Body 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) 2. The General Course of Infections The Response to An Initial Infection Occurs in 3 Phases Figure 2-1 Infection - A Series of Stages 1 2 3 4 5 The Course of A Typical Acute Infection 3. The Front Line of Host Defense Surface Epithelia Provide Barriers to Infection Figure 2-4 part 2 of 2 Lysozymes Figure Phagocytes Recognize Microbial Components LPS receptors (CD14) Toll-like receptor-4 (TLR-4) Scavenger receptor Mannose receptor Glucan receptor 2-5 Phagocytes Produce Bactericidal Agents on the Ingestion of Microorganisms Figure 2-6 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 4. Receptors of the Innate Immune System 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 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 of cytokines & chemokines Expression of co-stimulatory molecules, e.g., B7.1, B7.2 LPS Signals through the Toll-like Receptor 4 (TLR-4) Innate Immune Recognition by Toll-like Receptors LPS Induces the Migration of Langerhans’ Cells Langerhans’ cells: immature dendritic cells resident in the skin Structure of a Toll-like Receptor (TLR) (XLXXLXLXX) highly conserved among all members of the TIR family Toll/IL-1R 5. Induced Innate Responses to Infection Macrophages Release lipid mediators of Inflammation Prostaglandins Leukotrienes Platelet-activating facor (PAF) 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) 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) Macrophages Secret Pro-inflammatory Cytokine IL-6 Lymphocyte activation Increased antibody production Fever Induces acute-phase protein production (Fig. 2.39) Macrophages Secret Pro-inflammatory Cytokine IL-8 (CXCL8) Chemotactic factor recruits neutrophils, basophils, and T cells to site of infection (Fig. 2.39) Macrophages Secret Pro-inflammatory Cytokine IL-12 Activates NK cells Induces the differentiation of CD4 T cells into TH1 cells (Fig. 2.39) 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- stimulates migration to lymph nodes & maturation initiation of adaptive immune response (Fig 2.46) 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) 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 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) Adhesion Molecules in Leukocyte Interaction Selectins Bind carbohydrates, P-selectin (CD62P) Initiate leukocyte- E-selectin (CD62E) endothelial interaction Integrins Bind to cell-adhesion molecules & extracellular matrix Strong adhesion Ig superfamily Various roles in cell adhesion Ligand for integrins LFA-1 (CD11a/CD18) CR3 (CD11b/CD18) CR4 (CD11c/CD18) ICAM-1 (CD54) ICAM-2 (CD102) VCAM-1 (CD106) PECAM (CD31) (Fig. 2.42) Integrins Mediate Adhesion Neutrophils Cross the Blood Vessel Wall to Enter Inflammatory Sites Acute-phase Response Produces Molecules That Bind Pathogens But Not Host Cells Interferons Are Antiviral Proteins Produced by Cells in Response to Viral Infection NK Cells Are An Early Component of the Host Response to Viral Infection NK Cells Distinguish Infected from Uninfected Cells NK Cells Distinguish Infected from Uninfected Cells 6. The Course of the Adaptive Response to Infection In vertebrates, the immune system can be divided into two branches: “innate immunity” and “adaptive immunity”. 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. 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. - Engagement of antigen receptors by the cognate antigen triggers clonal expansion of the T and B lymphocytes. Summary of Adaptive Immune Response - Late (after 96 hr) - Inducible - Specific Ab & T cells - Memory Barrier functions IgA in luminal spaces IgE on mast cells local inflammation Response to extracellular pathogens IgG, FcR-bearing cells IgG + IgM + classical C pathway Response to intracellular pathogens T-cell activation of ф by IFN- Response to virus-infected cells cytotoxic T cells, IFN- The Time Course of Infection in Normal & Immunodeficient Mice & Humans Characteristics of Recognition Molecules of the Innate & Adaptive Immune Systems 7. The Mucosal Immune System The Mucosal Surfaces of the Body Are Particularly Vulnerable to Infection 1. Detect and kill pathogenic organisms gaining entry through the gut. 2. Avoid immune responses to food antigens. 3. Avoid immune responses to commensal bacteria ( > 400 species, ~ 1014 in the colon and ileum). GALT – gut-associated lymphoid tissues MALT – mucosa-associated lymphoid tissues Tonsils Adenoids Peyer’s patches (small intestine) Appendix Lymphoid follicles (large intestine and rectum) Peyer’s Patches Janeway Fig 1-10 M Cells Take Up Antigens from the Lumen of the Gut by Endocytosis Immune Response IgA Is the Major Ab Isotype in the Gut Transcytosis of IgA Ab Across Epithelia Is Mediated by the Poly-Ig Receptor, A Specialized Transport protein Janeway 9.20 Salmonella Can Penetrate the Gut Epithelial layer by 3 Routes Infection by Helicobactor pylori Causes Peptic Ulcers and Carcinoma of the Stomach 8. Immunological Memory Summary of Immunological Memory 1. Immunological memory is long-lived after infection or vaccination. 2. Both clonal expansion and clonal differentiation contribute to immunological memory in B cells. 3. Repeated immunizations lead to increasing affinity of antibody owing to somatic hypermutation and selection by antigen in germinal centers 4. Memory T cells are increased in frequency and have distinct activation requirements and cell-surface proteins that distinguish them from armed effector T cells. 5. In immune individuals, secondary and subsequent responses are mediated mainly by memory lymphocytes. Expression of Cell-surface Molecules on Memory T Cells Summary of Innate Immunity - Immediate (0 – 4 hr) - Nonspecific - Innate - No memory - No specific T cells Barrier functions skin, epithelia Response to extracellular pathogens phagocytes alternative C pathway MBL C pathway Response to intracellular pathogens macrophages Response to virus-infected cells NK cells Summary of Early Induced Response - Early (4 – 96 hr) - Nonspecific + specific - Inducible - No memory - No specific T cells Barrier functions Response to extracellular pathogens Response to intracellular pathogens Response to virus-infected cells local inflammation local TNF- mannan-binding lectin CRP, C T-independent B-cell Ab NK-dep ф activation IL-1, IL-6, TNF-, IL-12 IFN-, IFN- IL-12-activated NK cells