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Phagocytosis: An Evolutionarily Conserved Mechanism to Remove Apoptotic Bodies and Microbial Pathogens Phagocytosis of IgG-coated Targets by Macrophages 3 min 10 min Mast Cells Can Phagocytose Too! Extension of an F-actin-rich “Phagocytic Cup” Around Phagocytic Targets Motor Proteins and Exocytosis Power Phagocytosis From: Chavrier, Nature Cell Biol. 4:E169, 2002 Phagosome-Lysosome Fusion? Elie Metchnikoff, 1845-1916 QuickTime™ and a Cinepak decompressor are needed to see this picture. QuickTime™ and a Cinepak decompressor are needed to see this picture. QuickTime™ and a Cinepak decompressor are needed to see this picture. Post-phagocytic Events: Phagosome-Lysosome Fusion Pathogen Macrophage Lysosomes Phagolysosomes Phagocytosis of Bacteria is Followed by Phagosome-Lysosome Fusion 0-3 min From: Allen et al., J. Exp. Med. 191:115, 2000 1-5 min 30 min-hrs The Granuloma: a Delayed Response to Indigestible Pathogens and Particles in Macrophages Granulomas Granulomatous inflammation consists of epithelioid macrophages, giant cells, lymphocytes, plasma cells, and fibroblasts. Langhans-type Giant Cells Langhans-type giant cells represent fused macrophages. The nuclei are lined up around the peripheryof the cell. Epithelioid Cells Epithelioid cells accumulate around the center of a granuloma. They get their name from the fact that they have pink cytoplasm similar to squamous epithelia. Oxidant-dependent Killing of Bacteria and Fungi From: Lekstrom-Himes and Gallin, N Engl J Med, 343:1703, 2000 QuickTime™ and a Cinepak decompressor are needed to see this picture. Post-phagocytic Events: “Phagosome-Oxidase Fusion” Pathogen Macrophage 2O2 2O2- + H+ NADPH oxidase Post-phagocytic Events: Generation of H2O2 Pathogen Macrophage 2O2 2O2- + H+ NADPH oxidase O2- + O2- + 2H+ H2O2 + O2 Superoxide dismutase Post-phagocytic Events: Myeloperoxidase Activity Pathogen Macrophage 2O2 2O2- + H+ NADPH oxidase H2O2 + Cl- HOCl + OH Myeloperoxidase O2- + O2- + 2H+ H2O2 + O2 Superoxide dismutase Post-phagocytic Events: Peroxynitrite Production Pathogen Macrophage 2O2 2O2- + H+ NADPH oxidase 2O2- + NO ONOOPeroxynitrite H2O2 + Cl- HOCl + OH Myeloperoxidase O2- + O2- + 2H+ H2O2 + O2 Superoxide dismutase Bacterial Virulence Factors Subvert Host Defenses Modification of phagocytic receptors (P. aeruginosa) Escape from phagosome into cytosol (Listeria, Shigella) Ingestion phase impaired (Yersinia) Phagosome maturation stalled (M. tuberculosis; Legionella) Resistance to lysosomal degradation (Salmonella) Immunological Consequences of Phagocytosis Clearance of pathogens Death of pathogenic microbe Resolution of infection Persistence of pathogenic microbe Failure of resolution of infection Clearance of apoptotic corpses Suppression of inflammation Tolerance Inappropriate inflammation Break in tolerance Percent cytotoxicity Dendritic Cells Engulf Influenza-infected Monocytes and Cross-present Antigen From: Albert et al., Nature 392:86, 1998 Biology of Fcg Receptors Functional Sites on the IgG Molecule VH VL C1q binding site FcgR binding site Glycosylation site FcgReceptor Signaling: ITAM Phophorylation Opsonized Bacterium FcgRIIIA YYYYYYYYYYY gsubunit Src family TK Y YP Y Y YP Y FcgReceptor Signaling: Syk Activation Opsonized Bacterium YYYYYYYYYYY FcgRIIA ligandbinding domain PTPase Y PY YP YP Syk YP Y Y YP YP YP YP TK substrates Activating FcgR Inhibitory FcgR gg ITAM ITIM Syk SHIP + - Phagocytosis Clustering of the BCR by Antigen Initiates Signaling Ag Igb Iga ITAM Iga Igb Igb Iga ITAM Iga Igb Activating BCR Inhibitory FcgRIIB PIP3 ITAM Ig-a + BTK Ig-b Syk - ITIM SHIP PI3-kinase P PLC-g Ca2+, Proliferation Positive and Negative Regulation of the BCR Ag Ag C3d IgG CD21 (CR2) FcgRIIB CD19 CD22 Igb Iga SHIP Iga Igb ITAM PI 3-kinase - ITIM + SHP-1 SHP-1: A protein tyrosine phosphatase SHIP: A phosphoinositide phosphatase PI 3-kinase: Generates PIP3 The “Dark Side” of Fc Receptors: Immune Complex-mediated Injury Hypersensitivity Diseases The Arthus Reaction: A Model of Type III Hypersensitivity 1-2 hr Requirement of Activating FcgRs in Immune Complex-mediated Glomerulonephritis Absence of the g subunit of Fc receptors leads to enhanced survival in the F1 generation of NZB/NZW (lupus-prone) mice, a model for autoimmune, immune complex-mediated glomerulonephritis. From: Clynes et al., Science 279:1052, 1998. Requirement of Activating FcgRs in Immune Complex-mediated Glomerulonephritis Strain: g chain: C57Bl/6 NZB/NZW NZB/NZW -/- -/- +/- Glomerulonephritis is blocked in g chain-deficient NZB/NZW (lupus-prone) mice. Pathological features include mesangial thickening and hypercellularity evolving into end-stage sclerotic and crescentic changes. From: Clynes et al., Science 279:1052, 1998. Summary 1. Phagocytosis is a component of innate and aquired immunity. It is the principal means of destroying pathogenic bacteria and fungi. Phagocytosis initiates the process of antigen presentation. 2. Many phagocytic receptors recognize a diverse array of microbial pathogens. Some pathogens (e.g., S. pneumoniae) require opsonization for their clearance. 3. Bugs fight back. 4. Phagocytosis is an essential component of development and tissue remodeling. Ingestion of apoptotic bodies is immunologically “silent” and is normally accompanied by a suppression of inflammation. 5. Failure of this mechanism may result in autoimmunity. 6. Fc receptors come in two basic types: activating (ITAM-associated) and inhibitory (ITIM-associated). 7. The relative expression of activating and inhibitory Fc receptors determines the outcome of a given engagement of Fc receptors. 8. Fc receptor-driven pathology includes formation and deposition of immune complexes, which play a major role in autoimmunity.