Phagocytosis: An Evolutionarily Conserved Mechanism to Remove Apoptotic Bodies and Microbial Pathogens

Transcription

1 Phagocytosis of IgG-coated Targets by s Phagocytosis: An Evolutionarily Conserved Mechanism to Remove Apoptotic Bodies and Microbial s 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,

2 QuickTime and a Phagosome-Lysosome Fusion? Elie Metchnikoff, QuickTime and a QuickTime and a Phagosome-Lysosome Fusion Phagocytosis of Bacteria is Followed by Phagosome-Lysosome Fusion Lysosomes Phagolysosomes 0-3 min 1-5 min 30 min-hrs From: Allen et al., J. Exp. Med. 191:115,

3 The Granuloma: a Delayed Response to Indigestible s and Particles in s Granulomas Langhans-type Giant Cells Epithelioid Cells Oxidant-dependent Killing of Bacteria and Fungi Granulomatous inflammation consists of epithelioid macrophages, giant cells, lymphocytes, plasma cells, and fibroblasts. Langhans-type giant cells represent fused macrophages. The nuclei are lined up around the peripheryof the cell. 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. QuickTime and a From: Lekstrom-Himes and Gallin, N Engl J Med, 343:1703, 2000 Phagosome-Oxidase Fusion Generation of H 2 O 2 O O H + H 2 O 2 + O 2 Superoxide dismutase 3

4 Myeloperoxidase Activity Peroxynitrite Production 2O NO ONOO - Peroxynitrite H 2 O 2 + Cl - HOCl + OH Myeloperoxidase H 2 O 2 + Cl - HOCl + OH Myeloperoxidase O O H + H 2 O 2 + O 2 Superoxide dismutase O O H + H 2 O 2 + O 2 Superoxide dismutase Bacterial Virulence Factors Subvert Host Defenses Immunological Consequences of Phagocytosis Clearance of pathogens Modification of phagocytic receptors (P. aeruginosa) Escape from phagosome into cytosol (Listeria, Shigella) Death of pathogenic microbe Resolution of infection Persistence of pathogenic microbe Failure of resolution of infection Ingestion phase impaired (ersinia) Phagosome maturation stalled (M. tuberculosis; Legionella) Resistance to lysosomal degradation (Salmonella) Clearance of apoptotic corpses Suppression of inflammation Tolerance Inappropriate inflammation Break in tolerance Dendritic Cells Engulf Influenza-infected Monocytes and Cross-present Antigen Percent cytotoxicity Biology of Fc γ Receptors Infected Mφ + uninfected DC Unifected Mφ + uninfected DC Ininfected DC Uninfected DC Uninfected Mφ Ininfected Mφ From: Albert et al., Nature 392:86,

5 Functional Sites on the IgG Molecule Fc γ Receptor Signaling: Phophorylation V H Fc γ RIIIA Opsonized Bacterium V L γ subunit C1q binding site FcγR binding site Glycosylation site Src family TK P P Fc γ Receptor Signaling: Syk Activation Opsonized Bacterium Fc γ RIIA ligandbinding domain PTPase Syk TK substrates P P P P P P P P Activating Fc γ R γ γ Inhibitory Fc γ R Clustering of the BCR by Antigen Initiates Signaling Ag Syk ITIM SHIP + Phagocytosis 5

6 Activating BCR PIP 3 Inhibitory Fc γ RIIB Positive and Negative Regulation of the BCR IgG Fc γ RIIB Ag Ag C3d CD21 (CR2) Ig-α Ig-β + Syk PI3-kinase BTK SHIP ITIM CD22 CD19 P PLC-γ Ca 2+, Proliferation ITIM SHIP SHP PI 3-kinase SHP-1: A protein tyrosine phosphatase PI 3-kinase: 3 Generates PIP 3 SHIP: A phosphoinositide phosphatase Hypersensitivity Diseases The Dark Side of Fc Receptors: Immune Complex-mediated Injury The Arthus Reaction: A Model of Type III Hypersensitivity Requirement of Activating Fc γ Rs in Immune Complex-mediated Glomerulonephritis 1-2 hr Absence of the γ 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,

7 Requirement of Activating Fc γ Rs in Immune Complex-mediated Glomerulonephritis 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. Strain: C57Bl/6 NZB/NZW NZB/NZW γ chain: -/- -/- +/- Glomerulonephritis is blocked in γ 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, Failure of this mechanism may result in autoimmunity. 6. Fc receptors come in two basic types: activating (-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. 7