Phagocytosis: An Evolutionarily Conserved Mechanism to Remove Apoptotic Bodies
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Transcript of Phagocytosis: An Evolutionarily Conserved Mechanism to Remove Apoptotic Bodies
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
Elie Metchnikoff, 1845-1916
Phagosome-Lysosome Fusion?
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Post-phagocytic Events:Phagosome-Lysosome Fusion
Lysosomes
Pathogen Macrophage
Phagolysosomes
0-3 min 1-5 min 30 min-hrs
Phagocytosis of Bacteriais Followed by Phagosome-Lysosome Fusion
From: Allen et al., J. Exp. Med. 191:115, 2000
Granulomatous inflammationconsists of epithelioid macro-phages, giant cells, lymphocytes,plasma cells, and fibroblasts.
Epithelioid cells accumulate around the center of a granuloma. They get their name from the factthat they have pink cytoplasmsimilar to squamous epithelia.
Langhans-type giant cells represent fused macrophages.The nuclei are lined up around the peripheryof the cell.
The Granuloma: a Delayed Response to Indigestible Pathogens and Particles in Macrophages
Epithelioid Cells Granulomas Langhans-typeGiant Cells
Oxidant-dependent Killing ofBacteria and Fungi
From: Lekstrom-Himes and Gallin, N Engl J Med, 343:1703, 2000
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Post-phagocytic Events:“Phagosome-Oxidase Fusion”
NADPH oxidase
Pathogen Macrophage
2O2 2O2- + H+
Post-phagocytic Events:Generation of H2O2
NADPH oxidase
Pathogen Macrophage
2O2 2O2- + H+
O2- + O2- + 2H+ H2O2 + O2Superoxide dismutase
Post-phagocytic Events:Myeloperoxidase Activity
NADPH oxidase
Pathogen Macrophage
2O2 2O2- + H+
O2- + O2- + 2H+ H2O2 + O2Superoxide dismutase
H2O2 + Cl- HOCl + OHMyeloperoxidase
Post-phagocytic Events:Peroxynitrite Production
NADPH oxidase
Pathogen Macrophage
2O2 2O2- + H+
O2- + O2- + 2H+ H2O2 + O2Superoxide dismutase
H2O2 + Cl- HOCl + OHMyeloperoxidase
2O2- + NO ONOO-
Peroxynitrite
Bacterial Virulence Factors Subvert Host Defenses
Phagosomematuration stalled
(M. tuberculosis; Legionella)
Ingestion phaseimpaired(Yersinia)
Resistance tolysosomal degradation
(Salmonella)
Modification ofphagocytic receptors
(P. aeruginosa)
Escape from phagosome into cytosol (Listeria, Shigella)
Immunological Consequencesof Phagocytosis
Death of pathogenic microbe Persistence of pathogenic microbeResolution of infection Failure of resolution of infection
Clearance of pathogens
Clearance of apoptotic corpses
Suppression of inflammation Inappropriate inflammationTolerance Break in tolerance
Dendritic Cells Engulf Influenza-infected Monocytesand Cross-present Antigen
From: Albert et al., Nature 392:86, 1998
Perc
ent c
ytot
oxic
ityInf
ected
M +
unin
fecte
d DC
Unifec
ted M
+
unin
fecte
d DC
Ininf
ected
DC
Uninfe
cted
DC
Ininf
ected
M
Uninfe
cted
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Biology of Fc Receptors
C1q binding site
Glycosylation site
FcR binding site
Functional Sites on the IgG Molecule
VH
VL
Y
Y
YYPP
YYPP
Y
Y
FcRIIIA
subunitsubunit
Src familyTK
Y Y Y Y Y Y Y Y Y Y Y
Opsonized Bacterium
FcReceptor Signaling: ITAM Phophorylation
YPP
PTPase
YPP YPPYPP
YPPY Y
Y
TK substrates
FcRIIA ligand- binding domain
Y Y Y Y Y Y Y Y Y Y Y
Opsonized Bacterium
PPY YPP YPP
Syk
FcReceptor Signaling: Syk Activation
Syk SHIP
Phagocytosis
Activating FcR Inhibitory FcR
ITAMITAM ITIMITIM
IgIgIg Ig
ITAMITAM
Ag
Clustering of the BCR by Antigen Initiates Signaling
IgIgIg Ig
ITAMITAM
Ig-
Activating BCR Inhibitory FcRIIB
Syk
Ca2+, Proliferation
Ig-
ITAM
ITIM
PLC-
P
PIP3
BTKSHIP
PI3-kinasePI3-kinase
IgIgIg Ig
CD21 (CR2)CD21 (CR2)
ITIMITIM
CD19CD19
AgC3d
PI 3-kinase
-- ++SHP-1
CD22CD22
Positive and Negative Regulation of the BCR
Ag
SHIP
FcFcRIIBRIIB
ITAMITAM
YIgG
SHP-1: SHP-1: A protein tyrosine phosphatase PI 3-kinase:PI 3-kinase: Generates PIP3
SHIP:SHIP: A phosphoinositide phosphatase
The “Dark Side” of Fc Receptors:Immune Complex-mediated Injury
Hypersensitivity Diseases
The Arthus Reaction: A Model of Type IIIHypersensitivity
1-2 hr
Absence of the 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.
Requirement of Activating FcRs in Immune Complex-mediated Glomerulonephritis
From: Clynes et al., Science 279:1052, 1998.
Glomerulonephritis is blocked in chain-deficient NZB/NZW (lupus-prone)mice. Pathological features include mesangial thickening and hypercellularityevolving into end-stage sclerotic and crescentic changes.
Requirement of Activating FcRs in Immune Complex-mediated Glomerulonephritis
From: Clynes et al., Science 279:1052, 1998.
Strain: C57Bl/6 NZB/NZW NZB/NZW chain: -/- -/- +/-
Summary1. Phagocytosis is a component of innate and aquired immunity. It is the principalmeans of destroying pathogenic bacteria and fungi. Phagocytosis initiates theprocess 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 tissueremodeling. Ingestion of apoptotic bodies is immunologically “silent” and isnormally 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 determinesthe 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.