Attribution: University of Michigan Medical School ... · – Adhesion / migration ... Abas, and...
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Attribution: University of Michigan Medical School, Department of Microbiology and Immunology License: Unless otherwise noted, this material is made available under the terms of the Creative Commons Attribution–Noncommercial–Share Alike 3.0 License: http://creativecommons.org/licenses/by-nc-sa/3.0/
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Phagocytic Cells: Mechanisms of Bacterial Injury and Tissue
Injury M1 – Immunology Sequence
Joseph Fantone, MD
Winter 2009
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Phagocytic Cells: Mechanisms of Bacterial Killing and Tissue Injury
• Learning Outcomes:
– To understand the pathophysiologic role of phagocytic cells in host defense.
– To understand the role of reactive oxygen metabolites and lysosomal granules in phagocytic cell function
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Phagocytic Cells
• Peripheral Blood Leukocytes (nrml. 4.5-11,000cells/ul) – Lymphocytes (~ 30%) – Granulocytes (~ 70%)
• Granulocytes: – Neutrophils (~ 60% of total leukocytes in blood) – Eosinophils (~ 3%) – Basophils (<1%, rare) – Monocytes (~ 6%) – Monocytes Macrophages
(tissues) • Kupffer cells (lining liver sinusoids)
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Peripheral Blood Smear
Neutrophil
Lymphocyte
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Lymphocyte
Platelets
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Neutrophil
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Monocyte
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Neutrophils and Macrophages
• Function: – Injest foreign material – Kill bacteria and other microbes – Degrade necrotic tissue and foreign
antigens
• Tissue damage during prolonged inflammation
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Neutrophil Recruitment
Selectins/Addressins ß2 -Integrin/ICAM-1
flow rolling adhesion transmigration
inflammatory mediators
Tissue Injury (e.g. Bacterial infection)
chemoattractant (e.g. IL-8, C5a)
• phagocytosis • oxidant production • lysosomal granules
endothelium
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Phagocytic Cell Activation: Chemotactic Factors
plasma membrane
G-protein tyrosine kinases
protein phosphorylation
phosphoinositide metabolism
Ca 2+
functional responses
C5a
IP3
Other receptors: Toll-like receptor Mannose receptor
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Phagocytic Cell Functional Responses
• Adhesion (localization) • Chemotaxis (migration) • Phagocytosis • NADPH oxidase activation • Lysosomal granule fusion:
degranulation
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Opsonization and Phagocytosis
• Protein recognized by phagocytic cell binds to bacteria surface
• Enhances phagocytosis – Antibody Fc receptors: IgG,
IgM – Complement C3b receptors – Mannose binding protein MBP receptors
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Neutrophil Phagocytosis of Bacteria
Fc, C3b binding
Phagosome formation
Phagolysosome
Opsonization of Bacteria
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Source Undetermined
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Cell phagocytosis Oxygen radicals
Elastase Collagenase Acid hydrolases
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Stimulus added
100
0 + 2 + 4 + 6
TIME (minutes)
50
OxygenLevels(% of max.)
patient
normal
Respiratory Burst: NADPH Oxidase
J. Fantone
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Superoxide anion: O2- Hydrogen peroxide: H2O2 Hydroxyl radical: OH . Hypochlorous acid: HOCl myeloperoxidase = MPO
O2 + e- 2O2- + 2H+ H2O2 + Fe2+ H2O2
O2- H2O2 + O2 OH + OH- + Fe3+ HOCl + OH-
MPO
Reactive Oxygen Metabolites
Chronic Granulomatous Disease of Childhood (CGD): deficiency of NADPH Oxidase
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Nitric Oxide (NO ) Synthase
L-arginine NO hydroxyl radical peroxynitrites
- Endothelial cell - Macrophages (inducible): intracellular cytotoxic agent - Nervous system
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Oxidant Targets
a) unsaturated lipids: lipid peroxidation LOOH = lipid hydroperoxides
c) proteins - sulfhydryl groups - methionine - tyrosine
d) nucleic acids
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Degranulation
• Bactericidal proteins (e.g. defensins) • Proteases
– serine proteases (e.g. elastase) – metalloproteinases (e.g. collagenase,
gelatinase) • Acid hydrolases
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Anti-oxidants Anti-proteases
Oxidants Proteases
J. Fantone
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Pneumonia and Abscess
J. Fantone
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J. Fantone
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Protective Mechanisms
Anti-oxidant: specific vs. non-specific
Specific enzymes: Superoxide dismutase: 2O2- + 2H+ Catalase: 2H2O2 Glutathione peroxidase: H2O2 + 2GSH LOOH + 2GSH
H2O2 + O2 2H2O + O2 2H2O + GSSG H2O + LOH + GSSG
LOOH = lipid hydroperoxides GSH = reduced glutathione GSSG = oxidized glutathione
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Non- specific scavengers:
- Vitamin E
- Vitamin C - Beta-carotene
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Anti-proteases • α-1- anti-protease (anti-trypsin):
– plasma protein – binds proteases including elastase – inactivated by oxidants
• α-2- macroglobulin – plasma protein – binds proteases
• TIMPs: tissue inhibitors of metalloproteinases – cell derived
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Synergism: Inactivation of alpha-1-anti-trypsin
a-1-antitrypsin(active)
a-1-antitrypsin(inactive)
a-1-antitrypsin(active)
a-1-antitrypsin(inactive)
1. HOCI Dependent
PMNs HOCL
PMNs
2. Metalloproteinase Dependent
Metalloproteinase (collagenase)
J. Fantone
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Case: A 3 year old boy is brought to the emergency department
• CC: a productive cough, fever (temp 102.1 C), and headache.
• PEx: healthy boy with rales present on auscultation of the left lower chest.
• CxR:intra-alveolar infiltrate in the left lower lobe.
• Hx: mother reports multiple episodes (approx. 5 per year) of recurrent bacterial infections including otitis media, sinusitis, pneumonia, and purulent skin lesions. These infections usually responded to antibiotic treatment.
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List three different mechanisms that could account for this patients
increased susceptibility to bacterial infection:
1. _________________________________
2. _________________________________
3. _________________________________
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Neutrophil Recruitment
Selectins/Addressins ß2 -Integrin/ICAM-1
flow rolling adhesion transmigration
inflammatory mediators
Tisue Injury (e.g. Bacterial infection)
chemoattractant (e.g. IL-8, C5a)
• phagocytosis • oxidant production • lysosomal granules
endothelium
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Mechanisms Associated with Increased Susceptibility to Bacterial Infection:
1. Lack of neutrophils: leukopenia 2. Defective neutrophil function
– Adhesion / migration – Phagocytosis – Bacterial killing
3. Lack of chemoattractants: deficiency 4. Lack of opsoninization of bacteria
- antibody deficiency / complement def.
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Additional References:
Phagocytic Cells: Kumar, Abas, and Fausto: Pathologic Basis of Disease (7th ed.) pages 16-18, 53-62,71-74. Parham, The Immune System (2nd ed.): pgs. 15-17, 202-209.
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Slide 6: Regents of the University of Michigan Slide 7: Regents of the University of Michigan Slide 8: Regents of the University of Michigan Slide 9: Regents of the University of Michigan Slide 11: Regents of the University of Michigan Slide 12: Regents of the University of Michigan Slide 15: Regents of the University of Michigan Slide 16: Source Undetermined Slide 17: Regents of the University of Michigan Slide 18: J. Fantone Slide 23: J. Fantone Slide 24: J. Fantone Slide 25: J Fantone Slide 29: J. Fantone Slide 32: Regents of the University of Michigan
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