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02.10.09(b): Phagocytic Cells: Mechanisms of Bacterial Injury and Tissue Injury

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Page 1: 02.10.09(b): Phagocytic Cells: Mechanisms of Bacterial Injury and Tissue Injury

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/

We have reviewed this material in accordance with U.S. Copyright Law and have tried to maximize your ability to use, share, and adapt it. The citation key on the following slide provides information about how you may share and adapt this material. Copyright holders of content included in this material should contact [email protected] with any questions, corrections, or clarification regarding the use of content. For more information about how to cite these materials visit http://open.umich.edu/education/about/terms-of-use. Any medical information in this material is intended to inform and educate and is not a tool for self-diagnosis or a replacement for medical evaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to your physician if you have questions about your medical condition. Viewer discretion is advised: Some medical content is graphic and may not be suitable for all viewers.

Page 2: 02.10.09(b): Phagocytic Cells: Mechanisms of Bacterial Injury and Tissue Injury

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Page 3: 02.10.09(b): Phagocytic Cells: Mechanisms of Bacterial Injury and Tissue Injury

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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Page 7: 02.10.09(b): Phagocytic Cells: Mechanisms of Bacterial Injury and Tissue Injury

Lymphocyte

Platelets

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Page 8: 02.10.09(b): Phagocytic Cells: Mechanisms of Bacterial Injury and Tissue Injury

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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Page 18: 02.10.09(b): Phagocytic Cells: Mechanisms of Bacterial Injury and Tissue Injury

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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Page 33: 02.10.09(b): Phagocytic Cells: Mechanisms of Bacterial Injury and Tissue Injury

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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