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

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

  1. 1. Attribution: University of Michigan Medical School, Department of Microbiology andImmunologyLicense: Unless otherwise noted, this material is made available under the terms ofthe 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 touse, share, and adapt it. The citation key on the following slide provides information about how you may share andadapt this material.Copyright holders of content included in this material should contact open.michigan@umich.edu 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 areplacement for medical evaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to yourphysician 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.
  2. 2. Citation Key for more information see: http://open.umich.edu/wiki/CitationPolicyUse + Share + Adapt { Content the copyright holder, author, or law permits you to use, share and adapt. } Public Domain – Government: Works that are produced by the U.S. Government. (USC 17 § 105) Public Domain – Expired: Works that are no longer protected due to an expired copyright term. Public Domain – Self Dedicated: Works that a copyright holder has dedicated to the public domain. Creative Commons – Zero Waiver Creative Commons – Attribution License Creative Commons – Attribution Share Alike License Creative Commons – Attribution Noncommercial License Creative Commons – Attribution Noncommercial Share Alike License GNU – Free Documentation LicenseMake Your Own Assessment { Content Open.Michigan believes can be used, shared, and adapted because it is ineligible for copyright. } Public Domain – Ineligible: Works that are ineligible for copyright protection in the U.S. (USC 17 § 102(b)) *laws in your jurisdiction may differ { Content Open.Michigan has used under a Fair Use determination. } Fair Use: Use of works that is determined to be Fair consistent with the U.S. Copyright Act. (USC 17 § 107) *laws in your jurisdiction may differ Our determination DOES NOT mean that all uses of this 3rd-party content are Fair Uses and we DO NOT guarantee that your use of the content is Fair. To use this content you should do your own independent analysis to determine whether or not your use will be Fair.
  3. 3. Phagocytic Cells: Mechanisms of Bacterial Injury and Tissue Injury M1 – Immunology Sequence Joseph Fantone, MDWinter 2009
  4. 4. 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
  5. 5. 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)
  6. 6. Peripheral Blood SmearNeutrophil Lymphocyte Regents of the University of Michigan
  7. 7. Lymphocyte Platelets Regents of the University of Michigan
  8. 8. NeutrophilRegents of the University of Michigan
  9. 9. MonocyteRegents of the University of Michigan
  10. 10. Neutrophils and Macrophages•  Function: –  Injest foreign material –  Kill bacteria and other microbes –  Degrade necrotic tissue and foreign antigens•  Tissue damage during prolonged inflammation
  11. 11. Neutrophil RecruitmentSelectins/Addressins ß2 -Integrin/ICAM-1 flow rolling adhesion transmigration endothelium •  phagocytosis inflammatory •  oxidant production mediators •  lysosomal granules chemoattractant (e.g. IL-8, C5a) Tissue Injury (e.g. Bacterial infection)Regents of the University of Michigan
  12. 12. Phagocytic Cell Activation: Chemotactic Factors C5a plasma membrane G-protein tyrosine kinases protein phosphoinositide phosphorylation metabolism IP3 2+ CaOther receptors:Toll-like receptor functional responsesMannose receptor Regents of the University of Michigan
  13. 13. Phagocytic Cell Functional Responses•  Adhesion (localization)•  Chemotaxis (migration)•  Phagocytosis•  NADPH oxidase activation•  Lysosomal granule fusion: degranulation
  14. 14. 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
  15. 15. Neutrophil Phagocytosis of Bacteria Opsonization of Bacteria Fc, C3b binding Phagosome formation PhagolysosomeRegents of the University of Michigan
  16. 16. Source Undetermined
  17. 17. Oxygen radicals Cell phagocytosis Elastase Collagenase Acid hydrolasesRegents of the University of Michigan
  18. 18. Respiratory Burst: NADPH Oxidase Stimulus added 100 patient Oxygen Levels (% of max.) 50 normal 0 +2 +4 +6 TIME (minutes)J. Fantone
  19. 19. Reactive Oxygen MetabolitesSuperoxide anion: O2- O2 + e- O2-Hydrogen peroxide: H2O2 2O2- + 2H+ H2O2 + O2Hydroxyl radical: OH . H2O2 + Fe2+ OH + OH- + Fe3+Hypochlorous acid: HOCl H2O2 HOCl + OH- myeloperoxidase = MPO MPO Chronic Granulomatous Disease of Childhood (CGD): deficiency of NADPH Oxidase
  20. 20. Nitric Oxide (NO ) Synthase L-arginine NO hydroxyl radical peroxynitrites- Endothelial cell- Macrophages (inducible): intracellular cytotoxic agent- Nervous system
  21. 21. Oxidant Targetsa)  unsaturated lipids: lipid peroxidation LOOH = lipid hydroperoxidesc)  proteins - sulfhydryl groups - methionine - tyrosined)  nucleic acids
  22. 22. Degranulation•  Bactericidal proteins (e.g. defensins)•  Proteases – serine proteases (e.g. elastase) – metalloproteinases (e.g. collagenase, gelatinase)•  Acid hydrolases
  23. 23. Oxidants Anti-oxidants Proteases Anti-proteasesJ. Fantone
  24. 24. Pneumonia and AbscessJ. Fantone
  25. 25. J. Fantone
  26. 26. Protective MechanismsAnti-oxidant: specific vs. non-specificSpecific enzymes:Superoxide dismutase: 2O2- + 2H+ H2O2 + O2Catalase: 2H2O2 2H2O + O2Glutathione peroxidase: H2O2 + 2GSH 2H2O + GSSG LOOH + 2GSH H2O + LOH + GSSG LOOH = lipid hydroperoxides GSH = reduced glutathione GSSG = oxidized glutathione
  27. 27. Non- specific scavengers: - Vitamin E - Vitamin C - Beta-carotene
  28. 28. 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
  29. 29. Synergism: Inactivation of alpha-1-anti-trypsin 1. HOCI Dependent a-1-antitrypsin
 (active) PMNs HOCL a-1-antitrypsin
 (inactive) 2. Metalloproteinase Dependent a-1-antitrypsin
 (active) PMNs Metalloproteinase (collagenase) a-1-antitrypsin
 (inactive) J. Fantone
  30. 30. 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.
  31. 31. List three different mechanisms that could account for this patients increased susceptibility to bacterial infection:1.  _________________________________2.  _________________________________3.  _________________________________
  32. 32. Neutrophil RecruitmentSelectins/Addressins ß2 -Integrin/ICAM-1 flow rolling adhesion transmigration endothelium •  phagocytosis inflammatory •  oxidant production mediators •  lysosomal granules chemoattractant (e.g. IL-8, C5a) Tisue Injury (e.g. Bacterial infection)Regents of the University of Michigan
  33. 33. Mechanisms Associated with Increased Susceptibility to Bacterial Infection:1.  Lack of neutrophils: leukopenia2.  Defective neutrophil function –  Adhesion / migration –  Phagocytosis –  Bacterial killing3.  Lack of chemoattractants: deficiency4.  Lack of opsoninization of bacteria - antibody deficiency / complement def.
  34. 34. Additional References:Phagocytic Cells:Kumar, Abas, and Fausto: Pathologic Basis ofDisease (7th ed.) pages 16-18, 53-62,71-74.Parham, The Immune System (2nd ed.): pgs. 15-17,202-209.
  35. 35. Additional Source Information for more information see: http://open.umich.edu/wiki/CitationPolicySlide 6: Regents of the University of MichiganSlide 7: Regents of the University of MichiganSlide 8: Regents of the University of MichiganSlide 9: Regents of the University of MichiganSlide 11: Regents of the University of MichiganSlide 12: Regents of the University of MichiganSlide 15: Regents of the University of MichiganSlide 16: Source UndeterminedSlide 17: Regents of the University of MichiganSlide 18: J. FantoneSlide 23: J. FantoneSlide 24: J. FantoneSlide 25: J FantoneSlide 29: J. FantoneSlide 32: Regents of the University of Michigan

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