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Neutrophil – Innate Immune response

Neutrophil – Innate Immune response. Neutrophil. Know mediators that prime and stimulate the neutrophil function Know mediators secreted by the neutrophil Understand the role of anti-proteinases in neutrophil function Know immunomodulators of neutrophils function. Neutrophil. Neutrophil

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Neutrophil – Innate Immune response

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  1. Neutrophil – InnateImmuneresponse

  2. Neutrophil • Know mediators that prime and stimulate the neutrophil function • Know mediators secreted by the neutrophil • Understand the role of anti-proteinases in neutrophil function • Know immunomodulators of neutrophils function

  3. Neutrophil • Neutrophil • Granulocytes • Polymorphonuclear (PMNs) • Polymorphonuclear leukocytes (PMNLs) • Poly’s Note: Your text has only 4 pages devoted to neutrophils. Therefore your notes and these powerpoints are your key resources on this topic.

  4. Neutrophil

  5. Neutrophils – innate immune response Neutrophils eliminate bacterial infections Figure 8.21

  6. Neutrophil-associated diseases • Lung Adult Respiratory Distress Syndrome Asthma Asbestosis Emphysema Idiopathic pulmonary fibrosis

  7. Neutrophil-associated diseases

  8. Neutrophil-associated diseases • Kidney Glomerulonephritis Interstitial nephritis • Heart Myocardial reperfusion injury Ischemic heart disease • Joint Rheumatoid arthritis Gout • Systemic Scleroderma vasculitis

  9. Neutrophil • The neutrophil is specialized for the phagocytosis and destruction of micro-organisms and damaged or necrotic tissues.

  10. Neutrophils in the body • 3-6,000/mL of blood • ~70% of WBC • T1/2 = 6-7 hours in blood • T1/2 = 1-2 days in tissues KNOW

  11. Neutrophil I. Morphology • An abundance of granules • Multi-lobed nucleus • Prominent cytoskeleton for locomotion and chemotactic functions 1. microfilaments 2. microtubules 3. intermediate filaments

  12. Chemotaxis of the neutrophil

  13. Neutrophil II.Chemotaxis • Endogenous factors • C5a – complement fragment • IL-8 • Platelet Activating Factor (PAF) • Leukotriene B4 (LTB4) • Fragments of collagen and fibrin

  14. Neutrophil chemotaxis • C5a (C3a, C4a) act on specific receptors to produce similar local inflammatory responses (anaphylatoxins). • C5ais the most stable, has the highest specific biological activity, and acts on the best defined receptor. • All three induce smooth muscle contraction and increase vascular permeability.

  15. Neutrophil Chemotaxis • C5a also acts directly on neutrophils to increase their adherence to vessel walls, their migration toward sites of antigen deposition, and their ability to ingest particles.

  16. Neutrophil chemotaxis • IL-8 • Chemokine produced by endothelial cells, macrophages, bronchial epithelial cells, fibroblasts, and keratinocytes. • IL-8 is a very strong chemoattractant for neutrophils and T-lymphocytes

  17. Neutrophil chemotaxis • Platelet Activating Factor (PAF) • PAF is a small phospholipid (MW 300-500) which causes: • platelet aggregation • increased vascular permeability • chemotaxis

  18. Neutrophil chemotaxis II. Chemotaxis • Exogenous factors – bacterial products • N-formylated oligopeptides (FMLP) • Endotoxin (LPS)

  19. Neutrophil chemotaxis • The bacterial cell wall component, LPS (endotoxin), is first bound by a serum protein, lipopolysaccharide-binding protein (LBP). • The complex of LPS and LBP is then bound by CD14 on the surface of the neutrophil.

  20. Neutrophil chemotaxis • The interaction of CD14 with the LPS-LPB complex causes an increase in the adhesive activity of CR3 (CD11b/CD18) on neutrophils.

  21. Transvascular Migration of the Neutrophil

  22. Neutrophil activation • Surface changes from smooth to ruffled membrane • Adhesion to endothelial cells • On surface: opsonins binding to C3b or Fc portion of Ig • Membrane invaginates and forms phagosome • Release of enzymes which mediate destruction of target material

  23. Margination : Transmigration

  24. MARGINATION

  25. PHAGOCYTOSIS

  26. Enzymes of the Neutrophil

  27. Neutrophil enzymes • Azurophilic or Primary (blue) • These are the first granules formed in the developing neutrophil and peak degranulation is 90 minutes. • Specific or Secondary (pink) • These granules are formed later in the development of the neutrophil. These enzymes are released within 15 seconds after contact with the pathogen.

  28. Neutrophil enzymes Primary Granules Myeloperoxidase Defensins Lysozyme Elastase Others BPI Cathepsin G Alkaline phosphatase Proteinase 3 -glucuronidase -fucosidase Phospholipases A2, C, D -mannosidase

  29. Neutrophil enzymes • Myeloperoxidase (MPO): is an abundant granular enzyme (accounts for 5% of dry weight of the neutrophil). • This enzyme combines hydrogen peroxide with chloride ions to form hypochlorous acid (HOCl = bleach).

  30. Neutrophil enzymes • Elastase: is a serine protease which specifically hydrolyzes elastin. • Elastin is the major component of elastic fibers which stretch in the walls of blood vessels, lungs, and ligaments.

  31. Neutrophil enzymes • The activity of elastase is controlled by an inhibitor termed a1-anti-trypsin. • Human neutrophil elastase (HNE) has been demonstrated in pathogenesis of emphysema, adult respiratory distress syndrome (ARDS), chronic bronchitis, rheumatoid arthritis, and psoriasis.

  32. Neutrophil enzymes Secondary granules Lactoferrin Lysozyme Collagenase Others Gelatinase Vitamin B12-binding protein Cytochrome b558 fMLP receptor CD11b/CD18, CD11c/CD18 (integrins) Complement receptor 3 (CR3) Histaminase Plasminogen activator

  33. Neutrophil enzymes • Lysozyme: like MPO, is a microbicidal enzyme. • Lysozyme digests debris from cell walls of bacteria that have already been processed by other enzymes. • Another function of lysozyme is to modulate inflammation by suppressing neutrophil chemotaxis and oxidative metabolism.

  34. Neutrophil enzymes • Collagenase: cleaves collagen into two distinct and specific peptide fragments • Collagenaseis released by intact neutrophils during phagocytosis as a collagenase precursor (procollagenase) and is activated by trypsin, hypochlorous acid or rheumatoid synovial fluid.

  35. Neutrophil enzymes • Collagenase acts as an anticoagulant because it digests fibrinogen. • It is inhibited by a-1-antitrypsin and a-2-macroglobulin. • Some diseases associated with over abundant collagenase secretion include rheumatoid arthritis and certain diseases of the eye like ulcerated corneas.

  36. Within 30 seconds after a neutrophil ingests a particle, it begins to secrete specific granule components into the phagosome via phagolysosomal fusion. Within 3 minutes, azurophil granule components are discharged into the phagolysosome.

  37. Control of the Neutrophil Enzymes Anti-proteases

  38. Anti-proteinases • There are normal regulatory mechanisms for control of secreted neutrophil enzymes and control pathways to limit the enzyme action by anti-proteases. • These are highly important for neutralization of the enzymatic activities of the neutrophil proteases.

  39. Anti-proteinases • Protease inhibitors can comprise about 10% of the total protein of the blood. • Anti-protease activities are closely coupled to the generation of neutrophil reactive chlorinated oxidants (HOCl).

  40. a-1 Antitrypsin Deficiency (AATD) • What is it? • Alpha-1 antitrypsin is a protease inhibitor (PI), genotype MM, which protects tissues from the effects of neutrophil. • It is mainly produced in the liver.

  41. a-1 Antitrypsin Deficiency (AATD) • Who does it affect? • Alpha-1 antitrypsin deficiency is genetic and it is passed onto children by their parents.   • There are at least 75 different variations, or alleles, of the gene.   Each person has two alleles and can pass one of these on to their children.

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