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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
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
neutrophil1
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.

neutrophils innate immune response
Neutrophils – innate immune response

Neutrophils

eliminate

bacterial

infections

Figure 8.21

neutrophil associated diseases
Neutrophil-associated diseases
  • Lung Adult Respiratory Distress Syndrome

Asthma

Asbestosis

Emphysema

Idiopathic pulmonary fibrosis

neutrophil associated diseases1
Neutrophil-associated diseases
  • Kidney Glomerulonephritis

Interstitial nephritis

  • Heart Myocardial reperfusion injury

Ischemic heart disease

  • Joint Rheumatoid arthritis

Gout

  • Systemic Scleroderma vasculitis
neutrophil3
Neutrophil
  • The neutrophil is specialized for the phagocytosis and destruction of micro-organisms and damaged or necrotic tissues.
neutrophils in the body
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

neutrophil4
Neutrophil

I. Morphology

  • An abundance of granules
  • Multi-lobed nucleus
  • Prominent cytoskeleton for locomotion and chemotactic functions

1. microfilaments

2. microtubules

3. intermediate filaments

slide12

Chemotaxis

of the neutrophil

neutrophil5
Neutrophil

II.Chemotaxis

  • Endogenous factors
    • C5a – complement fragment
    • IL-8
    • Platelet Activating Factor (PAF)
    • Leukotriene B4 (LTB4)
    • Fragments of collagen and fibrin
neutrophil chemotaxis
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.
neutrophil chemotaxis1
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.
neutrophil chemotaxis2
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
neutrophil chemotaxis3
Neutrophil chemotaxis
  • Platelet Activating Factor (PAF)
  • PAF is a small phospholipid (MW 300-500) which causes:
    • platelet aggregation
    • increased vascular permeability
    • chemotaxis
neutrophil chemotaxis4
Neutrophil chemotaxis

II. Chemotaxis

  • Exogenous factors – bacterial products
    • N-formylated oligopeptides (FMLP)
    • Endotoxin (LPS)
neutrophil chemotaxis5
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.
neutrophil chemotaxis6
Neutrophil chemotaxis
  • The interaction of CD14 with the LPS-LPB complex causes an increase in the adhesive activity of CR3 (CD11b/CD18) on neutrophils.
slide23

Transvascular Migration

of the Neutrophil

neutrophil activation
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
neutrophil enzymes
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.
neutrophil enzymes1
Neutrophil enzymes

Primary Granules

Myeloperoxidase

Defensins

Lysozyme

Elastase

Others

BPI

Cathepsin G

Alkaline phosphatase

Proteinase 3

-glucuronidase

-fucosidase

Phospholipases A2, C, D

-mannosidase

neutrophil enzymes2
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).
neutrophil enzymes3
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.
neutrophil enzymes4
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.
neutrophil enzymes5
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

neutrophil enzymes6
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.
neutrophil enzymes7
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.
neutrophil enzymes8
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.
slide45

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.

slide46

Control of the

Neutrophil Enzymes

Anti-proteases

anti proteinases
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.
anti proteinases1
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).
a 1 antitrypsin deficiency aatd
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.
a 1 antitrypsin deficiency aatd1
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.
a 1 antitrypsin deficiency aatd2
a-1 Antitrypsin Deficiency (AATD)
  • Most people carry two copies of the M allele ie genotype MM.   People with AATD carry two copies of the Z allele ie genotype ZZ.
  • About 1 :  25 are MZ.  They are usually completely healthy but their partner will also have a 1 : 25 risk of being MZ.  If they have children, each child will have a 1 : 4 chance of being ZZ, so the overall risk for a child being ZZ is 1 : (25 x 25 x 4) = 1 : 2,500
a 1 antitrypsin deficiency aatd3
a-1 Antitrypsin Deficiency (AATD)
  • Alpha-1 antitrypsin deficiency is the most common genetic cause of liver disease children and of emphysema in adults.
  • It is also the most common genetic disease for which liver transplantation is undertaken in children.
emphysema
Emphysema
  • PROTEIN-ENZYME IMBALANCE Neutrophil elastase is released during times of inflammation. This action is normally helpful and is balanced (neutralized) by the protein a-1 antitrypsin produced in the liver.
  • One cause of damage to the alveoli of the lung is that elastase is produced by neutrophil but there is a genetically lack of a-1 antitrypsin.
anti proteases
Anti-proteases

Anti-protease

shield

prevents degradation

of normal tissues

Then how can the neutrophil

perform its normal functions?

deactivation of anti proteases
Deactivation of anti-proteases

STEP ONE

  • HOCl 1-protease inhibitor (1-PI), anti-leukoprotease (ALP), 2-macroglobulin (2-M), plasminogen activator inhibitor- 1 (PAI-1)

STEP TWO

  • Elastase metalloprotease (TIMP) a1-antichymotrypsin (a1-ACT)
anti proteases1
Anti-proteases
  • Subsequent to this two staged attack on anti-proteases, the neutrophil enzymes are free to damage the bacterial targets, necrotic tissues, or in pathological conditions, normal tissues.
neutrophil6
NEUTROPHIL

Monday will be Adhesion Proteins