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Neutrophileutrophil InnatennateImmunemmuneresponseesponse
Know mediators that prime and stimulate
the neutrophil function Know mediators secreted by the
neutrophil
Understand the role of anti-proteinases inneutrophil function
Know immunomodulators of neutrophilsfunction
Neutrophileutrophil
Neutrophil
Granulocytes
Polymorphonuclear (PMNs)
Polymorphonuclearleukocytes (PMNLs)
Polys
Neutrophileutrophil
Note: Your text has only 4 pages devoted to neutrophils.
Therefore your notes and these powerpoints are
your key resources on this topic.
Neutrophileutrophil
Neutrophilseutrophils innate immune responsennate immune response
Neutrophils
eliminatebacterial
infections
Figure 8.21
LungLung Adult Respiratory Distress SyndromeAdult Respiratory Distress Syndrome
AsthmaAsthmaAsbestosisAsbestosis
EmphysemaEmphysema
Idiopathic pulmonary fibrosisIdiopathic pulmonary fibrosis
Neutrophileutrophilassociated diseasesssociated diseases
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Neutrophileutrophilassociatedssociateddiseasesiseases KidneyKidney GlomerulonephritisGlomerulonephritis
Interstitial nephritisInterstitial nephritis
HeartHeart Myocardial reperfusion injuryMyocardial reperfusion injury
Ischemic heart diseaseIschemic heart disease
JointJoint Rheumatoid arthritisRheumatoid arthritis
GoutGout
SystemicSystemic SclerodermaScleroderma vasculitisvasculitis
Neutrophileutrophilassociated diseasesssociated diseases
The neutrophil is specializedfor the phagocytosis anddestruction of micro-organisms and damaged ornecrotic tissues.
Neutrophileutrophil 3-6,000/L of blood ~70% of WBC
T1/2 = 6-7 hours in blood
T1/2 = 1-2 days in tissues
Neutrophils in the bodyeutrophils in the body
KNOW
NeutrophileutrophilI. Morphology
A. An abundance of granules
B. Multi-lobed nucleusC. Prominent cytoskeleton for locomotion
and chemotactic functions
1. microfilaments
2. microtubules
3. intermediate filaments
Chemotaxishemotaxisof the neutrophilf the neutrophil
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Neutrophileutrophil
II. Chemotaxis
A. Endogenous factors
1. C5a complement fragment
2. IL-8
3. Platelet Activating Factor (PAF)
4. Leukotriene B4 (LTB4)
5. Fragments of collagen and fibrin
Neutrophil chemotaxiseutrophil chemotaxis C5aC5a (C3a, C4a) act on specific receptors
to produce similar local inflammatoryresponses (anaphylatoxins).
C5aC5a is the most stable, has the highestspecific biological activity, and acts on thebest defined receptor.
All three induce smooth muscle contraction
and increase vascular permeability.
Neutrophil Chemotaxiseutrophil Chemotaxis
C5aC5a also acts directly on neutrophilsto increase their adherence to vesselwalls, their migration toward sitesof antigen deposition, and theirability to ingest particles.
Neutrophil chemotaxiseutrophil chemotaxis ILIL--88
ChemokineChemokine produced by endothelial
cells, macrophages, bronchial epithelialcells, fibroblasts, and keratinocytes.
IL-8 is a very strong chemoattractant forneutrophils and T-lymphocytes
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Neutrophil chemotaxiseutrophil chemotaxis Platelet Activating Factor (PAFPAF)
PAFPAF is a small phospholipid (MW300-500) which causes:
platelet aggregation
increased vascular permeability
chemotaxis
Neutrophil chemotaxiseutrophil chemotaxis
II.II. ChemotaxisChemotaxis
B.B. Exogenous factorsExogenous factors bacterialbacterial
productsproducts
1. N-formylated oligopeptides (FMLP)
2. Endotoxin (LPS)
Neutrophil chemotaxiseutrophil chemotaxis The bacterial cell wall component,
LPS (endotoxin), is first bound by aserum protein, lipopolysaccharide-binding protein (LBPLBP).
The complex of LPSLPS and LBPLBP is thenbound by CD14CD14 on the surface of theneutrophil.
Neutrophil chemotaxiseutrophil chemotaxis
The interaction of CD14CD14 with the
LPSLPS--LPBLPB complex causes an increasein the adhesive activity of CR3(CD11b/CD18) on neutrophils.
Transvascularransvascular Migrationigrationof the Neutrophilf the Neutrophil
Neutrophil activationeutrophil activation1) Surface changes from smooth to
ruffled membrane
2) Adhesion to endothelial cells
3) On surface: opsonins binding to C3bor Fc portion of Ig
4) Membrane invaginates and formsphagosome
5) Release of enzymes which mediatedestruction of target material
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Margination : Transmigration MARGINATIONMARGINATION
PHAGOCYTOSISPHAGOCYTOSIS
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Enzymes of the Neutrophilnzymes of the Neutrophil
Neutrophil enzymeseutrophil enzymes Azurophilic or PrimaryAzurophilic or Primary ((blueblue))
These are the first granules formed in thedeveloping neutrophil and peak degranulationis 90 minutes.
Specific or SecondarySpecific or Secondary ((pinkpink))
These granules are formed later in thedevelopment of the neutrophil. Theseenzymes are released within 15 seconds after
contact with the pathogen.
Primary GranulesMyeloperoxidase
DefensinsLysozymeElastase
OthersBPI
Cathepsin G
Alkaline phosphatase
Proteinase 3-glucuronidase-fucosidasePhospholipases A2, C, D-mannosidase
Neutrophil enzymeseutrophil enzymes
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Neutrophil enzymeseutrophil enzymes
Myeloperoxidase (MPO)Myeloperoxidase (MPO): is anabundant granular enzyme (accounts for5% of dry weight of the neutrophil).
This enzyme combines hydrogen peroxidewith chloride ions to form hypochlorousacid (HOCl = bleach).
Neutrophil enzymeseutrophil enzymes
Elastase: is a serine protease whichspecifically hydrolyzes elastin.
Elastin is the major component of elasticfibers which stretch in the walls of bloodvessels, lungs, and ligaments.
Neutrophil enzymeseutrophil enzymes The activity of elastaseelastase is controlled by
an inhibitor termed 11--antianti--trypsintrypsin.
Human neutrophil elastase (HNE)Human neutrophil elastase (HNE) hasbeen demonstrated in pathogenesis ofemphysema, adult respiratory distresssyndrome (ARDS), chronic bronchitis,rheumatoid arthritis, and psoriasis.
Secondary granulesLactoferrin
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 enzymeseutrophil enzymes Neutrophil enzymeseutrophil enzymes LysozymeLysozyme: like MPO, is a microbicidal
enzyme.
LysozymeLysozyme digests debris from cell wallsof bacteria that have already beenprocessed by other enzymes.
Another function of lysozymelysozyme is tomodulate inflammation by suppressingneutrophil chemotaxis and oxidativemetabolism.
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Neutrophil enzymeseutrophil enzymes
CollagenaseCollagenase: cleaves collagen into twodistinct and specific peptide fragments
CollagenaseCollagenase is released by intactneutrophils during phagocytosis as acollagenase precursor (procollagenase)and is activated by trypsin, hypochlorousacid or rheumatoid synovial fluid.
Neutrophil enzymeseutrophil enzymes CollagenaseCollagenase acts as an anticoagulant
because it digests fibrinogen. It is inhibited by -1-antitrypsin and-2-macroglobulin.
Some diseases associated with overabundant collagenasecollagenase secretion includerheumatoid arthritis and certain diseasesof the eye like ulcerated corneas.
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.
Control of theontrol of theNeutrophil Enzymeseutrophil EnzymesAntintiproteasesroteases
Anti proteinases There are normal regulatory mechanisms
for control of secreted neutrophil enzymes
and control pathways to limit the enzymeaction by anti-proteases.
These are highly important forneutralization of the enzymatic activitiesof the neutrophil proteases.
Protease inhibitors can comprise about10% of the total protein of the blood.
Anti-protease activities are closely coupledto the generation of neutrophil reactivechlorinated oxidants (HOCl).
Anti proteinases
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-1 Antitrypsin Deficiency (AATD)
What is it?
Alpha-1 antitrypsin is a protease inhibitor(PI), genotype MM, which protects tissuesfrom the effects of neutrophil.
It is mainly produced in the liver.
-1 Antitrypsin Deficiency (AATD)
Who does it affect?
Alpha-1 antitrypsin deficiency is geneticand it is passed onto children by theirparents.
There are at least 75 different variations,or alleles, of the gene. Each person hastwo alleles and can pass one of these onto their children.
-1 Antitrypsin Deficiency (AATD)
Most people carry two copies of the Mallele ie genotype MM. People with AATDcarry two copies of the Z allele iegenotype ZZ.
About 1 : 25 are MZ. They are usuallycompletely healthy but their partner willalso have a 1 : 25 risk of being MZ. Ifthey have children, each child will have a1 : 4 chance of being ZZ, so the overallrisk for a child being ZZ is 1 : (25 x 25 x
4) = 1 : 2,500
-1 Antitrypsin Deficiency (AATD)
Alpha-1 antitrypsin deficiency is the mostcommon genetic cause of liver diseasechildren and of emphysema in adults.
It is also the most common geneticdisease for which liver transplantation isundertaken in children.
Emphysemamphysema PROTEIN-ENZYME IMBALANCE
Neutrophil elastase is released during times ofinflammation. This action is normally helpful and
is balanced (neutralized) by the protein -1antitrypsin produced in the liver.
One cause of damage to the alveoli of the lungis that elastase is produced by neutrophil butthere is a genetically lack of -1 antitrypsin.
Emphysema
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Emphysema Anti proteases
Anti-proteaseshieldprevents degradationof normal tissues
Then how can the neutrophilperform its normal functions?
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)
1-antichymotrypsin(1-ACT)
Deactivation of anti proteases Antintiproteasesroteases Subsequent to this
two staged attack onanti-proteases, theneutrophil enzymesare free to damagethe bacterial targets,necrotic tissues, or inpathologicalconditions, normaltissues.
NEUTROPHILEUTROPHIL
Monday will be Adhesion Proteins
