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No 3 Innate Immune System

Jun 04, 2018



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  • 8/13/2019 No 3 Innate Immune System


    Neutrophileutrophil InnatennateImmunemmuneresponseesponse

    Know mediators that prime and stimulate

    the neutrophil function Know mediators secreted by the


    Understand the role of anti-proteinases inneutrophil function

    Know immunomodulators of neutrophilsfunction




    Polymorphonuclear (PMNs)

    Polymorphonuclearleukocytes (PMNLs)



    Note: Your text has only 4 pages devoted to neutrophils.

    Therefore your notes and these powerpoints are

    your key resources on this topic.


    Neutrophilseutrophils innate immune responsennate immune response




    Figure 8.21

    LungLung Adult Respiratory Distress SyndromeAdult Respiratory Distress Syndrome



    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


    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


    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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    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


    Neutrophil chemotaxiseutrophil chemotaxis

    II.II. ChemotaxisChemotaxis

    B.B. Exogenous factorsExogenous factors bacterialbacterial


    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


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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



    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





    Vitamin B12-binding protein

    Cytochrome b558

    fMLP receptor

    CD11b/CD18, CD11c/CD18 (integrins)

    Complement receptor 3 (CR3)


    Plasminogen activator

    Neutrophil enzymeseutrophil enzymes Neutrophil enzymeseutrophil enzymes LysozymeLysozyme: like MPO, is a microbicidal


    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


    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.


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    Emphysema Anti proteases

    Anti-proteaseshieldprevents degradationof normal tissues

    Then how can the neutrophilperform its normal functions?


    HOCl 1-protease inhibitor (1-PI),anti-leukoprotease (ALP),

    2-macroglobulin (2-M),plasminogen activator inhibitor-

    1 (PAI-1)


    Elastase metalloprotease (TIMP)


    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.


    Monday will be Adhesion Proteins