No 3 Innate Immune System

8/13/2019 No 3 Innate Immune System

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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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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).


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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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.


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.


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


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

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No 3 Innate Immune System