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Innate Immunity > Neutrophils > Flashcards

Neutrophils Flashcards

1
Q

What happens to neutrophils

A

If do not encounter neutrophils then degrade around 6 hours

If encounter pathogen become active/apoptosis and taken up into tissues where last a couple of days

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2
Q

Neutropenia can?

A

Lead to severe conditions Kostman’s disease

Can be induced (by chemotherapy) as targets rapidly dividing cells
Including neutrophils

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3
Q

Acute myeloid leukaemia (AML) is

A

Neutrophilia
Immunocompromised state
Produce to many neutrophilia but not matured and hence non functional

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4
Q

What do neutrophils do

A

Migrate from blood to site of infection

Detect pathogens and inflammatory mediators from tissue macrophages and and mast cells.

Cause destruction of pathogens and also collateral tissue damage

Actively downregulate inflammation, undergo apoptosis and removed by macrophages

Neutrophils detect pathogens by PRRs

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5
Q

What is inflammation

A

General term for accumulation of fluid, plasma, proteins and leukocyte initiated by physical trauma,infection or immune response

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6
Q

Stages of inflammation

A

Activation, cellular migration and extravasation

Microbial detection and killing(mainly neutrophils, then macrophages)

Resolution, switching off and removal
OF cells

Unresolved inflammation which is chronic(>6 weeks) and mainly caused by macrophages and T-cells and leads to Fibrosis and granulomas formation

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7
Q

What is the time course if acute inflammation

A

Swelling occurs due to influx of tissue fluid

Vascular leakage from blood allows soluble molecules from blood to enter tissues
- occurs rapidly

Next stage involves neutrophils activity

Monocytes/macrophages then clear up site(clear up debris from neutrophilllic apoptosis

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8
Q

What does lipid mediator Thromboxanes do?

A

Vasoconstriction

Platlet aggregation

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9
Q

Lipid mediator Prostaglandins do?

A

Increase vascular permeability
Vascular dilation
Neutrophils chemotaxis

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10
Q

How does inflammation intiate?

A

Damaged cells, Bacterial uptake by macrophages and mast cell degranilation lead to increase in vessel permeability

This causes increase in soluble components from blood such as antibodies and complement

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11
Q

How are cells(what kind) recruited during inflammation

A

Neutrophils brought from blood to tissues via Chemoattractants

Adhesion molecules on endothelial cells and neutrophils upregulated

Heavily regulated as don’t want inflammation all the time

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12
Q

Examples of chemoattractants

A

IL-8 secreted by macrophages (also IL-1 and IL-6)

PAF platelet activating factor

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13
Q

How do chemoattractants work

A

Attract particular molecules toward cells

Peptides from bacteria bind to Receptors on neutrophil surface

Chemoattractants move towards these bound peptides as have formulated methionine

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14
Q

What are the main stages of leukocyte adhesion cascade?

A

Capture and rolling

Activation and arrest

Crawling and extravasation

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15
Q

Capture and rolling need?

A

Selectins—

Have high on/off binding rates

Binding is transient to allow leukocyte release

Facilitate rolling

Bind sialylation sugars

Signal PIKy to cause slow rolling

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16
Q

Activation and arrest

A

Integrity mediate leukocyte arrest via outside in and inside out signalling

Chemokins, TNF and chemoattractants activate integrins

Increase ICAM-1 binding on endothelial cells which is inside out signal

Increases by clustering and conformational change
Outside in via src kinases

17
Q

Leukocyte adhesion deficiency is?

A

Due to migration defects in neutrophils

Patients often die from recurrent infection

LAD1- lack cd18 crucial integrity

LAD2- lack fuckayktransferase that generates selectin ligand

LAD3- integrity activation defect

18
Q

Neutrophil killing steps

A

Once at site of inflammation neutrophils activated by PAMPS (LPS, b-glucans) and pro-inflammatory cytokines (TNF-a)

Neutrophils poses PRR and opsonic Receptors for recognition and uptake

19
Q

Antimicrobial molecule delivered by neutrophils?

A

Oxidative burst - NADPH used to create hydrogen peroxide leading oxygen free radicals which are highly antimicrobial

Nitric oxide synthetase- Reactive nitrogen species produced by this enzyme

Myeloperoxidase- formation of bleach (hypochlorous acid) Pus around wounds produced by dissolution of tissue by this strong acid

20
Q

What can evade neutrophil killing via disruption of NADPH oxidase complex formation?

A

Anaplasma phagocytophilum

21
Q

Primary antimicrobial granules produced by neutrophils?

Also known as Azurophilic

A 
BPI, 
Neutrophil elastase
Cathespin G
Protease 3
MPO
CAP38
Defensins
22
Q

Secondary antimicrobial granules produced by neutrophils?

A

Lactoferrin - binds to iron ions and sequesters nutrients from environment to prevent bacteria growing

Lipocalins - bind to Bacterial proteins binding onto ions

MMP8 MMP9 MMP25

23
Q

Tertiary antimicrobial granules produced by neutrophils?

A

Cathepsins and gelatinase

24
Q

What do neutrophils produce as antimicrobials in cytoplasm and host tissue damage

A

Calprotectin (divalent cation chelator)

Hypochlorous acid causes liquefaction and pus formation

Antimicrobial peptides like defensins and LL37 which punch little holes into membrane of gram negative bacteria

25
Q

What are NETs?

Why is it antimicrobial?

A

Neutrophil extracellular traps
I’m dying moments of neutrophils, genetic component comes out and DNA works to physically tap bacteria

Histone modification is essential for NET formation

His tones are antimicrobial and DNA binds to granular products

26
Q

How are NETs regulated?

A

IL-8 signalling and ROS production regulates NETs

Inhibited by effective phagocytosis

Induced by frustrated phagocytosis of larger pathogens/aggregates

27
Q

What is PADi4 in relation to neutrophils?

A

Gene encodes enzyme that converts arginine to citrulline.
These arginine normally interacts with negatively charged backbone of DNA.

Histone hypercitrullation is catalysed by PADI4
(Histone modification necessary for NET formation)

28
Q

Detail non-suicidal mitochondrial DNA catapults?

A

mtDNA with GM-CSF followed by TLR /C5a stimulation triggers mtDNA but not nuclear DNA

Priming is common mechanism of control for immune cells

Cells do not die - have delayed apoptosis

29
Q

How does Anaplasma phagocytophilum evade neutrophils?

A

Resides in intracellular vacuoles

Preventing cytochrome b558 delivery to NADPH oxidase complex– delaying apoptosis

30
Q

How does Staph aureus evade neutrophils?

A

MprF gene adds L-lysinse to lipids to repulse cationic defensins

Some bacteria express DNases, resistant to NET-mediated killing

31
Q

How do pseudomonas aeruginosa evade NET

A

Absorb sialoglycoproteins which bind to inhibitory Receptors thereby reducing NET generation

32
Q

Inflammation resolution

A

Not passive for active inflammation

Needs to be active apoptosis and generation of anti-inflammatory cytokines and anti-inflammatory mediators.

33
Q

How can you identify apoptosis cells

A

Observing their membranes.
Will be lipids on outside membrane.
ACAMP (apoptotic cell associated molecular patterns)

Will be bound to macrophages

Innate Immunity (5 decks)

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