Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Cellular and Molecular Immunology > 8. Innate immunity 3: Neutrophils > Flashcards

8. Innate immunity 3: Neutrophils Flashcards

1
Q

What are neutrophils?

A
  1. Polymorphonuclear granulocytes.
  2. They have a globulated nucleus.
  3. They are the most abundant blood cell in the body with 100 billion being produced and turned over a day.
  4. They are packed with vesicles containing antimicrobial products.
  5. They are the first responders to infection and injury. They recruit other innate and adaptive responses.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What is the problem with the short life span of neutrophils?

A
  1. They have a life span of 3-5 days.
  2. Energetically this is unfavourable to be making so many cells all the time.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

How were neutrophil swarms visualised?

A
  1. Labelling the neutrophils with GFP.
  2. Use a laser to make a wound in a mouse ear. This is the stimulus
  3. Observe how the neutrophils migrate in response.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What is a neutrophil swarm?

A
  1. DAMPs are released by the damaged cells.
  2. This causes the initial slow neutrophil migration towards to the wound.
  3. Generation of IL-1ß from macrophages and neutrophils speeds up migration and creates the swam of neutrophils.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What is the primary function of neutrophils?

A
  1. To produce and release granules filled with toxic antimicrobial molecules.
  2. This kills pathogens like bacteria and fungi
  3. But it can also cause damage to our tissues in autoimmunity.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What is neutropenia?

A

An abnormally low neutrophil count or complete lack of neutrophils.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Causes of neutropenia: Genetics

A
  1. Mutations in genes that are essential for neutrophil production.
  2. Congenital neutropenia
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Causes of neutropenia: Chemotherapy

A
  1. Chemo is myelosuppressive.
  2. This causes very low levels of neutrophils.
  3. Often, cancer treatment needs to be stopped to allow the neutrophils to recover, but this is bad for cancer outcomes.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Other causes of neutropenia

A
  1. Autoimmunity
  2. some infections
  3. Medications
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What infections are people with neutropenia susceptible to?

A
  1. Treat these like knockout experiments so you can see what neutrophils are important in dealing with.
  2. Fungi are a big problem for neutropenic patients as there are no neutrophils to deal with the spores so the infections take hold.
  3. Also Staph aureus, streptococci, pseudomonas aeruginosa
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

How can you treat neutropenia?

A

Sometimes treatment with granulocyte-colony stimulating factor works.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Where do neutrophils carry out their function?

A
  1. They circulate in the blood to get to different tissues.
  2. They carry out their effector functions in the tissues once they leave the blood vessels.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

How do neutrophils leave the blood vessels?

A
  1. Extravasation
  2. This is a binding to the endothelium and squeezing between the cells in the leukocyte adhesion cascade.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What is the leukocyte adhesion cascade?

A
  1. Done by leukocytes, monocytes and T cells.
  2. The cells bind to integrins.
  3. This slows down the cells and they start rolling.
  4. The cells can then move through the endothelial cells.
  5. This means the neutrophils can move quickly towards the site of infection.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What happens when neutrophils reach the site of infection?

A
  1. Phagocytosis using reactive oxygen species (ROS can also act as signalling molecules)
  2. Degranulation of necrotic molecules.
  3. NETosis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What is NETosis?

A
  1. A kamikaze form of cell death to kill extracellular pathogens.
  2. It is an extreme form of cell death.
  3. Very pro inflammatory
  4. involves the release of chromatin to trap pathogens.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Are there different types of granules in neutrophils?

A

Yes different classes of granules carry different cargo. All cargo is antimicrobial.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

How do neutrophils recognise pathogens for phagocytosis?

A
  1. Direct recognition of pathogens through TLR.
  2. Recognition of opsonised pathogens through FcR.
  3. Recognition of complement components on the pathogen membrane through complement receptors.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What happens when neutrophils internalise pathogens for phagocytosis?

A
  1. Enters a phagosome
  2. Lysosomes and granules fuse to the phagosome.
  3. They then dump their antimicrobials into the phagosome to create a hostile environment for the pathogen.
  4. The NADPH complex assembles on the phagosome membrane to make reactive oxygen species.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

How does NETosis occurs?

A

Through an active signalling cascade that is conserved.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

What is the mechanism of NETosis?

A
  1. The activation signal leads to increased permeability of the granules so the contents including elastase can leave.
  2. The nuclear membrane also increases in permeability.
  3. The elastase and other molecules enter the nucleus.
  4. Elastase is a protease that cleaves the histone tails in the chromatin.
  5. This causes rapid decondensation of the chromatin. This forms the NET.
  6. The chromatin and granule proteins explode out of the cell.
  7. This kills the neutrophil but it also traps and kills pathogens.
  8. Very pro inflammatory
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

What are the NETs made of?

A
  1. DNA/chromatin
  2. Histones
  3. Granule proteins like elastase
23
Q

What is NETosis dependant on?

A

ROS production and elastase

24
Q

What are the functions of NETosis?

A
  1. Killing of big extracellular pathogens that cannot be internalised.
  2. It is highly conserved process including in plants.
  3. It traps microbes to prevent them from spreading systemically which is important in eyes, lungs and skin.
  4. It is very pro-inflammatory and immune-activating.
25
Q

What does NETosis stand for?

A

Neutrophil extracellular traps

26
Q

What are immune functions does NETosis activate?

A
  1. Triggers the coagulation cascade.
  2. Priming and activation of macrophages.
  3. Activation of lymphocytes.
27
Q

How can NETs help cancer cells metastasise?

A
  1. If they are already formed they can grab and trap circulating cancer cells.
  2. This helps them grow and implant in metastatic sites.
28
Q

Neutrophils reacting to different forms of pathogens: Candida yeast cells

A
  1. These are less virulent and non-pathogenic but they need to be removed through phagocytosis.
  2. Neutrophils are activated phagocytose the yeast cells.
  3. They undergo low levels of degranulation.
  4. Ultimately the neutrophils turn off once the yeast is cleared.
  5. The neutrophil dies by apoptosis which is anti-inflammatory.
29
Q

Neutrophils reacting to different forms of pathogens: Candida hyphae cells

A
  1. The hyphae are very virulent and cause tissue damage by burrowing into tissues.
  2. They are much bigger so need to be kill extracellularly.
  3. NETosis from neutrophils.
  4. This is very pro-inflammatory, and there is also a loss of anti-inflammatory apoptotic neutrophils.
  5. This activates other parts of the immune system.
30
Q

Why does the way neutrophils die matter?

A

The way all immune cells die is important for shaping the immune response.

31
Q

What happens when neutrophils die by apoptosis?

A
  1. This happens after the neutrophil undergoes phagocytosis
  2. The macrophages eat/clear them.
  3. This sends anti-inflammatory signals to the macrophages and turns them into regulatory macrophages.
32
Q

What happens when neutrophils die by NETosis?

A
  1. Very pro-inflammatory and causes severe inflammation.
  2. Alarmins and inflammatory signals are released.
  3. No apoptotic neutrophils to produce anti-inflammatory signals.
33
Q

What are the 4 classes of antimicrobials in neutrophils?

A
  1. Reactive oxygen species
  2. Antibacterial peptides
  3. Degradative enzymes
  4. Metal binding proteins
34
Q

Neutrophil antimicrobials: Reactive oxygen species

A
  1. There are dedicated enzymes to generate ROS.
  2. ROS are good at killing bacteria due to cross linking peptides and oxidising DNA and lipids.
  3. NOX2 converts molecular oxygen to superoxide ion. This is very reactive but unstable.
  4. SOD converts superoxide to hydrogen peroxide, which is still reactive but more stable, so it can travel further.
  5. MPO converts hydrogen peroxide to hypohalous acids which are more stable and still reactive.
  6. HOCL is basically bleach and is pumped into the phagosome or extracellularly to kill microbes
35
Q

What are the enzymes that generate ROS?

A

NOX: NADPH oxidase
SOD: Superoxide dismutase
MPO: Myeloperoxidase

36
Q

How was the role of NOX2 discovered to be important in neutrophil action?

A
  1. A boy with recurrent infection with lungs full of fungal balls.
  2. Detected by PET scan, and antifungal drugs didn’t work.
  3. The neutrophils isolated couldn’t produce ROS or kill fungus.
  4. It was discovered he had a mutation in NOX2 meaning ROS couldn’t be produced.
37
Q

What is chronic granulomatous disease and how can it be treated?

A
  1. Mutation in NOX2
  2. A rare X-linked disorder
  3. Can be treated by gene therapy.
  4. Take the boy’s bone marrow and use an antivirus to replace the faulty gene with the original. The bone marrow is the put back into the boy.
  5. Neutrophil action and NETosis is restored after transplant.
38
Q

Neutrophil antimicrobials: Antibacterial peptides

A
  1. Mostly defensins
  2. They are positively charged short peptides to be attracted to negative bacterial cell walls.
  3. They punch holes in the bacteria membrane.
  4. They can also enter the bacteria and interfere with DNA synthesis.
  5. They act as alarmins.
  6. Found in phagosome, NETs and granules
39
Q

Neutrophil antimicrobials: degradative enzymes

A
  1. Lysozyme which breaks down bacterial peptidoglycan.
  2. Proteases that can cleave bacterial virulence factors to disarm them.
  3. Includes Protease 3, Cathepsin G, and Elastase.
  4. Found in phagosome, NETs and granules
40
Q

Neutrophil antimicrobials: Metal-binding proteins

A
  1. These are protein are sequester essential nutrients and ions that bacteria and fungi need to grow.
  2. This prevents the bacteria from getting them.
  3. This includes Lactoferrin, lipocalin and calgranulin.
41
Q

What is neutrophil abundance important for?

A

It is important for determining the outcome of disease.

42
Q

What are some diseases where neutrophils are protective?

A

Bacterial
Fungal
Viral
Parasitic
IBD
Periodontitis

43
Q

What are some diseases where neutrophils are detrimental?

A

Too many or too few neutrophils
Lupus
Rheumatoid arthritis
cystic fibrosis
Cancer
Diabetes
Malaria

44
Q

How are neutrophils produced?

A
  1. In the bone marrow mostly in the large leg bones during myelopoiesis.
  2. Originate from the haematopoietic stem cell.
  3. As the cascade progresses the cell gets more committed.
  4. The promyelocyte cell is fully committed to being a neutrophil and nothing else.
  5. Once the cell has granules it is terminally differentiated and can leave the bone marrow and enter circulation.
45
Q

What regulated neutrophil production?

A

G-CSF

46
Q

How does G-CSF regulate neutrophil production?

A
  1. Stimulate bone marrow to proliferate and make neutrophils
  2. It speeds up the production process.
  3. It extends the lifespan of existing neutrophils.
47
Q

What can produce G-CSF?

A
  1. Macrophages
  2. Endothelial cells
  3. Fibroblasts.
  4. Dendritic cells
48
Q

What regulates neutrophil numbers through G-CSF production?

A
  1. Apoptotic neutrophils
  2. Regulation signals from the microbiome
49
Q

How do apoptotic neutrophils act in homeostasis?

A
  1. Macrophages phagocytose apoptotic neutrophils.
  2. This turns the macrophages into resolution and regulatory macrophages. These are anti-inflammatory.
  3. Eating the apoptotic neutrophils suppresses pro-inflammatory cytokine production like IL-23.
  4. This reduced G-CSF production and maintains neutrophil levels at a steady number.
50
Q

How do apoptotic neutrophils regulate neutrophil production when there are too few neutrophils?

A
  1. There are too few neutrophils in circulation. due to infection or wound the neutrophils have entered the tissues.
  2. Macrophages detect the reduced numbers of apoptotic neutrophils in the tissues.
  3. Without the apoptotic neutrophils that macrophages become pro-inflammatory.
  4. The pro-inflammatory macrophages release IL-23 to activate Th17 cells.
  5. Th17 cells produce IL-17 which act on fibroblasts.
  6. The fibroblasts then produce G-CSF which speeds up and enhances neutrophil production.
51
Q

How do apoptotic neutrophils regulate neutrophil production when they are involved in disease?

A
  1. Leukocyte adhesion deficiency 1 is a mutation in ß2 integrins required to extravasation.
  2. This prevents neutrophils adhering to the endothelium and leaving the blood.
  3. Normally neutrophils exit the blood, spontaneously apoptose and are cleared making anti-inflammatory macrophages.
  4. During disease the neutrophils cannot enter the tissues so no neutrophils are detected.
  5. Macrophages enter the pro-inflammatory state, so they produce IL23, causing Th17 to produce IL-17 and fibroblasts to produce G-CSF.
  6. More neutrophils enter circulation but they cannot leave causing a build up and a constant cycle.
  7. However IL23 and IL17 also signal osteoblasts that cause loss of bone in the mouth and inflammatory damage.
  8. This is Periodontitis
52
Q

How does the gut microbiome regulate neutrophil production?

A
  1. The foetal microbiome is acquired just after birth.
  2. Through MAMP signalling and production of IL17 they trigger the signals needed for neutrophil development, maturation, activation and regulation.
  3. During 1st colonisation, the gut triggers the initial production of neutrophils through signalling ILCs that produce IL-17 and then G-CSF production.
  4. Without a gut microbiome you don’t get neutrophil production,
53
Q

How does gout trigger NETosis?

A
  1. Uric acid crystals are deposited in the joints.
  2. The joint cells are damaged so release DAMPs.
  3. This recruits and activates macrophages to remove the crystals by phagocytosis.
  4. Formation of Nlrp3 inflammasome in the macrophage and release of IL-1ß.
  5. This recruits neutrophils and causes the neutrophil swarm.
  6. The crystals are phagocytosed and trigger NETosis.
  7. More tissue damage and an escalating cycle of inflammation and damage.
54
Q

What are potential treatments for gout targeting the neutrophil activation mechanism?

A
  1. Inhibit Nlrp3 inflammasome
  2. DNase enzymes to break down the NETs
  3. Anti antibodies to some of the signalling molecules

Cellular and Molecular Immunology (17 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2025 Bold Learning Solutions. Terms and Conditions