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Immunology > Neutrophils > Flashcards

Neutrophils Flashcards

1
Q

How dominant are neutrophils in the blood?

A

They are they major white blood cell- 40-75%

1-6% granulosites: Eosinophil-basophils
2-10% monocytes
20-50% lymphocytes only

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2
Q

What are general stats for neutrophils and why are they needed

A

60 million Release from bone marrow in circulation with a very short life scan of a few hours; half life of 7 hours. However in tissues they may last longer.

They are the most abundant leukocyte; with about 5000 per ul of blood and over 55%/half of bone marrow dedicated to their production

Key role in host defence to host defence of bacteria and fungi (less so for viral)

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3
Q

What factors would increase neutrophil numbers?

A
  • Stress
  • injury
  • infection
  • increase in cytokines
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4
Q

What are the different ways neutrophils are made

A

1) in steady state; where there is no an obvious infection. what happens all the time whether asleep or awake.
2) Emergency situation where patterns are recognised and danger signs from pathogen.

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5
Q

What is the transcription factor important for STEADY STATE neutrophil development?

A

TF is C/EBP-a which is switched on at a late stage of differentiation of neutrophil and reduces the proliferation that occurs in late stage and promotes granulocyte differentiation

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6
Q

What is the transcription factor important for EMERGENCY STATE neutrophil development?

A

TF C/EBPa is downregulated, and C/EBP-beta is upregulation. This allows precursors to proliferate and at the same time differentiate.

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7
Q

Where are neutrophils produced and where there is a reserve of neutrophils?

A

Bone marrow, close to the blood vessels in an almost mature form.

Normally released slowly but where major infection occurs, they are released suddenly via signalling.This causes a “wave of neutrophils” into blood where they accumulate at site of infection.

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8
Q

What happens at site of infection

A

IL-1 induces inflammation from macrophage that signals neutrophils.

Neutrophils accumulate and engulf bacteria, kill it. They undergo apoptosis (nucleus condenses) in the tissue and are degraded by macrophages.

Controlled- dead cells must be cleared to prevent tissue damage. Neutrophils may have toxic components secreted, making inflammation worse.

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9
Q

How do neutrophils get from blood to tissue?

A

Bacteria trigger macrophages to produce chemokines which result in a series of changes in blood vessels. This results in neutrophils in blood to slow down movement and make contact with endothelium.”ROLLING) on cell surface until they stop completely.

Migrate via haemopatic factors, cells can migrate into tissues and detect bacterias haemopaic factors. contact bacteria and phagocyte it.

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10
Q

Describe molecules involved in neutrophil tissue migration. A three step paradigm: rolling, adhesion and diapedesis.

A

endothelial cells respond increasing expression of selectin adhesion molecules on the surface.
Selectin weakly interact with glycoproteins on neutrophil (selectin are lectin like- which bind carbohydrates) in a process called tethering, leading to slow rolling.

Chemokines on endothelial surface engages slowed neutrophils which causes signal back to neutrophil to activate adhesion molecule called integrins to activate (bent to elongated shape change) Activated integrins can bind strongly to other molecules on surface endothelial cells and neutrophils stop completely.

Integrin-ICAM and chemokine-Receptor allows Paracellular migration (between cells) via chemokines within tissues that create a gradient; the chemotax down from low to high concentration of chemotaxin factor. Neurophil into tissue.

Neutrophil can also be engulfed by endothilal cells and pass through cell in a vacuole.

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11
Q

How would you test neutrophil rolling?

A

Selectin stuck on plastic. Flow chamber flows neutrophils in a certain direction. Some move slowly, most move rapidly in the blood.

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12
Q

List the key molecules for rolling

A

Selecins and selectin counterreceptors

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13
Q

List the key molecules for firm adhesion

A

Activated integrins (elongated) and Ig like counterreceptors

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14
Q

List the key molecules for diapedesis, crawling through.

A

Integrins and endothelial cell adhesion molecules

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15
Q

List the key molecules for chemotaxis

A

Integrins and chemokines and chemokine receptors

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16
Q

How many types of selectin are there?

A

Three typesthat all have a terminal C-type lectin domain that binds carbohydrates.

2 types expressed on endothelial cells

1) E-selectin
2) P-selectin

Interact with carbohydrates on ESL-1 and PSGL-1

1 on leukocyte
L-selectin

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17
Q

What kind of carbohydrate do selectins recognise

A

They recognise a similar type of carbohydrate, an old blood antigen s-LE x; a tetrasaccahride

18
Q

Name the chemokine on endothelial surface that neutrophil binds to

A

IL-8.

Binding of receptor to IL8 activates neutrophil to make integrins.

19
Q

Name integrin on neutrophil

A

integrin called CD11A/LFA-1 and CD11B interact with proteins like I-CAM-1 on endothelial surface.

ICAM= intercellular adhesion molecule.

20
Q

Describe Beta2 integrins

A

Important adhesion molecules. They are dimeric proteins.

3 B2 Integrins with a common beta chain but different alpha chains

i) CD11a/LFA-1
ii) CD11b/Mac-1
iii) CD11c

There are different ligands which under go conformational change to become elongated and get a high affinity for strong binding

  • ICAM-1
  • Fibrinogen
  • denatured proteins
  • C3bi

Binding stops neutrophil rolling, and mediates further adhesion

21
Q

How can you test for chemotaxis migration?

A

Neutrophils chase after bacteria

Make a sterile injury with no bacteria in liver. Trauma to liver will release chemotactic factors attracting neutrophils. Using live cell imaging to show migration.

Adding antibody that stops integrin binding (Anti-CD11b) prevents neutrophil migration

22
Q

What is Chemotaxis?

A

Directional migration of leukocytes that are needed for recruitment to inflammatory sites..

This process is controlled by chemokines from immune system and chemotatic factors from pathogens

23
Q

How does chemotaxis work in terms of neutrophils?

A

Migration via polarisation and directed movement as a result of chemokines binding to G-protein coupled recptors on the neurophil

24
Q

List some chemotactic factors

A
  • PAF = platelet activating factor
  • FMLP = formulated peptide derived from bacteria
  • c5A, c5 breakdown fragments, anaphylotoxin
25
Q

List some chemokines

A
  • IL8

- MIP-1

26
Q

How do G-coupled proteins work?

A

High affinity chemokine binds to its receptor in he neutrophil membrane.

Binding triggers G protein (alpha, beta gamma complex) interaction allowing exchange from GDP in complex to GTP. This activates complex to activate and start signal transduction and alter gene expression

27
Q

List recognition receptors on neutrophil

A

1) LPS/CD14
2) CR4
3) Glycan
4) Scavenger
5) CR3
6) Mannose
7) N-formyl Met receptor

28
Q

What is needed for recognition? and phagocytosis?

A

Opsonins required-molecules that bind to target pathogen that act as a bridge between pathogen and specific receptor.

Phagocytosis only in the presence of opsonins

29
Q

List the three IgG Fc receptor classes?

A

1) Fc gamma R1 =CD64
2) Fc gamma R2 =CD32
3) Fc gamma R3 =CD16

Each class triggers different pathways but in all the FAB region interacts with organisms and FC interacts with receptor on neutrophil starting phagocytic response.

30
Q

Describe phagocytosis in neutrophils

A

Neutrophils have granules called AZUROPHILIC granules and SPECIFIC granules containing proteases, antibacterial peptides, hydroylases that fuse with vacuole that kill bacterium.

Lysosomes with hydrolyses then fuse with phagosome that completely degrade bacteria.

Neutrophil dies by apoptosis and phagocytosed by a macrophage.

31
Q

Bacterial killing: Describe acidifcation

A

when lysosome fuses with phagosome, the pH drops to 3-4.

32
Q

Bacterial killing: Describe oxygen derived products (important) also known as reactive oxygen species

A
  • Superoxide
  • Hydrogen peroxide

First event that occurs when neutrophil phagotosis a pathogen.

NADPH complex is made from phagosome membrane. There are many subunits that make up the NADPH Oxidase.
It acts on NADPH as a substrate to make NADP+.

NADPH oxidase is an elecron chain; there is electrons transported into phagosome by protein.

Electrons then reduce oxygen into Superoxide anions (primary product)

Superoxide anions produce hydrogen peroxide, which can lead to hydroxyl radicals.

All of these agents are toxic for bacteria..

33
Q

Bacterial killing: Describe antimicrobial peptides

A
  • defensins

- cationic protein

34
Q

Bacterial killing: Describe nitrogen oxides

A

toxic nitric oxide (NO)

35
Q

Bacterial killing: Describe enzymes

A
  • Lysozyme: dissolves bacteria walls

- Acid hydrolyses: further digest bacteria

36
Q

What is the purpose of Super oxide Dismutase?

A

This enzyme breaks down super oxide, which deence against this system.

37
Q

What happens if a subunit from NADPH Oxidase is missing?

A

B47 subunit missing or mutations leading incorrect assembly: Chronic Granulomatous disease where patient gets recurrent infections as they cannot make super oxide anions and so heir neutrophils cannot kill bacteria.

Symptoms include persistant infection of soft tissue, lungs, facial ache, pneumonia, excessive granulomas in all tissues, gingivitis in mouth.

38
Q

Name three different ways neutrophils can kill

A

1) Phagocytosis
2) Degraulation
3) NETs

39
Q

What are NETs?

A

Neutrophil extracellular traps.
When pathogen recognised, neutrophils decondense entire DNA and release DNA into cytoplasm to mix with antimicrobial peptides (from granules) and then extends to extracellular matrix outside of neutrophil in a web like structure in order to encapsulate bacteria.

It needs signal tranduction via recognition, granule enzyme peptidyl arginine deiminase-4, the reactive oxygen species, its actin cytoskeleton, and microtubules.

If there is no NADPH oxidase, NETs cannot form.

40
Q

What is the risk of NETs?

A

Release of DNA from cells not apoptotic poses the risk of autoimmune response. Excesses NETs causing anti-citrullinated proteins antibodies prevalent in ARTHRITIS.

41
Q

What are the two types of NET formations?

A

1) Suicidal NETosis (classic) where cell dies as a large number of pores were made to release DNA.
2) Vital NETosis where S.aureus and other bacteria signal different pathways leading to a non-sucidal mechanism; DNA is budded off. Pores not made in cell, so cell still has phagocytic function

42
Q

Summary

A
  • most abundant, deend against bacteria and fungi.
  • They are short lived but respond rapidly
  • Really Need opsonins and opsonic receptors for pathogen uptake. (and therefore needs complement)
  • Many antimicrobial activities like granule, oxidative burst, and NETs

Immunology (19 decks)

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