The Neutrophil Response to Infection

Question 1

List 2 distinct features of a neutrophil.

Answer 1

1 - A multi-lobed nucleus.

2 - Preformed granules.

Question 2

List the stages of neutrophil maturation.

Which of these are proliferation stages?

Answer 2

1 - Myeloblast.

2 - Promyelocyte.

3 - Myelocyte.

4 - Metamyelocyte.

5 - Band cell.

6 - Mature neutrophil.

• Stages 1-3 are the proliferation stages.

Question 3

What is the average rate of production of neutrophils?

Answer 3

1-2*10^11 per day.

Question 4

List 3 mediators of neutrophil lifespan.

Answer 4

1 - Complement proteins.

2 - Granulocyte colony stimulating factor (GCSF).

3 - Pro-inflammatory cytokines.

Question 5

List 3 changes that you might expect to see on a blood count with a generic infection.

Answer 5

1 - Reduced haemoglobin.

2 - Increased white cell count.

3 - Increased C-reactive protein (CRP).

Question 6

Which leukocyte is the most abundant in the body?

Answer 6

Neutrophils (70% of all leukocytes are neutrophils).

Question 7

What is the name of the process by which the concentration of neutrophils in the blood can increase rapidly (e.g. during infection)?

Answer 7

Neutrophil mobilisation.

Question 8

What is the average half life of neutrophils?

Answer 8

8-12 hours.

Question 9

What is the average neutrophil concentration in the blood?

Answer 9

2.5-7.5 *10^9 neutrophils/ml.

Question 10

Describe the process of chemotaxis.

Answer 10

1 - Inflamed or infected tissues release inflammatory cytokines.

2 - The cytokines are released systemically to form a gradient leading back to the site of injury.

3 - Cytokine signals can induce or stop migration of cells and alter the direction of travel, such that cells move up a concentration gradient of chemokine.

Question 11

List 4 signalling molecules that are involved in chemotaxis.

For each, state their function.

Answer 11

1 - IL-10, a molecule that promotes movement away from a site (retrograde chemotaxis).

2 - IL-8, a molecule that promotes chemotaxis towards a site.

3 - LTB4, a molecule that promotes chemotaxis towards a site.

4 - fMLP, a molecule that stops chemotaxis.

Question 12

List the stages of neutrophil migration from the circulation into tissues.

Answer 12

1 - Leukocytes roll on the surface of the endothelium by way of selectins, which looseley bind to carbohydrate selectin ligands on the endothelium.

2 - Triggering occurs when chemokines on the endothelium bind to chemokines receptors on the neutrophil.

3 - Firm adhesion occurs when cell adhesion molecules on the endothelium binds to activated integrins on the neutrophil.

4 - Extravasation occurs.

Question 13

Which receptors are responsible for the recognition of pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs)?

Answer 13

Pattern recognition receptors such as toll like receptors.

Question 14

Define phagolysosome.

Answer 14

The structure formed by fusion of a phagosome and a lysosome.

Question 15

List 2 properties of a lysosome that make it effective for killing pathogens.

Answer 15

1 - Low pH.

2 - Presence of toxic granules.

Question 16

List 2 intracellular pathogens (pathogens which can grow inside macrophages).

Answer 16

1 - Salmonella.

2 - Mycobacteria.

Question 17

What type of cell is a neutrophil?

Answer 17

A phagocytic granulocyte.

Question 18

List 3 proteins contained within granules.

Answer 18

1 - Proteases.

2 - Bactericidal proteins such as lactoferrin.

3 - Superoxide anions (part of the reactive oxygen species which lower the pH to optimise conditions for proteases).

Question 19

List the three states in which a neutrophil can exist.

Answer 19

1 - Quiescent state.

2 - Primed state.

3 - Activated state.

Question 20

List 2 characteristics of quiescent neutrophils.

Answer 20

1 - Rounded shape.

2 - No mobilisation of granules.

Question 21

List 2 characteristics of primed neutrophils.

Answer 21

1 - Cytoskeletal mobilisation results in a polarised bullet shape.

2 - Able to amount a fast response that is tenfold larger than activated cells.

Question 22

List 3 characteristics of activated neutrophils.

Answer 22

1 - Undergoes chemotaxis.

2 - Undergoes degranulation.

3 - Releases reactive oxygen species.

Question 23

List 4 effects of reactive oxygen species.

Answer 23

1 - Damage to DNA.

2 - Oxidation of fatty acids in lipids.

3 - Oxidation of amino acids in proteins.

4 - Deactivation of specific enzymes.

Question 24

What are neutrophil extracellular traps (NETs)?

Answer 24

Unraveled DNA coated in bactericidal proteins extruded by neutrophils.

Question 25

When are neutrophil extracellular traps (NETs) released?

Answer 25

During late infection and inflammation when the cell has reached phagocytic capacity but infection and inflammation is still present.

Question 26

Define efferocytosis.

Answer 26

The process by which a neutrophil is phagocytosed by a macrophage.

Question 27

Why is retrograde chemotaxis important?

Answer 27

If retrograde chemotaxis does not occur and efferocytosis is overwhelmed, cells will undergo necrosis, allowing their damaging contents to leak.

Question 28

What causes pus formation?

Answer 28

When there are too many neutrophils for macrophages to clear.

Question 29

List 2 conditions which prevent pus from forming.

Answer 29

1 - Leukocyte adhesion deficiency.

2 - Neutropenia.

Question 30

What is the general effect of neutrophilia?

Answer 30

Damage from neutrophil granules.

Question 31

What causes leukocyte adhesion deficiencies?

Answer 31

Defects in integrins on leukocytes.

Question 32

List 3 conditions that are caused by failure of granules or granule contents.

Answer 32

1 - Chronic granulomatous disease.

2 - MPO deficiency.

3 - Chediak-Higashi syndrome.

Question 33

Which values of neutrophil concentration define mild, moderate and severe neutropenia?

Answer 33

• Mild neutropenia: 1-1.5*10^9 neutrophils/ml.
• Moderate neutropenia: 0.5-1*10^9 neutrophils/ml.
• Severe neutropenia: <0.5*10^9 neutrophils/ml.

Question 34

Define chronic neutropenia.

Answer 34

Neutropenia that is still present after 3 months.

Question 35

Give an example of a sign of neutropenia.

Answer 35

Increased likelihood of infection with extracellular bacteria and fungi.

Question 36

List 3 causes of neutropenia.

Answer 36

1 - Decreased production in the bone marrow.

2 - Increased destruction.

3 - Marginalisation and sequestration.

Question 37

List 4 causes of decreased production of neutrophils in the bone marrow.

Answer 37

1 - Aplastic anaemia.

2 - Leukaemias.

3 - Hereditary disorders such as congenital neutropenia and cyclic neutropenia.

4 - Radiation.

Question 38

List 2 causes of increased destruction of neutrophils.

Answer 38

1 - Autoimmune neutropenia.

2 - Chemotherapy.

Question 39

List 2 causes of marginalisation and sequestration of neutrophils.

Answer 39

1 - Haemodialysis.

2 - Hypersplenism.

Question 40

What is benign ethnic neutropenia?

How is benign ethnic neutropenia treated?

Answer 40

• Asymptomatic neutropenia present in African and Middle East populations.
• No treatment needed as the bone marrow can still produce sufficient cells during challenge.

Question 41

List 6 age-associated chronic diseases whose pathophysiology involves neutrophil function.

Why might these diseases be associated with old age?

Answer 41

1 - COPD.

2 - Interstitial lung disease.

3 - Diabetes.

4 - Ischaemic heart disease.

5 - Inflammatory liver disease.

6 - Inflammatory bowel disease.

• These diseases might be associated with old age due to immunosenescence, causing reduced migration and reduced neutrophil burst.

Question 42

What is an alpha-1 antitrypsin deficiency?

Give an example of a complication of alpha-1 antitrypsin deficiency.

Answer 42

• A disease where neutrophil action is unopposed due to an abnormal structure of the alpha-1 antitrypsin protein which inhibits neutrophil elastase (a proteolytic enzyme).
• Often causes lung damage in smokers due to unopposed actions of neutrophil elastase, resulting in emphysema.

Question 43

Describe the pathophysiology of chronic granulomatous disease.

Answer 43

• The disease is caused by a failure to produce reactive oxygen species for the respiratory burst (rapid release of reactive oxygen species).
• Causes formation of granulomas.

Question 44

Define granuloma.

When do granulomas form?

Answer 44

• A structure formed during inflammation.
• It is a collection of macrophages.
• Granulomas form when the immune system attempts to wall off substances it perceives as foreign but is unable to eliminate.

Question 45

List 2 reasons why neutrophil concentration increases during infections.

Answer 45

1 - Increased production in the bone marrow.

2 - Reduced sequestration in the liver and spleen.