The Neutrophil Response to Infection Flashcards
List 2 distinct features of a neutrophil.
1 - A multi-lobed nucleus.
2 - Preformed granules.
List the stages of neutrophil maturation.
Which of these are proliferation stages?
1 - Myeloblast.
2 - Promyelocyte.
3 - Myelocyte.
4 - Metamyelocyte.
5 - Band cell.
6 - Mature neutrophil.
- Stages 1-3 are the proliferation stages.
What is the average rate of production of neutrophils?
1-2*10^11 per day.
List 3 mediators of neutrophil lifespan.
1 - Complement proteins.
2 - Granulocyte colony stimulating factor (GCSF).
3 - Pro-inflammatory cytokines.
List 3 changes that you might expect to see on a blood count with a generic infection.
1 - Reduced haemoglobin.
2 - Increased white cell count.
3 - Increased C-reactive protein (CRP).
Which leukocyte is the most abundant in the body?
Neutrophils (70% of all leukocytes are neutrophils).
What is the name of the process by which the concentration of neutrophils in the blood can increase rapidly (e.g. during infection)?
Neutrophil mobilisation.
What is the average half life of neutrophils?
8-12 hours.
What is the average neutrophil concentration in the blood?
2.5-7.5 *10^9 neutrophils/ml.
Describe the process of chemotaxis.
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.
List 4 signalling molecules that are involved in chemotaxis.
For each, state their function.
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.
List the stages of neutrophil migration from the circulation into tissues.
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.
Which receptors are responsible for the recognition of pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs)?
Pattern recognition receptors such as toll like receptors.
Define phagolysosome.
The structure formed by fusion of a phagosome and a lysosome.
List 2 properties of a lysosome that make it effective for killing pathogens.
1 - Low pH.
2 - Presence of toxic granules.
List 2 intracellular pathogens (pathogens which can grow inside macrophages).
1 - Salmonella.
2 - Mycobacteria.
What type of cell is a neutrophil?
A phagocytic granulocyte.
List 3 proteins contained within granules.
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).
List the three states in which a neutrophil can exist.
1 - Quiescent state.
2 - Primed state.
3 - Activated state.
List 2 characteristics of quiescent neutrophils.
1 - Rounded shape.
2 - No mobilisation of granules.
List 2 characteristics of primed neutrophils.
1 - Cytoskeletal mobilisation results in a polarised bullet shape.
2 - Able to amount a fast response that is tenfold larger than activated cells.
List 3 characteristics of activated neutrophils.
1 - Undergoes chemotaxis.
2 - Undergoes degranulation.
3 - Releases reactive oxygen species.
List 4 effects of reactive oxygen species.
1 - Damage to DNA.
2 - Oxidation of fatty acids in lipids.
3 - Oxidation of amino acids in proteins.
4 - Deactivation of specific enzymes.
What are neutrophil extracellular traps (NETs)?
Unraveled DNA coated in bactericidal proteins extruded by neutrophils.
When are neutrophil extracellular traps (NETs) released?
During late infection and inflammation when the cell has reached phagocytic capacity but infection and inflammation is still present.
Define efferocytosis.
The process by which a neutrophil is phagocytosed by a macrophage.
Why is retrograde chemotaxis important?
If retrograde chemotaxis does not occur and efferocytosis is overwhelmed, cells will undergo necrosis, allowing their damaging contents to leak.
What causes pus formation?
When there are too many neutrophils for macrophages to clear.
List 2 conditions which prevent pus from forming.
1 - Leukocyte adhesion deficiency.
2 - Neutropenia.
What is the general effect of neutrophilia?
Damage from neutrophil granules.
What causes leukocyte adhesion deficiencies?
Defects in integrins on leukocytes.
List 3 conditions that are caused by failure of granules or granule contents.
1 - Chronic granulomatous disease.
2 - MPO deficiency.
3 - Chediak-Higashi syndrome.
Which values of neutrophil concentration define mild, moderate and severe neutropenia?
- 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.
Define chronic neutropenia.
Neutropenia that is still present after 3 months.
Give an example of a sign of neutropenia.
Increased likelihood of infection with extracellular bacteria and fungi.
List 3 causes of neutropenia.
1 - Decreased production in the bone marrow.
2 - Increased destruction.
3 - Marginalisation and sequestration.
List 4 causes of decreased production of neutrophils in the bone marrow.
1 - Aplastic anaemia.
2 - Leukaemias.
3 - Hereditary disorders such as congenital neutropenia and cyclic neutropenia.
4 - Radiation.
List 2 causes of increased destruction of neutrophils.
1 - Autoimmune neutropenia.
2 - Chemotherapy.
List 2 causes of marginalisation and sequestration of neutrophils.
1 - Haemodialysis.
2 - Hypersplenism.
What is benign ethnic neutropenia?
How is benign ethnic neutropenia treated?
- Asymptomatic neutropenia present in African and Middle East populations.
- No treatment needed as the bone marrow can still produce sufficient cells during challenge.
List 6 age-associated chronic diseases whose pathophysiology involves neutrophil function.
Why might these diseases be associated with old age?
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.
What is an alpha-1 antitrypsin deficiency?
Give an example of a complication of alpha-1 antitrypsin deficiency.
- 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.
Describe the pathophysiology of chronic granulomatous disease.
- 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.
Define granuloma.
When do granulomas form?
- 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.
List 2 reasons why neutrophil concentration increases during infections.
1 - Increased production in the bone marrow.
2 - Reduced sequestration in the liver and spleen.
