The Neutrophil Response to Infection

Question 1

In the absence of infection, what is the lifecycle on a neutrophil?
How does this differ in infection?

Answer 1

• circulate in the blood for 12-16hrs and then removed by resident tissue macrophages in the spleen, liver and bone marrow.
• rapidly recruitment from the blood into affected tissue sites but the acute inflammatory response to phagocytose and kill invading bacteria and fungal pathogens

Question 2

State the names of the 4 steps of transendothelial migration of neutrophils

Answer 2

Neutrophils migrate from the circulating blood into affected tissue in a 4 step sequence
Step 1: Rolling/tethering 
Step 2: Triggering 
Step 3: Firm adhesion
Step 4: Extravasation

Question 3

Describe Step 1 of transendothelial migration of neutrophils

Answer 3

Step 1

• reversible binding to vascular endothelium
• selectins on activated endothelium
• carbohydrate selectin ligands on neutrophil
• bond is not very strong, continue to make and break contact - rolling

Question 4

Describe Step 2 of transendothelial migration of neutrophils

Answer 4

Step 2

• chemokines presented on luminal side of endothelium
• chemokines bind to chemokine receptors on neutrophil
• promotes neutrophil integrin activation

Question 5

Describe Step 3 of transendothelial migration of neutrophils

Answer 5

Step 3

• activated integrins on neutrophils bind to lingands expressed on endothelium
• ligands are intracellular adhesion molecules ICAMs
• results in firm adhesion and shape change to allow Step 4

Question 6

Describe Step 4 of transendothelial migration of neutrophils

Answer 6

Step 4

• neutrophil squeezes between endothelial cells through the vasculature into the tissue
• neutrophil can then respond to further chemokine gradient for correct positioning within tissue a homing to the infection foci

Question 7

What is the clinical application of neutrophil migration?

Answer 7

• Leukocyte Adhesion Deficiency LAD
• genetic mutation
• affecting phagocyte integrin expression
• recurrent bacterial and fungal infection as neutrophils are inhibited from exiting blood vessels into affected tissues

Question 8

Describe what occurs in tissue migration of the neutrophil

Answer 8

• move in a directional manner towards to foci of infection via a conc gradient of chemoattractants for which they express receptors
• proteases released from granules allow digestion and movement through ECM
• chemoattractants prime migrating neutrophils in a conc-dependent manner, increasingly activates as they approach infection foci
• CXCL-8 example of powerful neutrophil chemoattractant

Question 9

Neutrophils express complement receptors and immunoglobulin receptors.
When and how are each used?

Answer 9

Ig receptors = Fc-receptors
- Allows binding to pathogens that have been opsonised by antibody - secondary infection
Complement receptors
- Allows binding to pathogens that have been complement coated - primary/secondary infection

Question 10

What is phagocytosis?

Describe the process

Answer 10

The process by which pathogens and other particles are takin in by a cell

• phagocyte cell membrane surround the particle and engulfs it
• this forms a vacuole with the particle inside
• vacuole fuses with a lysosome containing granules
• the two structures together are called a phagolysosome

Question 11

Describe Phagocyte killing mechanisms

Answer 11

• variety of toxic products released that help to kill engulfed microorganisms
• reactive oxygen species (ROS) such as superoxide anions, hydrogen peroxide and nitric oxide
• primary and secondary granules –> hydrolytic enzymes, proteases and cationic peptides

Question 12

What is the difference between necrosis and apoptosis?

Answer 12

Necrosis - cell death in an unplanned inflammatory manner

Apoptosis - controlled, programmed, non inflammatory way

Question 13

Describe neutrophil apoptosis

Answer 13

The killing of microbes is a high energy process that promotes neutrophil cell death.
Dying cells express apoptotic ligands - eat me signals
Local macrophages ingest them to safely dispose of them and their toxic products
This does not activate macrophage PRRs and hence does not elicit an inflammatory response

Question 14

What happens when pathogens overwhelm the immune system and are not properly eliminated?

Answer 14

• the number of apoptotic neutrophils can outpace the capacity of local macrophages
• neutrophils lyse by secondary necrosis
• release toxic contents
• causes further cell and tissue damage
• associated with pus and abscess formation