VMED 5172 - Neutrophils

Sentinel cells (sometimes neutrophils) send messages to recruit more neutrophils from the blood, they go to the site of inflammation and then also send out more messages

How is there a positive feedback loop incorporated when neutrophil recruitment is initiated by sentinel cells?

Neutrophils

What is the most numerous WBC in many species with a very fast response time, acts as a first line of defense, and is critical in determining whether a microbe progresses past the tissue invasion phase?

short

Neutrophils have a relatively ___________ lifespan (days)

blood

Neutrophils should be most confined to the ______________ until recruited to the tissue

Liver, spleen, lungs, bone marrow

What are sites of many more neutrophils in the body in reserve (places that need to be able to recognize pathogens)?

extravasate

Neutrophils can ___________________ to tissues needed, which requires a defined sequence of interactions between adhesion molecules and chemokines to direct the cells to the site of insult

Selectins

What are the first adhesion molecules that play a role in extravasation and are lectins, which bind carbohydrates on cells or endothelium, slowing the neutrophils down so they can exit the blood stream at a certain point?

"rolling adhesion"

Selectins mediate __________________ which slows the WBC down in the blood stream but does not create a full stop

- P selectin and E selectin (on endothelium)

- L selectin (on WBCs)

What are the types of selectins involved in rolling adhesion and what surfaces are they on?

Integrins

What are the 2nd set of adhesion molecules that are on WBCs and are required for stable adhesion and stopping?

ligands

Integrins interact with integrin ____________ on endothelium surfaces to facilitate stopping of the neutrophils

•CD11a/CD18 = LFA1 (Leukocyte function-

associated antigen 1)

•CD11b/CD18 = Mac1

•CD11c/CD18

What are relevant integrins?

Leukocyte Adhesion Deficiency

What is the heritable disease where there is a CD18 deficiency resulting in neutrophils not being able to stop and get where they need to be?

Integrin-integrin ligand

_______________________ complexes are the second adhesion event during extravasation and mediate a more secure adhesion and stopping of neutrophils

- Intercellular adhesion molecule 1 (ICAM1)

- ICAM2

- ICAM 3

- Vascular cell adhesion molecule 1 (VCAM1)

What are some relevant integrin ligands?

- Circulating neutrophil is slowed -- selectins

- "Rolling" neutrophil is moving slow enough to be stopped by integrin-integrin ligand interactions

- Neutrophil is stopped, crawls out of vessel, follows IL-8 to insult

What are the steps in extravasation of neutrophils?

1.Neutrophils become activated

•Upon encountering activated endothelium and exposure to cytokines

2.Follow chemokines to insult

3.Encounter / adhere to target

4.Ingest / engulf target

5.Destroy target

What are the 5 major steps of phagocytosis of bacteria?

Antigen presentation by macrophages and DCs for lymphocytes to incorporate in adaptive immunity

What is the possible 6th step involved in phagocytosis (not really neutrophils' job)?

Opsonins

What can the body use to "tag" or coat the microbes by making them positively charged so that the negatively charged neutrophils can grab on to them easier?

- Antibodies bound to microbes

- Complement factors

What are the possible opsonins that can be used to coat microbes for neutrophils to grab and destroy?

Fc receptors

What are the receptors on the surface of neutrophils that bind antibodies acting as opsonins on microbes?

CR (complement receptors)

What are the receptors on the surface of neutrophils that bind complement proteins acting as opsonins on micrbobes?

engulf

After adhesion, neutrophils are able to ____________ the microbe in an phagosome that enters the cytoplasm

Phagosome joins with a lysosome to form a phagolysosome with contents to breakdown the microbe

How does the neutrophil destroy the bacteria after it has engulfed it?

- Respiratory burst - free radicals, reactive oxygen species

- Granule-associated lytic enzymes (proteolytic)

- Antimicrobial peptides (lactoferrins - bind bacteria's iron, defensins - bactericidal, activate WBCs)

What are the different components of the lysosome that allows the phagolysosome to destroy the bacteria?

- Polysaccharide capsules can inhibit binding

- Prevent fusion of phagosome to lysosome

- Some can survive in phagolysosomes

- Some can escape from phagolysosomes

How have microbes been able to avoid death by phagocytosis?

Neutrophil extracellular traps (NETs)

What are the long strands of DNA and lysosomes that activated neutrophils can extrude into the extracellular space and form nets that catch and kill microbes that are too big for them to phagocytize?