Neutrophils

Question 1

from which cells are neutrophils derived

Answer 1

myeloid

Question 2

what disease is caused by low numbers of neutrophils

Answer 2

neutropenia

Question 3

what disease is caused by too many neutrophils

Answer 3

neutrophilia- often leads to leukaemia

Question 4

describe the life cycle of neutrophils

Answer 4

1. the detect pathogens and inflammatory mediators
2. migrate from blood to site of invasion (extravasation)
3. kill pathogens

Question 5

why do neutrophils need tone carefully regulated

Answer 5

they can cause collateral tissue damage

Question 6

what are the clinical signs of inflammation

Answer 6

swelling, pain, redness, heat, loss of function

Question 7

describe initiation of inflammation

Answer 7

1. tissue damage leads to complement activation and activation of macrophages.
2. Macrophages are activated to M! macrophages which produce pro inflammatory cytokines such as IL-8, TNFa, IL1 and IL6 .
3. complement activates mast cells which release histamine, prostaglandins and leukotrienes
4. blood vessel leakage is increased allowing migration of cells into tissues
5. macrophages produce lipid mediators such as arachidonic acid which increase vascular pereability and chemotaxis of neutrophils towards site of infection
6. adhesion molecules are upregulated to help neutrophils bind to correct place on the endothelial cells

Question 8

what are the 3 main stages of the leukocyte adhesion cascade

Answer 8

capture and rolling, activation and arrest, crawling and extravasation

Question 9

how does capture and rolling of leukocytes occur

Answer 9

1. selectins slow down the molecules to capture them which bind to sugars. adhesion molecules including interns and ICAMs are required for binding

Question 10

how does activation and arrest of leukocytes occur

Answer 10

IL8 activates endothelial cells causing firm adhesion, as well as priming interns which increases their affinity for white blood cells. neutrophil binding to integrins also increases their affinity

Question 11

how does crawling and extravasation of leukocytes occur

Answer 11

after adhesion leukocytes either crawl through gaps between endothelial cells or, 20% of the time, they go through cells which is mediated by PCAMs

Question 12

what is the molecular basis of leukocyte adhesion deficiency 1, 2 and 3

Answer 12

1 lacks CD18 and 2 lacks a sugar which generates selection ligands. 3 is an integral activation defect

Question 13

what does the “Postcode Model” describe

Answer 13

it suggests that adhesion and migration is mediated by cell surface adhesion receptors and chemokine receptors found on the cells themselves

Question 14

how is neutrophil killing activated

Answer 14

by binding of PAMPS to PRRs on their PM as well as by pro inflammatory cytokines such as TNFa

Question 15

describe the 4 main methods of neutrophil killing

Answer 15

1. NADPH produced by NADPH oxidase
2. nitric oxide synthetase produces reactive NO species which targets almost any macromolecule
3. myeloperoxidase combines H2O2 with chlorine or bromine to form hyperchlorus acid
4. release of granules which are antimicrobial molecules in preformed packages. include elastase which digests collagen, serine protease 2, defensins which creat holes in membrane, lactoferrin which sequesters iron and lysozyme
5. NETS- neutrophil extracellular traps which is a suicidal method in which neutrophils “spit out” their genome physically trapping the bacteria/pathogen. this also helps to concentrate antimicrobial mediators

Question 16

how is NET release from neutrophils mediated

Answer 16

PAD4 causes citullation of DNA, neutralising it so it cannot bind histones, causing it to unravel.

Question 17

how does anaplasma phagocytophilum evade neutrophil killing

Answer 17

resides in intracellular vacuoles and prevents delivery of cytochrome b to th NADPH oxidase complex to delay apoptosis

Question 18

how does staph. aureus evade neutrophil killing

Answer 18

MprF gene adds L-lysine to lipids which repulses cationic defensins

Question 19

how do some bacteria evade killing by NETs

Answer 19

express DNases to degrade traps

Question 20

give an example of a disease caused by defects in neutrophil killing mechanisms

Answer 20

chronic granulomatous disease is caused by a defect in NADPH oxidase

Question 21

describe resolution of inflammation

Answer 21

active apoptosis occurs. this begins with DNA fragmentation and cell surface alterations called ACAPMs to tell other cells it is apoptotic. these include find me signals which are chemoattractants and eat me signals which allow macrophage recognition and removal
also lipid metabolites from neutrophils are anti-inflammatory and increase recruitment of monocytes and reduce recruitment of neutrophils