Neutrophils Flashcards
from which cells are neutrophils derived
myeloid
what disease is caused by low numbers of neutrophils
neutropenia
what disease is caused by too many neutrophils
neutrophilia- often leads to leukaemia
describe the life cycle of neutrophils
- the detect pathogens and inflammatory mediators
- migrate from blood to site of invasion (extravasation)
- kill pathogens
why do neutrophils need tone carefully regulated
they can cause collateral tissue damage
what are the clinical signs of inflammation
swelling, pain, redness, heat, loss of function
describe initiation of inflammation
- tissue damage leads to complement activation and activation of macrophages.
- Macrophages are activated to M! macrophages which produce pro inflammatory cytokines such as IL-8, TNFa, IL1 and IL6 .
- complement activates mast cells which release histamine, prostaglandins and leukotrienes
- blood vessel leakage is increased allowing migration of cells into tissues
- macrophages produce lipid mediators such as arachidonic acid which increase vascular pereability and chemotaxis of neutrophils towards site of infection
- adhesion molecules are upregulated to help neutrophils bind to correct place on the endothelial cells
what are the 3 main stages of the leukocyte adhesion cascade
capture and rolling, activation and arrest, crawling and extravasation
how does capture and rolling of leukocytes occur
- selectins slow down the molecules to capture them which bind to sugars. adhesion molecules including interns and ICAMs are required for binding
how does activation and arrest of leukocytes occur
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
how does crawling and extravasation of leukocytes occur
after adhesion leukocytes either crawl through gaps between endothelial cells or, 20% of the time, they go through cells which is mediated by PCAMs
what is the molecular basis of leukocyte adhesion deficiency 1, 2 and 3
1 lacks CD18 and 2 lacks a sugar which generates selection ligands. 3 is an integral activation defect
what does the “Postcode Model” describe
it suggests that adhesion and migration is mediated by cell surface adhesion receptors and chemokine receptors found on the cells themselves
how is neutrophil killing activated
by binding of PAMPS to PRRs on their PM as well as by pro inflammatory cytokines such as TNFa
describe the 4 main methods of neutrophil killing
- NADPH produced by NADPH oxidase
- nitric oxide synthetase produces reactive NO species which targets almost any macromolecule
- myeloperoxidase combines H2O2 with chlorine or bromine to form hyperchlorus acid
- 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
- 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
how is NET release from neutrophils mediated
PAD4 causes citullation of DNA, neutralising it so it cannot bind histones, causing it to unravel.
how does anaplasma phagocytophilum evade neutrophil killing
resides in intracellular vacuoles and prevents delivery of cytochrome b to th NADPH oxidase complex to delay apoptosis
how does staph. aureus evade neutrophil killing
MprF gene adds L-lysine to lipids which repulses cationic defensins
how do some bacteria evade killing by NETs
express DNases to degrade traps
give an example of a disease caused by defects in neutrophil killing mechanisms
chronic granulomatous disease is caused by a defect in NADPH oxidase
describe resolution of inflammation
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
