MW L4 Leukocyte Chemotaxis Flashcards
4 steps if leukocyte diapedesis
- circulating
- tethering/rolling
- firm adhesion
- transmigration
What is a leukocyte?
WBC
What guides tethering and rolling
selectins - specific homing receptors and their ligands
3 types of selectins
what expresses them
L (leucocytes)
P (platelets & endothelium)
E (endothelium)
What do L-selectins bind to?
Carbohydrates on the endothelium
Which selectins bind leukocytes?
P and E
L-selectin activation leads to….(2)
transient increase in avidity
rapid shedding by proteolytic cleavage (‘shedase’)
Where is P selectin stored?
When does it translocate to cell surface?
In granules
On cell activation (thrombin, histamine)
E selectin expression is induced by ….. (2)
cytokines
or
LPS
Expression of E selectin requires
de novo synthesis
Glucocorticoid effect on selectins?
E selectin is inhibited
LAD II stands for
leukocyte adhesion deficiency II
Pts with LAD II have normal ………………… in vitro
phagocytosis and respiratory burst
Pts with LAD II have defective …………. metabolism
this causes,,,,
fructose
leukocytes do not express selectins
LAD II causes decreased rolling response on ………. or ………
E or P selectins
severely impaired ……………………. in skin inflammation with LAD II
<90% decreased
Rolling along the endothelial surface activates …………..
where…………
Integrins
on the LEUKOCYTE surface
Integrins are …….. proteins
expressed where?
heterodimeric
expressed on the surface of leukocytes and most other cells
Integrins have a common ……. chain
Beta2 chain
There are ………… forms of alpha chain
this means ……… heterodimers are formed
3
alpha L /beta 2
alpha M/ beta 2
alpha X/ beta 2
Leukocyte adhesion changes avidity and affinity how?
Conformational change - affinity
Clustering of integrins - avidity
LAD I or II has pus?
neither - both have recurrent infections
LAD I what do leukocytes do in vitro?
they do not adhere to extracellular material
ICAM are…
intercellular adhesion molecules
ICAM-2 is expressed when and where?
basally on the endothelium
ICAM-1 is expressed when
induced by cytokines IL-1 and TNF
What binds to ICAM
intergrins
………… is expressed on eosinophils, monocytes and T cells
alpha4beta1
What binds to alpha4beta1??
What is this induced by?
VCAM-1 (vascular cell adhesion molecule)
cytokines induce
Treatment for recurrent MS (and maybe ulcerative colitis)
anti-alpha4 mAb (Natalizumab)
problem with anti-alpha4 mAb (Natalizumab)
increase incidence of viral brain infection (progressive multifocal leukoencephalopathy)
Improved efficacy of anti-alpha4 mAb (Natalizumab) with ……….
IFN beta
CAM pairs in inflammation
Beta 2 and ICAM-1
Alpha 4 and VCAM-1
Chemotaxis is stimulated by….
chemotaxis - no shit.
Chemotaxis activate leukocytes causing….
integrin affinity and avidity changes
movement
What is the source of the chemotaxis?
site of inflammation - presented to leukocytes - bind to EC surface
Non-selective chemotaxins
LTB 4
C3a C5a
formyl peptides
selective chemotaxins
chemokines
large family of 70-80aa proteins
chemokines are produced in response to
IL1, TNF, bacteria
What are chemokines?
GPCRs
CXC chemokines are found on
Monocytes
Resting T cells
Dendritic cells
Neutrophils
(CCL2 are expressed on activated cells and other places WAHHHH)
Cells move at different rates, what is fastest?
Neutrophils (acute inflammation)»_space; monocytes (chronic) > lymphocytes (chronic)
How do tissues get selectivity
different selectin and CAM expression
different chemokine expression
How do leukocytes get selectiity
different integrin expression
different chemokine receptor expression
….. used to tether leukocyte on the endothelium neat the inflammatory site
selectins
…………. are used for stronger adhesion on chemokine activation of leukocytes
integrins
………… are expressed by endothelium and are ligands for integrins
ICAM
