Test 1: lecture 11 leuko Flashcards
___ allows the rolling of leukocytes
binding by carbohydrates to E-selectin
steps of leukocyte binding and leaving blood stream
carb binds, cell rolls, strong binding by chemokines and ICAM, move across membrane (diapedesis), migration to injury site
gylocalyx
endothelial surface layer
carbs and molecules on surface of cell that helps with shear stress of blood flow and restricts migration of immune cells
The endothelial ___ forms a substantial endothelial surface layer (ESL) made of sialic acid-containing glycoproteins, proteoglycans and glycosaminoglycans.
glycocalyx
The ESL protects the endothelium from the ____ of blood flow.
shear stress
ESL promotes endothelial ___ and restricts ___ migration given its negative charge and the restricted exposure of cell adhesion molecules and chemokines
barrier integrity
leukocytes
ESL also restricts inflammatory responses and ___
coagulation.
heparanase
infection/sepsis causes the release of TNFaplha which activates heparanase and cleaves ESL to allow exposure of adhesion sites and binding of leukocytes to be taken out of the blood to tissues
heparin will block this enzyme and prevent leukocytes from leaving blood circulation
how does heparin work
infection/sepsis causes the release of TNFaplha which activates heparanase and cleaves ESL to allow exposure of adhesion sites and binding of leukocytes to be taken out of the blood to tissues
heparin will block this enzyme and prevent leukocytes from leaving blood circulation (acts as a competition ligand)
where does heparanase come from?
endothelial cells and immune cells
promotes cell adhesion by cleaving ESl
where are some special endothelial cells
kidney- very thick ESL to prevent unwanted filtration
blood brain barrier
choroid plexus- produce CSF- fenestrated barrier
meninges-
rolling is by ___
selectins → endothelial cells
sialyl lewis X → immune cells
arrest is by ___
chemokines and cell addition molecules (CAMs)
CAMs interact with integrins
Arrest and crawling (cell adhesion molecules CAMs (ICAM-1 and VCAM-1 – integrins [LFA1 and VLA4]) and (chemokines vs chemokine receptors)
two ways immune cell is moved out of blood vessel
paracellular diapedesis→ in between cells
transcellular diapedesis→ through cells
Adhesion receptors involved in paracellular migration are also relevant transcellularly and involve molecules interacting homophilically (PECAM1 – PECAM1, CD99 – CD99)
what is made by immune cells to help with capture and rolling
sialyl lewis X
binds to selectin on endothelial cell surface
what is produced by immune cells during arrest and crawling
integrins [LFA1 and VLA4] bind to cell adhesion molecules CAMs (ICAM-1 and VCAM-1 ) on the endothelial cell surface
chemokine receptors bind to chemokines produced by the endothelial cell
cell docking is through binding of ___ that cause ___
integrins and CAMs
change in epithelial cell → increase myosin contractility → increase EC contractility
- Adherent leukocytes can induce the formation of ‘transmigratory cups’, which are endothelial docking structures rich in CAMs and cytoplasmic molecules connecting the cup with the cytoskeleton.
- Cups are triggered by the engagement of CAMs with their leukocyte integrin ligands.
-CAM-integrin interactions induce clustering and subsequent association with cytoplasmic proteins to initiate transendothelial migration through a paracellular or a transcellular pathway.
Adherent leukocytes can induce the formation of ‘___’, which are endothelial docking structures rich in CAMs and cytoplasmic molecules connecting the cup with the cytoskeleton.
transmigratory cups
immune cells that leave vessels have to move through ___
endothelial cells
pericytes
basement membrane
what controls movement of immune cells in tissues
chemoattract mechanism
lipid mediators- LTB- gradient- can have long range that draws immune cell in certain direction
PAMPs and DAMPs- localized to site of injury - very strong signal
chemokines
integrin structure and activation
heterodimer → alpha and beta chains
inactive until binds to ligand, then changes shape and bind even better
CLAD (canine leukocyte adhesion deficiency) is mutation in integrin that inhibits binding of ligand → more infections cause immune cells (neutrophils) can’t bind and eat pathogens
Endothelial cells project transmigratory cups rich in actin and___ that anchor and embrace adherent leukocytes.
CAMs
Endothelial/leukocyte remodeling is required to support leukocyte ____ and involves CAM/integrin clustering and cytoskeletal rearrangements that induce dissociative and constrictive forces
transmigration
In addition to ___, immune cell migration is directed by the unique architecture of the ___ space
chemotactic gradients
perivascular (pericyte and extracellular matrix (ECM) distribution/conformation).
In addition to drive leukocyte adhesion to the endothelium, chemotactic gradients also drive the ___ migration of immune cells
tissular
___ are crucial in facilitating the interaction leukocyte-endothelium and are pharmacological targets in diseases characterized by massive immune cell infiltration.
Integrins
some medicine will target specific integrins to prevent cells from leaving blood stream (liver example)
The players involved in leukocyte migration are endothelial cells, the basement membrane, pericytes and ___
perivascular leukocytes.
(example mast cells)
Following transendothelial migration, leukocytes crawl along pericytes in an ____ dependent fashion.
ICAM1-LFA1/MAC1 ( chemokines/ chemogradient)
Abluminally crawling leukocytes extravasate through from regions of low ___ densities.
extracellular matrix protein
(holes in pericytes and basement membrane)
Perivascular immune cells assist in the formation of the extravasation ‘hot spots’. Macrophages/DCs can produce large quantities of ___and mast cells release chemoattractive and ___factors
chemokines
vasoactive
reverse migration
leukocytes leave blood and react to injury
some explode and cause inflammation
some return to circulation and can repair damage
others will return to circulation and cause inflammation elsewhere or will return to bone marrow and die peacefully
metastasis
