Test 1: lecture 11 leuko

Question 1

___ allows the rolling of leukocytes

Answer 1

binding by carbohydrates to E-selectin

Question 2

steps of leukocyte binding and leaving blood stream

Answer 2

carb binds, cell rolls, strong binding by chemokines and ICAM, move across membrane (diapedesis), migration to injury site

Question 3

gylocalyx

Answer 3

endothelial surface layer

carbs and molecules on surface of cell that helps with shear stress of blood flow and restricts migration of immune cells

Question 4

The endothelial ___ forms a substantial endothelial surface layer (ESL) made of sialic acid-containing glycoproteins, proteoglycans and glycosaminoglycans.

Answer 4

glycocalyx

Question 5

The ESL protects the endothelium from the ____ of blood flow.

Answer 5

shear stress

Question 6

ESL promotes endothelial ___ and restricts ___ migration given its negative charge and the restricted exposure of cell adhesion molecules and chemokines

Answer 6

barrier integrity

leukocytes

Question 7

ESL also restricts inflammatory responses and ___

Answer 7

coagulation.

Question 8

heparanase

Answer 8

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

Question 9

how does heparin work

Answer 9

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)

Question 10

where does heparanase come from?

Answer 10

endothelial cells and immune cells

promotes cell adhesion by cleaving ESl

Question 11

where are some special endothelial cells

Answer 11

kidney- very thick ESL to prevent unwanted filtration

blood brain barrier

choroid plexus- produce CSF- fenestrated barrier

meninges-

Question 12

rolling is by ___

Answer 12

selectins → endothelial cells

sialyl lewis X → immune cells

Question 13

arrest is by ___

Answer 13

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)

Question 14

two ways immune cell is moved out of blood vessel

Answer 14

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)

Question 15

what is made by immune cells to help with capture and rolling

Answer 15

sialyl lewis X

binds to selectin on endothelial cell surface

Question 16

what is produced by immune cells during arrest and crawling

Answer 16

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

Question 17

cell docking is through binding of ___ that cause ___

Answer 17

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.

Question 18

Adherent leukocytes can induce the formation of ‘___’, which are endothelial docking structures rich in CAMs and cytoplasmic molecules connecting the cup with the cytoskeleton.

Answer 18

transmigratory cups

Question 19

immune cells that leave vessels have to move through ___

Answer 19

endothelial cells

pericytes

basement membrane

Question 20

what controls movement of immune cells in tissues

Answer 20

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

Question 21

integrin structure and activation

Answer 21

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

Question 22

Endothelial cells project transmigratory cups rich in actin and___ that anchor and embrace adherent leukocytes.

Answer 22

CAMs

Question 23

Endothelial/leukocyte remodeling is required to support leukocyte ____ and involves CAM/integrin clustering and cytoskeletal rearrangements that induce dissociative and constrictive forces

Answer 23

transmigration

Question 24

In addition to ___, immune cell migration is directed by the unique architecture of the ___ space

Answer 24

chemotactic gradients

perivascular (pericyte and extracellular matrix (ECM) distribution/conformation).

Question 25

In addition to drive leukocyte adhesion to the endothelium, chemotactic gradients also drive the ___ migration of immune cells

Answer 25

tissular

Question 26

___ are crucial in facilitating the interaction leukocyte-endothelium and are pharmacological targets in diseases characterized by massive immune cell infiltration.

Answer 26

Integrins

some medicine will target specific integrins to prevent cells from leaving blood stream (liver example)

Question 27

The players involved in leukocyte migration are endothelial cells, the basement membrane, pericytes and ___

Answer 27

perivascular leukocytes.

(example mast cells)

Question 28

Following transendothelial migration, leukocytes crawl along pericytes in an ____ dependent fashion.

Answer 28

ICAM1-LFA1/MAC1 ( chemokines/ chemogradient)

Question 29

Abluminally crawling leukocytes extravasate through from regions of low ___ densities.

Answer 29

extracellular matrix protein

(holes in pericytes and basement membrane)

Question 30

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

Answer 30

chemokines

vasoactive

Question 31

reverse migration

Answer 31

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