Leukocyte Adhesion and Circulation

Question 1

Name the 3 major selectins.

Answer 1

P-selectin (CD62P)
E-selectin (CD62E)
L-selectin (CD62L)

Question 2

Where is P-selectin expressed?

Answer 2

Endothelium activated by histamine or thrombin

Question 3

What is the ligand for P-selectin?

Answer 3

Sialyl Lewis X on P-selectin glycoprotein ligand 1 (PSGL-1) and other glycoproteins on neutrophils, monocytes, and T cells (effector, memory)

Question 4

Where is E-selectin expressed?

Answer 4

Endothelium activated by microbial products (LPS) and/or cytokines (TNF, IL-1) produced by dendritic cells and macrophages

Question 5

What is the ligand for E-selectin?

Answer 5

Sialyl Lewis X (e.g. cutaneous leukocyte antigen 1 (CLA-1)) on glycoproteins on neutrophils, monocytes, and T cells (effector, memory)

Question 6

Where is L-selectin expressed?

Answer 6

Neutrophils, monocytes, T cells (naive and central memory), and B cells (naive)

Question 7

What is the ligand for L-selectin?

Answer 7

Sialyl Lewis X on GlyCAM-1, CD34, MadCAM-1 (sialomucins) on endothelium (HEV), which are collectively called peripheral node addressin (PNAd)

Question 8

What are lectins?

Answer 8

Carbohydrate-binding proteins

Question 9

Name 4 major integrins.

Answer 9

1.Leukocyte function-associated antigen, LFA-1 (CD11aCD18)
2. MAC-1 (CD11bCD18, CR3)
3. Very late antigen 4, VLA-4 (CD49aCD29)
4. a4B7 (CD49dCD29)

Question 10

What is/are the ligand(s) for LFA-1 (CD11aCD18)?

Answer 10

ICAM-1 (intercellular adhesion molecule) and ICAM-2 on endothelium

Question 11

What is/are the ligand(s) for MAC-1 (CD11bCD18)?

Answer 11

ICAM-1 and ICAM-2 on endothelium

Question 12

What is/are the ligand(s) for VLA-4 (CD49aCD29)?

Answer 12

VCAM-1

Question 13

What is/are the ligand(s) for a4B7?

Answer 13

VCAM-1 and MadCAM-1 on endothelium in gut and gut-associated lymphoid tissues

Question 14

What are selectins?

Answer 14

Carbohydrate-binding protein adhesion molecules

Question 15

What are selectin ligands?

Answer 15

Sialylated and fucosylated carbohydrate groups of Lewis X and Lewis A family present on glycoproteins of various cells

Question 16

What is the structure of integrins?

Answer 16

Heterodimeric proteins that contain an alpha chain and a beta chain

Extracellular head binds to ligands and intracellular domain interacts with cytoskeletal components like actin, tropomysin
Initiate interactions with cytoskeleton through G-protein coupled receptors

Question 17

What are chemokines?

Answer 17

Chemotactic cytokines that regulate movement of leukocytes

Question 18

How are chemokines named?

Answer 18

Based on cysteine residues

C family: single cysteine residue
CC family: 2 adjoining cysteine residues (beta chemokines)
CXC family: 2 cysteine residues separated by one amino acid (alpha chemokines)
CX3C: 2 cysteine residues separated by three amino acids

Question 19

Name key chemokines involved in mixed leukocyte recruitment

Answer 19

CCL2 and CCL3

Question 20

Name key chemokines involved in allergic processes

Answer 20

CCL5 (RANTES): Mixed leukocyte recruitment
CCL11 (Eotaxin): Eosinophil, basophil and Th2 recruitment
CCL17 (TARC): T cell recruitment

Question 21

Name two chemokines important for T cell and dendritic cell migration into parafollicular zones of lymph nodes. Which receptor do they bind?

Answer 21

CCL19, CCL21, which bind CCR7

Question 22

Name a chemokine important for neutrophil recruitment. Which receptors do they bind?

Answer 22

CXCL8 (IL-8), which binds CXCR1 and CXCR2 on neutrophils

Question 23

Which chemokine is important for B cell migration into lymph nodes? Which receptor does it bind?

Answer 23

CXCL13, which binds CCR5

Question 24

How do chemokines affect integrins?

Answer 24

1. Induce membrane clustering
2. Increase affinity for integrin receptors

Question 25

What are the 6 steps of leukocyte recruitment into a site of inflammation?

Answer 25

1. Tissue infection or injury 2. Rolling 3. Increase in integrin affinity 4. Adhesion 5. Migration through the endothelium 6. Migration of leukocytes to site of infection and tissue injury

Question 26

What is the cause of LAD type 1?

Answer 26

Defect in CD18, B subunit of integrin ligands LFA-1 (aLB2 = CD11aCD18) and Mac-1 (aMB2 = CD11bCD18)

Question 27

What is the cause of LAD type 2?

Answer 27

Lack of Golgi fucose transporter needed to express carbohydrates (sLeX) on E and P selectin ligands on neutrophils

Question 28

What is the cause of LAD type 3?

Answer 28

Defect in signaling pathway linking chemokine receptor to integrin activation (Kindlin 3)

Question 29

Name a chemokine receptor that mediates monocyte migration to sites of infection/injury. Which chemokine(s) does it bind?

Answer 29

CCR2 binds CCL2, MCP-1

Question 30

Name chemokine receptor(s) that mediate neutrophil migration to sites of infection/injury. Which chemokine(s) does it bind?

Answer 30

CXCR1, CXCR2 bind CXCL8 (IL-18) produced by macrophages

Question 31

Which cytokine is important for development of high endothelial venules?

Answer 31

Lymphotoxin

Question 32

What is the role of L-selectin on T cells?

Answer 32

Expressed on naive T cells Binds selectin ligands on high endothelial venules (HEV), peripheral node addressins (PNAd)

Question 33

Give two examples of peripheral node addressins (PNAd). Where are they expressed?

Answer 33

1. GlyCAM-1, which is expressed on high endothelial venules of lymph nodes 2. MadCAM-1, which is expressed in Peyer's patches

Question 34

What do peripheral node addressins (PNAd) bind?

Answer 34

L-selectin on naive T cells

Question 35

Which integrin on T cells mediates firm adhesion of naive T cells to high endothelial venules of lymph nodes?

Answer 35

LFA-1 (lymphocyte function-associated antigen 1)

Question 36

Which chemokine(s) activate naive T cell integrins to a high affinity state? Which receptor do they bind?

Answer 36

CCL19 and CCL21, which bind CCR7

Question 37

Where is there a high concentration of sphingosine 1 phosphate (S1P)?

Answer 37

Blood and lymph

Question 38

Where is there a low concentration of sphingosine 1 phosphate (S1P)?

Answer 38

Tissues

Question 39

Describe the mechanism by which activated T cells are retained in the lymph nodes.

Answer 39

Activated T cells express CD69 (IFN type 1) that binds the S1P receptor 1 (S1PR1), causing them to become insensitive to the S1P gradient.

Question 40

Describe the mechanism by which effector T cells exit the lymph node.

Answer 40

After differentiation into effector cells, T cells lose CD69, re-express S1PR1 and exit the lymph node

Question 41

Describe the mechanism of action of fingolimod.

Answer 41

Binds S1PR1 and causes T cells to remain in lymph nodes

Question 42

Where is MadCAM-1 expressed? What does it bind?

Answer 42

Mucosal addressin cell adhesion molecule 1 (MadCAM-1) binds: 1. L-selectin on T cells 2. Integrin alpha4beta7 on T cells

Question 43

Which molecules involved in naive T cell circulation are down-regulated by effector T cells?

Answer 43

CCR7 and L-selectin

Question 44

Which selectin ligand is important for homing to the skin?

Answer 44

Cutaneous lymphocyte antigen (CLA) binds E-selection on endothelial cells in the skin

Question 45

What is the mechanism of action of vedolizumab?

Answer 45

Anti-alpha4beta7, to prevent homing of T cells to the gut

Question 46

Which molecules are expressed on central and effector memory T cells?

Answer 46

Central memory T cells: high CD45RO, high CCR7, high L-selectin Effector memory T cells: high CD45RO, low CCR7, low L-selectin CCR7 and L-selectin mediate homing to secondary lymphoid organs (SLO)

Question 47

Which molecule(s) are important for migration of B lymphocytes into the spleen?

Answer 47

CXCR5 on B cells binds CXCL13 on white pulp

Question 48

Which molecule(s) are important for migration of B lymphocytes into the lymph nodes?

Answer 48

To enter lymph node: CXCR4 binds CXCL12 CCR7 binds CCL19 and CCL21 To enter follicle: CXCR5 binds CXCL13 produced by follicular dendritic cells

Question 49

Which molecule(s) are important for migration of B lymphocytes into Peyer's patches?

Answer 49

CXCR5 binds CXCL13 Integrin alpha4beta7 binds MadCAM1