Leukocyte Adhesion and Circulation Flashcards
Name the 3 major selectins.
P-selectin (CD62P)
E-selectin (CD62E)
L-selectin (CD62L)
Where is P-selectin expressed?
Endothelium activated by histamine or thrombin
What is the ligand for P-selectin?
Sialyl Lewis X on P-selectin glycoprotein ligand 1 (PSGL-1) and other glycoproteins on neutrophils, monocytes, and T cells (effector, memory)
Where is E-selectin expressed?
Endothelium activated by microbial products (LPS) and/or cytokines (TNF, IL-1) produced by dendritic cells and macrophages
What is the ligand for E-selectin?
Sialyl Lewis X (e.g. cutaneous leukocyte antigen 1 (CLA-1)) on glycoproteins on neutrophils, monocytes, and T cells (effector, memory)
Where is L-selectin expressed?
Neutrophils, monocytes, T cells (naive and central memory), and B cells (naive)
What is the ligand for L-selectin?
Sialyl Lewis X on GlyCAM-1, CD34, MadCAM-1 (sialomucins) on endothelium (HEV), which are collectively called peripheral node addressin (PNAd)
What are lectins?
Carbohydrate-binding proteins
Name 4 major integrins.
1.Leukocyte function-associated antigen, LFA-1 (CD11aCD18)
2. MAC-1 (CD11bCD18, CR3)
3. Very late antigen 4, VLA-4 (CD49aCD29)
4. a4B7 (CD49dCD29)
What is/are the ligand(s) for LFA-1 (CD11aCD18)?
ICAM-1 (intercellular adhesion molecule) and ICAM-2 on endothelium
What is/are the ligand(s) for MAC-1 (CD11bCD18)?
ICAM-1 and ICAM-2 on endothelium
What is/are the ligand(s) for VLA-4 (CD49aCD29)?
VCAM-1
What is/are the ligand(s) for a4B7?
VCAM-1 and MadCAM-1 on endothelium in gut and gut-associated lymphoid tissues
What are selectins?
Carbohydrate-binding protein adhesion molecules
What are selectin ligands?
Sialylated and fucosylated carbohydrate groups of Lewis X and Lewis A family present on glycoproteins of various cells
What is the structure of integrins?
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
What are chemokines?
Chemotactic cytokines that regulate movement of leukocytes
How are chemokines named?
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
Name key chemokines involved in mixed leukocyte recruitment
CCL2 and CCL3
Name key chemokines involved in allergic processes
CCL5 (RANTES): Mixed leukocyte recruitment
CCL11 (Eotaxin): Eosinophil, basophil and Th2 recruitment
CCL17 (TARC): T cell recruitment
Name two chemokines important for T cell and dendritic cell migration into parafollicular zones of lymph nodes. Which receptor do they bind?
CCL19, CCL21, which bind CCR7
Name a chemokine important for neutrophil recruitment. Which receptors do they bind?
CXCL8 (IL-8), which binds CXCR1 and CXCR2 on neutrophils
Which chemokine is important for B cell migration into lymph nodes? Which receptor does it bind?
CXCL13, which binds CCR5
How do chemokines affect integrins?
- Induce membrane clustering
- Increase affinity for integrin receptors
What are the 6 steps of leukocyte recruitment into a site of inflammation?
- Tissue infection or injury
- Rolling
- Increase in integrin affinity
- Adhesion
- Migration through the endothelium
- Migration of leukocytes to site of infection and tissue injury
What is the cause of LAD type 1?
Defect in CD18, B subunit of integrin ligands LFA-1 (aLB2 = CD11aCD18) and Mac-1 (aMB2 = CD11bCD18)
What is the cause of LAD type 2?
Lack of Golgi fucose transporter needed to express carbohydrates (sLeX) on E and P selectin ligands on neutrophils
What is the cause of LAD type 3?
Defect in signaling pathway linking chemokine receptor to integrin activation (Kindlin 3)
Name a chemokine receptor that mediates monocyte migration to sites of infection/injury. Which chemokine(s) does it bind?
CCR2 binds CCL2, MCP-1
Name chemokine receptor(s) that mediate neutrophil migration to sites of infection/injury. Which chemokine(s) does it bind?
CXCR1, CXCR2 bind CXCL8 (IL-18) produced by macrophages
Which cytokine is important for development of high endothelial venules?
Lymphotoxin
What is the role of L-selectin on T cells?
Expressed on naive T cells
Binds selectin ligands on high endothelial venules (HEV), peripheral node addressins (PNAd)
Give two examples of peripheral node addressins (PNAd). Where are they expressed?
- GlyCAM-1, which is expressed on high endothelial venules of lymph nodes
- MadCAM-1, which is expressed in Peyer’s patches
What do peripheral node addressins (PNAd) bind?
L-selectin on naive T cells
Which integrin on T cells mediates firm adhesion of naive T cells to high endothelial venules of lymph nodes?
LFA-1 (lymphocyte function-associated antigen 1)
Which chemokine(s) activate naive T cell integrins to a high affinity state? Which receptor do they bind?
CCL19 and CCL21, which bind CCR7
Where is there a high concentration of sphingosine 1 phosphate (S1P)?
Blood and lymph
Where is there a low concentration of sphingosine 1 phosphate (S1P)?
Tissues
Describe the mechanism by which activated T cells are retained in the lymph nodes.
Activated T cells express CD69 (IFN type 1) that binds the S1P receptor 1 (S1PR1), causing them to become insensitive to the S1P gradient.
Describe the mechanism by which effector T cells exit the lymph node.
After differentiation into effector cells, T cells lose CD69, re-express S1PR1 and exit the lymph node
Describe the mechanism of action of fingolimod.
Binds S1PR1 and causes T cells to remain in lymph nodes
Where is MadCAM-1 expressed? What does it bind?
Mucosal addressin cell adhesion molecule 1 (MadCAM-1) binds:
1. L-selectin on T cells
2. Integrin alpha4beta7 on T cells
Which molecules involved in naive T cell circulation are down-regulated by effector T cells?
CCR7 and L-selectin
Which selectin ligand is important for homing to the skin?
Cutaneous lymphocyte antigen (CLA) binds E-selection on endothelial cells in the skin
What is the mechanism of action of vedolizumab?
Anti-alpha4beta7, to prevent homing of T cells to the gut
Which molecules are expressed on central and effector memory T cells?
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)
Which molecule(s) are important for migration of B lymphocytes into the spleen?
CXCR5 on B cells binds CXCL13 on white pulp
Which molecule(s) are important for migration of B lymphocytes into the lymph nodes?
To enter lymph node:
CXCR4 binds CXCL12
CCR7 binds CCL19 and CCL21
To enter follicle:
CXCR5 binds CXCL13 produced by follicular dendritic cells
Which molecule(s) are important for migration of B lymphocytes into Peyer’s patches?
CXCR5 binds CXCL13
Integrin alpha4beta7 binds MadCAM1
