L6: Cell Trafficking Flashcards
1
Q
Roles of cell trafficking under normal circumstances:
A
- Leukocyte homing
- Initiation of immune response in dendritic cells
- Platelet clotting
- HSCs (bone marrow)
2
Q
Relevance of cell trafficking in disease:
A
- Leukocytes to heart (MI, joints in RA, lung in asthma
- Cancer cells in metastasis
3
Q
When is inflammation useful?
A
Responding to…
- Pathogens
- Parasites
- Tumours
- Wound healing
4
Q
Diseases caused by uncontrolled immune response:
A
- Myocardial reperfusion injury
- Atherosclerosis
- Ischaemic heart disease
- Rheumatoid arthritis
- Asthma
- Septic or traumatic shock
5
Q
Changes to endothelial cells during inflammation:
A
- Exposure of endothelium to IL-1 or TNF alters phenotype -> more adhesive for leukocytes (able to catch and slow down the leukocytes as they flow past)
- Effect depends on protein synthesis
- IL-1, TNF: Key pro-inflammatory cytokines
6
Q
Multistep paradigm of leukocyte migration:
A
- Tethering and rolling
- Signalling (integrin activation)
- Firm adhesion
- Extravasation
7
Q
How does tethering and rolling occur: (leukocytes)
A
- Cytokine activated endothelial cells express adhesion molecules
- This allows leukocytes to ‘marginate’ from the peripheral pool to the marginal pool -> mediated by selectins and adressins
- Tethering = 4000 microns / sec
- Rolling = 40 microns / sec
- In this process, momentum breaks the tether, but gradually the effect of many interactions slows the cell to a roll (where new interactions form at leading edge)
- Similar process occurs in metastasis of tumour cells
8
Q
Addressins:
A
- PGs (cell adhesion molecules)
9
Q
Selectins: Rough structure and types
A
- Type I TM glycoproteins which bind carbohydrates in a calcium-dependent manner
- Rod-like structure made up of 3 domains…
- C-type Lectin domain (Ca-dependent), EGF-like domain and consensus repeats -> tethered to PM
- 3 types called L, P and E
- PSGL1 is able to bind to all 3 types (many binding partner interactions possible)
10
Q
What do selectins bind to?
A
- Main variant: Sialyl Lewis X
- Fucose residue within this molecule is essential for binding
11
Q
How is specificity in Sialyl Lewis X conferred?
A
- Sulphation of Gal or GlcNAc increases binding to L-selectin and inhibits P-selectin binding
- PSGL-1 contains highly fucosylated structures but no sulphation and E-selectin just needs fucosylation
12
Q
Atopic dermatitis: Overview and therapeutic approach
A
- Unwanted inflammatory response caused by E-selectin overexpression
- Can inhibit sLex produciton by Fuc-T-VII enzyme by ectopic application of inhibitor (or inhibitor of binding)
- This enzyme prevents fucosylation during sLex production
13
Q
4-F-GalNAc as a therapy:
A
- Contains large fluorine atom
- Alters synthesis of PSGL1, reducing selectin interaction due to great steric hindrance
- Leukocytes roll faster, extravasation reduced
- -> Therapeutically impacting inflammation
14
Q
+ PSGL1
A
- Mucin-like selectin ligand
- Found on surface of leukocyte, as well as myeloid and dendritic cells
- Binds all 3 selectins with differing affinity
15
Q
+ What diseases does L-selectin overexpression play a role in? (3 examples)
A
- HIV infection
- MS
- Allergy
