Lecture 21 - Mast Cells: friend and foe

Question 1

The mast cell has dense granules packed full of …

Answer 1

mediators that can do alot of harm and good

Question 2

Mast cells are best known for their role in ..

Answer 2

Allergic diseases

Elevated allergen-specific immunoglobin E levels - atopy

Allergic rhinitis
asthama
anaphylaxis

Question 3

Where are mast cells particularly located?

Answer 3

body sites in contact with the external envirnoment - skin/gut/lung

commonly found close to BVs/nerves/glands

Question 4

What kind of stimuli can activate Mast cells?

Answer 4

Antigen - via IgE

complement fragments

neuropeptides

cytokines/chemokines/growth factors

bacterial componenets

physical trauma

Question 5

Degranulation of mast cells happens how?

Answer 5

granules fusing with the cell membrane

Question 6

What are the types of granulation?

Answer 6

peace-mule degranulation: fuse with the membrane, release and be reintegrated
(kiss-and-run)

Compound degranulation - one will fuse, and then lots with will fuse the first granule to form a large space of content release

Question 7

What is in the granules?

Answer 7

Histamine
Tryptase/chymase
other protease - kinase
(cytokines)

There are some pre-formed cytokines, early stage inflammatory response

Arachidonic acid pathway triggers: Leukotrience C4 (LTC4) and PGD2

Transcriptional regulators to upregulate cytokine and chemokines genes (TNF-a) for long, sustained response

Question 8

What is the mast cells activation receptor?

Answer 8

FceRI Receptor

which activates

ITAMS - Immunireceptor Tyrosine-based Activation MotifS (have a consensus sequence)

Question 9

What are the core elements of the FceRI Receptor signaling?

Answer 9

1. receptor crossing linking
2. draw together Src kinases, leads to phosporylation of ITAM motifs
3. Draws in other tyrosine kinases (Syk) - which has lots of downstream substrates
4. Adaptor proteins + second messengers (IP3) and Ca2+ which eventually leads to the process of degranulation
5. Activation of phospholipases and transcription factors

Question 10

ITAM-mediated signalling is commonly found along with what inhibitory version?

Answer 10

ITIM - Immunoreceptor tyrosine-based inhibitory motif - ITIM

Question 11

ITAM-mediated signalling is a common pathway in what…

Answer 11

Immune regulating receptors
b-cell receptor
T-cell receptor
Fc receptors for other immunoglobulins

Question 12

What two ways have mast cells been examined?

Answer 12

Mast cell deficient mice - mutation in stem cell factor system:ligand, receptor, gene promotor

mast cell “stabilising’ drug - Disodium cromoglycate (DSCG) - not known how it works, can also effect other cells

Question 13

Mast cell deficient aniamls can be reconsituted with…

Answer 13

mast cells grown in culture

Mast cells will then repopulate the areas where they should go

So shows whether the phenotype is reversed with the mast cells are introduced

Question 14

Other than Allegric disease, where else does mast cells do bad things?

Answer 14

CV disease
kidney disease
Rheumatoid arthritis
Obestity
CNS - multiple sclerosis
Cancer
infectious diseases

Question 15

In Asthma how is mast cells bad?

Answer 15

mast cells uniquely elevated in asthmatic airways - found in close proximity to airway smooth muscle cells

Causes the ‘twitchyness”

Question 16

In Obesity how is mast cells bad?

Answer 16

increase amount in human white adipose tissue from obese donors - enhanced serum levels of tryptase

mast cell deficient animals gain less weight on western diet

Question 17

Whats a way mast cells could be killed?

Answer 17

Fc2’3 - PE40

IgE - Fc portion binds to FceRI

Fused with Pseudomonas exotoxin A (PE40)

This toxin causes cell death

means of targeting and selectively eliminating mast cells

Question 18

What situations are mast cells friendly?

Answer 18

Immunity to infection

certain parasites
certain bacteria
certain viruses

but not just infection

Venoms
UV skin damage
CNS - anxiey
Cancer - can reduce growth in some types of cancer

Question 19

ES-62 is glycoportein secreted by some parasites that tries to..

Answer 19

dampen down the mast cell degranulation

Question 20

Mast cell deficient animals have a very poor survival in a _____ ______ model

Answer 20

bacteria infection

Question 21

What are the ways of targeting mast cells

Answer 21

Anti-histamines (for hayfever etc..)

Omalizumab (humanised anti0IgE antibody) block the IgE-dependent activation pathway

Selective syk kinase inhibitors - block the IgE-dependent activation pathway

Question 22

What are the ways of utilising mast cell?

Answer 22

Enhance mast cell activation in immunity as a vaccine adjuvant

Compound 48/80 - mast cell stimulator given at the time of vaccine - get protection from death