Lecture 21 - Mast cells - Friend or Foe Flashcards Preview

BIOM30001 - Frontiers in Biomedicine > Lecture 21 - Mast cells - Friend or Foe > Flashcards

Flashcards in Lecture 21 - Mast cells - Friend or Foe Deck (24):
1

Who discovered mast cells?

Paul Ehrlich

2

List the manifestations of atopy

• Allergic rhinitis (hay fever)
• Asthma
• Eczema
• Urticaria
• Anaphylaxis

3

Where are mast cells found in the body?

Particularly under epithelial surfaces:
• Skin
• Gastric mucosa
• Lung mucosa

Close to blood vessels, nerves, glands

4

List stimuli that can activate mast cells

• Ag (via IgE)
• C' fragments
• Neuropeptides
• Cytokines
• Chemokines
• Bacterial components

5

Describe what happens to mast cells when they become activated

Mast cells undergo profound changes when activated:

1. Degranulation
• Histamine
• Tryptase / chymase
• Other proteases
• Cytokines (results in a transient, localised pulse of cytokines)

2. Metabolism of membrane phospholipids
• Production of:
• Leukotrienes (LTC4)
• Prostaglandin (PGD2)

3. Cytokine and chemokine production
• IL-4, 5, 13

6

How do mast cells interact with antigen?

Through IgE bound by FcεRI

7

Describe the structure of FcεRI

Three components:
FcεRIα (1, 2)
• Extracellular heads

FcεRIβ
• Intracellular tail with ITAM

FcRγ
• Intracellular tails with ITAMs

8

What are ITAMs?

Intracellular tyrosine-based activation motifs

Sequences of amino acids that serve as a site for recruitment of other proteins that have catalytic actions

FcεR1 does not itself have intrinsic catalytic activity

9

What is piecemeal and compound degranulation?

Piecemeal degranulation:
Release of contents through fusion, then retraction and re-internalisation

Compound degranulation:
Fusion of multiple granules in the cytoplasm
Results in mass degranulation

10

Describe signalling through FcεR1

1. Binding of IgE to FcεR1

2. Antigen cross linking of adjacent IgE molecules, bringing together FcεRs

3. Src kinases phosphorylate the Tyr-residues in the ITAMs

4. Recruitment of Syk, which phosphorylates a variety of down-stream substrates

5. Lyn kinase

...

Result:
• Degranulation
• Activation of phospholipases → arachidonic acid metabolites
• Production of transcription factors → cytokine transcription

11

Where are ITAMs found?

• BCR
• TCR
• FcRs

12

What are ITIMs?

Inhibitory motifs

Often found in conjunction with ITAMs

13

What is Disodium chromoglycate (DSCG)?

Self-administered by a British researcher
Found to have a beneficial effect on asthma

Action:
• "Mast cell stabiliser"
• Precise mechanism still unknown
• Not highly specific

DSCG is used as a tool by researchers to investigate mast cell function

14

Which tools are used to investigate mast cell function?

1. DSCG
• "Mast cell stabiliser"
• Precise mechanism still unknown
• Not highly specific

2. Kit-/- mice
• Mast cell deficient mice
• Mutation in 'stem cell factor' system, which is critical for the growth and maturation of mast cells

3. Transgenics
• More precise knocking out of genes needed for mast cells

4. Mast cell deficient mice, reconstituted with mast cells
• Def mice: stem cell factor KO; no mast cells
• Mice were then reconstituted with leukocytes from WT mice
• This resulted in a reversal of autoimmune phenomena
• Neatly shows the effect of mast cells

15

What is stem cell factor?

Factor vital for the maturation and development of mast cells

KO used to study mast cells

However, it is also important for the development of other cells

16

List some diseases in which mast cells play a primary role

• Allergic disease
• CVD
• Renal disease
• RA
• Obesity

etc.

17

Describe mast cell observations in asthma

Individuals with asthma have increased frequency of mast cells in the airway smooth muscle, compared to individuals without asthma

18

Describe mast cell observations of mast cells in obesity

• Increased frequency of mast cells in the adipose tissue of obese individuals, compared to non-obese

• Increased serum typtase in obese individuals

• Mast cell def. mice less susceptible to obesity on western style diet, than WT mice

19

How could mast cells be depleted in individuals?

Why would one want to do this?

Conjugation of Pseudomonas exotoxin to Fc of IgE
This brings the exotoxin directly to mast cells, resulting in selective depletion

Why?
• Mast cells are involved in so much pathology
• However, mast cells play a beneficial role...

20

Which beneficial processes are mast cells involved in?

Infection:
• Parasite immunity
• Bacterial & viral immunity

Other:
• Envenomation
• UV skin damage
• CNS - anxiety
• Cancer

21

What is ES-62?

Glycoprotein released by nematodes

Dampens the activation of mast cells

(parasites are co-evolving strategies to avoid mast cells)

22

Describe the mast cell role in bacterial immunity

Mast cells play an important role in bacterial immunity

This was shown through CLP model of sepsis:
• Mast cell deficient animals show poor survival in this particular model of sepsis (CLP), compared to WT mice

CLP: caecal ligation puncture model of sepsis

23

Describe the role of mast cells in envenomation

Experimentally:
• In mast cell deficient animals, administration of a certain venom results in profound body temperature drop
• WT animals do not suffer from this when envenomated in the same way

Proposed mechanism:
1. Some components of the venom activate mast cells
2. Mast cells release proteases
3. Proteases degrade the especially nasty components of the venom

24

How are mast cells pharmacologically targeted?

-- Reduction of mast cell activity --

1. Antihistamines
• Targets histamine receptor

2. Omalizumab
• Humanised anti-IgE Ab
• Binds to the Fc region of IgE, so that is can not bind to FcεRI

3. Selective Syk kinase inhibitors
• An important mediator of the transduction pathway of the FcεRI

-- Stimulation of mast cells --

4. Compound 48/80
• Mast cell stimulator
• When administered, can lead to better survival of mice when infected with vaccinia virus
• Can be used as a vaccine adjuvant
• Components of the granules channeled to LNs which result in TNFa, which enhances Ag presentation