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

Lecture 21 - Mast cells - Friend or Foe Flashcards

1
Q

Who discovered mast cells?

A

Paul Ehrlich

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2
Q

List the manifestations of atopy

A
  • Allergic rhinitis (hay fever)
  • Asthma
  • Eczema
  • Urticaria
  • Anaphylaxis
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3
Q

Where are mast cells found in the body?

A

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

Close to blood vessels, nerves, glands

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4
Q

List stimuli that can activate mast cells

A
  • Ag (via IgE)
  • C’ fragments
  • Neuropeptides
  • Cytokines
  • Chemokines
  • Bacterial components
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5
Q

Describe what happens to mast cells when they become activated

A

Mast cells undergo profound changes when activated:

1. Degranulation
 • Histamine
 • Tryptase / chymase
 • Other proteases
 • Cytokines (results in a transient, localised pulse of cytokines)
  1. Metabolism of membrane phospholipids
    • Production of:
    • Leukotrienes (LTC4)
    • Prostaglandin (PGD2)
  2. Cytokine and chemokine production
    • IL-4, 5, 13
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6
Q

How do mast cells interact with antigen?

A

Through IgE bound by FcεRI

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7
Q

Describe the structure of FcεRI

A

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

FcεRIβ
• Intracellular tail with ITAM

FcRγ
• Intracellular tails with ITAMs

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8
Q

What are ITAMs?

A

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

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9
Q

What is piecemeal and compound degranulation?

A

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

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10
Q

Describe signalling through FcεR1

A
  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

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11
Q

Where are ITAMs found?

A
  • BCR
  • TCR
  • FcRs
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12
Q

What are ITIMs?

A

Inhibitory motifs

Often found in conjunction with ITAMs

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13
Q

What is Disodium chromoglycate (DSCG)?

A

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

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14
Q

Which tools are used to investigate mast cell function?

A
  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
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15
Q

What is stem cell factor?

A

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

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16
Q

List some diseases in which mast cells play a primary role

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

etc.

17
Q

Describe mast cell observations in asthma

A

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

18
Q

Describe mast cell observations of mast cells in obesity

A
  • 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
Q

How could mast cells be depleted in individuals?

Why would one want to do this?

A

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
Q

Which beneficial processes are mast cells involved in?

A

Infection:
• Parasite immunity
• Bacterial & viral immunity

Other:
 • Envenomation
 • UV skin damage
 • CNS - anxiety 
 • Cancer
21
Q

What is ES-62?

A

Glycoprotein released by nematodes

Dampens the activation of mast cells

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

22
Q

Describe the mast cell role in bacterial immunity

A

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
Q

Describe the role of mast cells in envenomation

A

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
Q

How are mast cells pharmacologically targeted?

A

– 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 –

  1. 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

BIOM30001 - Frontiers in Biomedicine (35 decks)

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