Cellular & Molecular Aspects of Allergy Flashcards
Where are mast cells particular prevalent?
At sites where the body is in contact with the external environment e.g. skin/gut/lungs and near blood vessels, nerves and glands
What do mast cells respond to?
polybasic drugs, mechanical stimulation, UV light/heat, allergen, stings, hypertonic saline, activated complement, neuropeptides
What is a potential mechanism for exercise induced asthma?
Exercise causes the airway surface fluid to dry out and the hyperosmolarity triggers mast cell activation
What causes allergen induced mast cell degranulation?
Cross linking of IgE bound to FcepsilonR1
What is the structure of the FcepsilonR1 receptor?
An alpha chain which binds to Fc region of IgE, a beta chain and two gamma chains. The beta and gamma chains each have one immunoreceptor tyrosine based activation motif (ITAM).
How does binding of the FcepsilonR1 receptor by antigen bound IgE lead to mast cell degranulation?
There is a tyrosine kinase (Lyn) which is constitutively associated with the beta chain of the receptor. Cross linking of the receptor allows Lyn to phosphorylate the ITAMS. Tyrosine phosphorylation of the ITAMS initiates the signalling cascade. First there is recruitment and activation of other cellular tyrosine kinases. Then this leads to phospholipase C phospohrylation and activation. PLC activation leads to production of Inositol triphosphate and diacylglycerol. IP3 causes an elevation in calcium levels and DAG causes activation of protein kinase C. PKC phorphorylates myosin light chain and disassembles the actin myosin complex under the plasma membrane which allows the granules to come into contact with the plasma membrane and causes degranulation. The calcium promotes SNARE complex formation and membrane fusion.
How does binding of the FcepsilonR1 receptor by antigen bound IgE lead to the production of arachidonic acid metabolites?
The signalling cascade also produces MAP kinase which in turn activates phospholipase A2. PLA2 hydrolyses membrane phospholipids which releases substrates which are converted to mediators such as leukotrienes, prostaglandins
How does binding of the FcepsilonR1 receptor by antigen bound IgE lead to the production of cytokines?
There are preformed cytokines (TNFalpha) within the granules that are released on degranulation. But the signalling cascade also results in cytokine gene transcription. MAP kinase leads to cytokine gene transcription. This leads to the production of IL-4, IL-5 and GM-CSF
What do the preformed granules contain?
histamine, heparin, tryptase and TNFalpha
How long does it take for the contents of granules to be released after an antigen binds to IgE?
30-45 seconds
What are the arachidonic acid metabolites that are produced?
Cysteinyl leukotrienes and prostaglandin D2
How long does it take for the leukotrienes and prostaglandin D2 to be produced?
10-30 mins
How long does it take for cytokines IL-4, IL-5 and GM-CSF to be produced?
hours
What are the action of histamine?
- pain and itch
- bronchospasm
- mucus secretion
- vasodilation
- increased vascular leak
- positive inotropic and chronotropic
- gastric acid secretion
- increased wakefulness
What are the cysteinyl leukotrienes?
LTC4 and its degraded products LTD4 and LTE4