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
Which enzyme results in the production of LTC4?
5-lipoxygenase - an enzyme which is only present in inflammatory cells, has no role outside of inflammation and is activated by increased intracellular calcium
What is the receptor for cysteinyl leuktorienes?
CysLT1
What drug blocks the CysLT1 receptor?
leukotriene receptor antagonists
What is the physiological role of cysteinyl leukotrienes?
There is no physiological role outside of inflammation
What is the pathophysiological role of cyteinyl leukotrienes in anaphylaxis?
Causes hypotension by vasodilation, diminished cardiac output and hypovolemia by leaky vessels
What is the pathophysiological role of cysteinyl leuktorienes in asthma?
Causes airway obstruction by mucus production, oedema and smooth muscle shortening
What is the pathophysiological role of cysteinyl leukotrienes in hay fever?
Blocks the nasal passages with mucus and oedema
What is the action of glucocorticoids?
Inhibits phospholipase A2 - stops leukotrienes and prostaglandins
What are the actions of cytokines in allergy?
To induce gene expression changes for inflammatory cell infiltration and structural changes
Which cytokine is not down regulated by glucocorticoids?
IL-4
What are some endogenous inhibitors of mast cell activation?
prostaglandin E2, adrenaline, cortisol
What are some pharmacological inhibitors of mast cell activation?
disodium cremoglycate, nedocromil sodium (mechanism unclear)
What is omalizumab?
A humanised anti-IgE antibody which binds and prevents IgE from binding to the FcepsilonR1
How is omalizumab used?
It is administered subcutaneously in some asthma therapy to reduce sensitisation over a period of time
Can NSAIDs be used as anti-allergic agents?
In some allergies but not in asthma, and aspirin may provoke symptoms in asthmatics
What are H1 receptor antagonists used for?
urticaria, atopic dermatitis, hayfever, anaphylaxis, angiodema, bites and stings, motion sickness - not for asthma
What are the three generations of H1 receptor antagonists?
sedative, non sedative with cardiac effects, non sedative without cardiac effects
What are certirizine and loratidine?
H1 receptor antagonists that are non sedative without cardiac effects
Which asthma patients are leukotriene receptor antagonists useful for?
Aspirin induced asthma patients
What is montelukast?
A leukotriene receptor antagonist
What is used to treat anaphylaxis?
Adrenaline
What are the three ways of treating allergy?
Inhibiting mast cell activation (omalizumab), inhibiting mediator production (glucocorticoids), inhibiting mediator actions (antihistamines and leukotriene receptor antagonists)
