Allergy Flashcards
1
Q
Why aren’t antihistamines useful in treating asthma?
A
- some asthmatics are allergic
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2
Q
Where are mast cells found?
A
- Predominantly in surfaces that engage with external environment
- skin, lung, & gut
- commonly associated with blood vessels, nerves, glands in the parenchyma of all organs
3
Q
What triggers mast cells to be activated?
A
- polybasic drugs (positively charged)
- morphine, vancomycin
- allergens via IgE
- mechanical stimulants
- heat, cold, UV light
- polybasic peptides in stings, venom, bites
- hyperosmolarity of airway surface fluid in exercise
- exercise induced bronchospasm (airway drying when Ve goes up)
4
Q
How is mast cell degranulation induced by allergens?
A
- cross-linking of IgE with mast cell FcER1
- requires antigen-specific IgE
- overproduced in atopic subjects to both general and specific allergens
5
Q
What is the mechanism of mast cell degranulation?
A
- adjacent IgE bind to allergen
- causes FcER1 receptors to cluster
- beta and gamma chains on cytoplasmic FcER1 tails (ITAMS) are phosphorylated by Lyn (a Syk/spleen tyrosine kinase)
- **ITAMS have no integral kinase activity until they are cross-linked with allergen and the receptors migrate to lipid rafts
- leads to recruitment and activation of other cellular tyrosine kinases
- phospholipase C is activated (and other signalling enzymes)
- releases diacylglycerol
- inositol triphosphate
- these + protein kinase C and Ca2+, respectively, cause explosive degranulation
-
takes about 30-45 seconds
- this is only the quick part; histamine is released immediately but there are other phases that generate response
6
Q
What do mast cell granules contain?
A
- histamine
- heparin
- VEGF
- FGF
- preformed cytokines (for immediate action)
7
Q
What are the immediate mediators released by mast cell degranulation?
A
-
preformed mediators, ~30-45 seconds
- histamine
- heparin (anticoagulant)
- tryptase (protease activator receptor II ligand)
- TNFa
8
Q
What are the rapid (second) mediators released on mast cell degranulation?
A
-
rapid mediators, ~2-5 minutes, peak ~10-30 minutes but made at elevated levels for next several hours
- mobilized arachidonic acid leads to formation of PGD2 (by COX) and cysteinyl leukotrienes (5-lipox)
- both are potent bronchoconstrictors
9
Q
What are the slow mediators released by mast cell degranulation?
A
- related to transcriptional events (hence slow), takes some hours
- perpetuate the allergic response
- cytokines:
- IL-4
- IL-5
- GM-CSF
- promote infiltration of eosinophils and T-cells, attract more mast cells
- sensitizes and activates site for many days post-event
10
Q
What are the effects of immediately released histamine?
A
- acts on H1 receptors
- pain and itch via sensory nerve activation
- bronchospasm of smooth muscle
- increased mucous secretion
- vasodilation (if systemic, can cause hypotension)
- endothelial retraction causing increased vascular leak, hypovolemia
- positive ionotropic and chronotropic effects on the heart (H2)
- increased gastric acid secretion, causing colic pain (H2)
- promotes wakefullness in CNS
11
Q
What is the action of leukotrienes in allergic/anaphylactic response?
A
- potent bronchoconstrictors (LTC4, LTD4, LTE4) active at the CysLT1 receptor
- reinforce systemic hypotension caused by histamine
- vasodilation in skeletal muscle
- diminsh cardiac output
- cause vascular leak and potentially hypovolemia (in conjunction with other mediators that cause vascular leak and loss of tone in vascular muscles)
- airway obstruction in asthma
- cause vasoconstriction, increased mucous production, oedema
- promote dilation and leakiness of nasal vessels (mucous and oedema) in allergic rhinitis/hayfever
12
Q
What are the effects of delayed release cytokines by mast cell degranulation?
A
- act through inducing changes in gene expression in target cells
- recruitment of inflammatory cells (can be over several days)
- structural changes as a chronic allergic response
13
Q
What are the targets of anti-inflammatory glucocorticoids from mast cell degranulation?
A
- many of the cytokines released in the delayed/long-term response:
- IL-1, TNF, IL-5 (predominantly)
- IL-4 (not as tightly)
14
Q
What are the endogenous inhibitors of mast cell activation?
A
- PGE2
- adrenaline
- acts on beta2 receptors to +cAMP and +circulating cortisol
- minor in those who suffer from allergic disease; must rely on pharmacological inhibitors in these pt
15
Q
What are the pharmacological inhibitors of mast cell activation?
A
- disodium cromoglycate and nedocromil sodium
- weak anti-inflammatory agents
- not absorbed, tf:
- applied topically
- does not access systemic circulation (well-tolerated)
- must be taken preventatively
- not useful in all patients
- reduce mast cell activation, neurogenic inflamation, and eosinophil activation
- may cause release of annexin-1, a protein mediatior of glucocorticoid activity
- turns off ongoing inflammatory responses
- used in tx of allergic responses of mucosal surfaces (nasal, airway, gut)
