67 - Cellular and Molecular Aspects of Allergy Flashcards
Where are mast cells often found?
Body sites in contact with external environment: skin, gut, lung Often close to blood vessels, nerves, glands
Things that can stimulate mast cells 1) 2) 3) 4) 5) 6) 7) 8)
EXTERNAL FACTORS 1) Polybasic drugs (vancomycin, morphine) 2) Mechanical stimulation 3) UV light, heat 4) Allergen (IgE-mediated) 5) Stings 6) Osmotic stimuli (hypertonic saline) INTERNAL FACTORS 7) Activated C’ 8) Neuropeptides
Unusual feature of ITAMS
No integral kinase activity. Activity arises when they cluster
Atopy
Genetic predisposition to overproduction of IgE against a specific antigen
Diseases associated with asthma
RSV, rhinovirus, strongly implicated as risk factors in development of asthma, if caught at an early age.
Mechanism of degranulation
Channels form in membrane, through which granule contents exit cell
Subunits of FceRI
Alpha1, alpha2 make up binding site, beta (4-pass transmembrane loop), 2xgamma
FceRI subunits with ITAMs
Beta and gamma1, 2
Pathways stimulated by FceRI stimulation 1) 2) 3)
1) MAPK 2) NF-kB 3) Phospholipase C
Immediate factors released by activated mast cells
Histamine Heparan sulphate Tryptase TNFa These are preformed mediators
How long does it take for mast cells to release preformed mediators?
~30-45 seconds
Phases of mast cell response 1) 2) 3)
1) Immediate (preformed mediators) 2) Rapid (arachidonic acid mediators) 3) Slow (transcription, translation of cytokines)
Rapid mediators released by mast cells
Cyteinyl leukotrienes PGD2
How long does it take for mast cells to release rapid mediators
Peak around 10-30 minutes
Slow mediators released by mast cells
IL-4, IL-5, GM-CSF
Timeframe for slow action of mast cells
Occurs over hours to days
Action of histamine stimulation of H1 receptors 1) 2) 3) 4) 5) 6)
1) Pain, itching 2) Bronchospasm 3) Mucus secretion 4) Vasodilation (hypotension) 5) Increased vascular lead (hypovolaemia) 6) Increased wakefulness (CNS activity)
Action of histamine stimulation of H2 receptors 1) 2)
1) Gastric acid secretion 2) Positive inotropic, chronotropic effect on heart (increases contractility, heart rate)
Cysteinyl leukotriene production
Glutathione-S-transferase converts LTA4 to LTC4
Cells producing cysteinyl leukotrienes
Macrophages, eosinophils, mast cells
Stimuli leading to LTC4 production 1) 2) 3)
1) Allergen 2) C5a 3) Platelet-activating factor
Mediators active at CysLT1 receptor
LTC4 and metabolites (LTD4, LTE4)
Physiological roles of LTC4
None known
Pathophysiological roles of LTC4 1) 2) 3) 4) 5) 6)
1) Hypotension during anaphylactic shock 2) Vasodilator in skeletal muscle 3) Diminished cardiovascular output 4) Hypovolaemia 5) Airway obstruction in asthma (mucus, oedema, airway smooth muscle shortening) 6) Nasal congestion in hayfever (mucus, oedema)
*Arachidonic acid pathway
What activates arachidonic acid pathway?
Increase in cytosolic Ca2+ by stimuli produced in infection, allergic responses, other forms of inflammation
CysLT1 receptor antagonist
Montelukast
Arachidonic-acid-derived chemotactant
Leukotriene B4
Glucocorticoid effect
Activates annexin-1, which inhibits phospholipase A2. This prevents arachidonic acid being cleaved from cell membrane
Inhibitors of COX I and II 1) 2) 3)
1) Aspirin 2) NSAIDs 3) Coxibs
Leukotrienes that are blocked by montelukast
LTC4, and LTC4 metabolites (LTD4, LTE4)
PGD4 effect
Bronchoconstrictor released from mast cells
When does arachidonic acid become available to mast cells?
When they are activated
Minimum amount of time for a transcriptional response (in a mast cell)
45 minutes (at the shortest) to two or three hours
Why is there a delay in mast cell production of lipid mediators?
Phospholipase A2 only de-esterifies membrane phospholipids to arachidonic acid upon mast cell activation.
Cytokines released by mast cells that can be regulated with glucocorticoids
IL-1, TNFa
Cytokines released by mast cells that aren’t well regulated by glucocorticoids
IL-4
Endogenous inhibitors of mast cell activity 1) 2) 3)
1) PGE2 2) Adrenaline 3) Cortisol
Pharmacological inhibitors of mast cell activity
Sodium cromoglycate Nedocromil sodium
Effect of sodium cromoglycate and nedocromil sodium 1) 2) 3) 4) 5)
1) Moderate reduction in inflammation 2) Reduction in mast cell degranulation 3) Reduction in C-fibre activation 4) Reduction in eosinophil activation 5) Cause annexin-1 release
Where are sodium cromoglycate and nedocromil sodium used?
For airway inflammation. Not orally-available
MAB inhibitor of mast cell activation
Omalizumab. Prevents IgE binding to FceRI.
Pros and cons of lack of oral efficacy of sodium cromoglycate and nedocromil sodium
Only active at mucosal sites (pro) Can’t reach deeper tissues (con)
Alternate activity of H1 receptor antagonists
Have anti-muscarinic activity. Good for motion sickness treatment
Effect of NSAIDs and COXII inhibitors on allergy
No net benefit for asthma or hayfever. May provoke symptoms in ~10% of asthmatics and hayfever sufferers.
Example of a glucocorticoid used to treat asthma
Budesonide
Indications for H1 receptor antagonists 1) 2) 3) 4) 5) 6)
1) Urticaria 2) Atopic dermatitis 3) Hayfever 4) Anaphylaxis and angioedema 5) Bites, stings 6) Motion sickness (anti-muscarinic activity
Alternative name for H1 receptor antagonists
Antihistamines
H1 receptor antagonists
Competitive, reversible antagonists of H1 receptors
Three classes of antihistamines 1) 2) 3)
1) Sedative (promethazine) 2) Non-sedative (terfenadine, astemizole) 3) Newer non-sedative (cetirizine, loratidine)
Why were newer non-sedative antihistamines produced?
Terfenadine and astemizole caused rare, sudden ventricular arrhythmias.
Effect of antagonising LTC4
Modest bronchodilation Especially indicated for aspirin-induced or exercise-induced asthma
LTC4 antagonist cotherapy
Administered with a glucocorticoid or beta2 adR agonist
Reason for why colic pain is a feature of anaphylaxis
Increased gastric acid secretion from H2 stimulation by histamine in the GIT
