Cellular and Molecular Aspects of Allergy Flashcards
What is the action of local mediators or autocoids in the action of allergy?
Local Mediators (aka Autocoids)
- Act locally as they are often quite labile or are rapidly metabolized close to their site of release
- They serve many modulatory functions including:
- smooth muscle tone/length
- glandular secretion
- fluid leak/oedema (vascular and airway)
- sensory nerves (pain and Itch)
- There are many examples such as histamine and Cysteinyl LTs
What are some targets of mast cells?
Mast Cells These are inflammatory secretory cells targeting: 1. inflammatory cell activation 2. mediator production 3. mediator actions 4. Prevention and desensitisation
Where are mast cells located?
- Mast cells are located everywhere. They are particularly prevalent at body sites in contact with the external environment (skin, gut, lung) and are commonly found close to blood vessels/nerves/glands.
Explain mast cell degranulation?
- Mast cells can be degranulated by allergens. This is done by cross linking of IgE bound FcεR1. It requires antigen-specific IgE- produced in atopic subjects (heritable trait)
What receptor is activated during mast cell degranulation?
The FcεRI Receptor which exhibit ITAMS [Immunoreceptor Tyrosine-based Activation MotifS (have a consensus sequence)]
Explain the concept surrounding Communication Across the Mast cell membrane.
- Adjacent IgE molecules bind allergen (external)
- Adjacent ΙgΕ receptor FcεR1 (α, β & 2γ) cluster
- β & γ chains phosphorylated (internal) (Lyn/Syk)
- Recruitment and activation of cellular tyrosine kinases
- Phospholipase C phosphorylation and activation
What happens immediately following mast cell degraulation?
- Activation of Mast cells produces dramatic changes in the cell surface Topography.
- The mast cell communicates with the internal environment in several ways:
Immediate --> Release of Preformed Mediators - Histamine - Heparin - Tryptase - TNF-α' Initial Reaction ~ 30-45 seconds
Rapid
- Cys-LTs
- PGD2
- -> Peaking 10 - 30 min
Slow
- IL-4
- IL-5
- GM-CSF
- -> Late, T-cell& eosinophil dependent reaction
Explain some of the mediators that are released immediately in an allergic response?
Histamine - acts on H1 receptors (and sometimes H2); H3 & H4 histamine receptors - antagonists in development
- The actions of histamine include:
- Pain & itch (sensory nerve activation)
- Bronchospasm
- Mucus secretion
- vasodilatation - hypotension
- Increased vascular “leak” - hypovolemia
- Positive inotropic and chronotropic (H2 receptors)
- Gastric acid secretion (H2 receptors)
- CNS - increased wakefullness
Explain the delayed response of allergic reactions.
Cysteinyl Leukotrienes
- Glutathione-S-transferase - LTC4 from LTA4
- Production: eosinophils, mast cells & macrophages
- Stimuli: allergen, C5a, Platelet-activating factor (PAF)
- LTC4 & metabolites (LTD4, LTE4) are active at CysLT1 receptor
- Pathophysiological roles (no known physiological roles)
> Hypotension during anaphylactic shock - vasodilator in skeletal musculature; diminished cardiac output; hypovolemia
> Airway obstruction in asthma - mucus, oedema, ASM shortening
> Nasal obstruction in hayfever - mucus, oedema
Why are some elements of the allergic response delayed?
- There is often a reason for the delayed release of some of these elements, for example…
Phospolipase A2:
- It De-esterifies the acyl lipid stored in phospholipids (C20:4 eicosatetraenoic acid (arachidonic acid, AA) - diet C20:5 eicosapentaenoic acid (EPA))
- The activity of Phospolipase A2 is determined by:
- amount of PLA2 (some isoforms are inducible)
- signal transduction (Ca2+ /extracellular regulated kinase (MAPK) activity)
- levels of inhibitors eg annexin I
- Free AA is metabolised to different products depending on the activation status & enzymes expressed in the cell.
Leukotriene B4:
No direct actions on smooth muscle; promotes inflammation by attracting leukocytes
Explain the role of cytokines in the allergic response.
Delayed & Protracted Release:
Cytokines (Interleukins; colony-stimulating factors; TNF; chemokines)
- slow onset/slow offset;
- context-dependent actions;
- outcome dictated by network of target cells
- responding to (integrating) complex signals
- Induce gene expression changes
- inflammatory cell infiltration
- structural changes
- Some highly regulated by glucocorticoids (eg IL-1, TNF), others not (eg IL-4)
What are some sites of drug action in anti-allergy medications?
- Inhibitors of Mast Cell Activation
- Inhibiting Mediator Production
- Inhibiting Mediator Actions
What are some features of drugs that inhibit mast cell activation?
1. Inhibitors of Mast Cell Activation Endogenous PGE2, adrenaline, cortisol Pharmacological Disodium cromoglycate/Nedocromil sodium
- Well tolerated, but only modestly anti-inflammatory
- Not effective in all patients?
- Reduction in:
- mast cell degranulation
- C-fibre activation
- eosinophil activation
- Cause annexin-1 release: annexin-1 resolves inflammation
- Indicated for treatment of allergic responses of mucosal surfaces: nasal, airway & gut (not orally active)
What are some ways that mast cell activation can be inhibited?
There are several ways that drugs can target mast cells:
- Block the IgE-dependent activation pathway:
Omalizumab
- a humanised murine monoclonal antibody; binds and prevents IgE binding to α chain of FcεR1 –> IgE & FcεR1 levels decrease
- administered subcutaneously
- expensive: positioning in asthma therapy is limited
NSAIDs and COX-2 Selective Inhibitors
(Aspirin, Indomethacin, Celecoxib)
- There are mixed roles of prostaglandins in allergy and they are shown to have beneficial and detrimental actions
- No net benefit of these treatments in asthma or hayfever
- May provoke symptoms in ~10% of asthmatics & hayfever sufferers due to excessive production of LTs
- aspirin (NSAID) induced asthma may be treated with leukotriene receptor antagonists (LTRA)
What are some of the features of the drugs Inhibiting Mediator Production in allergy?
- Glucocorticoids – mechanism dealt with in airway pharmacology
Benefit in allergy partly explained by reducing mast cell cytokine production - Anti-inflammatory use:
- Asthma (eg budesonide)
- hypersensitivity states (allergic reactions)
- skin, eye, etc. (topical)
- (eg beclomethasone dipropionate)
- Systemic anaphylaxis (oral/intramuscular)
- (eg hydrocortisone)
- skin, eye, etc. (topical)
