L18 Atopy, allergy and dth 2 Flashcards
Detection of allergen-specific IgE in vivo: skin testing
Skin prick testing
- Allergen extract applied as drops
- Top layers of epidermis punctured with lancet
- A wheal with flare response after 15 mins is positive
- Result needs interpretation in clinical context
Detection of allergen-specific IgE in vitro
- Performed by radioallergosorbant (RAST) assay a very long time ago
- Now usually by ELISA, but term ‘RAST’ still widely used clinically
Process of allergen-specific IgE in vitro
- Plastics coated with purified allergen of interest
- Incubate with patient serum
- IgE antibodies in sera of sensitised patient bind to allergens
- Immobilised IgE antibodies detected with polyclonal anti-IgE detection antibody
Treatment of allergy: pure symptom relievers
- Nasal decongestants
- B2 agonists
- Epinephrine
Nasal decongestants
eg oxymetazoline
- Act on alpha1 adrenoreceptors to cause vasoconstriction
- Only for short-term use topical and systemic
B2 agonists
eg salbutamol
- Act on lung B2 adrenoreceptors, cause smooth muscle relaxation
Epinephrine
- Systemic adrenergic effects oppose vasodilatation and bronchoconstriction
Treatment of allergy: drugs acting on early-phase mediators
- Mast cell stabilisers
- H1 antihistamines
- Leukotriene receptor antagonists
Mast cell stabilisers
eg sodium cromoglycate
- Reduce mast cell degranulation by unknown mechanism
- Not orally absorbed - topical use only
- Short half-life requires frequent dosing
- Main benefit is steroid-free, but efficacy very poor
H1 antihistamines
- Inverse agonists at H1 histamine receptor
- Best used before exposure to allergen
1st gen H1 antihistamines
Chlorpheniramine
- considerable sedation, drug interactions
2nd gen H1 antihistamines
Cetirizine, loratidine, desloratidine, fexofenadine
- No/minimal sedation, once-daily
Leuktriene receptor antagonists
- Only UK drug is montelukast
- Effective in reducing early allergic responses, but inferior to H1 antihistamines
- Unlike anti-histamines, beneficial in chronic asthma, which is the main indication for their use
Treatment of allergic disease: corticosteroids
- Steroid receptors are found in the cytoplasm complexed with a heat-shock protein Hsp90
- Steroids cross the cell membrane and bind to the steroid receptor complex, releasing Hsp90
- The steroid:receptor complex can now cross the nuclear membrane
- In the nucleus, the steroid receptor binds to specific gene regulatory sequences and activates transcription
How do steroids reduce immune activation
- Steroids reduce immune activation by altering gene expression in numerous cell types, including T cells, B cells and cells of the innate immune system
- Their onset of action is delayed and they must be taken regularly
Examples of corticosteroids
Inhaled eg beclometasone, fluticasone
Nasal eg beclometasone, mometasone, fluticasone
Also for skin(eg hydrocortisone) and ophthalmic drops. Topical preparations may cause local and even systemic side effects
Oral, intravenous and depot preparations available
Treatment of allergic disease: omalizumab
- Omalizumab is a monoclonal antibody directed against IgE, used for atopic asthma (amongst other things)
Treatment of allergic disease; allergen-specific immunotherapy
- Allergen doses administered by subcutaneous injection or sublingually
- Provide long-term protection
- Mainly venom allergy and rhinitis
Allergen-specific immunotherapy - multiple immunological effects
- Induce regulatory T cell responses to allergens
- Reduce Th2 responses
- Induce allergen-specific IgG antibodies
- Reduction in mast cell responsiveness
- Reduce allergen-specific IgE levels
Early effect of allergen-specific immunotherapy
Desensitization of mediator release from mast cells and basophils to allergen exposure is the first change noted with the initiation of allergen immunotherapy
Intermediate effect of allergen-specific immunotherapy
As allergen dosing is increased in the course of immunotherapy, the next most notable response is a change in T cell subset distribution with the generation of allergen specific T regulatory (T reg) cells and a decrease in Th2 cells
Repeated allergen exposure stimulates IL-10 and TGF-β expression by allergen-specific, inducible, type 1, peripheral T regulatory (Tr1) cells, which act in an autocrine fashion to further activate these Tr1 cells and initiate peripheral tolerance
Late effect of allergen-specific immunotherapy
The late changes include decrease in IgE production by B cells and an increase in IgG4 and IgA serum levels. These changes are responsible for the clinical effect of ameliorating allergy symptoms.
Key overall change as a result of allergen immunotherapy
One of the key changes resulting from allergen immunotherapy is the generation of T-reg cells resulting in peripheral tolerance
The newly generated T reg cells from immunotherapy have several suppressive mechanisms including the expression of two cytokines, IL-10 and TGF-β.
Type IV, delayed-type hypersensitivity
Mediated by antigen-specific effector T cells
- Antigen-specific - implies that a specific antigen stimulus is required, which is then processed and presented to relevant T cells which are responsible for reaction
- Effector T cell - T cells that have previously met antigen and are ‘primed’ to produce a rapid, robust response
- Because it takes time to process and present antigen, these reactions do not develop for at least 24 hrs following exposure
