THE EARLY PHASE REACTION
i) what leads to rapid development of symptoms in allergic individuals?
ii) how quickly does this reaction develop after exposure? what does it result from? (which two cells are involved)
iii) define allergen
iv) name two cells that produce allergen specific IgE antibodies
v) label diagram
i) exposure to allergens leads to symptoms
ii) occurs within seconds or minutes after exposure
- results from binding of allergens to pre formed IgE antibodies on the surface of mast cells and basophils
iii) allergen = substance to which IgE antibodies may be produced
iv) B cells and plasma cells
v) A - allergen specific IgE antibodies
B - FceR1 high affinity IgE receptor
EVENTS THAT FOLLOW MAST CELL IGE LIGATION
i) what does IgE bind? what does this cause the IgE antibodies to do?
ii) what activates the mast cell? what happens to the intracellular portion of the receptor?
iii) name two things released from the mast cell when it degranulates
i) IgE binds its specific allergen
- this causes cross linking of IgE antibodies > clustering of FceR1 receptors
ii) cross linking of antibodies and clustering of Rs activates mast cell > intracell portion of R is phosphorylated
iii) mast cell releases histamine and tryptase
DELAYED MEDIATORS - LEUKOTRIENES
i) what enzyme does inflammation from mast cell activation activate? what molecule does this lead to production of?
ii) which enzyme pathway produces leucotrienes?
iii) what molecule do LT have similar pharma effects to? give an example? what condition is this important in
i) inflamm activates phospholipase A2 > arachadonic acid
ii) 5 lipoxygenase pathway > LTs
iii) LTs have a similar pharm effect to histamine eg smooth muscle contraction in asthma
PHARMA EFFECTS OF MAST CELL MEDIATORS AND LTS
i) what effect do they have on the GI tract/airway/blood vessels? what does each lead to?
ii) what type of clinical test can be used to monitor this?
iii) what type of reaction is produced in the skin?
iv) what is seen in the nose and eyes?
v) what is seen in the lungs? how does peak flow change on antigen challenge? does this resolve quick or slow
i) GI tract - increase fluid secretion and peristalsis
- causes expulsion of GI contents eg N+V
airway - bronchoconstriction/inc mucus secretion
- wheeze/cough/swelling and mucus secretion in nose
blood vessel - vasodilation and increased permeability
- increased fluid in tissues (swelling), inc lymph in LNs, increased cell and proteins in tissues
ii) use skin prick test
iii) see wheel and flare reaction in the skin
iv) nose = rhinitis (sneeze/discharge), eyes = conjunctivitis
v) see wheeze in the lungs
- rapid decrease in peak flow around 30 mins post antigen challenge which quickly resolves
SOURCES OF ALLERGEN
i) what type of allergens is IgE allergen generally mediated by?
ii) name three allergens that may be involved
i) innocuous enviro proteins
ii) pollen, house dust mite faeces, stinging insect venom
GENERAL CHARACTERISTICS OF ALLERGENS
i) what type of molecule are they almost always? what is the reason for this
ii) what physical property is favoured in these allergens? why? what is their usual solubility and mw?
iii) how homologous are they with self protein? why is this important?
i) almost always proteins - important as only protein can produce a T and therefore B cell response
ii) proteins that cross mucous membranes because they need to do this to activate immunity
- high solubility and low mw
iii) moderate homology to self protein
- low homology = wouldnt bind MHC
- high homology - would be deleted during neg selection
i) what type of reaction is it?
ii) what does systemic release of histamine cause? (2)
iii) name four classic symptoms assoc with skin, gut, mucosa, circulation
iv) what are the three most common triggers in the UK?
v) how quickly does it occur post exposure? does it improve quick or slowly?
i) generalised allergic reaction
ii) generalised vasodilation and fluid loss from circ > tiss (swelling)
iii) skin - hives and angioedema
gut - vom and diarrhoea
mucosa - histamine release > laryngeal oedema and bconstric
circulation - vasodilat, hypoten and circ collapse
iv) most common triggers are food, drugs and insect venom
v) occ rapidly post exposure and improves quickly
ORAL ALLERGY SYNDROME
i) what is it the most common type of in the UK?
ii) what is IgE directed against? what do these cross react with?
iii) what happens on exposure to raw fruit, nuts and vegetables
iv) what pollen mediates it most commonly in the uk? which fruits?
i) most common type of food allergy in adults
ii) IgE directed against pollen proteins
- cross reac with homologous proteins in plant derived foods eg fruits
iii) exposure > oral itching
iv) pollen = birch
fruit = rosaecea fruit eg apple
IGE MEDIATED AIRWAY DISEASE
i) give three symptoms of rhinitis
ii) give a symptom of lower airway obstruction
iii) name two seasonal allergens that may cause this? name two episodic causes?
iv) what type of symptoms cant be explained in terms of mast cell degranulation?
i) sneezing, rhinorhoea (runny nose), blockage
iii) seasonal - pollen/moulds
episodic - episodic/animal dander
iv) when symptoms are chronic the inflam becomes established and cant be explained simply by mast cell degran
CHRONIC ALLERGIC INFLAMMATION - ASTHMA
i) what duration of symptoms do these patients have?
ii) what are most patients sensitised to?
iii) what does biopsy of airways show? (2) what is this known as? what is seen in relation to the basement membrane and smooth muscle?
iv) what is found in the middle of the airway? what happens to goblet cells?
i) on going symptoms
ii) sensitised to a variety of airbourne allergens
iii) biopsy shows inflammatory infiltrate and airway changes
- known as remodelling
- see thickened basement membrane and smooth muscle hyperplasia
iv) mucus plug with trapped inflam cells in the middle
- goblet cells undergo metaplasia
LATE PHASE ALLERGIC REACTION
i) what time frame does it occur after the early phase reac?
ii) what does biopsy of this phase principally show? name three specific cells seen
iii) how is this measured? what happens to PEFR and how is this different to the early phase response?
iv) what main class of T cells are seen?
i) occurs hours after
ii) biopsy shows infiltration with allergy cells
- CD4 T cells, eosinophils and mast cells
iii) measured by giving an asthmatic patient an allergen and checking their peak flow
- late phase see a more gradual decrease in PEFR
iv) T helper 2 cells
T CELL SUBSETS AND TH2 HYPOTHESIS
i) name four interleukins that Th2 cells produce
ii) what have Th2 responses consistently been associated with? how has this been shown in vivo and in vitro?
iii) what is IL-4 required for? what do IL-4/13 promote? what is IL-5 req for? what does IL-9 recruit?
ii) Th2 responses consistently associated with allergic disease
- in vivo - biopsy from allergic inflam are rich in Th2
- in vitro - T cells from allergic patients stimi;ated with allergen in the lab to produce Th2 cytokines
iii) IL-4 req for B cell class switch to IgE
IL-4/13 promote mucus hypersecretion
IL-5 req for eosinophil survival
IL-9 recruits mast cells
CHRONIC ALLERGIC DISEASE - ASTHMA
i) what do inflammatory mediators cause in relation to mucus and smooth muscle? what does this lead to?
ii) name a cell that will be recruited from the circulation
iii) what leads to chronic disease?
iv) what effect do IL-4,13,5,9 have?
v) what does this model suggest?
i) inflam mediators cause increased mucus secretion and smooth muscle contract > airway obstruc
ii) recruit Th2 cells from the circ
iii) chronic disease caused by products released from Th2 cells
iv) IL4 - mucus hypersecretion
iL-13 - bronchial hyper-responsiveness
IL-5 - eosino recruit
IL-9 - mast cell recruit
v) model suggests a true role for T cells in chronic inflam rather than just causing IgE production
GENETICS AND ALLERGY
i) what is childhood allergy strongly predicted by?
ii) what is the main contributor in allergy?
iii) is allergy more common is HIC or LIC?
i) strongly predicted by presence of allergy in parents
iii) more in HIC
i) what do low hygiene levels, high pathogen load and helminth infection skew immunity to and from? what cells may be induced?
ii) what do high hygiene levels, low pathogen load, absence of helminth infection skew immunity towards? what cells may be reduced?
i) low hygiene etc skews immunity from Th2 to Th1
- may induce regulatory T cells
ii) high hygiene levels etc skews immunity towards Th2
- reduced production of regulatory T cells
DETECTION OF ALLERGEN SPECIFIC IGE IN VIVO
i) what test can be used?
ii) what response is seen if there is a reaction? how long does this take?
iii) what is used as a positive and negative control?
iv) is this diagnostic? why?
i) skin prick test
ii) see a wheal and flare response after 15 mins if positive
iii) positive = histamine
negative = dilutent
iv) not diagnostic as lots of false positives - needs interpretation in clinical context
DETECTION OF ALLERGEN SPECIFIC IGE IN VITRO
i) what test used to be used? what is used now?
ii) explain the three steps - what happens if the patient is senitised to the allergen?
iii) what allows detection of a positive test?
i) used to use RAST now use ELISA
ii) well coated with purified allergen of interest
- incubate with patient seru,
- if patient is sensitised then IgE antibodies in the serum will bind the allergen
- immobilised IgE antibod detected with polycolonal anti IgE detection antibody
iii) use of a detection antibody labelled with fluorescence
TREATMENT OF ALLERGY - SYMPTOM RELIVERS
i) what do these act on?
ii) which receptors do nasal decongestants act on? what does this cause? how long should they be used for? give two methods of admin
iii) what receptor does salbutamol act on? what class of drug is it? what does it cause?
iv) what is adrenaline used to treat? what type of effects does it have? name two things it opposes? how is it usually admin?
i) acts on other pathways that oppose the actions of the mediators of the the allergy, not the mediators themselves
ii) nasal decongestants act on a1 adrenoreceptors
- to cause vasoconstriction
- only for short term use > topical and systemic admin
iii) salbutamol is an agonist at lung b2 adrenoreceptors
- causes smooth muscle relaxation
iv) adrenaline is used to treat anaphylaxis
- has systemic adrenergic effects
- opposes vasodilation and bronchoconstriction
- give by IM injection
TREATMENT OF ALLERGY - EARLY PHASE MEDIATORS
i) name a drug that works on histamine
ii) name a drug that works on leucotrienes
iii) what type of drug acts on mast cells? name a drug
iv) what do drugs that work on mast cells do? how must they be administered? how often do they need to be given? why?
v) what is the main benefit and disadvantage of these drugs
i) H1 antihistamines
ii) leucotriene receptor antagonists
iii) mast cell stabilisers work on mast cells
- sodium cromoglycate
iv) mast cell stabilisers reduce mast cell degranulation by an unknown mechanism
- need be be given frequently as they have a short half life
v) main benefit is that they are steroid free but efficacy is very poor
i) what effect do they have at the H1 histamine receptor?
ii) when are they best used?
iii) name a first generation H1 antihist? name two disadvantages
iv) name a second generation anti hist? name two advantages
i) inverse agonists at the H1 histamine receptor
ii) best used before exposure to allergen
iii) 2st gen = chlorpheniramine
- sedation and drug interactions
iv) second gen = loratidine
- no/minimal sedation and given once daily
LEUCOTRIENE RECEPTOR ANTAGONISTS
i) what is the only licensed drug in this class in the UK?
ii) what are they effective in reducing? are they better or worse at this than H1 anti histamines?
iii) which condition are they most beneficial in? which drugs are not so beneficial here?
ii) effective in reducing early allergic response but inferior to H1 anti histamines
iii) most beneficial in chronic asthma
TREATING ALLERGIC DISEASE WITH CORTICOSTEROIDS
i) what are steroid receptors complexed to in the cytoplasm before the binding of a steroid?
ii) what happens when the steroid binds its receptor? (3)
iii) what effect do steroids have on immune activation? how do they do this?
iv) how quickly is their onset of action? how often must they be taken?
i) complexed to heat shock protein hsp90
ii) binds steroid > Hsp90 is released > steroid receptor complex crosses nuclear membrane to regulate gene expression
iii) steroids reduce immune activation by altering gene expression in different cell types eg T cells and B cells
iv) delayed onset of action and must be taken regularly
i) what can be used as a preventative inhaler?
ii) what can be used in a nasal spray?
iii) what can be used on the skin?
iv) name a side effect of opthalmic eye drops
v) are oral preparations commonly used? when may an IV prep be used?
i) brown inhaler - beclamethosome
ii) beclamathasome can be given in nasal spray
iii) hydrocortisone can be used on the skin
iv) SE of opthalmic eye drops is glaucoma therefore needs monitoring
v) oral preps are toxic so not often used and IV preps are used in emergency
i) what is it? what is it directed against?
ii) what is it mainly used for?
iii) what does it bind? and what does this lead to?
iv) what happens to IgE receptors over time? what does this ultimately cause?
v) how quickly does it work? what type of allergy is it not useful in?
i) monoclonal antibody directed against IgE (binds the non antigen binding part of IgE)
ii) mainly used for severe/atopic asthma
iii) binds to free IgE to form complexes which leads to less cell bound IgE in the circulation
iv) over time there is decreased expression of high affinity IgE receptors which means IgE cant bind > less mediator release and allergic inflammation
v) takes a while to work and not useful in food allergy
ALLERGEN SPECIFIC IMMUNOTHERAPY
i) what is given to the patient? how is it given?
ii) what type of protection can it provide? which two allergies is it mainly used in?
iii) how does it affect regulatory T cells? Th2 responses? allergen specific IgG antibodies? mast cell responses? allergen specific IgE levels?
i) give patient large dose of allergen - subcut or sublingual
ii) can provide long term protection
- used in venom allergy and rhinitis
iii) induce Treg response to allergens
- reduces Th2 responses
- induces allergen specific IgG antibodies
- reduction in mast cell responsiveness
- reduce allergen specific IgE levels
CONTACT DERMATITIS (TYPE IV) VS TYPE I ALLERGY
i) what are the clinical features of each?
ii) how quickly are there symptoms after exposure in each?
iii) what is the causative agent in each?
iv) what is the effector mechanism in each?
v) which clinic should assess each one?
vi) what type of management for each
i) type I - mast cell degranulation
type IV - eczematous skin reaction
ii) type I - quickly post exposure then resolves quick
type IV - delayed - due to T cell activation
iii) type I - naturally occuring molecules
IV - synthetic molecules
iv) I - allergen specific IgE, mast cell degran
IV - antigen specific effector Th1 cells
v) I - allergy clinic
IV - dermatology clinic - patch test
vi) I - avoidance, pharma, immuno therapy
IV - avoidance only
SKIN PRICK VS PATCH TESTING
i) what is each used for?
ii) what is the indication for each?
iii) what is the test format for each?
iv) what is seen in a positive test for each?
i) skin prick for IgE and patch for contact dermatitis
ii) skin prick if history is suggestive of IgE mediated allergy
patch - history suggest contact dermatitis
iii) skin prick - allergen drops applied to skin, puncuture, read after 15 mins
patch - tst antigen applied under dressing and read after 48 hrs
iv) pos test skin prick - wheal and flare
patch test - eczematous rash