17. atopy, allergy and delayed type hypersensitivity Flashcards
allergen definition
substance to which IgE antibodies may be produced
early phase allergic reaction
in allergic individuals, allergen exposure lead to rapid development of symptoms (seconds-minutes)
allergens bind to IgE antibodies on mast cells and basophils
IgE ligation in allergy
IgE binds specific allergen
cross-linking of IgE by allergen beads to clustering of receptors
intracellular portion of receptor becomes phosphorylates
intracellular cascade leads to cell activation
mast cells degranulate - release histamine, tryptase and other preformed mediators
leukotrienes
delayed mediators
similar pharmacological effect to histamine
phospholipase A2 from mast cell activation starts pathway
derived from arachidonic acid
pharmacological effects of mast cell mediators and leukotrienes
skin - wheal and flare
nose - discharge, sneezing
eyes - conjunctivitis
lungs - wheeze
mast cell activation and granule release - GI tract
increased fluid secretion
increased peristalsis
expulsion on gastrointestinal tract contents (diarrhoea, vomiting)
mast cell activation and granule release - airways
decreased diameter
increased mucus secretion
congestion and blockage of airways (wheezing, coughing, phlegm)
swelling and mucus secretion in nasal passages
mast cell activation and granule release - blood vessels
increased blood flow
increased permeability
increased fluid in tissues - increased flow of lymph to lymph nodes, increased cells and protein in tissues
increased effector response in tissues
allergen sources
almost always otherwise innocuous environmental proteins
pollen, house dust mite faeces, stinging insect venom
general characteristics of allergens
proteins (minor exceptions) - only protein can produce T/B cell response
physical properties favour transition across mucus membrane (soluble, low molecular weight)
biologically active (often enzymes)
moderate homology with self-proteins
clinical allergy syndromes: anaphylaxis
generalised allergic reaction
systemic release of histamine
causes generalised vasodilation and fluid loss from circulation into tissues
foods, drugs and insect venom = most common in UK
anaphylaxis symptoms
hives, angioedema
vomiting, diarrhoea, laryngeal oedema, bronchoconstriction
vasodilatation, hypotension
anaphylaxis cardinal features
typical symptoms
multi-system and dramatic
rapidly follows exposure to allergen
tends to improve quickly thereafter
clinical allergy syndromes: oral allergy syndrome
most common type of food allergy in the UK
IgE against pollen proteins cross-reacts with homologous proteins in plant-derived food
oral itching on exposure to raw fruit, nuts and vegetables
UK - pollen mainly birch, food mainly Rosaceae fruits
clinical allergy syndromes: airway disease
rhinitis - sneezing, rhinorrhoea, blockage (type 1 allergy)
lower airway obstruction - wheeze (type 1 allergy)
allergens may be seasonal (pollens) or episodic (animal dander)
when symptoms are chronic, inflammation becomes established - cannot be explained by mast cell degranulation
immunological tightrope
self vs non self
dangerous infection vs commensal organisms
environmental allergens, food/pollen
activation for defence vs tolerance to prevent autoimmune and inflammatory diseases
origins of allergic disease
allergic/atopic math - progression of disease observed from infancy
eczema, food allergy, rhinitis, asthma
most children outgrow eczema and many food allergies
rhinitis/asthma may or may not be outgrown
allergic disease may present de novo in adults
chronic allergic inflammation: asthma
ongoing symptoms
most patients are sensitised to variety of airborne allergens
biopsy shows inflammatory infiltrate and airway changes (remodelling - thickened basement membrane, smooth muscle hyperplasia)
early allergic reaction phase does not provide good explanation by itself
late phase allergic reaction
early phase reaction is followed some hours later by a late phase reaction
biopsy of let tase shows infiltration with inflammatory cells
CD4 T cells, eosinophils, mast cells in particular
some insight into chronic allergic inflammation
T cell subsets (CD4)
Th1 - releases IFN gamma
Th2 - releases IL-4,-5,-9,-13
Th17- releases IL-17
Treg - releases IL-10, contact dependent mechanisms
Th2 hypothesis
Th2 responses to allergens consistently associated with allergic disease
biopsies of allergic inflammation are rich in T cells expressing Th2 cytokines
why might Th2 be important in allergy?
IL-4 required for B cell class switching to IgE
IL-4 and IL-13 promotes mucus hypersecretion
IL-5 required for eosinophil survival
IL-9 recruits mast cells
asthma acute responses
inflammatory mediators cause increased mucus secretion and smith muscle contraction - leads too airway obstruction
cells are recruited from the circulation
asthma chronic responses
caused by cytokines and eosinophil products
genetics
childhood allergy strongly predicted by parent with allergy
numerous genetic risk factors identified
hygiene hypothesis
low hygiene levels, high pathogen load and helminth infection = immunity skewed to Th1, Treg cells induced
high hygiene levels, low pathogen load, no helminth infection = immunity skewed to Th2, reduced production of Treg cells
detection of allergen specific IgE in vivo
skin prick testing
allergen extract applied as drops
top layers of epidermis punctured with lan net
wheal and flare response within 15 mins = positive
result needs interpretation in clinical context
detection of allergen specific IgE in vitro
usually ELISA
purified allergen, stuck, incubated with sera
IgE antibodies in sera binds to allergen
immobilised IgE antibodies detected with detection antibody
allergy treatment
symptom relievers drugs acting on early phase mediators corticosteroids monoclonal antibodies immunotherapy
allergy symptom relievers
nasal decongestants - eg. oxymetazoline - alpha 1 adrenoreceptors - cause vasoconstriction - short term b2 agonists - eg salbutamol - act on lung adrenoreceptors - cause smooth muscle relaxation adrenaline - systemic adrenergic effects - oppose vasodilation and bronchconstriction
drugs acting on early phase mediators
mast cell stabilisers
H1 antihistamines
leukotriene receptor antagonists
mast cell stabilisers
eg sodium cromoglycate reduce mast cell degranulation (unknown mechanism) topical only short half life main benefit = steroid free
H1 antihistamines
inverse agonists at H1 histamine receptor
best used before exposure to allergen
1st generation: clorpheniramine (sedation, drug interactions)
2nd generation: cerizine, loratadine (minimal/no sedation)
leukotriene receptor antagonists
only UK drug = montelukast
effective in reducing early allergic responses
inferior to H1 antihistamines
beneficial in chronic asthma
corticosteroids
reduce immune activation
alter gene expression in T cells, B cells, and cells of the innate immune system
onset of action is delayed
omalizumab
monoclonal antibody
directed against IgE
used for atopic asthma
allergen specific immunotherapy
allergen doses administered by subcutaneous injection long term protection mainly venom allergy and rhinitis
immunotherapy immunological effects
induce Treg cell responses to allergens reduce Th2 responses induce allergen-specific IgG antibodies reduction in mast cell responsiveness reduce allergen-specific IgE levels
delayed type hypersensitivity
mediated by antigen specific effector T cells
antigen specific definition
implies that a specific antigen stimulus is required, chichis them processed and presented to relevant T cells responsible for reaction
effector T cell definition
T cells that have previously met antigen, and are ‘primed’ to produce a rapid and robust response
contact dermatitis - sensitisation
molecules react with self proteins to create protein-hapten complexes
complexes are picked up by Langerhans cells which migrate to lymph nodes
Langerhans cells process and present antigen on MHC class II
in some individuals, complexes are recognised as foreign
activated T cells migrate to the dermis
hapten
small molecule that cannot individually invoke an immune response, but can bind to protein to alter its immunogenicity
contact dermatitis - elicitation
chemokines recruit macrophages
Th1 cells secrete IFN gamma (increases expression of vascular adhesion molecules, activates macrophages)
TNF alpha/beta stimulates local inflammation
poison ivy
poison ivy lipid can cross skin and modify intracellular proteins
proteins are processed and presented on MHC class I to T cells
causes contact dermatitis
not everyone is susceptible
patch testing for contact dermatitis
antigen impregnated patch placed on back
nickel, chrome, epoxy resin etc
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