Allergy and Hypersensitivity Flashcards
Type I hypersensitivity
Immediate reaction to environmental AGs mediated via IgE.
Atopy
Inherited trait for type I hypersensitivity.
Allergens
AGs that trigger allergic reactions.
Sensitisisation
APC to Th2 (IL-4, IL-13) -> B-cells secrete IgE.
How does the B-cell go from IgM to IgE?
Naive B-cell
Rearranged DNA in IgM
Recombination of S(u) with S(epsilon); deleting intervening C genes.
Transcription; RNA splicing (epsilon)mRNA
Translation (epsilon)protein
Mast cell degranulation
AG binds to receptor on mast cell causes internal signalling cascade which results in degranulation.
PTK -> PLC (PIP2 to DAG and IP3)
DAG -> PKC
IP3 -> ER -> Ca2+ vesicles move.
PTK -> MAPK = activation of transcription factors.
What type of IgE receptors are there?
Mast cell (tetramer) alpha, beta, two gamma.
Basophil (trimer) alpha, two gamma.
Eosinophil CD23.
What are the early phase mediators?
(ALL PRE-FORMED)
Histamine: vasodilation, increased capillary permeability, chemokinesis, bronchoconstriction.
Tryptase + Chymotrypsin + Carboxypeptidase A: increased vascular permeability, airway hyperresponsiveness, cell recruitment.
Leukotrienes
Prostaglandins
Interleukins
PAF: mediator release
TNF-alpha
Granule release from mast cells contains…(additional) (ALL PRE-FORMED)
Proteoglycan: binds granule proteases
Neutral proteases: activates C3
Beta-glucosaminidase: splits glucosamine
Eosinophil and neutrophil chemotactic factor: respective chemotaxis.
IL-3,4,5,6, GM-CSF, TNF: macrophage activation, trigger acute phase proteins.
Mast cell mediators can be
Pre-formed (granule release) or newly synthesised (lipoxygenase pathway).
What is the product of the lipoxygenase pathways?
Leukotrienes C4, D4, B4: vasoactive, bronchoconstriction, chemotaxis.
What is the product of the cyclo-oxygenase pathway?
PGs and thromboxanes: affect bronchial muscle, platelet aggregation and vasodilation.
Clinical manifestations of allergy…
Due to histamine, tryptase, chymotrypsin, leukotrienes, PGs, ILs.
What are the symptoms of an allergic reaction?
Trouble breathing
Itching
Sneezing
Runny nose
Headache
Red/watery eyes
Hives/rash
The early phase response is driven by…
The pre-formed granules
The late phase response (8-12 hours later)
Cytokines released in the immediate stage activate basophils, eosinophils, and neutrophils even though the antigen is no longer present.
What are the conditions that elicit a type I hypersensitivity reaction?
Allergen characteristics
Host factors
Environmental influences
What makes certain proteins allergenic?
Allergens can introduce a strong IgE
Protease activity: Der p1
Surface feature of protein: Ves v 5
Glycosylation pattern of protein: ARa h1
What does protease activity Der p1 involve?
Th2 bias
Reduced IL-12
Reduced allergen blockade
Disruption of endothelial membrane
Disruption of negative feedback on IgE synthesis
IgE-independent degranulation
The structure of the protein
Hydrophobic areas Ves V5 (bee stings)
Specific glycosylation patterns: ara h1 (peanuts)
Host factors and gene targets
MHC II on APC
TCR on naive T cell
GATA-3 which aids the differentiation of Th2.
Cytokines (IL-4) produced by Th2.
IL-4 Receptors on B cells
FC(epsilon)-RI on Mast cells
TNF-alpha in mast cells.
Environmental influences
Education of the immune system - APC
Hygiene hypothesis (Naive to Th2)
Immune regulation theory (Naive to Th1)
Hygiene hypothesis
Diet - microbes/microbiota: diversity and composition.
Two possibilities: archaic how rural farming causes environmental exposure (in utero). leading to tolerance and healthy individuals.
Westernised: pollution and environmental exposure leads to inflammation and asthma allergy.
What are pseudo-type I reactions?
Drugs
Psychological stress
Nutritional status
Auto-immune disease
Concurrent infection
Physical stress
What are the clinical manifestations?
Allergic rhinitis
Allergic conjunctivitis
Atopic dermatitis
Urticaria/angioedema
Asthma
Food allergy
Drug allergy
Venom allergy
Anaphylaxis
What are the treatment options for anaphylaxis?
Adrenaline/epinephrine
Antihistamines
Corticosteroids
Fluid resuscitation
Bronchodilation
Others: allergen avoidance, topical corticosteroids, antihistamines.
What other treatment option is licensed in asthma and urticaria?
Anti-IgE (Omalizumab) in asthma and urticaria.
Leukotriene antagonists in asthma.
Desensitisation or allergen-specific immunotherapy
Immune system is exposed to gradually increasing doses of allergen in order to develop tolerance.
Subcut or sublingual route.
Used in: allergic rhinitis, venom allergy and drug allergies predominantly.
Why is asthma different?
Type I hypersensitivity but also has type IV (cell mediated) and type V (tissue driven) mechanisms.
Large proportion of asthmatics have Th2-hi inflammation. Numerous ABs are available.
Monoclonal Antibodies in asthma treatment.
Itepekimab - IL-33
Tezepelumab - TSLP
Astegolimab - IL-33R
Benralizumab - IL-5Ra
Mepolizumab
Reslizumab - IL-5
Dupilumab - IL-13
Omalizumab - IgE
