Allergy and Hypersensitivity

Question 1

Type I hypersensitivity

Answer 1

Immediate reaction to environmental AGs mediated via IgE.

Question 2

Atopy

Answer 2

Inherited trait for type I hypersensitivity.

Question 3

Allergens

Answer 3

AGs that trigger allergic reactions.

Question 4

Sensitisisation

Answer 4

APC to Th2 (IL-4, IL-13) -> B-cells secrete IgE.

Question 5

How does the B-cell go from IgM to IgE?

Answer 5

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

Question 6

Mast cell degranulation

Answer 6

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.

Question 7

What type of IgE receptors are there?

Answer 7

Mast cell (tetramer) alpha, beta, two gamma.

Basophil (trimer) alpha, two gamma.

Eosinophil CD23.

Question 8

What are the early phase mediators?
(ALL PRE-FORMED)

Answer 8

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

Question 9

Granule release from mast cells contains…(additional) (ALL PRE-FORMED)

Answer 9

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.

Question 10

Mast cell mediators can be

Answer 10

Pre-formed (granule release) or newly synthesised (lipoxygenase pathway).

Question 11

What is the product of the lipoxygenase pathways?

Answer 11

Leukotrienes C4, D4, B4: vasoactive, bronchoconstriction, chemotaxis.

Question 12

What is the product of the cyclo-oxygenase pathway?

Answer 12

PGs and thromboxanes: affect bronchial muscle, platelet aggregation and vasodilation.

Question 13

Clinical manifestations of allergy…

Answer 13

Due to histamine, tryptase, chymotrypsin, leukotrienes, PGs, ILs.

Question 14

What are the symptoms of an allergic reaction?

Answer 14

Trouble breathing

Itching

Sneezing

Runny nose

Headache

Red/watery eyes

Hives/rash

Question 15

The early phase response is driven by…

Answer 15

The pre-formed granules

Question 16

The late phase response (8-12 hours later)

Answer 16

Cytokines released in the immediate stage activate basophils, eosinophils, and neutrophils even though the antigen is no longer present.

Question 17

What are the conditions that elicit a type I hypersensitivity reaction?

Answer 17

Allergen characteristics

Host factors

Environmental influences

Question 18

What makes certain proteins allergenic?

Answer 18

Allergens can introduce a strong IgE

Protease activity: Der p1
Surface feature of protein: Ves v 5
Glycosylation pattern of protein: ARa h1

Question 19

What does protease activity Der p1 involve?

Answer 19

Th2 bias

Reduced IL-12

Reduced allergen blockade

Disruption of endothelial membrane

Disruption of negative feedback on IgE synthesis

IgE-independent degranulation

Question 20

The structure of the protein

Answer 20

Hydrophobic areas Ves V5 (bee stings)

Specific glycosylation patterns: ara h1 (peanuts)

Question 21

Host factors and gene targets

Answer 21

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.

Question 22

Environmental influences

Answer 22

Education of the immune system - APC

Hygiene hypothesis (Naive to Th2)

Immune regulation theory (Naive to Th1)

Question 23

Hygiene hypothesis

Answer 23

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.

Question 24

What are pseudo-type I reactions?

Answer 24

Drugs

Psychological stress

Nutritional status

Auto-immune disease

Concurrent infection

Physical stress

Question 25

What are the clinical manifestations?

Answer 25

Allergic rhinitis
Allergic conjunctivitis
Atopic dermatitis
Urticaria/angioedema
Asthma
Food allergy
Drug allergy
Venom allergy
Anaphylaxis

Question 26

What are the treatment options for anaphylaxis?

Answer 26

Adrenaline/epinephrine

Antihistamines

Corticosteroids

Fluid resuscitation

Bronchodilation

Others: allergen avoidance, topical corticosteroids, antihistamines.

Question 27

What other treatment option is licensed in asthma and urticaria?

Answer 27

Anti-IgE (Omalizumab) in asthma and urticaria.

Leukotriene antagonists in asthma.

Question 28

Desensitisation or allergen-specific immunotherapy

Answer 28

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.

Question 29

Why is asthma different?

Answer 29

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.

Question 30

Monoclonal Antibodies in asthma treatment.

Answer 30

Itepekimab - IL-33
Tezepelumab - TSLP
Astegolimab - IL-33R

Benralizumab - IL-5Ra
Mepolizumab
Reslizumab - IL-5
Dupilumab - IL-13
Omalizumab - IgE