Allergy Flashcards
Allergy?
‘disease following a response by the immune system to an otherwise innocuous antigen’
Where do allergies reside?
Allergies reside within hypersensitivities, defined as ‘harmful immune responses that produce tissue damage.’
What are the 4 types of hypersensitivity reaction?
Type 1 = IgE
Type 2 = IgG
Type 3= IgG
Type 4= driven by T cells (no evidence of antibodies involved)
What are allergies mediated by?
When does it take place?
IgE
- always occurs on exposure to an allergen, so an initial exposure event has always taken place.
Where are allergies common?
In the west,,
Often between 25% - 50% of the population have an allergy
-
When do allergies occur?
When IgE triggers mast cell degranulation
(Preformed granules can be released upon triggering)
What is IgE produced by?
Plasma B cells in lymph nodes or locally at site of inflammation.
Where is IgE located?
What is it bound to?
- Mostly in tissues (hence low serum concentration)
- bound to mast cell surfaces through high affinity IgE receptor Fc3R1
What will favour production of IgE?
What do the Th2 cells also do?
- certain antigens and routes of delivery (eg- transmucosal at low doses is often a common route)
- CD4+ T cells of the Th2 phenotype that produces IL4 cytokines favour IgE responses.
- Th2 T cells also force B cells to switch the isotope of the Ig they secrete from IgM to IgE
What 3 molecules will effector T cells produce?
CD8 cytotoxic = IFNy, TNFa (target cell lysis)
CD4 Th1= IFNy, GM-CSF, TNFa (macrophage activation)
CD4 Th2= IL4, IL5 (B cell activation)
What are common inhaled allergens?
-plant pollens
- dander of domesticated animals
- mol spores
- feces of very small animals (house dust mice)
Common allergens of injected materials?
- insect venoms
- vaccines
- drugs
- therapeutic proteins
Common allergens of ingested material?
Common allergens of contacted materials?
Ingested = food, orally administered drugs
Contacted materials=
- plant leaves
- products made from plants
- metals
What are the 6 features of some inhaled allergens?
Protein = only proteins induce T cell responses
Enzymatically active= allergens are often proteases
Low dose = favours IL4 producing CD4 T cells
Small size = allergens can diffuse out of particle
Highly soluble = elites readily from particle
Stable = allergen can survive desiccation.
why is IgE a major part of the host defence?
- IgE is thought to be crucial in host defence against parasites, many of which gain access by secreting proteolytic enzymes.
Give an example of how a major allergen gains greater access in the host.
How does the host’s immune system respond to this?
The major allergen in faeces of house dust mites is Der p 1, which can cleave tight junctions between epithelial cells in the airway, thus enhancing access
Der p 1 can be taken up by dendritic cells of the host’s immune system and presented to CD4+ T cells of the Th2 phenotype, which force B cells to secrete IgE.
on exposure to pollen what will happen in an allergy?
- first exposure to pollen
- extraction of antigen
- activation of antigen-specific T cells
- production of IgE and binding to mast cells.
why is the route of the allergen delivery crucial?
where do inhaled antigens effect?
what may also accompany it?
what causes allergic asthma?
- the location and distribution of the antigen is the most important factor in what symptoms occur
- inhaled antigens will affect nasal epithelium, causing allergic rhinitis (hay fever)
- may be accompanied by oedema and nasal discharge often containing eosinophils
- allergic asthma can be caused by induced degranulation further down the airway
what is allergic asthma?
what does it cause?
what does the inflammation insue with?
what does it driven by?
resulting in what?
- allergic asthma is bronchial constriction
- it causes increased secretion of fluid and mucus, trapping inhaled air.
- chronic inflammation may ensue with continued presence of Th2 T cells, eosinophils, neutrophils
what is chronic asthma driven by?
chronic asthma is driven by specific allergens, but then may result in hyperactive airways to other irritants such as cigarette smoke and other pollutants.
what is the asthmatic response in airways:
What is FEV?
How does this affect FEV (forced expiratory volume)?
Forced expiratory volume (FEV) refers to the volume of air that an individual can exhale during a forced breath in t seconds
This acute response leads to a large decrease in FEV
allergens entering at skin sites will cause what?
what is the first wheal and flare response?
what happens around 8 hours after this response?
- they will cause rashes
- wheal and flare, first appearing within a few minutes as a result of vasodilation after mast cell degranulation, localised redness.
- around 8 hours later more diffuse oedema at site due to influx of lymphocytes and other leukocytes, attracted by chemokine
what are the 3 potential symptoms of ingested allergens?
1) Activation (degranulation) of GI Mast cells results in transepithelial fluid loss and smooth muscle contraction, leading to diarrhoea and vomiting
2) If allergen enters bloodstream, a generalised disseminated rash is caused, (Urticaria aka hives).
3) In severe cases of food allergy, eg nuts and shellfish, life threatening generalised anaphylaxis and cardiovascular collapse may occur
What 4 groups of inflammatory mediators do mast cell granules contain?
1) Lipids
2) Toxic mediators
3) Cytokines
4) Enzymes
What 3 lipids do mast cell granules contain?
What is their mechanism of action?
1) Prostaglandins
* Increases vascular permeability, which increases body temperature
2) Platelet activating factor
* Increases adhesion between endothelium and neutrophils
3) Leukotrienes
* attract and activate neutrophils, which increases vascular permeability
What 2 toxic mediators do mast cell granules contain?
What is their mechanism of action?
1) Histamine
* Increases vascular permeability, and promotes movement of fluid from the vasculature by constricting vascular smooth muscle
2) Heparin
* Inhibits coagulation
What 4 cytokines do mast cell granules contain?
What is their mechanism of action?
1) IL-4, IL-13
* Amplifies Th2 response
2) IL-3, IL-5, GM-CSF
* Promotes eosinophil activation and production
3) TNF-α
* Pro-inflammatory
* Activates endothelium chemokines (involved in chemotaxis)
4) MIP-1α
* Attracts macrophages and neutrophils
What 4 enzymes do mast cell granules contain?
What is their mechanism of action?
1) Tryptase
2) Chymase
3) Cathepsin G
4) Carbopeptidase
These enzymes remodel connective tissue matrix
What are 2 main types of treatment for allergy?
- desensitisation
- blockade of effector pathways
What 5 things future therapies might include?
1) Recombinant allergens
2) Hypoallergenic derivatives
3) T cell peptides
4) B cell peptides
5) DNA vaccines
what is the aim of desensitisation treatment?
how is it done?
what are potential risks?
- the aim is to shift the response from IgE dominated to IgG dominated
- patients injected with escalating doses of allergen, gradual shift from Th2 to Th1 T cells.
- potential risk of anaphylaxis.
How does blockade treatment occur?
What is another mechanism that can be used?
Blocking treatment occurs by using anti-histamines to cause H1 receptor blocking
Topical or systemic corticosteroids can also be used to supress chronic inflammation in asthma and rhinitis
how should severe anaphylaxis be treated?
what is the dose?
- potentially life threatening reactions should be treated with epinephrine injection
- 0.15mg adrenaline dose is used for children
0.3mg adrenaline dose is used for adults.
Why are injections not done in small areas?
If the epinephrine is injected by mistake into small areas such as fingers and hands, blood vessels will constrict at the site of injection.
This can decrease blood flow to the area.
Less blood flow means that less oxygen is getting to the tissue. This could cause a serious injury in rare circumstances
What are 4 reasons why allergies are more common in developed countries?
1) Less exposure to pathogens/allergens
* Early childhood exposure to Th1 inducing pathogen (bacterial or viral) may prevent bias towards Th2 responses later.
2) Lower levels of pathogens/allergens
3) Dietary differences
4) Pollution levels
where is allergies and asthma less common?
- allergies and asthma is less common in areas with high helminth burdens.
- IgE is a key defence in Helminth expulsion.
- data suggests that helminth infection induces a new set of T cells, regulatory T cells that actively suppress Th2 cells.
what are the 5 genetic influences on allergy?
IL-4 : promoter variants affect levels of IL-4 secretion
IL-4 receptor: variants have different signalling responses
B2- adrenergic receptors: variants increase bronchial hyperactivity
5- lipoxygenase: variation in leukotriene levels.
epigenetic influences: modifying gene behaviour by methylation, either in utero or in childhood, may effect subsequent responses.
