3. Type 2 Responses in Allergic Disease Flashcards
What is an Allergen?
an antigen that causes allergy
What is “Atopy”?
Circulating IgE that is specific to allergens
What is “Allergy”?
Harmful Type 2 response to harmless allergens, characterised by “Atopy”.
-Skin prick test for atopy against specific allergens “Wheal and Flare”
Allergic Diseases:
[Give 5 examples]
- Atopic dermatitis (eczema)
- Allergic rhinitis (hayfever)
- Wasp/bee sting allergy
- Food allergy
- Asthma
Anaphylaxis: [Severity] [Symptoms] [What causes it?] [Severity due to?]
Most severe allergic response, can kill
Characterised by:
- Rash
- Nausea
- Vomiting
- Diarrhoea
- Breathing difficulty
- Sense of impending doom
- Swelling of throat/mouth
- Weak pulse
- Loss of
Occurs due to cross-linking of IgE on mast cells leading to overwhelming systemic histamine release
Death occurs due to swelling blocking airways and vasodilation leading to falling blood pressure
Asthma:
[What happens at a biological level to cause its symptoms]
Increased smooth muscle, thickened airway walls, less flexible
Mucous hyper-secretion helps block airways
Hyper-responsive to stimuli = change in nerves = more muscle = more able to contract, primed immune cells (e.g. mast cells)
Allergic effectors cells:
[Give 2 + details about what they do]
Eosinophils:
- Release toxic granule contents (ROS, ECP, etc.)
- Produce pro-fibrotic cytokines IL-13 and TGF-β
Mast Cells:
- Express high affinity IgE (FCεR1)
- IgE-FcεR1 cross-linking leads to degranulation (anaphylaxis)
- Granules contain inflammatory mediators, especially histamine, and also lipid mediators (prostaglandins) and TH2 cytokines
Allergic effector cytokines:
[Give 4 + details about their role]
IL-4: Important for class-switching to IgE by B cells
IL-5: Eosinophil expansions and recruitment
IL-9: Mast cell response
IL-13: Remodelling of the lung, mucous hyper-secretion
Allergy Inducing Cells:
[Give 3 + details about their role]
B Cell:
- Produce allergen specific IgE
- Binds mast cells - cross-linking of IgE receptor (FcεR1) leads to histamine release
CD4+ TH2 Cell:
- Produces IL-4, IL-5, IL-13
- Allergen-specific response
Type 2 Innate Lymphoid Cell:
- Produces IL-5, IL-13
- Fast acting in response to epithelial cytokines IL-25 and IL-33
Innate Lymphoid Cells:
[Antigen specificity?]
[Derived from?}
[Comparison with T helper cells]
Innate cells (No antigen receptor)
Derived from common lymphoid precursor cell in bone marrow
ILC1s, ILC2s, and ILC3s reflect TH1, TH2, and TH17/22 cells respectively (Same transcription factors and similar cytokines produced). Difference is that the T cells are antigen specific while ILCs are not.
ILC2: [Implicated in?] [Responds to?] [Produces?] [Location?] [Rarity?] [Pathway?]
Implicated in allergic disease and anti-parasite responses
Responds to stromal cell cytokines (mostly from the epithelium)
Produces large amounts of IL-5 and IL-13 very rapidly
Tissue-resident, in barrier sites (lung, gut, skin)
Very rare (0.1-1% of barrier site leukocytes)
Epithelial cells
- –(IL-25 and IL-33)—> ILC2
- –(IL-5 and IL-13)—> Eosinophils
HDM mouse model of Asthma:
HDM = House Dust Mite extract, a very common human allergen in asthma.
Repeated administration into the airways results in strong TH2 response, eosinophilia, airway remodelling, and fibrosis.
IL-1 in HDM Asthma:
TLR4 signals induce Asthma in HDM model
IL-1 receptor also required (on epithelial cells)
TLR4 signals induce IL-1α release
IL-33 and GM-CSF:
IL-1 receptor signalling leads to IL-33 and GM-CSF release from epithelial cells.
IL-33 and GM-CSF both required for TH2 response to HDM
Summary of HDM TH2 Induction:
[7 Steps]
- LPS originates from faeces of House Dust Mite
- LPS binds to TLR4
- TLR4 signal on epithelial cell causes release of IL-1α from epithelial cell
- IL-1α acts on epithelial cells and causes release of IL-33 and GM-CSF
- IL-33 activates ILC2 as part of initiating the type 2 immune response
- GM-CSF causes dendritic cells to expand/recruit, causing TH2 induction
- Causes Asthma
