3. Type 2 Responses in Allergic Disease Flashcards
(21 cards)
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
“Alternaria alternata” Innate Immune Response:
“Alternaria alternata” is a common fungus associated with development and exacerbation of asthma.
Can induce immune response rapidly (independent of adaptive immune system).
IL-33 is produced constitutively by epithelium and is bound to chromatin in the nucleus to prevent its release while the cell is alive. IL-33 is only released under conditions of necrosis (caspases cleave and inactivate IL-33 upon apoptosis)
- “Alternaria alternata” contains proteases
- These proteases cause cell death of epithelial cells
- Necrosis of epithelial cells releases IL-33
—-(IL-33)—-> ILC2 —–(IL-5 and IL-13)—–> Asthma
Inside-out hypothesis for Atopic Dermatitis development
Allergic immune responses develop, causing skin damage
Allergen enters healthy skin, causing defective skin
Outside-in hypothesis for Atopic Dermatitis development
Pre-existing defect in skin barrier leads to allergic sensitisation
(Allergen would not normally enter healthy skin, but only enters due to defective skin barrier caused by pre-existing condition)
Filaggrin: [Type of protein] [Location of expression] [Connection to Atopic Dermatitis] [Does this example support inside-out or outside-in hypothesis?]
Filament aggregating protein
Expressed in skin
Atopic Dermatitis is genetically linked to haploinsufficiency of filaggrin (expressed at 50% of normal levels)
This example supports the outside-in hypothesis
“Atopic March”
Get one allergy, more likely to develop others
Example: First get Atopic Dermatitis, enables other allergens to enter through damaged skin
TNFAIP3/A20:
TNFAIP3/A20 mediates protection
TNFAIP3/A20 is a suppressor of TLR signalling
Epithelial cell specific deletion of TNFAIP3/A20 ablates suppressive effect of LPS inhalation
Chronic low dose environmental LPS induces TNFAIP3/A20, suppressing subsequent response to allergens
