Exam 3: Hypersensitivity Type I Flashcards
what type of immune response is hypersensitivity type I
antibody mediated immune response
humoral
what kind of antigens trigger type I hypersensitivity
allergies
parasite worms
characteristics of type I hypersensitivity (4)
exaggerated Th2 response
excessive amounts of IgE = atopy
genes + environmental factors = allergies
intestinal microflora
what does early contact with allergens lead to
less susceptible to get allergies
what are some non microbial antigens that can cause allergies
food
insects
pollen
fur
what is the normal concentration of IgE in serum
low
what happens to IgE concentration in type I hypersensitivity
IgE overproduction
what happens to IL-4 in type I hypersensitivity
IL-4 overproduction
what does IL-4 overproduction cause
increased Th2 activation and B cell stimulation
when B cells differentiate –> IL-4 increases production of IgE
what are the receptors of IgE and what type of binding to the antibody do they have
irreversible binding to antibody
FcεR
FcεRI
FcεRII
FcεR
FcεRI
FcεRII
FcεR - has high affinity and irreversible binding
FcεRI - present in mast cells, basophils, neutrophils, eosinophils, macrophages, dendritic cells
FcεRII - present in B cells, NK cells, macrophages, dendritic cells, eosinophils, platelets
mechanism of type I hypersensitivity reactions
numerous biologically active molecules are released by mast cells and basophils when antigen cross-links two IgE molecules on the mast cell surface
some are produced immediately, others may be synthesized within minutes or hours
- antigen + mast cell with IgE
- Degranulation - cytokines, enzymes, chemotactic molecules, vasoactive molecules
- acute inflammation and systemic effects
the role of IL-4 in induction if IgE response - normal humoral response
IL-4 is produced by Th2 cells
Once released, IL-4 promotes development of more Th2 cells
Th2 cells are major sources of this cytokine and promote IgE responses
Degranulation of mast cells also releases IL-4 to further promote this reaction
NK cells may serve as an initial source of IL-4
what inhibits response of IL-4
Response to IL-4 inhibited by IFN-y and IL-12
the allergy loop
dendritic cells express trimeric FcεRI as can bind antigen-IgE complexes
this antigen, once processed, stimulates Th2 responses
these Th2 cells in turn secrete cytokines, which further promote the IgE response
mast cell resposne
the combination of Fcε receptors with their ligands stimulates many different responses in mast cells
what is CR2
CR2 is a complement receptor located in B cells, T cells, and dendritic cells
mast cell response FcεRI
antigen –> IgE –> FcεRI (high affinity) –> mast cell degranulation, eosinophil ADCC, dendritic cells, macrophages
mast cell response FcεRII
antigen –> IgE –> FcεRII (low affinity) –> B cell down regulation, Macrophage phagocytosis, NK cells, Dendritic cells, Eosinophils
mast cell response FcεRIII
CR2 –> FcεRIII –> B cell stimulation and survival
mast cell - characteristics
located in intestine, skin, airways, around nerves
close to blood vessels
release proinflammatory mediators
what do mast cells release in connective tissue/skin and what is their life span
histamine
heparin
life span > 6 months
what do mast cells release in intestine/lung and what is their life span
chondroitin sulfate
few histamine
life span < 40 days
mast cells - molecules released from exocytosed granules within seconds
histamine serotonin tryptase kallikreins proteases proteoglycans
mast cells - eicosanoid synthesis and secretion within minutes
leukotrienes
prostaglandins
platelet activating factor
These all induce inflammation
mast cells - cytokine synthesis and secretion over several hours
IL-4 IL-5 IL-6 IL-13 TNF-a MIP-1a
Biological properties of IL-33 Innate lymphocytes Macrophages Neutrophils B cells Th2 cells Eosinophils Basophils Mast cells Neurons
Innate lymphocytes - Th2 cytokines, IFN-y, TNF-a, IL-2
Macrophages - M2 polarization, tissue repair
Neutrophils - phagocytosis
B cells - IgM
Th2 cells - IL-5, IL-13 –> exotoxins
Eosinophils - IL-8, degranulation –> terminal effector cells of the allergic response
Basophils - IL-3, IL-4, IL-6, IL-13, histamine, GM-CSF –> basophil differentiation in bone marrow
Mast cells - IL-6, IL-13 –> degranulation in presence of IgE
Neurons - itch
what does IL-33 do
stimulates the production of inflammatory cytokines and chemokines from many different cell types
major mediator in type I hypersensitivity
what happens when an allergen binds to a IgE that is attached to a mast cell
the mast cell releases granules and begin to synthesize several other factors that have effects on GI tract, airways, blood vessels
effects of mast cell degranulation on GI tract
fluid secretion, peristalsis
emptying of GI tract (diarrhea, vomiting)
effects of mast cell degranulation on respiratory tract
mucous secretion, bronchoconstriction
difficulty breathing
effects of mast cell degranulation on blood vessels
increased vascular permeability
movement of fluids, proteins, and cells out of blood vessels and into inflamed tissues
what inhibits mast cell degranulation
blocking a adrenoreceptors
stimulating B adrenoreceptors: isoproterenol, epinephrine, salbutamol
what enhances mast dell degranulation
stimulation of a adrenoreceptors: norepinephrine, phenylephrine
blocking B adrenoreceptors: propranolol
what happens when mast cell degranulation enhanced
immediate inflammation 10-20 minutes
late phase reaction 6-12 hours
what happens when a receptor stimulated and B receptor blocked
Mast cells - enhanced degranulation
Smooth muscle - contracts
Blood vessels - constricts
what happens when B receptor stimulated and a receptor blocked
Mast cells - suppressed degranulation
Smooth muscle - relaxes
Blood vessels - dilates
what happens when basophils bind IgE
- Bind IgE
- Basophil degranulation
- increasing vascular permeability
characteristics of basophils
long term allergic states (chronic allergic dermatitis)
initiate helminth immune response as APC (Th2)
protective role in helminth, tick, bacterial infections, degrade toxins in venom, contribute to tumor rejection
Eosinophils respond to
parasites
pathogens
PAMPs and DAMPs
eosinophils produce
oxidants and enzymes
lipid mediators
cationic granule proteins
cytokines
chemokines
eosinophils - oxidants and enzymes effects
tissue damage and inflammation
eosinophils - lipid mediators effects
pain
smooth muscle contraction
mucus production
eosinophils - cationic granule proteins effects
tissue damage and inflammation
eosinophils - cytokines effects
macrophage activation
dendritic cell activation
neutrophil activation
endothelial cell activation
eosinophils - chemokines effects
T cell chemotaxis and activation
clinical type I hypersensitivity
allergic anaphylaxis
milk allergy
food allergy
allergy to vaccines and drugs (penicillin)
allergies to parasites, midges, black flies, stable flies, fleas
allergic inhalant dermatitis
atopic dermatitis (house dust mites, molds, trees, weeds, grass pollen)
hygiene hypothesis
which breeds are more susceptible to atopic dermatitis
retrievers terriers beagles boxers bulldogs shar-pei
what is most affected in dogs with allergic anaphylaxis
liver - hepatic veins
what is affected in most species with allergic anaphylaxis
respiratory tract and intestines
what is used in severe allergic anaphylaxis reactions
epinephrine – epi-pen
is allergic anaphylaxis a severe, life threatening systemic hypersensitivity reaction
yes
can be fatal
immune response in atopic dermatitis
allergens --> trauma --> keratinocytes --> cytokines --> TSLP --> sensory neurons (with input from IL-31) --> itch
which IL is most important in atopic dermatitis and what does it do
IL-31
Gives itching sensation
diagnosis of type I hypersensitivity
intradermal skin testing
passive cutaneous anaphylaxis (PCA)
measuring IgE
treatment of type I hypersensitivity
avoid exposure to allergen
corticosteroids
antihistamines
B stimulants - epinephrine, isoprenaline, salbutamol
a antagonists - methoxamine, phenyleprine
allergen specific immunotherapy
intradermal allergy test
bunch of injections into skin to see which allergens you react to
immunotherapy
injections or oral drops
injections or oral drops contain small amounts of the allergen –> vaccines
objective of these vaccines is tolerance and increased IgG production (class switching from IgE)
why do we want increased IgG production in immunotherapy
higher amounts of IgG will compete with IgE to bind allergen and allergen will be eliminated/destroyed
canine atopic dermatitis
caninized anti-cIL-31 monoclonal antibody (mAb)
mAb specifically targets and neutralizes canine IL-31 which is involved in sending itch signal to brain
interrupts cycle of itch and inflammation
how apoquel works
best treatment for type I hypersensitivity in humans
have a chihuahua dog
because they help with asthma apparently
but no scientific explanation (or evidence really)
