Type I Hypersensitivity

Question 0

Types of hypersensitivity

Answer 0

Antibody mediated (rapid, Ab's can be detected, can transfer via Ab's)
- type I = immediate, IgE
- type II = cytotoxic
- type III = Ag-Ab complexes
Cell-mediated (slower, can only be transferred via cells)
- type IV = delayed

Question 1

“hypersensitivity”

Answer 1

Inflammation and tissue damage from exaggerated or inappropriate immune response to antigens that are normally innocuous (vs pathogens)

Question 2

“allergy”

Answer 2

= type I hypersensitivity (IgE mediated, atopic)
Reaction to allergen (ie dust, coachroach, dander, peanuts)
Most common sites = GI, skin, respiratory
Ex: hives, rhinitis, GI, anaphylaxis, bronchial asthma

Question 3

Anaphylaxis

Answer 3

severe, whole-body Type I hypersensitivity
release of mast cell and basophil granules ->
vasodilation, bronchoconstriction, edema, etc

Can be triggered directly (ie not through IgE)
- NSAIDs, IV contrast, cold air, exercise

Question 4

Dev’t of allergic sensitivity

Answer 4

Requires prior and repeated exposure (ie multiple vaccine shots)
Exposure -> T cell activation -> B cell activation -> IgE -> IgE binds to FcER on mast cells (“armed”)
Repeat exposure -> FcER IgE -> degranulation of mast cell

Question 5

IgE characteristics

Answer 5

Responsible for Type I hypersensitivity, also active against helminths

Normally low levels in serum
Short half life -> binds quickly to FcER of mast cells
Normal mast cells bind many polyclonal IgE
“Atopic” patients have up to 10% specificity of bound IgE for allergen, higher circulating levels

Question 6

Cellular mediators of type I

Answer 6

Mast cells - in vessels, subcutaneous, submucosal, peritoneal
- degranulate -> release histamine
Basophils - similar to mast cells but circulating
- have histamine (H2) receptors -> negative feedback
Eosinophils - late phase of allergy (present in tissue)
- IgE -> release cytokines (prostaglandins, leukotrienes, PAF), toxins

Question 7

Mast cell and basophil activation

Answer 7

Key is cross-linking of IgE receptors by binding divalent IgE
Triggers:
- antigen (specific to IgE)
- anti IgE antibody or receptor
- lectins (ie strawberries)
Can also be direct from complement anaphylotoxins (C3a, C5a)

Question 8

Etiology of allergies

Answer 8

Multifactorial…

• pollution
• genes (HLA match to antigen)
• hygeine/microbiome
• breastfeeding (higher IgA)
• glycosylation of IgE (-> crosslinking)
• serum IgE levels

B cell class switching via CD-40L and T cell cytokines
 - Th2 -> IL-4 -> IgE (vs Th1 -> IFN-g -> IgG, macrophages, complement)

Question 9

Pharmacologic mediators of type I hypersensitivity

Answer 9

Histamine -> permeability, smooth muscle contraction, inc mucous production, GI secretion (via H2)
- some negative feedback to limit release
Slow-reacting substance of anaphylaxis (SRS-A) aka leukotrienes
- from arachidonic acid -> released from cytoplasm (not granules) -> bronchconstriction, permeability and vasodilation, mucous secretion, cerebral and coronary vasoconstriction, dec heart contractility, GI secretion
Leukotriene B4 - venous leakage, also chemotactic for PMNs
Prostaglandin D2 - vasodilator, coronary and cerebral vasocontrictor, bronchoconstrictor, inhibits platelets, also chemotactic for PMNs
Platelet activating factor - vasodilator, bronchoconstrictor, permeability, platelet aggregation and granule release, chemotactic for PMNs and eosinophils
Proteases -> kinin, complement -> permeability, etc

Question 10

Chemotactic mediators of type I hypersensitivity

Answer 10

Leukotriene B4
 - potent for neutrophils, eosinophils, macrophages
 - also promotes endothelial adhesion and degranulation
IL-8
C5a
Prostaglandin D2
Platelet activating factor
RANTES
eotaxin

Question 11

Tissue destruction mediators of type I hypersensitivity

Answer 11

Mast cell granules -> hydrolases and proteases (ex tryptase)
Neutrophils, macrophages, mast cells -> oxide radicals
Eosinophils -> major basic proteins

Question 12

Late phase of type I hypersensitivity

Answer 12

Acute phase -> transcriptional activation ->
Cytokines ->
Eosinophils -> further mediators released

Question 13

Drugs for type I hypersensitivity

Answer 13

H1 receptor blockers (benadryl, chlortrimeton)
-> symptom relief but don’t block mediators
Glucocorticoids (dexamethasone, beclomethasone, fluticasone)
-> block production of most mediators, blocks some mediator effects
Specific inhibitors
- Zileuton -> leukotriene synthesis
- Monteleukast -> leukotriene action
- Cromolyn -> histamine release
- Xolair = IgE antibody (-> uptake)
Anaphylaxis -> epinephrine and beta2 agonists counter vasodilation and bronchoconstriction

Question 14

Subcutaneous immunotherapy

Answer 14

Increasing doses ->
T reg response ->
more IgG and IgA response -> removes allergen prior to IgE (without releasing mediators)