Lecture 15 - Type I Hypersensitivity

What is hypersensitivity?

An excessive immune response directed against harmless molecules

Hypersensitivity involves...

Allergy and autoimmunity

Allergy

An immune response to normally harmless environmental molecules

Autoimmunity

An immune response to the body's own molecules (self-antigens)

Type I hypersensitivity (allergic/immediate) is mediated by...

IgE

Type II hypersensitivity (cytotoxic) is mediated by...

IgG/IgM

Type III hypersensitivity (immune-complex) is mediated by...

IgG

Type IV hypersensitivity (delayed) is mediated by...

Cell (Th1)

IL-4 and IL-13 are important for __ class switching

IgE

IFN-gamma and IL-4 are important for __ class switching

IgG

TGF-beta and IL-10 are important for __ class switching

IgA

What triggers type I hypersensitivity reactions?

Soluble allergens cross-link IgE bound to FcεRI on mast cells

How do type I hypersensitivity reactions work?

Mast cell degranulation releases histamine and other mediators

What are common symptoms of type I hypersensitivity?

Urticaria, asthma, or anaphylaxis

Appear within minutes, immediate allergic reaction

How are parasites eliminated by the immune system?

When exposure occurs, TH2 cells are generated and secrete cytokines IL-4/IL-13 to induce IgE class switching

IgE binds to mast cells

Antigen binds to IgE causing release of inflammatory mediators (histamine, cytokines IL-5)

IL-5 activates eosinophils

Eosinophils produce MBP and ECP to damage and expel parasite

For the following allergen category, list examples, common species affected, and associated conditions.

Flea salivary antigens

Examples: Ctenocephalides felis, saliva proteins

Common species affected: dogs, cats

Associated conditions: flea allergy dermatitis

For the following allergen category, list examples, common species affected, and associated conditions.

Environmental antigens

Examples: pollen, dust mites, molds

Common species affected: dogs, cats, horses

Associated conditions: atopic dermatitis, respiratory hypersensitivity

For the following allergen category, list examples, common species affected, and associated conditions.

Food allergens

Examples: beef, chicken, dairy

Common species affected: dogs, cats

Associated conditions: food allergy

For the following allergen category, list examples, common species affected, and associated conditions.

Insect allergens

Examples: bee stings, mosquitoes, biting midges

Common species affected: dogs, horses

Associated conditions: local swelling, pruritus, sweet itch, anaphylaxis

For the following allergen category, list examples, common species affected, and associated conditions.

Drug allergens

Examples: vaccines, antibiotics, serum proteins

Common species affected: all species

Associated conditions: urticaria, anaphylaxis, vomiting, collapse

What are the clinical signs of canine atopic dermatitis?

Hair loss, skin redness, and thickening

Affected animals often rub, lick, chew, bite, or scratch at their feet, muzzle, ears, armpits, or groin

What triggers canine atopic dermatitis?

It is triggered by environmental allergens such as dust mites, pollens, and molds

What species does atopic dermatitis occur in?

Dogs and cats

What is flea allergy dermatitis (FAD)?

A common allergic skin disease in dogs and cats caused by hypersensitivity to flea saliva antigens

What causes flea allergy dermatitis?

Hypersensitivity to flea saliva antigens, typically involving a combination of type I and type IV hypersensitivity

What is food allergy dermatitis?

A condition in dogs and cats that causes pruritic dermatitis (itchy skin lesions) due to food allergies

What are the clinical signs associated with food allergy dermatitis?

It causes pruritic dermatitis, which includes itchy skin lesions

Vomiting and diarrhea

What factors influence the risk of allergic disease?

Both genetic and environmental factors

What does the hygiene hypothesis suggest?

Early microbial exposure helps train the immune system and lowers the risk of atopy

What may happen to children with a genetic predisposition, limited microbial exposure, or received multiple antibiotics in infancy?

They may develop impaired immune regulation, increasing the risk of asthma, allergic rhinitis, or eczema

What is the mechanism of the sensitization phase of a type I hypersensitivity?

1. Dendritic cells capture and process allergens

2. Dendritic cells migrate to lymph nodes

3. Antigen is presented to naïve T cells, which differentiate into Th2 cells

4. Th2 cytokines drive IgE class switching in B cells

5. IgE binds to Fce receptor on mast cells, arming them for future allergen exposure

3 signals needed for T cell activation

Antigen presentation

Co-stimulatory stimulation

Cytokine stimulation

What cytokine is needed for differentiation of a naive CD4 T cell into a Th1 cell? What cytokines does it then produce?

IFN-gamma and IL-12

IFN-gamma

What cytokine is needed for differentiation of a naive CD4 T cell into a Th2 cell? What cytokines does it then produce?

IL-4

IL-4, IL-5, IL-13

What cytokine is needed for differentiation of a naive CD4 T cell into a Th17 cell? What cytokines does it then produce?

TGF-beta, IL-6, IL-23

IL-17, IL-22

What cytokine is needed for differentiation of a naive CD4 T cell into a TFH cell? What cytokines does it then produce?

IL-6, IL-21

IL-21

What cytokine is needed for differentiation of a naive CD4 T cell into a Treg cell? What cytokines does it then produce?

TGF-beta

TGF-beta, IL-10

What is the mechanism of the effector phase of a type I hypersensitivity?

Re-exposure to allergen, allergen cross links IgE

Mast cells degranulate and release histamine

In the effector phase, what is the result of histamine release and how does it relate to clinical signs?

Nerve stimulation -> itching

Vasodilation -> redness

Vascular permeability increase -> swelling

What are the mast cell mediator in the immediate effector phase of allergy?

Histamine

Tryptase

TNF-a

What is the function of histamine?

・Vasodilation, pruritus, increased vascular permeability

・Cause smooth muscle contraction

・Primary driver of the rapid wheal-and-flare reaction

What is the function of tryptase?

・Increased vascular permeability,

・Activate other inflammatory cells

・Tissue injury (Breaks down proteins)

What is the function of TNF-alpha?

・Increase vascular permeability

・Activate vascular endothelial cells

What occurs in the degranulation of mast cells?

Occurs when an antigen binds to IgE attached to Fce receptors on the mast cell surface

Releases mediators such as histamine, which cause immediate allergic reactions

How does an immediate allergic reaction occur?

It is triggered when an allergen cross-links IgE bound to Fce receptors on mast cells, leading to degranulation and the release of mediators (histamine) that cause rapid inflammatory symptoms

What are the two parts of the effector phase of a type I hypersensitivity?

Immediate reaction and late phase reaction

What is the immediate reaction of the effector phase of a type I hypersensitivity?

Occurs within minutes

Mediated primarily by histamine from mast cells

Rapid onset of symptoms: redness, swelling, itching, bronchoconstriction and mucus secretion

What is the late phase reaction of the effector phase of a type I hypersensitivity?

Occurs 8-12 hours after re-exposure

Mediated by Th2 cells, eosinophils and basophils

Leads to sustained inflammation, tissue damage and chronic allergic changes

What are the mast cell mediators in the late-phase effector phase of allergy?

Cytokines IL-4, IL-5, IL-13

Chemokines CCL5, CCL11

Leukotrienes (lipid mediators)

What is the function of IL-4 and IL-13?

Promotes Th2 differentiation

Promotes IgE class switching in B cells

What is the function of IL-5?

Promote eosinophil growth, survival, and activation

What is the function of CCL5 and CCL11?

Selectively attract eosinophils and basophils

What is the function of leukotrienes?

Maintain bronchoconstriction and mucus hypersecretion

Increase vascular permeability (recruit leukocytes)

What is anaphylaxis?

A severe allergic reaction

Involves multiple organ systems

Acute and potentially life threatening

If left untreated, can progress to shock/respiratory failure/cardiac arrest/death

Intradermal Skin Testing (IDST)

Commonly used in canine and feline atopic dermatitis

Detect allergen-specific IgE reactivity in the skin

Inject small amounts of allergen intradermally; evaluate wheal/flare reaction after 15-30 min

Elimination-Provocation (Challenge) trial

Gold standard for diagnosing food allergy in dogs and cats

Feed a strict elimination diet

Reintroduce the suspected ingredient to confirm relapse of symptoms

What are the 3 ways to treat anaphylaxis?

Epinephrine, oxygen therapy, and IV fluids

How does epinephrine treat anaphylaxis?

First line emergency drug, life saving

Cause blood vessel constriction (swelling↓)

Heart contractility and heart rate

Relaxes airway smooth muscles

IM or IV

How do IV fluids treat anaphylaxis?

Restore circulating volume and blood pressure/correct hypotension

How do we treat chronic/mild allergies?

Allergen avoidance: most effective preventive measure

Antihistamines: control pruritus (itching) and swelling

Corticosteroids/anti-inflammatory drugs: used to control flare-ups

ASIT

Among the anti-inflammatory actions of glucocorticoids, what plays the predominant role?

Transcriptional repression

What is allergen specific immunotherapy (ASIT)?

Immunotherapy involves the gradual introduction of small, controlled doses of allergens into the body

This process helps the immune system become less reactive over time

Unlike symptomatic treatments, ASIT modifies the natural course of allergic diseases and can provide long-term relief

SubQ or sublingual