HI19 - Type I Hypersensitivities

Biomedical Sciences IV

What is a Type I hypersensitivity reaction?

A rapid, IgE-mediated immune response to non-self environmental antigens (allergens).

What evolved purpose does IgE serve?

Defense against helminths and multicellular parasites.

Why do Type I hypersensitivity reactions occur in modern environments?

Reduced exposure to parasites and microbes leads to a misguided IgE response against harmless antigens.

Where are mast cells predominantly located?

At boundaries between tissues and the external environment, including:

• Dermis

• Mucosal membranes

• Around blood vessels

They act as sentinel cells.

What receptor do mast cells express at high levels?

High-affinity FcεRI receptors that bind IgE.

What triggers mast cell degranulation?

Crosslinking of IgE bound to FcεRI by multivalent antigen.

What are granulocytes?

White blood cells containing cytoplasmic granules filled with biologically active chemicals.

What are the three granulocytes important in Type I hypersensitivities?

• Mast cells

• Basophils

• Eosinophils

Where are basophils located?

They circulate in the blood, unlike mast cells which reside in tissues.

What receptor do basophils also express?

High-affinity FcεRI for IgE.

Where are eosinophils found?

Circulate in blood (normally <5% of WBCs) and reside in hematopoietic and lymphatic organs.

What is an allergen?

A non-self environmental antigen that triggers a hypersensitivity reaction.

What is atopy?

A genetic/environmental predisposition to allergies. A person with genetic predisposition to allergies and who was raised in a very hygenic environment has a high atopy.

How soon can a Type I hypersensitivity reaction occur?

Seconds, typically within 15–30 minutes, up to 24 hours.

Where is IgE found in highest concentration?

Bound to mast cells and basophils, not free in serum.

What is the half-life of serum IgE?

Approximately 2 days.

What is the half-life of IgE when bound to mast cells?

Weeks to months, because FcεRI is very stable.

Why can one mast cell respond to many allergens?

It is coated with IgE molecules of many different antigen specificities.

How does the antigen specificity of a mast cell differ from a B cell?

• B cell: Single antigen specificity

• Mast cell: Many specificities due to diverse IgE molecules

Why is IgE important against helminths and worms?

They are too large to phagocytose, so immune ejection mechanisms are required.

Why are helminths less antigenic?

They are eukaryotic and share proteins with humans, reducing opportunities for PRR activation.

How does the body expel helminths?

• Coughing

• Sneezing

• Vomiting

• Diarrhea

• Mucus production

• Itch-induced scratching

What does IgE do to fight parasites?

Arms mast cells, basophils, and eosinophils → degranulation → explosive inflammatory reactions → ejection.

What is the allergy rate in parasite-endemic regions?

Very low, because IgE is directed at parasites instead of allergens.

What is the hygiene hypothesis?

Improved sanitation lowers parasite exposure → Th2 immunity becomes unguided → IgE misdirected toward allergens.

What population trend supports the hygiene hypothesis?

Sharp increase in allergy rates over the last 150 years following sanitation improvements.

What correlation exists between parasite load and allergy rates?

High parasite exposure → low allergies
Low parasite exposure → high allergies

What is the biodiversity hypothesis?

Exposure to natural environments increases microbiome diversity, promoting immune balance and reducing allergies.

What modern environmental changes reduce microbiome diversity?

Indoor living, reduced green space, processed foods, paved surfaces, air conditioning, reduced exposure to soil and animals.

What similarity exists between allergens and helminth antigens?

Many allergens have structural similarities to helminth proteins.

What increases a child's genetic risk for allergies?

Having one or both allergic parents.

What are major characteristics of allergens?

• Proteins

  • Presented on MHC II → Th2 polarization

• Small

• Soluble

• Stable: resistant to digestion

• Low dose exposure favored

• Often have protease activity

Why are proteins such potent allergens?

• Need T cell help to produce germinal centers and get IgE class switching

• Low dose and ability to be presented on MHC Class II favors CD4+ TH2 polarization

Which allergens commonly have protease activity?

Allergens from dust mites, cockroaches, pollen, fungi, and
bacteria

Why is protease activity important in allergens?

Proteases disrupt epithelial tight junctions, allowing allergens to access immune cells.

What PRRs recognize proteases?

Specialized protease-recognition PRRs, enhancing inflammation.

What is required before any allergic reaction can occur?

Sensitization, the initial creation of IgE against the allergen.

Does sensitization cause symptoms?

No — the first exposure does NOT produce symptoms.

What happens during the sensitization phase?

• Allergen uptake by APCs

• Transport to secondary lymphoid tissue

• IL-4 production

• Th2 differentiation

• B cell class switching to IgE

• IgE binds FcεRI on mast cells/basophils

Why are small allergen doses more likely to cause sensitization?

Low doses favor MHC II presentation and Th2 polarization.

What Ig is produced first before class-switching?

IgM.

What cytokine induces IgE class switching?

IL-4 (from Th2 cells).

What triggers the response phase?

Re-exposure → allergen crosslinks IgE → mast cell degranulation.

Why is cell proliferation unnecessary in the response phase?

Mast cells are already armed with IgE and ready to respond.

What are the two phases of the IgE allergic response (Immedicate Response Phase)?

• Immediate phase

• Late phase

When does the immediate phase occur?

Within seconds to minutes (typically 15–30 min).

What mediators act in the immediate phase?

• Histamine

• TNF-α (pre-formed)

• Mast cell proteases

• Heparin (vasodilation/anticoagulation)

What are the major effects of histamine?

• Bronchoconstriction

• Vasodilation

• Increased capillary permeability

• Mucus secretion

• Itching

• Hives (wheal and flare)

• Hypotension (systemic reaction)

When does the late phase occur?

Hours after the immediate phase subsides.

What mediators act in the late phase?

• Leukotrienes

• Prostaglandins

• Cytokines

• Chemokines

What symptoms do late mediators cause?

Prolonged bronchospasm, inflammation, mucus secretion, tissue swelling.