Hypersensitivity Type I: Mechanism and Clinical Manifestation

Various diseases result from inappropriate and immediate immune responses to common environmental components which are otherwise not harmful. Scientists Coombs and Gell have classified such responses as hypersensitivity type I reactions. IgE antibodies are the leading cause of this reaction.

Type I hypersensitivity reaction is called immediate hypersensitivity, as an IgE response is immediate. Similarly, it is called an anaphylactic reaction (opposite of prophylaxis or protection, i.e., harmful) or allergy. The term allergy refers to the changed reactivity of the host when encountering the antigen on a second or subsequent exposure.

Hypersensitivity type I is extremely common, where the release of pharmacological mediators, such as histamine, occurs by IgE-sensitized mast cells and produces an acute inflammatory response with symptoms like asthma or rhinitis. Manifestations can be local or systemic, leading to anaphylactic shock and even death.

Components of Hypersensitivity Type I

1. Allergen

The allergens are antigens capable of stimulating IgE production and type I hypersensitivity responses in allergic individuals on repeated exposure.

Foreign serum and egg albumin are potent antigens, whereas pollen is a weak antigen.

Table: Common allergens associated with hypersensitivity I (Souce: Kuby Immunology)

Common allergen	Examples
Proteins	Foreign serum, vaccine
Plant pollen	Ryegrass, ragweed, Timothy grass, birch trees
Drugs	Penicillin, sulfonamides, local anesthetics, salicylates
Foods	Nuts, seafood, eggs, peas, beans, milk
Insect products	Bee venom, wasp venom, ant venom, cockroach calyx, dust mites
Mold spores
Animal hair and dander latex soap

2. IgE

Usually, among all of the antibodies, IgE is secreted in the lowest amount, whereas IgE secretion rises in parasitic infection. In such cases, a high serum IgE successfully eliminates parasites. Atopy is a hereditary predisposition to developing immune hypersensitivity reaction against the common environmental antigen. This condition allows non-parasitic antigen to stimulate inappropriate IgE production, leading to tissue-damaging type I hypersensitivity. Hence, atopic patients secrete IgE 10 times more than a normal condition.

On the other hand, TH1 suppresses IgE production with the help of interferon-gamma. IgE is also called reagin since it is involved in an allergic reaction and is a cytotoxic antibody.

3. Mast cells and basophils

The basophils are granulocytes that circulate in the blood. These are recruited into tissues at the sites of inflammation.

Mast cells are found throughout connective tissue, mainly near blood, lymphatic vessels, and nerves. These are also found in the respiratory and gastrointestinal tract, skin, and mucous membranes.

Mast cells and basophils contain pharmacologically active mediators. These mediators are released from the granules on activation, manifesting a type I hypersensitivity reaction.

4. IgE binding Fc receptor

The reaginic activity of IgE depends on its ability to bind to a receptor specific to the Fc region of IgE. High-affinity and low-affinity receptors are present in receptor cells like mast cells and basophils.

5. Mediators and cytokines

Clinical manifestations of type I reaction result from mediators released during mast cells or basophil degranulation. These mediators act on local tissues and effector cells like eosinophils, neutrophils, monocytes, T lymphocytes, and platelets. If they respond to parasitic infection, the effect is beneficial. But if allergens induce the response, this results in an unnecessary increase in vascular permeability and inflammation, which is far more detrimental than helpful. 

The mediators are classified as either primary or secondary. The primary mediators are pre-made before degranulation and are stored in the granules. The secondary mediators are either synthesized after target cell activation or released by the breakdown of the cell membrane during the degranulation process. The examples of primary and secondary mediators are given in the table.

Mechanism

Two steps take place in type I hypersensitivity. The first step is sensitization, and the second subsequent exposure gets serious.

Activation of B lymphocytes to produce IgE and sensitization of mast cells

This is the step where there is sensitization of the host and formation of IgE antibodies, which, once formed, attaches to the receptors on mast cells or basophil. This step is asymptomatic.

1. Formation of IgE

Breathe, or ingested molecule (allergen), is captured by phagocytes or antigen-presenting cells (APC) and is taken to the lymph node. APC presents allergen to T-helper cells living there. Now TH differentiates into TH2 cells. TH2 cells release interleukins (IL-4, IL-5, IL-13), switching B-cell to form plasma cells secreting IgE.

Allergen induces humoral antibody response to plasma cells that produce antibodies and memory cells, as in humoral immunity. But, plasma cells secrete IgE in response to the activity of allergen-specific TH2 cells.

2. Binding of IgE to mast cells and basophils and sensitization

Sensitization of mast cells and basophils requires IgE. IgE has a high affinity to the Fc receptor of the mast cell and basophil cell. Thus, when these cells are coated with antibodies, they become sensitized. Locally produced IgE will first sensitize the local mast cells, and the rest of the IgE enters the circulation and binds to the Fc receptors on basophils and mast cells throughout the body. The half-life of serum IgE is only 2.5 days, while mast cells may remain sensitized for up to 12 weeks.

Mast cells release chemical mediators and adversely affect the second exposure

This is the step of reaction in response to the shocking dose. The second step includes the activation of mast cells or basophils and degranulation.

1. IgE cross-linkage and activation of mast cells and basophils

Months later, exposure to the same allergen cross-links the membrane-bound IgE on sensitized mast cells and basophil cells. This causes degranulation following various harmful effects.

2. Degranulation of the sensitized cells

A mediator from granules damages both invading and nearby cells. This leads to vasodilation and smooth muscle contraction, causing systemic and local infection.

IL5 production and activation of eosinophils and granulocytes take place in this step. It is an active process involving calcium influx, the release of primary mediators, and secondary mediators, including cytokines and chemokines. Since the patients have histamine effects, it is called histamine poisoning.

Table: Principal mediators involved in type I hypersensitivity (Source: Kuby Immunology)

Mediators	Type	Effects
Primary	Histamine, heparin	Increased vascular permeability, smooth muscle contraction
	Eosinophil and neutrophil chemotactic factors	Chemotaxis
	Protease (tryptase, chymase)	Bronchial mucus secretion, degradation of blood vessel basement membrane, generation of complement split products
Secondary	Platelet-activating factor	Platelets aggregation and degranulation; contraction of pulmonary smooth muscle
	Leukotrienes	Increased vascular permeability, contraction of pulmonary smooth muscles
	Prostaglandins	Vasodilation, contraction of pulmonary smooth muscles, platelets aggregation
	Bradykinin	Increased vascular permeability, smooth muscle contraction
(Secondary) Cytokines	IL–1 and TNF	Systemic anaphylaxis, increased expression of CAMs on venular endothelial cells
	IL-4 and IL-13	Increased IgE production
	IL-3, IL-5, IL-6, IL-10	Various effects on innate and adaptive immunity

Reactions of Immediate Hypersensitivity

Type I hypersensitivity has two presentations: an immediate reaction and a late-phase reaction.

1. Immediate Reaction

When a patient is exposed to an allergen, an intradermal injection of the same antigen causes redness and swelling on the injection site. This soft swelling is called a wheal, and the red rim at the margin of the wheal is a flare. This reaction occurs within 5 to 10 minutes and usually subsides in less than an hour. The cytoplasmic granules are released due to sensitization of dermal mast cells by IgE bound to the Fc receptor by cross-linking the IgE by antigen. Immediate hypersensitivity reactions include skin and mucosal allergies, food allergies, asthma, and systemic anaphylaxis.

2. Late phase reaction

It starts in 2-8 hours and lasts 2-3 days. Wheal and flares follow 2 to 4 hours later by a late phase reaction consisting of an accumulation of inflammatory leukocytes, including neutrophils, eosinophils and basophils, and Th2 cells; or without a detectable preceding immediate hypersensitivity reaction. E.g., bronchial asthma.

Late phase reaction usually is due to secondary mediators and inflammatory cell reaction. The late phase activation of mast cells and their mediators ultimately damages tissue. 

Clinical manifestations

The type 1 reaction can range from the life-threatening anaphylactic reaction to milder forms associated with common allergies.

Immediate hypersensitivity reactions are seen in the URT (upper respiratory tract), GIT (gastrointestinal tract), and skin. Most allergic responses occur on the mucus membrane surface when an allergen enters the body by inhalation or ingestion. Vascular and smooth muscle reaction develops after repeated exposure to the allergen (the immediate response).

Diseases associated with hypersensitivity I can be described in two types: localized and systemic.

1. Localized Reaction

• Skin allergies, Hay fever, allergic rhinitis, asthma, food allergy
• Rashes or blisters in the skin, pruritus (hives, atopic dermatitis, eczema)
• Increased eye and nasal secretions, itching, sneezing (allergic rhinitis/hay fever, allergic conjunctivitis)
• Oropharyngeal mucosal edema (food allergies)
• Gastrointestinal abnormalities, like abdominal pain, diarrhea, vomiting (food allergies)
• Bronchospasm, wheezing (bronchial asthma)
• Urticaria and eczema

2. Systemic anaphylaxis

• Anaphylaxis is a severe, life-threatening systemic hypersensitivity reaction occurring within minutes of exposure to an allergen.
• Large quantities of inflammatory mediators are released due to rapid systemic vasodilation, vascular permeability, hypotension, and extensive tissue edema. Fluids may be in the lungs and constrict the airways. Patients can undergo shortness of breath, lethal suffocation, cardiovascular collapse, and loss of consciousness.

Lab Diagnosis

Skin testing

Hypersensitivity type I can commonly be identified and assessed by skin testing. A small amount of potential allergen is introduced at a specific skin site. Wheal and flare are seen within 30 minutes, which confirms the type I reaction.

Serum testing

Serum level of total IgE antibody can be tested based on radioimmunoassay. It can detect nanomolar levels of total IgE.

Control

Type I hypersensitivity can be controlled by applying the following measures:

• Contact with known allergens should be avoided. Removing house pets, dust, and offending foods should be done as far as possible.
• In severe cases, hypo sensitization or desensitization can help patients, i.e., immunotherapy with repeated injections of increasing doses of allergens, to reduce the severity or to eliminate them.
• The use of humanized monoclonal anti-IgE can also be helpful.
• Drug therapies, like, antihistamines, are most useful in allergic rhinitis. Glucocorticoids are also used.
• Anaphylaxis is a medical emergency requiring immediate airway access with the administration of epinephrine and fluid resuscitation.

References

1. Kindt et al. (2007). Kuby Immunology. W. H. Freeman and Company. 6^th edition.
2. Abbas et al. (2007). Cellular and Molecular Immunology. Saunders, Elsevier. 6^th edition.
3. https://labpedia.net/elementary-immunology/chapter-11-type-1-hypersensitivity-reaction-anaphylaxis-atopy-and-treatment/
4. https://www.lecturio.com/concepts/type-i-hypersensitivity-reaction/