Type I Hypersensitivity Reactions
Under some circumstances, immune responses produce damaging and sometimes fatal results, known collectively as hypersensitivities. Hypersensitivity reactions differ from protective immune responses in that they are exaggerated or inappropriate and damaging to the host. Hypersensitivity reactions are classified by the immune mechanism.
Type I hypersensitivity reaction (also known as immediate hypersensitivity) occurs upon the reaction of allergen (an antigen that elicits an allergic response) with specific IgE antibody that is bound to high affinity receptors on the surface of mast cells and basophils.
Sensitization phase
Initial contact with the allergen leads to proliferation and differentiation of the specific TH and B-cell populations. This is known as sensitization and does not generate allergic symptoms. After sensitization, IgE associates with mast cells and allergic reactions can be elicited upon re-exposure to the allergen. All normal individuals can make IgE specific for a variety of different antigens; however, some individuals (atopic) are more prone to developing IgE and experiencing allergic responses. The tendency to develop IgE-mediated responses does appear to have a genetic component. The pattern of inheritance is not yet understood, although MHClinked genes appear to be involved in some cases.
Activation phase
Cross-linking and clustering of the mast cell–bound IgE by the presence of allergen leads to the rapid release of mast cell granules containing many preformed inflammatory mediators (histamine, proteases, and TNF-a) and the synthesis of longer acting agents (leukotrienes, prostaglandins, and cytokines) that mediate the late phase response. The initial degranulation occurs within minutes, whereas the late phase response usually begins within 4 to 6 hrs and can last 24 hrs. Direct activation of mast cells via non–IgE-mediated events can also lead to the clinical features resulting from rapid mast cell degranulation. Complement components (C3a and C5a) act directly on mast cells, as do some food additives and certain drugs (e.g., aspirin, angiotensin-converting-enzyme [ACE] inhibitors, opioids) in some sensitive patients.
Effector phase
The symptoms of the type I hypersensitivity reactions are due to the inflammatory mediators released by the activated mast cells.
- Histamine binds rapidly to a variety of cells via histamine receptors; H1 and H2 receptors are chiefly involved in the type I hypersensitivity reaction. Histamine binds to H1 receptors on smooth muscles (airway constriction, gastric muscular contractions) and endothelial cells (vascular permeability). Binding of histamine to H2 receptors, chiefly present at mucosal surfaces, results in increased mucous secretion and increased gastric acid production.
- Cytokines and chemotactic factors are important for the growth and differentiation of leukocyte cell types, such as TH2s and eosinophils, as well as recruitment of leukocytes, including eosinophils and neutrophils.
- Leukotrienes and prostaglandins, which are both synthesized as part of the late phase response, lead to prolonged constriction of smooth muscle (bronchoconstriction) and continued vascular permeability.
Clinical presentations of type I hypersensitivities
Allergic rhinitis is the most common atopic disorder worldwide. Airborne allergens react with IgE-sensitized mast cells in the nasal mucosa and conjunctiva, resulting in degranulation of these mast cells, increased mucous secretion, localized vasodilation, and increased vascular permeability. Typical respiratory allergens include grass, tree, and weed pollens; fungal spores; dust mite allergens; and pet dander.
Asthma is a syndrome characterized by a generalized but reversible airway obstruction, bronchial hyperresponsiveness, and airway inflammation. Asthma cannot be explained solely based on IgE-mediated mast cell processes; however, most cases occur in patients who also show immediate hypersensitivity to defined environmental allergens. Airway inflammation plays a major role in the pathogenesis of asthma; recruitment of inflammatory cells, particularly eosinophils, can ultimately lead to remodeling of the respiratory tissue.
Food allergies are caused by the intake of certain foods that then interact with sensitized mast cells of the GI tract. Mast cell degranulation and mediator release leads to smooth muscle contraction (nausea and vomiting) and increased mucous and acid secretion. Typical food allergens include nuts, eggs, milk, and shellfish. In some cases, the food can be absorbed systemically, leading to mast cell degranulation in the skin (hives or atopic urticaria) or anaphylaxis from systemic mast cell degranulation.
Anaphylaxis is due to a generalized degranulation of IgE-sensitized mast cells following allergen exposure and is characterized by bronchospasm and cardiovascular collapse. Common allergens associated with anaphylaxis include bee and wasp stings, certain foods, and drugs (most notably, penicillin).
Clinical tests for allergies and intervention
Sensitivity is normally assessed by the introduction of small amounts of allergen into the skin either via skin prick (scratch test) or intradermal injection, followed by assessment for the wheal and flare (swelling and redness) reaction within 30 mins. Alternatively, allergen-specific serum IgE can be measured by radioallergosorbent test (RAST) or the enzyme-linked immunosorbent assay (ELISA). Skin tests and antigen-specific IgE blood tests are not always an accurate assessment for food allergies.
Treatments
- For some patients, the easiest means to control allergies or asthma is to avoid exposure to known allergens or asthma triggers.
- Modulation of the immunologic response or desensitization by injection of small amounts of allergen can lessen the hypersensitivity reaction to those specific allergens. Desensitization is thought to occur via a stimulation of TH1 cells rather than TH2 cells and, in some cases, a production of increased amounts of IgG rather than IgE. Recent desensitization clinical trials using oral introduction of allergen shows promise, particularly with respect to food allergies, and is thought to occur via the stimulation of TREG cells. Sublingual immunotherapy (SLIT, currently used in Europe for desensitization to environmental allergies) and specific oral tolerance induction (SOTI, used in investigational studies) are not currently approved by the U.S. Food and Drug Administration (FDA) and are considered experimental.
- Another strategy in the treatment of severe, persistent, allergic asthma uses an anti-IgE monoclonal antibody (omalizumab) to inhibit the binding of IgE to the mast cell.
- Mast cell stabilization. Cromolyn sodium (sodium cromoglycate) renders mast cells more resistant to triggering and activation.
- Mediator antagonists. Antihistamines (ethanolamines, most notably diphenhydramine) are H1-receptor competitive antagonists of histamine. Cimetidine and ranitidine competitively inhibit histamine H2 receptors. Epinephrine acts through its α-agonist and β-agonist effects and is the most important drug for the treatment of anaphylaxis.
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