Fig. 5.12 • Activation of TH2 cells and production of IgE antibody. Allergens may be introduced by inhalation, ingestion, or injection. Variables that probably contribute to the strong TH2 responses to allergens include the route of entry, dose, and chronicity of antigen exposure, and the genetic makeup of the host. It is not clear if allergenic substances also have unique structural or chemical properties that endow them with the ability to elicit TH2
Allergen (e.g., pollen) Mucosal lining
Production of IgE IgE
Binding of IgE to
Repeat exposure to allergen
Activation of mast cell; release of mediators
Vasoactive amines, Cytokineslipid mediators
Immediate hypersensitivity Late phase reaction reaction (minutes after (2–24 hours after repeat repeat exposure to allergen) exposure to allergen)
Fig. 5.12 Sequence of events in immediate (type I) hypersensitivity. Immediate hypersensitivity reactions are initiated by the introduction of an allergen, which stimulates TH2 responses and IgE production in genetically susceptible individuals. IgE binds to Fc receptors (FcεRI) on mast cells, and subsequent exposure to the allergen activates the mast cells to secrete the mediators that are responsible for the pathologic manifestations of immediate hypersensitivity. See text for abbreviations.
responses. Immediate hypersensitivity is the prototypical TH2-mediated reaction. The TH2 cells that are induced secrete several cytokines, including IL-4, IL-5, and IL-13, which are responsible for essentially all the reactions of immediate hypersensitivity. IL-4 stimulates B cells specific for the allergen to undergo heavy-chain class switching to IgE and to secrete this immunoglobulin isotype. IL-5 activates eosinophils that are recruited to the reaction, and IL-13 acts on epithelial cells and stimulates mucus secretion. TH2 cells often are recruited to the site of allergic reactions in response to chemokines that are produced locally; one of these chemokines, eotaxin, also recruits eosinophils to the same site.
Sensitization of mast cells by IgE antibody. Mast cells are derived from precursors in the bone marrow and widely distributed in tissues, often residing near blood vessels and nerves and in subepithelial locations. Mast cells express a high-affinity receptor for the Fc portion of the ε heavy chain of IgE, called FcεRI. Even though the serum concentration of IgE is very low (in the range of 1 to 100 µg/mL), the affinity of the mast cell FcεRI receptor is so high that the receptors are always occupied by IgE. These antibody-bearing mast cells are sensitized to react if the specific antigen (the allergen) binds to the antibody molecules. Basophils are circulating cells that resemble mast cells. They also express FcεRI, but their role in most immediate hypersensitivity reactions is not established (since these reactions occur in tissues and most basophils are in the circulation). The third cell type that expresses FcεRI is eosinophils, which often are present in these reactions.
Activation of mast cells and release of mediators. When a person who was sensitized by exposure to an allergen is reexposed to the allergen, the allergen binds to antigen-specific IgE molecules on mast cells, usually at or near the site of allergen entry. Cross-linking of these IgE molecules triggers a series of biochemical signals that culminate in the secretion of various mediators from the mast cells.
Three groups of mediators are important in different immediate hypersensitivity reactions: