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Ref Robbins 9/e p202 Immediate (Type I) Hypersensitivity Immediate hypersensitivity is a tissue reaction that occurs rapidly (typically within minutes) after the interaction of antigen with IgE antibody that is bound to the surface of mast cells in a sensitized host. The reaction is initiated by entry of an antigen, which is called an allergen because it triggers allergy. Many allergens are environmental substances that are harmless for most persons on exposure. Some people apparently inherit genes that make them susceptible to allergies. This susceptibility is manifested by the propen- sity of such persons to mount strong TH2 responses and, subsequently, to produce IgE antibody against the aller- gens. The IgE is central to the activation of the mast cells and release of mediators that are responsible for the clinical and pathologic manifestations of the reaction. Immediate hypersensitivity may occur as a local reaction that is merely annoying (e.g., seasonal rhinitis, or hay fever), severely debilitating (asthma), or even fatal (anaphylaxis). Sequence of Events in Immediate Hypersensitivity Reactions Most hypersensitivity reactions follow the same sequence of cellular responses (Fig. 4-7): * Activation of TH2 cells and production of IgE antibody. Aller- gens 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 propeies that endow them with the ability to elicit TH2 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 acti- vates eosinophils that are recruited to the reaction, and IL-13 acts on epithelial cells and stimulates mucus secre- tion. TH2 cells often are recruited to the site of allergic reactions in response to chemokines that are produced locally; among these chemokines is eotaxin, which also recruits eosinophils to the same site. * Sensitization of mast cells by IgE antibody. Mast cells are derived from precursors in the bone marrow, are widely distributed in tissues, and often reside near blood vessels and nerves and in subepithelial locations. Mast cells described in Chapter 2. Eosinophils are recruited by eotaxin express a high-affinity receptor for the Fc poion of the e heavy chain of IgE, called FceRI. Even though the serum concentration of IgE is very low (in the range of 1 to 100 ug/mL), the affinity of the mast cell FceRI recep- tor is so high that the receptors are always occupied by IgE. These antibody-bearing mast cells are "sensitized" to react if the antigen binds to the antibody molecules. Basophils are the circulating counterpas of mast cells. They also express FceRI, but their role in most immedi- ate hypersensitivity reactions is not established (since these reactions occur in tissues and not in the circula- tion). The third cell type that expresses FceRI is eosino- phils, which often are present in these reactions and also have a role in IgE-mediated host defense against hel- minth infections, described later. * Activation of mast cells and release of mediators. When a person who was sensitized by exposure to an allergen is reexposed to the allergen, it binds to multiple specific IgE molecules on mast cells, usually at or near the site of allergen entry. When these IgE molecules are cross- linked, a series of biochemical signals is triggered in the mast cells. The signals culminate in the secretion of various mediators from the mast cells. Three groups of mediators are the most impoant in different immediate hypersensitivity reactions (Fig. 4-8): Vasoactive amines released from granule stores. The gran- ules of mast cells contain histamine, which is released within seconds or minutes of activation. Histamine causes vasodilation, increased vascular permeability, smooth muscle contraction, and increased secretion of mucus. Other rapidly released mediators include adenosine (which causes bronchoconstriction and inhibits platelet aggregation) and chemotactic factors for neutrophils and eosinophils. Other mast cell granule contents that may be secreted include several neutral proteases (e.g., tryptase), which may damage tissues and also generate kinins and cleave comple- ment components to produce additional chemotactic and inflammatory factors (e.g., C3a) (Chapter 2). The granules also contain acidic proteoglycans (heparin, chondroitin sulfate), the main function of which seems to be as a storage matrix for the amines. Newly synthesized lipid mediators. Mast cells synthesize and secrete prostaglandins and leukotrienes, by the same pathways as do other leukocytes (Chapter 2). These lipid mediators have several actions that are impoant in immediate hypersensitivity reactions. Prostaglandin D2 (PGD2) is the most abundant media- tor generated by the cyclooxygenase pathway in mast cells. It causes intense bronchospasm as well as increased mucus secretion. The leukotrienes LTC4 and LTD4 are the most potent vasoactive and spasmo- genic agents known; on a molar basis, they are several thousand times more active than histamine in increas- ing vascular permeability and in causing bronchial smooth muscle contraction. LTB4 is highly chemotac- tic for neutrophils, eosinophils, and monocytes. Cytokines. Activation of mast cells results in the syn- thesis and secretion of several cytokines that are impoant for the late-phase reaction. These include TNF and chemokines, which recruit and activate leu- kocytes (Chapter 2); IL-4 and IL-5, which amplify th TH2-initiated immune reaction; and IL-13, which stimulates epithelial cell mucus secretion. In summary, a variety of compounds that act on blood vessels, smooth muscle, and leukocytes mediate type I hypersensitivity reactions (Table 4-2). Some of these com- pounds are released rapidly from sensitized mast cells and are responsible for the intense immediate reactions associ- ated with conditions such as systemic anaphylaxis. Others, such as cytokines, are responsible for the inflammation seen in late-phase reactions. Often, the IgE-triggered reaction has two well-defined phases (Fig. 4-9): (1) the immediate response, characterized by vasodilation, vascular leakage, and smooth muscle spasm, usually evident within 5 to 30 minutes after expo- sure to an allergen and subsiding by 60 minutes; and (2) a second, late-phase reaction that usually sets in 2 to 8 hours later and may last for several days and is characterized by inflammation as well as tissue destruction, such as mucosal epithelial cell damage. The dominant inflammatory cells in the late-phase reaction are neutrophils, eosinophils, and lymphocytes, especially TH2 cells. Neutrophils are recruited by various chemokines; their roles in inflammation were described in Chapter 2. Eosinophils are recruited by eotaxinTH2-initiated immune reaction; and IL-13, which stimulates epithelial cell mucus secretion. In summary, a variety of compounds that act on blood vessels, smooth muscle, and leukocytes mediate type I hypersensitivity reactions (Table 4-2). Some of these com- pounds are released rapidly from sensitized mast cells and are responsible for the intense immediate reactions associ- ated with conditions such as systemic anaphylaxis. Others, such as cytokines, are responsible for the inflammation seen in late-phase reactions. Often, the IgE-triggered reaction has two well-defined phases (Fig. 4-9): (1) the immediate response, characterized by vasodilation, vascular leakage, and smooth muscle spasm, usually evident within 5 to 30 minutes after expo- sure to an allergen and subsiding by 60 minutes; and (2) a second, late-phase reaction that usually sets in 2 to 8 hours later and may last for several days and is characterized by inflammation as well as tissue destruction, such as mucosal epithelial cell damage. The dominant inflammatory cells in the late-phase reaction are neutrophils, eosinophils, and lymphocytes, especially TH2 cells. Neutrophils are recruited by various chemokines; their roles in inflammation were described in Chapter 2. Eosinophils are recruited by eotaxin