Hypersensitive Reactions CHAPTER 16 369 FIGURE 16-7 Kinetics of major bio- chemical events that follow crosslinkage of bound igE on cultured human ba ex IgE Curves are shown for phospholipid methylation(solid blue). CAMP produc. (solid black ) Ca + influx(dashed blue), and histamine release(dashed black). In control experiments with e anti-IgE Fab fragments, no significant ine release changes were observed. /Adapted from T. Ishizaka et al., 1985, Int. Arch. Allergy 2宝 Appl ImmunoL. 77: 137) Anti-IgE Fab 2 Time. min as an amplifier and effector of an antigen-antibody interac- receptors on various target cells. Three types of histamine re- tion. When generated in response to parasitic infection, these ceptors-designated H1, H2, and Hy-have been identified; mediators initiate beneficial defense processes, including these receptors have different tissue distributions and medi vasodilation and increased vascular permeability, which ate different effects when they bind histamine brings an influx of plasma and inflammatory cells to attack Most of the biologic effects of histamine in allergic reac the pathogen. On the other hand, mediator release induced tions are mediated by the binding of histamine to H, recep by inappropriate antigens, such as allergens, results in unnec- tors. This binding induces contraction of intestinal and bron essary increases in vascular permeability and inflammation chial smooth muscles, increased permeability of venules, and hose detrimental effects far outweigh any beneficial effect. increased mucus secretion by goblet cells. Interaction of his The mediators can be classified as either primary or sec- tamine with H2 receptors increases vasopermeability and ondary (Table 16-3). The primary mediators are produced dilation and stimulates exocrine glands. Binding of hista before degranulation and are stored in the granules. The mine to H2 receptors on mast cells and basophils suppresses most significant primary mediators are histamine, proteases, degranulation; thus, histamine exerts negative feedback on eosinophil chemotactic factor, neutrophil chemotactic fac- the release of mediators tor, and heparin. The secondary mediators either are synthe- sized after target-cell activation or are released by the break- LEUKOTRIENES AND PROSTAGLANDINS down of membrane phospholipids during the degranulation As secondary mediators, the leukotrienes and prostaglandins process. The secondary mediators include platelet-activating are not formed until the mast cell undergoes degranulation factor,leukotrienes, prostaglandins, bradykinins, and various and the enzymatic breakdown of phospholipids in the cytokines. The differing manifestations of type I hypersens- plasma membrane. An ensuing enzymatic cascade generates tivity in different species or different tissues partly reflect the prostaglandins and the leukotrienes(see Figure 16-6).It variations in the primary and secondary mediators present. therefore takes a longer time for the biological effects of these The main biological effects of several of these mediators are mediators to become apparent. Their effects are more pro- described briefly in the next sections nounced and longer lasting, however, than those of histamine leukotrienes mediate bronchoconstriction, increased vas- HISTAMIN cular permeability, and mucus production. Prostaglandin D2 Histamine, which is formed by decarboxylation of the amino causes bronchoconstriction. acid histidine, is a major component of mast-cell granules, The contraction of human bronchial and tracheal smooth accounting for about 10% of granule weight. Because it is muscles appears at first to be mediated by histamine, but tored-preformed-in the granules, its biological effects are within 30-60 s, further contraction is mediated by the leuko- observed within minutes of mast-cell activation. Once re- trienes and prostaglandins. Being active at nanomole levels, leased from mast cells, histamine initially binds to specific the leukotrienes are as much as 1000 times more potentas an amplifier and effector of an antigen-antibody interac￾tion. When generated in response to parasitic infection, these mediators initiate beneficial defense processes, including vasodilation and increased vascular permeability, which brings an influx of plasma and inflammatory cells to attack the pathogen. On the other hand, mediator release induced by inappropriate antigens, such as allergens, results in unnec￾essary increases in vascular permeability and inflammation whose detrimental effects far outweigh any beneficial effect. The mediators can be classified as either primary or sec￾ondary (Table 16-3). The primary mediators are produced before degranulation and are stored in the granules. The most significant primary mediators are histamine, proteases, eosinophil chemotactic factor, neutrophil chemotactic fac￾tor, and heparin. The secondary mediators either are synthe￾sized after target-cell activation or are released by the break￾down of membrane phospholipids during the degranulation process. The secondary mediators include platelet-activating factor, leukotrienes, prostaglandins, bradykinins, and various cytokines. The differing manifestations of type I hypersensi￾tivity in different species or different tissues partly reflect variations in the primary and secondary mediators present. The main biological effects of several of these mediators are described briefly in the next sections. HISTAMINE Histamine, which is formed by decarboxylation of the amino acid histidine, is a major component of mast-cell granules, accounting for about 10% of granule weight. Because it is stored—preformed—in the granules, its biological effects are observed within minutes of mast-cell activation. Once re￾leased from mast cells, histamine initially binds to specific receptors on various target cells. Three types of histamine re￾ceptors—designated H1, H2, and H3—have been identified; these receptors have different tissue distributions and medi￾ate different effects when they bind histamine. Most of the biologic effects of histamine in allergic reac￾tions are mediated by the binding of histamine to H1 recep￾tors. This binding induces contraction of intestinal and bron￾chial smooth muscles, increased permeability of venules, and increased mucus secretion by goblet cells. Interaction of his￾tamine with H2 receptors increases vasopermeability and dilation and stimulates exocrine glands. Binding of hista￾mine to H2 receptors on mast cells and basophils suppresses degranulation; thus, histamine exerts negative feedback on the release of mediators. LEUKOTRIENES AND PROSTAGLANDINS As secondary mediators, the leukotrienes and prostaglandins are not formed until the mast cell undergoes degranulation and the enzymatic breakdown of phospholipids in the plasma membrane. An ensuing enzymatic cascade generates the prostaglandins and the leukotrienes (see Figure 16-6). It therefore takes a longer time for the biological effects of these mediators to become apparent. Their effects are more pro￾nounced and longer lasting, however, than those of histamine. The leukotrienes mediate bronchoconstriction, increased vas￾cular permeability, and mucus production. Prostaglandin D2 causes bronchoconstriction. The contraction of human bronchial and tracheal smooth muscles appears at first to be mediated by histamine, but, within 30–60 s, further contraction is mediated by the leuko￾trienes and prostaglandins. Being active at nanomole levels, the leukotrienes are as much as 1000 times more potent as Hypersensitive Reactions CHAPTER 16 369 45Ca uptake, cpm × 10–3/106 cells ( ) Histamine release, % ( ) 8 6 4 2 50 30 10 Methylation cAMP Ca2+ uptake Anti-IgE Fab Histamine release 1 2 3 5 8 10 Time, min [3H] Methyl incorporation, cpm × 10–3/106 cells ( ) cAMP, pmol/106 cells ( ) 6 4 2 6 5 4 3 2 FIGURE 16-7 Kinetics of major bio￾chemical events that follow crosslinkage of bound IgE on cultured human ba￾sophils with F(ab )2 fragments of anti￾IgE. Curves are shown for phospholipid methylation (solid blue), cAMP produc￾tion (solid black), Ca2+ influx (dashed blue), and histamine release (dashed black). In control experiments with anti–IgE Fab fragments, no significant changes were observed. [Adapted from T. Ishizaka et al., 1985, Int. Arch. Allergy Appl. Immunol. 77:137.]