Hypersensitive Reactions CHAPTER 16 generated by autoproteolysis of the membrane receptor, has (a) Allergen crosslinkage of (c)Chemical crosslinkage ingly, atopic individuals have higher levels of CD23 on their Ab nd lg been shown to enhance igE production by B cells. Interest- Crosslinking chemical s andn macrophages and higher levels of scD23 in their serum than do nonatopic individuals. IgE Crosslinkage Initiates Degranulation F The biochemical events that mediate degranulation of mast 5 cells and blood basophils have many features in common Mast cell For simplicity, this section presents a general overview of (d)Crosslinkage of IgE mast-cell degranulation mechanisms without calling atten tion to the slight differences between mast cells and baso b)Antibody crosslinkage receptors by of IgE phils. Although mast-cell degranulation generally is initiated Anti-receptor by allergen crosslinkage of bound igE, a number of other stimuli can also initiate the process, including the anaphyla toxins(C3a, C4a, and C5a)and various drugs. This section focuses on the biochemical events that follow allergen crosslinkage of bound igE. RECEPTOR CROSSLINKAGE (e) Enhanced Ca2+ influx IgE-mediated degranulation begins when an allergen cross- Anti-idiotype Ab tha links ige that is bound (fixed) to the Fc receptor on the sur- increases membrane face of a mast cell or basophil. In itself, the binding of igE to permeability to Ca2+ FcERI apparently has no effect on a target cell. It is only after Ca2+ allergen crosslinks the fixed igE-receptor complex that de- Ionophore granulation proceeds. The importance of crosslinkage is in- dicated by the inability of monovalent allergens, which can- not crosslink the fixed IgE, to trigger degranulation. granulation is crosslinkage of two or more FceRI mole- FIGURE 16-5 Schematic diagrams of mechanisms that can trigger cules--with or without bound IgE. Although crosslinkage is degranulation of mast cells. Note that mechanisms(b)and (c)do not normally effected by the interaction of fixed IgE with diva- require allergen: mechanisms (d)and (e)require neither allergen nor lent or multivalent allergen, it also can be effected by a vari- gE and mechanism(e)does not even require receptor crosslinkage ty of experimental means that bypass the need for allergen and in some cases even for IgE (Figure 16-5) Intracellular Events Also Regulate last-Cell Degranulation intracellular stores in the endoplasmic reticulum(see Figure 16-6). The Ca increase eventually leads to the formation of The cytoplasmic domains of the B and y chains of fceRI are arachidonic acid, which is converted into two classes of age of the FcERI receptors activates the associated PTKs. ure 16-6). The increase of Ca2+also promotes the assembly resulting in the phosphorylation of tyrosines within the of microtubules and the contraction of microfilaments, both ITAMs of the y subunit as well as phosphorylation of resi- of which are necessary for the movement of granules to the dues on the p subunit and on phospholipase C. These phos- plasma membrane. The importance of the Ca increase in phorylation events induce the production of a number of mast-cell degranulation is highlighted by the use of drugs second messengers that mediate the process of degranulation such as disodium cromoglycate(cromolyn sodium), that (Figure 16-6) block this influx as a treatment for allergies Within 15 s after crosslinkage of FceRl, methylation of Concomitant with phospholipid methylation and Ca in various membrane phospholipids is observed, resulting in an crease, there is a transient increase in the activity of membrane- increase in membrane fluidity and the formation of Ca+ bound adenylate cyclase, with a rapid peak of its reaction prod channels. An increase of Ca+ reaches a peak within 2 min of uct, cyclic adenosine monophosphate( cAMP), reached about FcERI crosslinkage( Figure 16-7). This increase is due both to 1 min after crosslinkage of FcERI(see Figure 16-7). The effects of the uptake of extracellular Ca and to a release of Ca* from cAMP are exerted through the activation of cAMP-dependentgenerated by autoproteolysis of the membrane receptor, has been shown to enhance IgE production by B cells. Interest￾ingly, atopic individuals have higher levels of CD23 on their lymphocytes and macrophages and higher levels of sCD23 in their serum than do nonatopic individuals. IgE Crosslinkage Initiates Degranulation The biochemical events that mediate degranulation of mast cells and blood basophils have many features in common. For simplicity, this section presents a general overview of mast-cell degranulation mechanisms without calling atten￾tion to the slight differences between mast cells and baso￾phils. Although mast-cell degranulation generally is initiated by allergen crosslinkage of bound IgE, a number of other stimuli can also initiate the process, including the anaphyla￾toxins (C3a, C4a, and C5a) and various drugs. This section focuses on the biochemical events that follow allergen crosslinkage of bound IgE. RECEPTOR CROSSLINKAGE IgE-mediated degranulation begins when an allergen cross￾links IgE that is bound (fixed) to the Fc receptor on the sur￾face of a mast cell or basophil. In itself, the binding of IgE to FcRI apparently has no effect on a target cell. It is only after allergen crosslinks the fixed IgE-receptor complex that de￾granulation proceeds. The importance of crosslinkage is in￾dicated by the inability of monovalent allergens, which can￾not crosslink the fixed IgE, to trigger degranulation. Experiments have revealed that the essential step in de￾granulation is crosslinkage of two or more FcRI mole￾cules—with or without bound IgE. Although crosslinkage is normally effected by the interaction of fixed IgE with diva￾lent or multivalent allergen, it also can be effected by a vari￾ety of experimental means that bypass the need for allergen and in some cases even for IgE (Figure 16-5). Intracellular Events Also Regulate Mast-Cell Degranulation The cytoplasmic domains of the and  chains of FcRI are associated with protein tyrosine kinases (PTKs). Crosslink￾age of the FcRI receptors activates the associated PTKs, resulting in the phosphorylation of tyrosines within the ITAMs of the  subunit as well as phosphorylation of resi￾dues on the subunit and on phospholipase C. These phos￾phorylation events induce the production of a number of second messengers that mediate the process of degranulation (Figure 16-6). Within 15 s after crosslinkage of FcRI, methylation of various membrane phospholipids is observed, resulting in an increase in membrane fluidity and the formation of Ca2+ channels. An increase of Ca2+ reaches a peak within 2 min of FcRI crosslinkage (Figure 16-7). This increase is due both to the uptake of extracellular Ca2+ and to a release of Ca2+ from intracellular stores in the endoplasmic reticulum (see Figure 16-6). The Ca2+ increase eventually leads to the formation of arachidonic acid, which is converted into two classes of potent mediators: prostaglandins and leukotrienes(see Fig￾ure 16-6). The increase of Ca2+ also promotes the assembly of microtubules and the contraction of microfilaments, both of which are necessary for the movement of granules to the plasma membrane. The importance of the Ca2+ increase in mast-cell degranulation is highlighted by the use of drugs, such as disodium cromoglycate (cromolyn sodium), that block this influx as a treatment for allergies. Concomitant with phospholipid methylation and Ca2+ in￾crease, there is a transient increase in the activity of membrane￾bound adenylate cyclase, with a rapid peak of its reaction prod￾uct, cyclic adenosine monophosphate (cAMP), reached about 1 min after crosslinkage of FcRI (see Figure 16-7).The effects of cAMP are exerted through the activation of cAMP-dependent Hypersensitive Reactions CHAPTER 16 367 (a) Allergen crosslinkage of cell-bound IgE (b) Antibody crosslinkage of IgE (c) Chemical crosslinkage of IgE (d) Crosslinkage of IgE receptors by anti-receptor antibody (e) Enhanced Ca2+ influx by ionophore that increases membrane permeability to Ca2+ IgE Fc receptor IgE Allergen Mast cell Anti-isotype Ab Anti-idiotype Ab Crosslinking chemical Anti-receptor Ab Ionophore Ca2+ FIGURE 16-5 Schematic diagrams of mechanisms that can trigger degranulation of mast cells. Note that mechanisms (b) and (c) do not require allergen; mechanisms (d) and (e) require neither allergen nor IgE; and mechanism (e) does not even require receptor crosslinkage.