368 paRI I Immune Effector mechanisms FceRI FCeRI ③ PMT (MTIPE ATP cAMP( transient个 Protein kinase⑥ Protein kinase inactive Swollen.么 Mediators (e.g, histamine) Arachidonic acid doplasmic reticulum Leukotriene A,< >Prostaglandin D? LTB4 LTCA LTD4 SRS-A LTEA Secretion Secretion FIGURE 16-6 Diagrammatic overview of biochemical events in face of the plasma membrane causes an increase in membrane fluidity mast-cell activation and degranulation. Allergen crosslinkage of bound and facilitates the formation of Ca+ channels. The resulting influx of IgE results in FCERI aggregation and activation of protein tyrosine ki- Ca activates phospholipase A2, which promotes the breakdown of nase(PTk).(1)PTK then phosphorylates phospholipase C, which con- PC into lysophosphatidylcholine(lyso PC)and arachidonic acid verts phosphatidylinositol-4, 5 bisphosphate(PIP2)into diacylglycerol(5) Arachidonic acid is converted into potent mediators: the leuko- (DAG)and inositol triphosphate(IP3).(2)DAG activates protein ki- trienes and prostaglandin D. (6)FceRI crosslinkage also activates the nase C(PKC), which with Ca* is necessary for microtubular assembly membrane adenylate cyclase, leading to a transient increase of CAMP and the fusion of the granules with the plasma membrane. IP3 is a po- within 15 S. A later drop in cAMP levels is mediated by protein kinase tent mobilizer of intracellular Castores. (3)Crosslinkage of FcERI also and is required for degranulation to proceed. (7)cAMP-dependent pro- ctivates an enzyme that converts phosphatidylserine(PS)into phos. tein kinases are thought to phosphorylate the granule-membrane pro- phatidylethanolamine(PE). Eventually, PE is methylated to form phos- teins, thereby changing the permeability of the granules to water and phatidylcholine(PC)by the phospholipid methyl transferase enzymes I Ca. The consequent swelling of the granules facilitates fusion with the and ll(PMT I and Ii). (4)The accumulation of PC on the exterior sur- plasma membrane and release of the mediators protein kinases, which phosphorylate proteins on the granule Several Pharmacologic Agents Mediate membrane, thereby changing the permeability of the granules Type I Reactions of the granules facilitates their fusion with the plasma mem- The clinical manifestations of type I hypersensitive reactions brane,releasing their contents. The increase in cAMP is tran- are related to the biological effects of the mediators released sient and is followed by a drop in camP to levels below base- during mast-cell or basophil degranulation. These mediators line(see Figure 16-7). This drop in cAMP appears to be are pharmacologically active agents that act on local tissues necessary for degranulation to proceed; when cAMP level as well as on populations of secondary effector cells, includ increased by certain drugs, the degranulation process is ing eosinophils, neutrophils, T lymphocytes, monocytes, and blocked. Several of these drugs are given to treat allergic disor- platelets. The mediators thus amplifying termin ders and are considered later in this section effector mechanism, much as the complement system seryprotein kinases, which phosphorylate proteins on the granule membrane, thereby changing the permeability of the granules to water and Ca2+ (see Figure 16-6). The consequent swelling of the granules facilitates their fusion with the plasma mem￾brane, releasing their contents. The increase in cAMP is tran￾sient and is followed by a drop in cAMP to levels below base￾line (see Figure 16-7). This drop in cAMP appears to be necessary for degranulation to proceed; when cAMP levels are increased by certain drugs, the degranulation process is blocked. Several of these drugs are given to treat allergic disor￾ders and are considered later in this section. Several Pharmacologic Agents Mediate Type I Reactions The clinical manifestations of type I hypersensitive reactions are related to the biological effects of the mediators released during mast-cell or basophil degranulation. These mediators are pharmacologically active agents that act on local tissues as well as on populations of secondary effector cells, includ￾ing eosinophils, neutrophils, T lymphocytes, monocytes, and platelets. The mediators thus serve as an amplifying terminal effector mechanism, much as the complement system serves 368 PART III Immune Effector Mechanisms Swollen granule Allergen IgE Adenylate cyclase PMT II Phospho￾lipase C PKC PKC S S S S PIP2 DAG Active Inactive Ca2+ Ca2+ Ca2+ cAMP (transient) ATP Protein kinase inactive Protein kinase active IP3 Endoplasmic reticulum PC PE PS PMT I Lyso PC Phospho￾Degranulation Fusogens Microtubules and microfilaments Arachidonic acid Ca2+ Ca2+ Granule Prostaglandin D2 (PGD2) Leukotriene A4 LTB4 LTC4 LTD4 LTE4 SRS-A Secretion Secretion lipase A2 Mediators (e.g., histamine) PTK PTK PTK 1 2 6 3 4 7 5 PKC FCεRI FCεRI FIGURE 16-6 Diagrammatic overview of biochemical events in mast-cell activation and degranulation. Allergen crosslinkage of bound IgE results in FcRI aggregation and activation of protein tyrosine ki￾nase (PTK). (1) PTK then phosphorylates phospholipase C, which con￾verts phosphatidylinositol-4,5 bisphosphate (PIP2) into diacylglycerol (DAG) and inositol triphosphate (IP3). (2) DAG activates protein ki￾nase C (PKC), which with Ca2+ is necessary for microtubular assembly and the fusion of the granules with the plasma membrane. IP3 is a po￾tent mobilizer of intracellular Ca2+ stores. (3) Crosslinkage of FcRI also activates an enzyme that converts phosphatidylserine (PS) into phos￾phatidylethanolamine (PE). Eventually, PE is methylated to form phos￾phatidylcholine (PC) by the phospholipid methyl transferase enzymes I and II (PMT I and II). (4) The accumulation of PC on the exterior sur￾face of the plasma membrane causes an increase in membrane fluidity and facilitates the formation of Ca2+ channels. The resulting influx of Ca2+ activates phospholipase A2, which promotes the breakdown of PC into lysophosphatidylcholine (lyso PC) and arachidonic acid. (5) Arachidonic acid is converted into potent mediators: the leuko￾trienes and prostaglandin D2. (6) FcRI crosslinkage also activates the membrane adenylate cyclase, leading to a transient increase of cAMP within 15 s. A later drop in cAMP levels is mediated by protein kinase and is required for degranulation to proceed. (7) cAMP-dependent pro￾tein kinases are thought to phosphorylate the granule-membrane pro￾teins, thereby changing the permeability of the granules to water and Ca2+ . The consequent swelling of the granules facilitates fusion with the plasma membrane and release of the mediators