370 paRI I Immune Effector mechanisms TABLE 16-3 Principal mediators involved in type I hypersensitivity Mediat Effects PRIMARY Histamine, heparin Increased vascular permeability; smooth-muscle contraction serotonin Increased vascular permeability; smooth-muscle contraction Eosinophil chemotactic factor(ECF-A) eosinophil chemotaxis Neutrophil chemotactic factor (NCF. eutrophil chemotaxis Proteases Bronchial mucus secretion; degradation of blood-vessel basement membrane generation of complement split products SECONDARY Platelet-activating factor Platelet aggregation and degranulation; contraction of pulmonary smooth muscles Leukotrienes(slow reactive substance of anaphylaxis, SRS-A Increased vascular permeability: contraction of pulmonary smooth muscles Prostaglandins Vasodilation contraction smooth muscles; platelet aggregation B Increased vascular perme ooth-muscle contraction IL-1 and TNF-c Systemic anaphylaxis; increased expression of CAMs on venular endothelial cells IL-2, IL-3, IL-4, IL-5, IL-6, TGF-B, and GM-CSF Various effects(see Table 12-1) bronchoconstrictors than histamine is, and they are also reaction. This was the response observed by portier and more potent stimulators of vascular permeability and mucus Richet in dogs after antigenic challenge. Systemic anaphy secretion. In humans, the leukotrienes are thought to con laxis can be induced in a variety of experimental animals and tribute to the prolonged bronchospasm and buildup of mu- is seen occasionally in humans. Each species exhibits charac Is seen in asthmatics teristic symptoms, which reflect differences in the distribu tion of mast cells and in the biologically active contents of CYTOKINES their granules. The animal model of choice for studying sys- Adding to the complexity of the type I reaction is the variety temic anaphylaxis has been the guinea pig Anaphylaxis can of cytokines released from mast cells and eosinophils. Some be induced in guinea pigs with ease, and its symptoms closely of these may contribute to the clinical manifestations of type I hypersensitivity. Human mast cells secrete IL-4, IL-5, IL-6, Active sensitization in guinea pigs is induced by a single and TNF-a These cytokines alter the local microenviron- injection of a foreign protein such as egg albumin. After an ment, eventually leading to the recruitment of inflammatory incubation period of about 2 weeks. the animal is usually cells such as neutrophils and eosi inophils. IL-4 increases ige challenged with an intravenous injection of the same pro production by B cells. IL-5 is especially important in the tein. Within 1 min, the animal becomes restless, its respira- recruitment and activation of eosinophils. The high concen- tion becomes labored, and its blood pressure drops.As the trations of TNF-a secreted by mast cells may contribute to smooth muscles of the gastrointestinal tract and bladder shock in systemic anaphylaxis. (This effect may parallel the contract, the guinea pig defecates and urinates. Finally bron chiole constriction results in death by asphyxiation within role of TNF-a in bacterial septic shock and toxic-shock syn- 2-4 min of the injection. These events all stem from the sys- drome described in Chapter 12. temic vasodilation and smooth-muscle contraction brought on by mediators released in the course of the reaction. Post Type I Reactions Can Be Systemic mortem examination reveals that massive edema, shock, and or localized bronchiole constriction are the major of death The clinical manifestations of type I reactions can range from Systemic anaphylaxis in humans is characterized by a sim- ilar sequence of events. a wide range of antigens have been life-threatening conditions, such as systemic anaphylaxis and shown to trigger this reaction in susceptible humans, includ asthma, to hay fever and eczema, which are merely annoying. ing the venom from bee, wasp, hornet, and ant stings; drugs, such as penicillin, insulin, and antitoxins; and seafood and SYSTEMIC ANAPHYLAXIS If not treated quickly, these re be fatal. Epi- Systemic anaphylaxis is a shock-like and often fatal state nephrine is the drug of choice for systemic anaphylactic reac- hose onset occurs within minutes of a type I hypersensitive tions. Epinephrine counteracts the effects of mediators suchbronchoconstrictors than histamine is, and they are also more potent stimulators of vascular permeability and mucus secretion. In humans, the leukotrienes are thought to con￾tribute to the prolonged bronchospasm and buildup of mu￾cus seen in asthmatics. CYTOKINES Adding to the complexity of the type I reaction is the variety of cytokines released from mast cells and eosinophils. Some of these may contribute to the clinical manifestations of type I hypersensitivity. Human mast cells secrete IL-4, IL-5, IL-6, and TNF- These cytokines alter the local microenviron￾ment, eventually leading to the recruitment of inflammatory cells such as neutrophils and eosinophils. IL-4 increases IgE production by B cells. IL-5 is especially important in the recruitment and activation of eosinophils. The high concen￾trations of TNF- secreted by mast cells may contribute to shock in systemic anaphylaxis. (This effect may parallel the role of TNF- in bacterial septic shock and toxic-shock syn￾drome described in Chapter 12.) Type I Reactions Can Be Systemic or Localized The clinical manifestations of type I reactions can range from life-threatening conditions, such as systemic anaphylaxis and asthma, to hay fever and eczema, which are merely annoying. SYSTEMIC ANAPHYLAXIS Systemic anaphylaxis is a shock-like and often fatal state whose onset occurs within minutes of a type I hypersensitive reaction. This was the response observed by Portier and Richet in dogs after antigenic challenge. Systemic anaphy￾laxis can be induced in a variety of experimental animals and is seen occasionally in humans. Each species exhibits charac￾teristic symptoms, which reflect differences in the distribu￾tion of mast cells and in the biologically active contents of their granules. The animal model of choice for studying sys￾temic anaphylaxis has been the guinea pig. Anaphylaxis can be induced in guinea pigs with ease, and its symptoms closely parallel those observed in humans. Active sensitization in guinea pigs is induced by a single injection of a foreign protein such as egg albumin. After an incubation period of about 2 weeks, the animal is usually challenged with an intravenous injection of the same pro￾tein. Within 1 min, the animal becomes restless, its respira￾tion becomes labored, and its blood pressure drops. As the smooth muscles of the gastrointestinal tract and bladder contract, the guinea pig defecates and urinates. Finally bron￾chiole constriction results in death by asphyxiation within 2–4 min of the injection. These events all stem from the sys￾temic vasodilation and smooth-muscle contraction brought on by mediators released in the course of the reaction. Post￾mortem examination reveals that massive edema, shock, and bronchiole constriction are the major causes of death. Systemic anaphylaxis in humans is characterized by a sim￾ilar sequence of events. A wide range of antigens have been shown to trigger this reaction in susceptible humans, includ￾ing the venom from bee, wasp, hornet, and ant stings; drugs, such as penicillin, insulin, and antitoxins; and seafood and nuts. If not treated quickly, these reactions can be fatal. Epi￾nephrine is the drug of choice for systemic anaphylactic reac￾tions. Epinephrine counteracts the effects of mediators such 370 PART III Immune Effector Mechanisms TABLE 16-3 Principal mediators involved in type I hypersensitivity Mediator Effects PRIMARY Histamine, heparin Increased vascular permeability; smooth-muscle contraction Serotonin Increased vascular permeability; smooth-muscle contraction Eosinophil chemotactic factor (ECF-A) Eosinophil chemotaxis Neutrophil chemotactic factor (NCF-A) Neutrophil chemotaxis Proteases Bronchial mucus secretion; degradation of blood-vessel basement membrane; generation of complement split products SECONDARY Platelet-activating factor Platelet aggregation and degranulation; contraction of pulmonary smooth muscles Leukotrienes (slow reactive substance of anaphylaxis, SRS-A) Increased vascular permeability; contraction of pulmonary smooth muscles Prostaglandins Vasodilation; contraction of pulmonary smooth muscles; platelet aggregation Bradykinin Increased vascular permeability; smooth-muscle contraction Cytokines IL-1 and TNF- Systemic anaphylaxis; increased expression of CAMs on venular endothelial cells IL-2, IL-3, IL-4, IL-5, IL-6, TGF-, and GM-CSF Various effects (see Table 12-1)