Anaphylaxis mediators

Dombrowicz D, Brini AT, Ramand V, Hicks E, Snouwaert JN, Kinet JP, Koller BH. Anaphylaxis mediated through a humanized high affinity IgE receptor. J Immunol 1996 157 1645-1651. 

Horie and coworkers synthesized a series of flavones that showed promising inhibitory activity against archidonate 5-lipooxygenase. This enzyme is responsible for the initiation of bioactive leukotrienes that are chemical mediators of anaphylaxis and inflammation. Under standard K-R conditions o-hydroxyarylketone 66 and anhydride 67 in presence of the corresponding anhydride 68 delivered flavones 69 in yields of 42-65%. Subsequent hydrogenation of 69 afforded the flavone inhibitors 70. 

Chloro-oxazolo[4,5-/i]quinoline-2-carboxylic acid methyl ester was the most active compound in tests for inhibitors of antigen-induced release of histamine in vitro from rat peritoneal mast cells (IC50 of 0.3 p,M) and as inhibitors of IgE-mediated passive cutaneous anaphylaxis in the rat (ED50 (intraperitoneal) of 0.1 mg/kg in dose 0.5 mg/kg as an inhibitor of the test)—10 times and 60 times more potent, respectively, than the disodium salt of cromoglycic acid (85JMC1255). 

The attractive properties of cromolyn as an inhibitor of the release of mediators of anaphylaxis has inspired many attempts to improve on the antiasthmatic characteristics of that substance. One such agent is cromitrile (6). In this case, a tetrazolyl unit is introduced as a carboxy group... 

There are also other immimological mechanisms, especially via IgG or IgM antibodies with immune complex formation, which can lead to similar clinical conditions [20, 34, 42] as has been shown in dextran anaphylaxis (table 1). Triggering of mast cells and basophils leads to release of various vasoactive mediators, among which histamine was the first recognized in 1908 (fig. 3,4) [6]. 

This chapter highlights the mechanisms responsible for mast cell activation during anaphylactic responses to environmental substances. In addition to discussing in detail the activation of mast cells and basophils by IgE and antigen, we also will describe how mouse models have been used to analyze the importance of various proteins, cells, mediators and activation mechanisms in the expression of anaphylaxis in that species. 

In mice and humans, it is possible that mast cells and basophils contribute to the pathophysiology of anaphylaxis both via direct effects on end organ targets and also by indirect effects, including the ability of mast cells and basophils to influence the responsiveness of such target cells to mediators generated in subjects with anaphylaxis. 

It remains to be determined whether, and, if so under what circumstances, IgG-mediated anaphylaxis exists in humans. 

There may be substantial variation both within and among species (e.g., in mice vs. humans) in the expression of various proteins, receptors and/or ligands that influence the activation of mast cells (or basophils or other potential effector cell types), or that can regulate the responsiveness of end organ target cells (e.g., bronchial or gastrointestinal smooth muscle cells, vascular endothelial cells) to potential mediators of anaphylaxis derived from mast cells. 

Although human anaphylaxis is a systemic reaction, the mouse model of passive cutaneous anaphylaxis (PGA) has been used extensively to enhance our understanding of mechanisms which also may contribute to systemic anaphylaxis. Unlike systemic anaphylaxis in the mouse, PGA appears to be entirely dependent on mast cells [4,6]. While IgE appears to be the primary antibody isotype that mediates PCA reactions in actively immunized mice, activation of FcyRIII by a fraction of IgGl antibodies (called anaphylactic IgGl) can also mediate PCA reactions in mice [4]. 

Adding another layer of complexity to the regulation of mast cell activation levels in vivo is the observation that activated mast cells can respond to, and in some cases produce, a myriad of mediators that may serve to amplify FceRI-induced responses. For example, stem cell factor (SCF), the ligand for KIT, both can enhance FceRI-dependent activation of mouse or human mast cells and, under certain circumstances, can directly induce mast cell degranulation [6, 25, 62]. Thus, elevated SCF levels and/or activating KIT mutations (such as those that occur in mastocytosis) may exacerbate mast cell-driven reactions. Indeed, patients (both adult and children) with extensive skin disease associated with mastocytosis are at increased risk to develop severe anaphylaxis [63]. Moreover, it was recently reported that cases of idiopathic anaphylaxis are... 

TsujimuraY, ObataK, Mukai K, Shindou H, Yoshida M, Nishikado H, Kawano Y, Minegishi Y, Shimizu X Karasuyama H Basophils play a pivotal role in SS immunoglobulin-G-mediated but not immuno-globulin-E-mediated systemic anaphylaxis. Immunity 2008 28 581-589. 

Kinet JP, GaUi SJ Systemic anaphylaxis in the mouse can be mediated largely through IgGl and FcyRIII. Assessment of the cardiopulmonary changes, mast cell degranulation, and death associated with active 35 or IgE- or IgGl-dependent passive anaphylaxis. J Clin Invest 1997 99 901-914. 

Strait RT, Morris SC, Finkelman FD IgG-blocking antibodies inhibit IgE-mediated anaphylaxis in vivo through both antigen interception and FcyRIIb cross-linking. J Clin Invest 2006 116 833-841. 

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