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Establishing the etiology of recurrent anaphylaxis is a critical aspect of treatment, as the identification of causal allergens allows the use of either avoidance or immunotherapy in the management. Assigning etiology is limited, however, by the number of known antigenic exposures associated with anaphylaxis. Given that anaphylaxis is a severe allergic reaction that can be rapid and occasionally fatal, identification of novel agents that can cause anaphylaxis provides an important step forward in diagnosis and management. The discovery of IgE antibodies to the oligosaccharide alpha-gal has made it possible to investigate several novel aspects of allergic disease, including the role of glycosylation in creating a risk for severe hypersensitivity reactions. The recombinant anti-IgE antibody, omalizumab, has the potential to inhibit allergen-induced mast cell activation regardless of the allergen specificity of the IgE molecules. The mechanisms of action of omalizumab are discussed with specific attention to the role that this monoclonal antibody may have in treating anaphylactic events. In addition to omalizumab, other potential treatments for anaphylaxis may include molecules that can induce tolerance without causing degranulation/secretion of allergic mediators. Certainly the preference of patients and providers alike is the ability to avoid triggering allergens; hence, the continued search for targets of specific IgE remains critical to recommending appropriate avoidance. [ABSTRACT FROM AUTHOR]

Anaphylaxis is shock mediated by cells of the innate immune system. Studies in murine models demonstrate at least three pathways: (1) antigen cross-linking of IgE bound to Fcε(epsilon)RI leads to mast cell degranulation with release of histamine and PAF; (2) antigen-IgG complexes cross-link Fcν(gamma)RIII on mast cells and basophils with secretion of PAF; and (3) complement activation leads to production of C3a and C5a, which activate mast cells, basophils, and macrophages. C3a and C5a appear unable to induce shock by themselves in the murine models, but can exacerbate anaphylaxis induced by the other mechanisms. Anaphylaxis can also be exacerbated by IL-4 and IL-13, which increase effector cell responsiveness to vasoactive mediators, and by β(beta)-adrenergic receptor antagonists, which decrease ability to compensate for vascular leak and decreased intravascular volume. IgG-dependent anaphylaxis requires much higher concentrations of antibody and antigen than IgE-mediated anaphylaxis; consequently, IgG antibodies can block the development of anaphylaxis when antigen quantity is low by binding to antigen before it can cross-link mast cell-associated IgE, but can mediate anaphylaxis when antigen quantity is high. Inhibitory receptors, such as Fcν(gamma)RIIb, can suppress mast cell activation and anaphylaxis, but this effect is less important in our models than IgG neutralization of antigen. Although human IgE anaphylaxis is well established, the existence of IgG-mediated human anaphylaxis is unproven. However, we believe that studies of human anaphylaxis associated with infusion of large quantities of foreign proteins, such as chimeric monoclonal antibodies, make it likely that this type of human anaphylaxis can occur. Elucidation of these mechanisms suggests prophylactic and therapeutic approaches and goals for future anaphylaxis research. [ABSTRACT FROM AUTHOR]

Mast cells are derived from hematopoietic progenitors, which complete their maturation in peripheral tissues. Mast cells are particularly abundant in tissues exposed to the environment, such as the skin, airways, and gastrointestinal tract. Mast cells can be activated to secrete a wide spectrum of mediators, such as histamine and other stored mediators; lipid mediators such as cysteinyl leukotrienes and prostaglandins; and many cytokines, chemokines, and growth factors. IgE-dependent activation of mast cells and basophils and the rapid release of mediators by these cells represent the primary effector mechanisms responsible for the acute manifestations of allergen-induced anaphylaxis in humans. This chapter reviews the basic biology of mast cells, and describes methods for characterizing the functions of mast cells in vivo. We will particularly emphasize the results of studies designed to assess the importance of mast cells in mouse models of active and passive systemic anaphylaxis, and will briefly describe some approaches that are being used to therapeutically target IgE-dependent activation of mast cells. [ABSTRACT FROM AUTHOR]

It seems anti-intuitive that a phenomenon such as anaphylaxis, with explosive -manifestations and distinct symptoms, should be difficult to define. However, since its discovery as a medical event in humans, there have been numerous different definitions. These definitions have evolved over approximately one century since the first demonstration of an anaphylactic event in an animal model. Although we clearly understand the mechanism of production of anaphylactic events, and a successful treatment paradigm has been discovered, there is still debate as to the proper definition of the term ˵anaphylaxis.″ This debate has revolved around the different mechanisms of production, specifically whether the event in question is mediated by IgE, other immunologic mechanisms, or is non-immunologic. The discussion has also revolved around the clinical manifestations required to clearly establish the presence of an anaphylactic event, versus, for example, an immediate hypersensitivity disorder not reaching the requirements for an anaphylactic episode. Thus, a number of meetings have been called and a number of physician statements have been published over the years in an attempt to refine the definition of anaphylaxis and to gather a consensus as to all it includes. This chapter traces the history of the various definitions of this condition, and focuses on those that have more recently appeared in the literature. It also briefly discusses the mechanism of production of these events and their clinical manifestations that have prompted the various definitions in question. [ABSTRACT FROM AUTHOR]

Immunoglobulin E (IgE) is an antibody whose primary response is to allergic reactions and parasitic infections. Most of the body's IgE is bound to specialized tissue cells; little is available in the circulating blood. IgE binds to the membrane of special granulocytes called Ibasophilsi in the circulating blood and Imast cellsi in the tissues. Basophil and mast cell membranes have receptors for IgE. Mast cells are abundant in the skin and the tissues lining the respiratory and alimentary tracts. When IgE antibody becomes cross-linked with antigen/allergen, the release of histamine, heparin, and other chemicals from the granules in the cells is triggered. A sequence of events follows activation of IgE that affects smooth muscle contraction, vascular permeability, and inflammatory reactions. The inflammatory response allows proteins from the bloodstream to enter the tissues. Helminths (worm parasites) are especially susceptible to immunoglobulin-mediated cytotoxic chemicals. The inflammatory reaction proteins attract macrophages from the circulatory system and granulocytes, such as eosinophils, from circulation and bone marrow. Eosinophils also contain enzymes effective against the parasitic invaders. [ABSTRACT FROM AUTHOR]