The pathophysiology of anaphylaxis

Abstract

Anaphylaxis is a severe systemic hypersensitivity reaction that is rapid in onset; characterized by life-threatening airway, breathing, and/or circulatory problems; and usually associated with skin and mucosal changes. Because it can be triggered in some persons by minute amounts of antigen (eg, certain foods or single insect stings), anaphylaxis can be considered the most aberrant example of an imbalance between the cost and benefit of an immune response. This review will describe current understanding of the immunopathogenesis and pathophysiology of anaphylaxis, focusing on the roles of IgE and IgG antibodies, immune effector cells, and mediators thought to contribute to examples of the disorder. Evidence from studies of anaphylaxis in human subjects will be discussed, as well as insights gained from analyses of animal models, including mice genetically deficient in the antibodies, antibody receptors, effector cells, or mediators implicated in anaphylaxis and mice that have been "humanized" for some of these elements. We also review possible host factors that might influence the occurrence or severity of anaphylaxis. Finally, we will speculate about anaphylaxis from an evolutionary perspective and argue that, in the context of severe envenomation by arthropods or reptiles, anaphylaxis might even provide a survival advantage.

Keywords: Anaphylaxis; IgE; basophils; cysteinyl leukotrienes; epinephrine; food allergy; histamine; mast cells; platelet-activating factor; urticaria.

Figure 1. Multiple potential pathways in antibody-mediated anaphylaxis

A Antigen-specific IgE antibodies and FcεRI-bearing effector cells (e.g. mast cells, basophils) play a dominant role in anaphylaxis induced (sometimes by very small amounts of antigen) when concentrations of IgG antibodies are low. B. Mouse models of anaphylaxis suggest that IgG antibodies and FcγR-bearing effector cells (e.g. basophils, macrophages, neutrophils, as well as mast cells) can be important effectors of anaphylaxis induced by large amounts of antigen in the presence of high concentrations of IgG antibodies. Some examples of anaphylaxis likely involve both pathways (A and B). Note that co-engagement of ITAM-containing activating FcγRs or FcεRI with the ITIM-bearing FcγRIIB (on mast cells [in mice, but perhaps not in humans] or basophils [in humans and mice]) can act to diminish effector cell activation. In red: Strong evidence for the importance of these mediators in human anaphylaxis induced by antigen; in blue: These elements can participate in models of anaphylaxis in mice but their importance in human anaphylaxis is not yet clear; in grey: Elements with the potential to influence anaphylaxis, but their importance in human or mouse anaphylaxis not yet clear (e.g., human mast cells are thought to make little or no serotonin).

Figure 2. Pathophysiological changes in anaphylaxis and mediators that have been implicated in these processes

Note: As mentioned in the text, first line treatment of anaphylaxis consists of the rapid administration of epinephrine (see Castells et al.). Although there is evidence that the mediators shown in the figure, particularly histamine and cysteinyl leukotrienes, contribute to some of the various signs and symptoms of anaphylaxis, and anti-histamines are routinely administered to patients with anaphylaxis, pharmacological targeting of such mediators represents second line treatment and should not be considered as an alternative to epinephrine. In red: Strong evidence for the importance of that mediator, in humans, in the development of some of the signs and symptoms listed in the adjacent box; in blue: these elements can be important in mouse models of anaphylaxis but their importance in human anaphylaxis is not yet clear (studies in human subjects suggest that cysteinyl leukotrienes may contribute importantly to the bronchoconstriction and enhanced vascular permeability associated with anaphylaxis [see text]); in grey: elements with the potential to influence anaphylaxis, but their importance in human or mouse anaphylaxis not yet clear. Note that some mediators (underlined) are likely to contribute to the development of late consequences of anaphylaxis.