IgE-dependent and independent effector mechanisms in human and murine anaphylaxis

Abstract

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 Fcγ(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 Fcγ(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. © 2011 Springer Science+Business Media, LLC.