Pathways of anaphylaxis in the mouse

Abstract

Background: Although anaphylaxis is classically mediated by IgE, FcϵRI, mast cells, and histamine, several rodent studies suggest that an alternative pathway involving IgG, FcγRIII, macrophages and platelets, and platelet-activating factor (PAF) may be more important in the anaphylactic response to antigen challenge. Objectives: We sought to determine the relative roles of the classical and alternative pathways of anaphylaxis in a mouse model characterized by mastocytosis and a high level of antigen-specific IgE antibody. Methods: Wild-type, IgE-deficient, FcϵRI-deficient, and mast cell–deficient mice were immunized with goat anti-mouse IgD antibody, which induces mastocytosis and a large IgE and IgG anti-goat IgG response, and then challenged 14 days later with antigen (goat IgG) or rat anti-mouse IgE mAb. Specific vasoactive mediators, cell types, Ig isotypes, or Ig receptors were blocked or eliminated before challenge in some experiments. The severity of anaphylaxis was gauged by changes in body temperature, physical activity, and mortality. Results: Equal doses of antigen or anti-IgE mAb induced similar anaphylactic responses. Anti-IgE mAb-induced anaphylaxis was FcϵRI and mast cell dependent and mediated predominantly by histamine. In contrast, neither mast cells nor platelets appeared important for antigen-induced anaphylaxis, which was FcγRIII and macrophage dependent and mediated predominantly by PAF. Conclusions: Antigen-induced anaphylaxis in the mouse proceeds primarily through the IgG, FcγRIII, macrophage, and PAF pathway, even in an experimental model that is characterized by strong mast cell and IgE responses. The presence of FcγRIII on human macrophages makes it possible that the IgG, FcγRIII, macrophage, and PAF pathway also contributes to human anaphylaxis. (J Allergy Clin Immunol 2002;109:658-68.)