SummaryMast cells have long been believed to be the central effector cells in the development of immunoglobulin (Ig)E-dependent anaphylaxis. In this study, we investigated the role of mast cells in IgE-dependent hapten-induced active fatal anaphylaxis using mast cell-deficient WBB6F1-W/W v ( W/W v ) and congenic normal ( ϩ / ϩ ) mice. Although a 5-min delay in shock signs and death were observed in W/W v mice, 100% fatal reactions to penicillin V (Pen V) occurred in both ϩ / ϩ and W/W v mice. Administration of monoclonal anti-IL-4 antibody completely prevented the fatal reactions, and the effect of anti-IL-4 was associated with its suppressive activity on Pen V-specific serum levels of IgE, but not IgG. The platelet-activating factor (PAF) antagonist, BN 50739, completely prevented the fatal reactions in both strains of mice. Our kinetic study revealed, in contrast to no elevation of plasma histamine level in W/W v mice, high levels of PAF in the circulation after challenge in both ϩ / ϩ and W/W v mice, albeit to a lesser degree in the latter case. These data indicate that cells other than mast cells are sufficient to induce an IgE-dependent active fatal anaphylaxis by elaborating PAF, which is the critical mediator for fatal murine anaphylaxis. Thus, mast cells may not contribute importantly to protein-induced anaphylaxis. Some evidence indicates that protein-induced anaphylaxis can be elicited by IgG Abs (9, 10) even in the absence of IgE Abs (11), suggesting that cells other than mast cells that bind IgG Abs elaborate sufficient mediators leading to fatal reactions. Nevertheless, mast cells have long been believed to be the central effector cells in the development of IgE-dependent anaphylaxis. However, the in vivo extent to which the reactions are mast cell-dependent remains to be elucidated due to the lack of a suitable animal model of IgE-dependent anaphylaxis.We have recently developed a murine model of IgEdependent, penicillin V (Pen V)-induced active fatal anaphylaxis (12). The reaction was 100% fatal in C57BL/6 mice and was exclusively IgE dependent, since ( a ) IgE, but not IgG, Abs against Pen V passively sensitized normal mice to develop severe anaphylactic reactions; ( b ) anti-IL-4 mAb completely prevented the fatal reaction; and ( c ) the effect of anti-IL-4 was associated with its suppressive activity on Pen V-specific serum IgE, but not IgG, levels. This model allowed us to investigate the role of mast cells in IgE-dependent anaphylaxis. In this study, the role of mast cells in IgE-dependent Pen V-induced anaphylaxis using genetically mast cell-deficient WBB6F1-W/W v ( W/W v ) and congenic normal ( ϩ / ϩ ) mice was investigated. It was 1 Abbreviations used in this paper: CGG, chicken gammaglobulin; NP, nitrophenol; PAF, platelet-activating factor; PCA, passive cutaneous anaphylaxis; Pen V, penicillin V.

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