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FcεRI activation on mast cells/basophils follows a bell-shaped dose–response curve.Supra-optimal antigen concentrations engage negative signaling elements, e.g. SHIP1.FcεRIβ, Lyn, PKC-δ, and SHIP1 may form part of an inhibitory signalosome.Inhibitory signaling could potentially be exploited for therapeutic purposes.IgE-mediated, antigen-triggered activation of mast cells and basophils often results in bell-shaped dose–response curves for the release of various pro-inflammatory mediators. The degree of suppression of mediator release observed following supra-optimal stimulation varies widely for different allergens as well as for different experimental agents that cause crosslinking of high-affinity IgE receptors (FcεRI) on these cells. While the reasons for these differences have not yet been resolved it has become increasingly apparent that supra-optimal stimulation in many cases causes a shift in the balance of stimulatory and inhibitory signal transduction mechanisms arising from FcεRI triggering. In particular, the lipid phosphatase SHIP1 has been shown to be centrally involved in explaining the bell-shaped phenomena in both mast cells and basophils in different species and appears to play a fundamental role in limiting the IgE responsiveness of these allergic effector cells. Elucidating the nature of this inhibitory signaling pathway may provide crucial knowledge in order to optimize desensitization strategies in the treatment of allergic diseases.