Two recent studies including ours demonstrated that mouse mast cell survival and growth are promoted by monomeric IgE binding to FceRI (Immunity, 14:791, 2001; Immunity 14:801, 2001). These observations, together with earlier studies on IgE-induced upregulation of cell surface expression of FceRI, indicate that IgE binding to FceRI is not simply a "sensitization" step prior to stimulation with antigen, but it is an active signaling process. However, the two studies differ in their potential anti-apoptotic mechanisms: Krystal?s group showed that IgE-bound mast cells produce and secrete a variety of cytokines and render the cells resistant to growth factor deprivation-induced cell death in an autocrine fashion. Consistent with robust cytokine production and prolonged survival, the IgE-bound mast cells exhibit enhanced Bcl-XL and activation of MAP kinases and Akt. By contrast, we did not detect the secretion of any cytokines or activation of MAP kinases and Akt. The anti-apoptotic process does not involve the FasL/Fas death pathway or several Bcl-2 family proteins. To resolve the differences, we have compared anti-apoptotic ability of various monoclonal IgE molecules. Our results demonstrate that all of the various IgE molecules tested show anti-apoptotic effects on mast cells, but that the different IgEs exhibit a wide spectrum in their ability to induce the production and secretion of cytokines by mast cells. At one extreme, the most "highly cytokinergic" (HC) IgEs induce strong anti-apoptotic effects by an autocrine mechanism. At the other end of the spectrum, "poorly cytokinergic" (PC) IgEs induce less robust survival effects, but without inducing detectable cytokine production. Importantly, several lines of evidence indicate that binding of both HC and PC IgEs leads to FceRI aggregation in the absence of specific antigen, with more extensive FceRI aggregation induced by HC than by PC IgEs. Thus, HC IgEs induce degranulation, leukotriene release, receptor internalization, and proliferation. These IgE activities require Syk and are inhibited by monovalent hapten. In IgE hybridoma-transplanted mice, mast cell numbers in some mucosal tissues are correlated with serum IgE levels. Therefore, two types of IgE may affect the pathogenetic process of allergy in a distinctly different manner (Kitaura et al., submitted).