We demonstrate that binding of different IgE molecules (IgEs) to their receptor, FcRI, induces a spectrum of activation events in the absence of a specific antigen and provide evidence that such activation reflects aggregation of FcRI. Highly cytokinergic IgEs can efficiently induce production of cytokines and render mast cells resistant to apoptosis in an autocrine fashion, whereas poorly cytokinergic IgEs induce these effects inefficiently. Highly cytokinergic IgEs seem to induce more extensive FcRI aggregation than do poorly cytokinergic IgEs, which leads to stronger mast cell activation and survival effects. These effects of both types of IgEs require Syk tyrosine kinase and can be inhibited by FcRI disaggregation with monovalent hapten. In hybridoma-transplanted mice, mucosal mast cell numbers correlate with serum IgE levels. Therefore, survival effects of IgE could contribute to the pathogenesis of allergic disease. M ast cells are major effector cells for immediate hypersensitivity and allergic diseases. Cross-linking of IgE bound to its high-affinity receptor, FcRI, with multivalent antigen initiates the activation of mast cells by promoting the aggregation of FcRI (1, 2). This FcRI-dependent activation results in degranulation (secretion of preformed mediators that are stored in the cytoplasmic granules, such as vasoactive amines, neutral proteases, proteoglycans, etc.), the de novo synthesis of proinflammatory lipid mediators, and the synthesis and secretion of cytokines and chemokines. In addition to these IgE͞antigen-induced activation events, IgE binding to FcRI in the absence of a specific antigen induces the up-regulation of FcRI surface expression in mast cells and basophils (3, 4) and the prolonged survival of mouse mast cells under growth factor-limiting conditions (5, 6). The enhanced surface expression of FcRI by IgE has been shown to be caused by the stabilization and accumulation of FcRI on the mast cell surface in the presence of continued basal levels of protein synthesis (7,8).Two studies on the survival effect of monomeric IgE (5, 6) suggest differences in the potential mechanisms: Kalesnikoff et al. (6) found that IgE binding induces secretion of a variety of cytokines that enhance cell survival by an autocrine mechanism.In support of this model, they also found tyrosine phosphorylation of the FcRI ␤ subunit and activation of Akt and mitogen-activated protein kinases (MAPKs) in IgE-treated mast cells. In contrast, Asai et al. (5) did not detect significant cytokine secretion or any signaling events, which are known to be elicited by IgE͞antigen-induced FcRI aggregation (9, 10), in IgEtreated mast cells (5).We have addressed why the two studies detected different antiapoptotic mechanisms, and we have performed experiments to elucidate further the mechanisms responsible for these effects. Our results demonstrate that all of the various IgE molecules (IgEs) tested showed antiapoptotic effects on mast cells, but that the different IgEs exhibited a wide spectrum in their ability to induce...

Mast cells play critical roles in hypersensitivity and in defense against certain parasites. We provide evidence that mouse mast cell survival and growth are promoted by monomeric IgE binding to its high-affinity receptor, Fc epsilon RI. Monomeric IgE does not promote DNA synthesis but suppresses the apoptosis induced by growth factor deprivation. This antiapoptotic effect occurs in parallel with IgE-induced increases in Fc epsilon RI surface expression but requires the continuous presence of IgE. This process does not involve the FasL/Fas death pathway or several Bcl-2 family proteins and induces a distinctly different signal than Fc epsilon RI cross-linking. The ability of IgE to enhance mast cell survival and Fc epsilon RI expression may contribute to amplified allergic reactions.

Mast cells (MCs) are key effector cells in allergic reactions. However, the inhibitory mechanism that prevents excessive activation of MCs remains elusive. Here we show that leukocyte mono-immunoglobulin-like receptor 3 (LMIR3; also called CD300f) is a negative regulator of MC activation in vivo. LMIR3 deficiency exacerbated MC-dependent allergic responses in mice, including anaphylaxis, airway inflammation, and dermatitis. Both physical binding and functional reporter assays via an extracellular domain of LMIR3 showed that several extracellular lipids (including ceramide) and lipoproteins were possible ligands for LMIR3. Importantly, MCs were frequently surrounded by extracellular ceramide in vivo. Upon engagement of high-affinity immunoglobulin E receptor, extracellular ceramide-LMIR3 binding inhibited MC activation via immunoreceptor tyrosine-based inhibitory and switch motifs of LMIR3. Moreover, pretreatment with LMIR3-Fc fusion protein or antibody against either ceramide or LMIR3 interfered with this binding in vivo, thereby exacerbating passive cutaneous anaphylaxis. Thus, the interaction between extracellular ceramide and LMIR3 suppressed MC-dependent allergic responses.