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...

We investigated the role of Bruton's tyrosine kinase (Btk) in FcεRI-dependent activation of mouse mast cells, using xid and btk null mutant mice. Unlike B cell development, mast cell development is apparently normal in these btk mutant mice. However, mast cells derived from these mice exhibited significant abnormalities in FcεRI-dependent function. xid mice primed with anti-dinitrophenyl monoclonal IgE antibody exhibited mildly diminished early-phase and severely blunted late-phase anaphylactic reactions in response to antigen challenge in vivo. Consistent with this finding, cultured mast cells derived from the bone marrow cells of xid or btk null mice exhibited mild impairments in degranulation, and more profound defects in the production of several cytokines, upon FcεRI cross-linking. Moreover, the transcriptional activities of these cytokine genes were severely reduced in FcεRI-stimulated btk mutant mast cells. The specificity of these effects of btk mutations was confirmed by the improvement in the ability of btk mutant mast cells to degranulate and to secrete cytokines after the retroviral transfer of wild-type btk cDNA, but not of vector or kinase-dead btk cDNA. Retroviral transfer of Emt (= Itk/Tsk), Btk's closest relative, also partially improved the ability of btk mutant mast cells to secrete mediators. Taken together, these results demonstrate an important role for Btk in the full expression of FcεRI signal transduction in mast cells.