High-affinity IgE receptor (FcepsilonRI)-mediated mast cell activation is thought to be critical to the pathogenesis of asthma and other allergic diseases and the host defense against certain parasites. Recently, we have found that mouse mast cell survival and growth are promoted by monomeric IgE binding to FcepsilonRI. Monomeric IgE does not promote DNA synthesis but suppresses the apoptosis induced by growth factor deprivation. This anti-apoptotic effect occurs in parallel with IgE-induced increases in FcepsilonRI surface expression but requires the continuous presence of IgE. These and other data have led us to hypothesize that monomeric IgE binding to FcepsilonRI promotes mast cell growth by suppressing apoptosis. The signal generated by monomeric IgE binding is distinctly different from those generated by FcepsilonRI cross-linking. The anti-apoptotic process initiated by IgE-bound FcepsilonRI involves accelerated degradation of p75NTR, a pro-apoptotic low-affinity receptor for nerve growth factor and other neurotrophins. In order to expand this hypothesis, 1) we will investigate the in vitro effects of monomeric IgE on the growth and survival of rodent and human mast cells and basophils. In light of our data that IgE on the growth facilitates in vitro differentiation of mouse mast cells, we will investigate the IgE effects on the phenotype and functionality of mast cells generated in the presence of IgE. 2) We will analyze the molecular mechanisms by which monomeric IgE interferes with p75NTR-mediated signaling events during the apoptotic process induced by growth factor deprivation in mast cells. To extend our in vitro observations to in vivo studies, 3) we will investigate in vivo effects of IgE on mast cell/basophil growth and survival. These proposed studies are expected not only to shed novel insight into the IgE-dependent process of mast cell biology but also to provide a theoretical basis for the therapeutic approaches aimed at reducing circulating IgE using anti-IgE mAb or soluble FcepsilonRIalpha to the treatment of asthma and other allergic diseases.
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