IgE Regulation of Mast Cell Growth and Survival

高亲和力IgE受体（Fc ε RI）介导的肥大细胞活化被认为是哮喘和其他过敏性疾病的发病机制以及宿主对某些寄生虫的防御的关键。 最近，我们已经发现，小鼠肥大细胞的存活和生长的促进单体IgE结合Fc ε RI。 IgE不促进DNA合成，但抑制生长因子剥夺诱导的细胞凋亡。这种抗细胞凋亡作用与IgE诱导的FcepsilonRI表面表达增加平行发生，但需要IgE的持续存在。 这些和其他数据使我们假设，单体IgE结合Fc ε RI通过抑制细胞凋亡促进肥大细胞生长。 单体IgE结合产生的信号与Fc ε RI交联产生的信号明显不同。 由IgE结合的FcepsilonRI启动的抗凋亡过程涉及p75 NTR的加速降解，p75 NTR是神经生长因子和其他神经营养因子的促凋亡低亲和力受体。 为了扩展这一假设，1）我们将研究单体IgE对啮齿动物和人类肥大细胞和嗜碱性粒细胞的生长和存活的体外作用。 根据我们的数据，IgE对生长促进小鼠肥大细胞的体外分化，我们将研究IgE对在IgE存在下产生的肥大细胞的表型和功能的影响。2)我们将分析在肥大细胞中生长因子剥夺诱导的凋亡过程中，单体IgE干扰p75 NTR介导的信号传导事件的分子机制。 为了将我们的体外观察扩展到体内研究，3）我们将研究IgE对肥大细胞/嗜碱性粒细胞生长和存活的体内作用。 这些拟议的研究不仅有望为肥大细胞生物学的IgE依赖性过程提供新的见解，而且还为旨在使用抗IgE mAb或可溶性FcepsilonRI α降低循环IgE以治疗哮喘和其他过敏性疾病的治疗方法提供理论基础。

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.