IgE Regulation of Mast Cell Growth and Survival

高亲和力IgE受体(FcepsilonRI)介导的肥大细胞活化被认为在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中起关键作用。最近，我们发现与FcepsilonRI结合的单体IgE可以促进小鼠肥大细胞的存活和生长。单体IgE不促进DNA合成，但抑制生长因子剥夺诱导的细胞凋亡。这种抗凋亡作用与IgE诱导的FcepsilonRI表面表达增加同时发生，但需要IgE的持续存在。这些和其他数据使我们假设，单体IgE与FcepsilonRI结合通过抑制凋亡促进肥大细胞生长。单体IgE结合产生的信号与FcepsilonRI交联产生的信号明显不同。由IgE结合的FcepsilonRI启动的抗凋亡过程包括加速p75NTR的降解，p75NTR是一种促凋亡的神经生长因子和其他神经营养因子的低亲和力受体。为了扩大这一假说，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生长和存活的影响。鉴于我们的研究结果表明，IgE对小鼠肥大细胞的体外分化有促进作用，我们将研究在存在IgE的情况下，IgE对肥大细胞表型和功能的影响。2)我们将分析在生长因子剥夺诱导肥大细胞凋亡过程中，单体IgE干扰p75NTR介导的信号事件的分子机制。为了将我们的体外观察扩展到体内研究，3)我们将在体内研究IgE对肥大细胞/嗜碱性粒细胞生长和存活的影响。这些研究不仅有望为肥大细胞生物学中的IgE依赖过程提供新的见解，还将为利用抗IgE单抗或可溶性FcepsilonRIpha降低循环中的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.