CD23 Destabilization and IgE Regulation

目前的研究表明，针对CD23茎区域的抗体导致 人体外和小鼠体内系统中IgE合成的增强。CD23 转基因小鼠在所有淋巴细胞和滤泡树突状细胞上过度表达CD23，表现出 在蠕虫和明矾/银模型中，IgE的产生都显著减少。这些数据表明了一个模型 CD23的作用最初是作为天然免疫的一个组成部分，以产生IgE的信号 通过变得不稳定和被切割，然后通过它在细胞表面的过度表达而下调 IGE制作。本项目将对这些影响的机制(S)进行研究。目标1 检查小鼠系统，其中不稳定的单抗19G5在体内提供增强的IgE合成。 重要的是，金属蛋白酶ADAM10已被确定为小鼠主要的CD23脱落酶 和人类。ADAM10在过敏性疾病中的作用将通过制造转基因小鼠来模拟 过度表达ADAM10或形成显性负值ADAM10。此外，我们还将研究 19G5依赖促进免疫球蛋白E产生的机制 CD23和另一个负信号分子LAX，最近被证明两者都调节 CD23的表达和调节IgE水平。目的：研究CD23过表达对人类免疫功能的影响。 CD23在小鼠哮喘模型中的失稳及其调节和加重 疾病。我们将同时利用IgE和新的ADAM10转基因药物来评估其发病机制(S) 抑制嗜酸性粒细胞增多以及CD23调节哮喘表型的能力。在……里面 此外，Lyn缺陷小鼠将被用来评估CD23调节极端的能力 哮喘表型。目的#3将研究人的体外免疫球蛋白E合成模型 用抗茎抗体和合成观察与IgE合成增强有关的机制 抑制，可见某些抗凝集素单抗。ADAM10在人CD23裂解中的作用 还将探索IgE的产生以及LAX的参与。最后，我们将确定IgE是否 不稳定对正常人和过敏者B细胞的产生有不同的影响 或CD23的稳定。总而言之，这些研究考察了一种天然的 IgE产生的调节因子CD23，目标是开发增强CD23的方案 表达，从而减少IgE的产生，以此类推，减少过敏性疾病，如哮喘 其中IgE占主导地位。

Current studies have indicated that antibodies directed against the stalk region of CD23 cause enhancement of IgE synthesis in both the human in vitro and mouse in vivo systems. CD23 transgenic mice, which overexpress CD23 on all lymphocytes and follicular dendritic cells, exhibit drastically reduced IgE production in both helminth and alum/Ag models. The data suggest a model where the role of CD23 is initially to serve as a component of innate immunity to signal for IgE production by becoming destabilized and cleaved, and later by its overexpression at the cell surface to downmodulate IgE production. This project will investigate the mechanism(s) of these effects. Aim#1 examines the mouse system where the destabilizing mAb 19G5 gives enhanced IgE synthesis in vivo. Importantly, the metalloprotease, ADAM10, has been identified as the primary CD23 sheddase in mouse and humans. The role of ADAM10 in allergic disease will be modeled by making transgenic mice that overexpress ADAM10 or make a dominant negative ADAM10. In addition, we will examine the mechanism for the 19G5-dependent enhancement of IgE production by investigating the association of CD23 with another negative signaling molecule, LAX, which has recently been shown to both modulate CD23 expression and regulate IgE levels. Aim#2 will investigate the affect of CD23 overexpression and CD23 destabilization on the mouse asthma model with respect to both modulation and exacerbation of disease. We will utilize both IgE and the new ADAM10 transgenics to evaluate the mechanism(s) of the suppression of eosinophilia as well as the capacity of CD23 to modulate the asthma phenotype. In addition, Lyn deficient mice will be used to evaluate the capacity of CD23 to modulate the extreme asthma phenotype. Aim#3 will investigate the human in vitro IgE synthesis models with respect to the mechanisms involved in IgE synthesis enhancement, seen with anti-stalk antibodies and synthesis suppression, seen with certain anti-lectin mAbs. The importance of ADAM10 in human CD23 cleavage and IgE production will also be explored as will the involvement of LAX. Finally, we will determine if IgE production by B cells obtained from normal and allergic subjects is affected differently by destabilization or stabilization of CD23. In summary, these studies examine the mechanism of action of a natural regulator of IgE production, CD23, with the objective of developing protocols to enhance CD23 expression and thereby diminish IgE production, and, by analogy, allergic diseases such as asthma in which IgE plays a dominant role.