CD23 Destabilization and IgE Regulation

目前的研究表明，针对CD 23的茎区的抗体引起了 增强人体外和小鼠体内系统中的IgE合成。CD23 在所有淋巴细胞和滤泡树突状细胞上过表达CD 23的转基因小鼠， 在蠕虫和明矾/Ag模型中均显著降低IgE产生。数据显示 其中CD 23的作用最初是作为先天性免疫的组分来发出IgE产生的信号 通过变得不稳定和切割，以及随后通过其在细胞表面的过表达以下调 IgE产生。本项目将研究这些影响的机制。目标1 检查小鼠系统，其中去稳定化mAb 19 G5在体内产生增强的IgE合成。 重要的是，金属蛋白酶ADAM 10已被鉴定为小鼠中的主要CD 23脱落酶， 还有人类ADAM 10在过敏性疾病中的作用将通过制造转基因小鼠来建模， 过表达ADAM 10或产生显性负性ADAM 10。此外，我们亦会研究 通过研究19 G5依赖性IgE产生增强的机制， CD 23与另一种负信号分子LAX，最近已被证明既调节 CD 23表达和调节IgE水平。目标#2将研究CD 23过表达的影响， CD 23在小鼠哮喘模型中的不稳定性与哮喘的调节和加重有关。 疾病我们将利用IgE和新的ADAM 10转基因来评估免疫抑制的机制。 抑制嗜酸性粒细胞增多以及CD 23调节哮喘表型的能力。在 此外，将使用林恩缺陷型小鼠来评估CD 23调节极端免疫应答的能力。 哮喘表型目标#3将研究人体外IgE合成模型， 与IgE合成增强有关的机制，见于抗茎抗体和合成 抑制，用某些抗凝集素mAb观察到。ADAM 10在人CD 23切割中的重要性 和IgE的生产也将探讨将LAX的参与。最后，我们将确定IgE是否 从正常和变应性受试者获得的B细胞的产生受到去稳定化的不同影响 或CD 23的稳定化。总之，这些研究检查了天然药物的作用机制。 IgE产生的调节剂，CD 23，目的是开发方案，以提高CD 23 表达，从而减少IgE的产生，并通过类比，过敏性疾病，如哮喘， 其中IgE起主导作用。

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.