Bright Function in the Immune System

描述(由申请人提供)：了解B淋巴细胞如何发育和免疫球蛋白是如何产生的，对于开发有效的疫苗和干预抗体过度表达或不足的免疫疾病至关重要。适当的免疫球蛋白表达与正常的B细胞发育直接相关。转录因子Bright(免疫球蛋白重链转录的B细胞调节因子)促进免疫球蛋白的转录，并与X-连锁免疫缺陷疾病中的缺陷酶Bruton‘s Tyroine Kinase(BTK)有关。BTK缺乏的小鼠和患者表现出B细胞分化受阻，导致血清免疫球蛋白水平异常低。现在的数据表明，Bright Activity非常需要BTK功能。因此，这项提案的目标是确定Bright活性是如何调节的，以及它是否是正常B细胞发育和免疫球蛋白产生所必需的。产生显性阴性光明的转基因小鼠已经被培育出来，并将被评估是否有合适的免疫反应和B细胞亚群的发育。第三种蛋白质与Bright功能有关，它将被进一步鉴定，并将使用传统的报告分析方法研究其对Bright活性和重链转录的贡献。此外，导致活性Bright复合体信息的转录和翻译后调节事件将通过对Bright启动子的直接分析、通过识别Bright转录所需的信号中间体以及通过确定Bright复合体成员之间的蛋白质相互作用的要求来确定。这些实验的结果将有助于我们从总体上理解免疫球蛋白重链转录，并将为了解Bright活性、正常B细胞发育和免疫缺陷疾病之间的关系提供重要的见解。

DESCRIPTION (provided by applicant): Understanding how B lymphocytes develop and how immunoglobulin is produced is critical for development of effective vaccines and for intervention in immunologic diseases where antibodies are either over-or under-expressed. Appropriate immunoglobulin expression is directly linked to normal B cell development. The transcription factor, Bright (B cell regulator of immunoglobulin heavy chain transcription) enhances immunoglobulin transcription and associates with Bruton's tyrosine kinase (Btk), the defective enzyme in X-linked immunodeficiency disease. Mice and patients with Btk deficiencies exhibit blocks in B cell differentiation that result in abnormally low serum immunoglobulin levels. Data now suggest that Bright activity critically requires Btk function. Therefore, the objectives of this proposal are to determine how Bright activity is regulated and whether it is required for normal B cell development and immunoglobulin production. Transgenic mice producing dominant negative Bright have been produced and will be assessed for appropriate immune responses and development of B cell subpopulations. A third protein has been implicated in Bright function, and it will be further characterized and its contribution to Bright activity and heavy chain transcription will be addressed using conventional reporter assays. In addition, the transcriptional and post-translational regulatory events that result information of active Bright complexes will be identified by direct analysis of the Bright promoter, by identifying signaling intermediates necessary for Bright transcription and by determining the requirements for protein interactions among members of the Bright complex. The results of these experiments will contribute to our understanding of immunoglobulin heavy chain transcription in general, and will provide important insights regarding the relationships between Bright activity, normal B cell development and immunodeficiency disease.