CD22 ALLELE SPECIFIC DIFFERENCES IN B CELL SIGNALING

B 细胞信号转导中的 CD22 等位基因特异性差异

• 批准号: 2886284
• 负责人: LORI D KLAMAN
• 金额: $ 4万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2886284
• 关键词: B cell receptor; B lymphocyte; CD22 molecule; alleles; autoimmunity; biological signal transduction; cell line; fusion gene; immunoprecipitation; laboratory mouse; transfection

CD22 is a B-lineage restricted phosphoprotein that plays a key modulatory role in B-cell responses. CD22 associates with the B cell antigen receptor complex (BCR) and is rapidly phosphorylated on tyrosyl residues following surface immunoglobulin (sIg) cross-linking. Tyrosyl-phosphorylated CD22 recruits protein tyrosine kinases (PRKs) to the BCR, and also binds to and activates SHP-1, a protein tyrosine phosphatase (PTP) that negatively regulates BCR-mediated signaling. Genetic analyses, in inbred mice, maps the CD22 locus to a region of chromosome 7 that has been linked to the genesis of lupus-like disease. Recent data from the Neel laboratory provides tantalizing evidence to suggest that one of two alleles, encoding mouse CD22, may be defective in regulating PTK and PTP pathways within B cells. Such a defect could lead to anomalous B cell signaling, potentially resulting in autoantibody production or other immune dysfunction. Preliminary analysis suggest that allele-specific B cell lines, which lack expression of this CD22 allele, are defective in the association of SHP-1 and CD22. Moreover, these cells exhibit aberrant tyrosyl phosphorylation of Be cell substrates. By examining CD22 allelic-specific and CD22 null isolates of WEHI-231 cells, as well as primary B cells from autoimmune mice, I will explore the hypothesis that one of two alleles encoding CD22 is defective in B cell signaling. The domains responsible for the functional differences between CD22 allelic isoforms will be identified. In addition, the consequences of expressing variant CD22 allelic-proteins for B cell signaling will be explored in vivo using a transgenic model. Together, these findings provide a framework to explore the exciting possibility that an allelic variant of CD22 contributes to the development of B cell abnormalities, and potentially autoimmune disease, in mouse and man.

CD 22是一种B系限制性磷蛋白， B细胞反应的调节作用。 CD 22与B细胞相关 抗原受体复合物（BCR），并迅速磷酸化 表面免疫球蛋白（sIg）交联后的酪氨酸残基。 酪氨酰磷酸化CD 22募集蛋白酪氨酸激酶（PRKs） BCR，也结合并激活SHP-1，一种蛋白酪氨酸 磷酸酶（PTP）负调节BCR介导的信号传导。 在近交系小鼠中，遗传分析将CD 22基因座定位到 7号染色体与狼疮样 疾病 尼尔实验室的最新数据提供了诱人的 有证据表明，编码小鼠CD 22的两个等位基因之一， 在调节B细胞内的PTK和PTP途径方面有缺陷。 等 缺陷可能导致异常的B细胞信号传导， 导致自身抗体产生或其它免疫功能障碍。 初步分析表明，等位基因特异性B细胞系， 缺乏该CD 22等位基因的表达，在关联中有缺陷， SHP-1和CD 22。 此外，这些细胞表现出异常的酪氨酰 Be细胞底物的磷酸化。 通过检测CD 22 WEHI-231细胞的等位基因特异性和CD 22无效分离物，以及 自体免疫小鼠的原代B细胞，我将探讨这一假设 编码CD 22的两个等位基因之一在B细胞中是有缺陷的 发信号。 导致功能差异的域 将鉴定CD 22等位基因同种型之间的差异。 此外该 表达变体CD 22等位基因蛋白对B细胞的影响 将使用转基因模型在体内探索信号传导。 总之，这些发现提供了一个框架，以探索令人兴奋的 CD 22的等位基因变异体有助于 B细胞异常和潜在的自身免疫性 在老鼠和人身上。