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: 2003068
• 负责人: LORI D KLAMAN
• 金额: $ 2.96万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-31 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2003068
• 关键词: B cell receptor; B lymphocyte; CD antigens; 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.

CD22 是一种 B 谱系限制性磷蛋白，在 B 细胞反应中的调节作用。 CD22 与 B 细胞结合 抗原受体复合物 (BCR) 并被快速磷酸化 表面免疫球蛋白 (sIg) 交联后的酪氨酰残基。 酪氨酰磷酸化 CD22 募集蛋白酪氨酸激酶 (PRK) 结合 BCR，还结合并激活 SHP-1（一种蛋白质酪氨酸） 磷酸酶 (PTP) 负向调节 BCR 介导的信号传导。 在近交小鼠中进行遗传分析，将 CD22 基因座定位到 7 号染色体与狼疮样疾病的发生有关 疾病。 尼尔实验室的最新数据提供了诱人的信息 有证据表明编码小鼠 CD22 的两个等位基因之一可能 在调节 B 细胞内的 PTK 和 PTP 通路方面存在缺陷。 这样的 缺陷可能导致 B 细胞信号异常 导致自身抗体产生或其他免疫功能障碍。 初步分析表明等位基因特异性 B 细胞系 CD22 等位基因缺乏表达，关联有缺陷 SHP-1 和 CD22。 此外，这些细胞表现出异常的酪氨酰 Be 细胞底物的磷酸化。 通过检查 CD22 WEHI-231 细胞的等位基因特异性和 CD22 无效分离株，以及 来自自身免疫小鼠的原代 B 细胞，我将探索这个假设 B 细胞中编码 CD22 的两个等位基因之一有缺陷 发信号。 造成功能差异的域 CD22 等位基因异构体之间的差异将被鉴定。 此外， B 细胞表达变体 CD22 等位基因蛋白的后果 将使用转基因模型在体内探索信号传导。 这些发现共同提供了一个框架来探索令人兴奋的 CD22 的等位基因变体可能有助于 B 细胞异常的发展，以及潜在的自身免疫 小鼠和人类的疾病。