CD22, A REGULATOR OF B CELL ACTIVATION

CD22，B 细胞激活的调节因子

• 批准号: 2887810
• 负责人: Henry H. Wortis
• 金额: $ 17.35万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2887810
• 关键词: B cell receptor; B lymphocyte; CD22 molecule; biological signal transduction; calcium flux; immunoprecipitation; laboratory mouse; leukocyte activation /transformation; phosphorylation; protein structure function; receptor expression; site directed mutagenesis; tissue /cell culture

DESCRIPTION (Adapted from Investigator's abstract): Loss of function mutations affecting proteins required for B-cell activation typically lead to immune deficiency or impairment of antibody production, as in X-linked agammaglobulinemia (XLA) or deletional mutation of CD19. Conversely, mutation of negative regulators, such as the hematopoietic phosphatase SHP-1 (as in motheaten), FAS (as in lymphoproliferative disorder [lpr]) or deletional mutation of CD22, can result in increased production of autoantibodies. This suggests that detailed knowledge of these negative regulatory pathways would aid in the identification of targets for pharmacologic or genetic intervention in auto-immune disorders. Our overall goal is to achieve a better understanding of the mechanisms by which one negative regulator, CD22, functions. CD22, which is expressed exclusively on B cells, is a type 1 transmembrane surface molecule that has been implicated as a negative regulator of the B cell receptor. Functional and biochemical studies indicate that ligation of CD22 alters the signals transduced as a result of B cell receptor (BCR) cross-linking. Deletion mutation of CD22 leads to profound alteration in B cell function that can result in the production of increased amounts of autoantibodies. A combination of genetic and biochemical approaches will be used in a detailed structure/function analysis of this molecule. We will exploit unique tools that we have recently created, which include a transformed B cell line derived from CD22 knockout mice, a CD22 allele-loss variant of the well characterized B cell line WEH1 231, and a CD22 overexpression line. We expect to define the functions of CD22's six cytoplasmic tyrosine residues; determine if the transmembrane and highly conserved juxtamembrane domains of CD22 have specific functions; and determine if the sialic acid binding domains are necessary for function or for the known association with the BCR. We will also characterize molecules that interact with CD22 and participate in the negative regulation of B cell function. An understanding of genes encoding molecules required for negative regulation would aid in future searches for allelic variants that might predispose to autoimmunity.

描述(改编自调查者摘要)：功能丧失 影响B细胞激活所需蛋白质的突变通常会导致 免疫缺陷免疫缺陷或抗体产生障碍，如X-连锁 无丙种球蛋白血症(XLA)或CD19缺失突变。相反， 负调控因子突变，如造血磷酸酶SHP-1 Fas(淋巴组织增生性疾病[LPR])或 CD22的缺失突变，可导致产量增加 自身抗体。这表明，对这些负面因素的详细了解 监管途径将有助于确定目标 自身免疫性疾病的药物或遗传干预。 我们的总体目标是通过以下方式更好地理解这些机制 哪种负向调节因子CD22起作用。CD22，它表达 是一种1型跨膜表面分子，具有 被认为是B细胞受体的负调节因子。功能性 生化研究表明，CD22的连接改变了信号 由于B细胞受体(BCR)的交联而被转导。删除 CD22突变导致B细胞功能发生深刻变化 导致产生更多的自身抗体。一个 遗传和生化方法的结合将在一个详细的 该分子的结构/功能分析。我们将利用独特的工具 我们最近创造的，其中包括一个转化的B细胞系 来自CD22基因敲除小鼠，Well的CD22等位基因缺失变体 鉴定了B细胞系WEH1 231和CD22高表达系。我们 期望明确CD22‘S 6个胞质酪氨酸残基的功能； 确定其跨膜结构域和高度保守的膜旁结构域是否 CD22具有特定的功能；并确定唾液酸结合 域对于功能或已知的与 BCR。我们还将描述与CD22和CD22相互作用的分子 参与B细胞功能的负性调节。一种理解 编码负调控所需分子的基因将有助于 未来寻找可能易患自身免疫的等位基因变异。