CD81 AND B CELL ANTIGEN RECEPTOR SIGNALING

描述(改编自调查者摘要)：本报告的目的 项目是分析CD81的作用，CD81是补体的一个组成部分 受体2(CR2)复合体与CD21、CD19和Leu13一起，通过 B细胞抗原受体(BCR)。与CR2复合体的共连接 BCR通过BCR放大信号转导。为了努力 了解CD81在B细胞发育和功能中的作用 研究人员已经培育出CD81基因被破坏的小鼠。初步 对这些小鼠的分析显示，T和B细胞发育完全正常 除了B1细胞数量有较大幅度下降外。CD81-/-小鼠 表达了他们B细胞上CD19的数量显著减少，但他们 血清IgM和IgA升高，表现出夸大的抗体反应 II型T非依赖性抗原TNP-Ficoll，并产生抗DNA 抗体。这些结果表明，CD81缺陷小鼠的B细胞是 对通过BCR发出的信号反应过度。齐西科夫博士建议 研究这种高反应性，并描绘CD81上的残基 对于其在调制BCR信号中的作用是重要的。具体的 目标是：1)对BCR信令进行详细分析 CD81缺陷的B细胞，包括B细胞增殖的检查， 蛋白质酪氨酸磷酸化和交联后的钙离子通量 2)分析膜免疫球蛋白的功能和物理相互作用 BCR及其辅助受体CD19、CD22和磷酸酶，以及3) 对小鼠B细胞系的CD81功能进行突变分析 在表达CD81突变形式的转基因小鼠中。建议进行的研究 CD81在BCR信号转导中的作用可能对 自身免疫性疾病的认识和治疗。

DESCRIPTION (Adapted from the Investigator's Abstract): The purpose of this project is to analyze the role of CD81, a component of the complement receptor 2 (CR2) complex, along with CD21, CD19 and Leu13, in signaling via the B cell antigen receptor (BCR). Co-ligation of the CR2 complex with the BCR amplifies signal transduction through the BCR. In an effort to understand the role of CD81 in B cell development and function, the investigator has generated mice with the CD81 gene disrupted. Preliminary analysis of these mice reveals grossly normal T and B cell development except for a large decrease in the number of B1 cells. CD81-/- mice expressed markedly decreased amounts of CD19 on their B cells, yet they had increased serum IgM and IgA, exhibited an exaggerated antibody response to the type II T-independent antigen TNP-Ficoll, and produced anti-DNA antibodies. These results suggest that B cells from CD81-deficient mice are hyperresponsive to signaling via the BCR. Dr. Tsitsikov proposes to investigate this hyperresponsiveness and to delineate residues in CD81 that are important for its function in modulating BCR signaling. The specific aims are: 1) to perform a detailed analysis of BCR signaling in CD81-deficient B cells, including examination of B cell proliferation, protein tyrosine phosphorylation, and calcium fluxes following crosslinking of membrane IgM, 2) to analyze the functional and physical interactions of the BCR and its co-receptors, CD19 and CD22 and phosphatases, and 3) to perform a mutational analysis of CD81 function in a murine B cell line and in transgenic mice expressing mutant forms of CD81. The proposed studies of the role of CD81 in BCR signaling may have important implications for the understanding and treatment of autoimmune diseases.