Human B cell Differentiation in a Model system

模型系统中的人类 B 细胞分化

• 批准号: 6624145
• 负责人: LORI Ruth COVEY
• 金额: $ 22.92万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-15 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6624145
• 关键词: B lymphocyte; CD antigens; CD40 molecule; Epstein Barr virus; biological signal transduction; cell differentiation; child (0-11); female; gene complementation; gene mutation; gene rearrangement; genetic promoter element; genetic techniques; human subject; hyperglobulinemia; immunoglobulin M; immunoglobulin genes; interleukin 4; molecular pathology; patient oriented research; transcription factor; transfection /expression vector

DESCRIPTION (provided by the applicant): The differentiation of IgM+ B cells into Ab secreting cells occurs in response to an array of signals provided by activated CD4+ T cells. A critical molecule in this regard is the CD40 ligand (CD154) expressed by activated T cells which through its cognate interaction with CD40 on B cells drives the proliferation and differentiation of antigen-activated IgM+ B cells. The relationship between proximal CD40 signaling events and downstream functions are not fully elucidated however, it is known that this multi-step process requires that activation of numerous signal transduction pathways. Our laboratory has had an ongoing interest in defining the early cytokine- and CD40-mediated signals required for class switch recombination (CSR) in human B cells. Although the critical roles of these signals in CSR are well recognized, the molecular mechanisms utilized by B cells to integrate these distinct classes of signals are poorly characterized. We have identified a B cell immunodeficiency that is distinguished by defective responses to CD40 and IL-4 signaling. B cells from a young female patient (pt#1) diagnosed with hyper-IgM syndrome have normal expression of CD40 but are clearly deficient in a subset of CD40- and IL-4-responsive functions including CD23 expression and early signals required for switch recombination. One intriguing characteristic of the patient B cells is that under specific in vitro conditions they regain "functional responsiveness" and undergo switching in express downstream isotypes. We propose that the pt#1 defect is in an overlapping pathway important for both CD40- and IL-4-medicated B cell differentiation. To test this hypothesis, we propose to 1) identify signaling pathways that are directly affected by the pt#1 defect, 2) use CD23 and I-gamma promoter constructs to investigate transcription factor function, and 3) identify the defect using genetic complementation techniques. Completion of these studies should significantly increase our knowledge of how B cells utilize CD40 and IL-4 signaling cascades to activate CSR and B cell differentiation. Furthermore, results from these proposed experiments should increase our understanding of hyper-IgM syndrome by identifying a novel gene involved in the pathogenesis of this disease.

描述（由申请人提供）：IgM+ B 细胞的分化 进入抗体分泌细胞是响应一系列信号而发生的 激活的 CD4+ T 细胞。这方面的一个关键分子是 CD40 配体 (CD154) 由活化的 T 细胞表达，通过其同源相互作用 B 细胞上的 CD40 驱动 B 细胞的增殖和分化 抗原激活的 IgM+ B 细胞。近端CD40之间的关系 然而，信号事件和下游功能尚未完全阐明 众所周知，这个多步骤过程需要激活许多 信号转导途径。我们的实验室一直对 定义课程所需的早期细胞因子和 CD40 介导的信号 人类 B 细胞中的开关重组 (CSR)。虽然关键角色 CSR 中的这些信号已得到广泛认可，其利用的分子机制 B 细胞整合这些不同类别的信号的能力很差 特点。我们已经确定了一种 B 细胞免疫缺陷病 其特征是对 CD40 和 IL-4 信号传导的缺陷反应。 B细胞来自a 诊断患有高 IgM 综合征的年轻女性患者 (pt#1) 的健康状况正常 CD40 的表达，但明显缺乏 CD40- 和 IL-4 响应功能，包括 CD23 表达和所需的早期信号 用于开关重组。患者 B 细胞的一项有趣特征 是在特定的体外条件下它们恢复了“功能” 响应性”并经历快速下游同种型的转换。我们 提出 pt#1 缺陷位于对两者都很重要的重叠途径中 CD40 和 IL-4 介导的 B 细胞分化。为了检验这个假设，我们 建议 1) 确定直接受 pt#1 缺陷，2) 使用 CD23 和 I-gamma 启动子构建体进行研究 转录因子功能，以及 3) 使用遗传识别缺陷 互补技术。完成这些研究应该显着 增加我们对 B 细胞如何利用 CD40 和 IL-4 信号级联的了解 激活 CSR 和 B 细胞分化。此外，这些结果 拟议的实验应该通过以下方式增加我们对高 IgM 综合征的理解： 鉴定出参与该疾病发病机制的新基因。