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（由申请方提供）：IgM + B细胞的分化 进入抗体分泌细胞的发生是对一系列信号的响应，这些信号由 活化的CD4 + T细胞。在这方面，关键分子是CD40配体 活化T细胞表达的CD154，通过其同源相互作用， 与B细胞上的CD40结合，驱动了 抗原激活的IgM + B细胞。近端CD40与肿瘤细胞增殖的关系 信令事件和下游功能没有被完全阐明， 已知这种多步骤方法需要激活许多 信号转导途径我们的实验室一直对 定义早期细胞因子和CD40介导的信号， 人B细胞中开关重组（CSR）。虽然关键作用 CSR中的这些信号是公认的， B细胞整合这些不同类型的信号的能力很差， 表征了我们已经确定了一种B细胞免疫缺陷， 其特征在于对CD40和IL-4信号传导的缺陷反应。B细胞来自 诊断为高IgM综合征的年轻女性患者（患者#1）具有正常的 表达CD40，但在CD40亚群中明显缺乏， IL-4应答功能，包括CD23表达和所需的早期信号 用于开关重组。患者B细胞的一个有趣特征是 在特定的体外条件下， 反应性"并在表达下游同种型中经历转换。我们 我提出，pt#1缺陷是在一个重叠的途径，对两者都很重要， CD40和IL-4介导的B细胞分化。为了验证这个假设，我们 建议1）确定直接受 pt#1缺陷，2）使用CD23和I-γ启动子构建体来研究 转录因子功能，和3）使用遗传学方法鉴定缺陷 互补技术。这些研究的完成将大大 增加我们对B细胞如何利用CD 40和IL-4信号级联的知识 以激活CSR和B细胞分化。此外，这些结果 拟议的实验应该增加我们对高IgM综合征的理解， 鉴定一种参与这种疾病发病机制的新基因。