The Impact of T Cell Help on Anti-dsDNA B Cells

T 细胞帮助抗 dsDNA B 细胞的影响

• 批准号: 6648502
• 负责人: JAN S. ERIKSON
• 金额: $ 30.56万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-17 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6648502
• 关键词: B lymphocyte; CD95 molecule; antibody formation; antinuclear autoantibody; cell cell interaction; cell differentiation; dendritic cells; disease /disorder model; genetically modified animals; helper T lymphocyte; laboratory mouse; leukocyte activation /transformation; systemic lupus erythematosus

DESCRIPTION (provided by applicant): Anti-dsDNA antibodies (Abs) are one of the diagnostic criteria of systemic lupus erythematosus (SLE). To understand how these autoAbs are regulated in healthy individuals and to identify the mechanisms underlying their expression in autoimmunity, we have used an immunoglobulin transgenic (Ig Tg) model. The advantage of this model is that the development of anti-dsDNA B cells can be tracked in the context of a diverse B cell repertoire in non-autoimmune and autoimmune-prone (lpr/lpr) backgrounds. We present data showing that T cells play a determining role in the phenotype of anti-dsDNA B cells. Using Ab depletion to remove CD4 cells, we have demonstrated that the phenotypic changes in anti-dsDNA B cells in Fas-deficient mice - their follicular entry and maturation - are dependent on T cell help. Additionally, using a model system to provide T cell help, we can induce follicular entry, maturation, and Ab production from anti-dsDNA B cells in Fas-sufficient mice. Collectively, these results suggest that the availability of T cell help is responsible for determining whether anti-dsDNA B cells are functionally silent or become activated. Finally, we have identified unique attributes of the lpr/lpr dendritic cells (DCs) that we hypothesize play a central role in generating the (auto)reactive T cell help in vivo. Here, we propose to extend these preliminary findings to identify first, the nature of the CD4 T cell help in young Fas-deficient mice that promotes follicular entry but not terminal differentiation of anti-dsDNA B cells, and the requirements for T cell help in promoting autoAb production in 10-week-old animals. We will test the ability of distinct classes of T cells to provide T cell help to BALB/c anti-dsDNA B cells in Fas-sufficient mice and to alter the kinetics of autoAb production in lpr/lpr mice. Second, we will examine DC function in lpr/lpr mice, and determine the extent to which alterations in DC phenotype in lpr/lpr mice are involved in the initiation of autoimmunity or are secondary to the dysregulation of T and/or B cells. Defining the processes that release certain self-reactive B cells from their tolerant state is critical to the understanding and eventual treatment of autoimmune disease.

描述（由申请人提供）：抗DSDNA抗体（ABS）是其中之一 全身性红斑狼疮（SLE）的诊断标准。了解如何 这些自动ab在健康的个体中受到监管，并确定 它们在自身免疫性中表达的机制，我们使用了 免疫球蛋白转基因（Ig Tg）模型。该模型的优点是 可以在A的背景下跟踪抗DSDNA B细胞的发展 非自动免疫和自身免疫性免疫的多种B细胞曲目（LPR/LPR） 背景。我们提供数据，显示T细胞在 抗DSDNA B细胞的表型。使用AB耗竭去除CD4细胞，我们 已经证明了抗DSDNA B细胞中的表型变化 缺乏FA的小鼠 - 它们的卵泡进入和成熟 - 取决于T 细胞帮助。此外，使用模型系统提供T细胞帮助，我们可以 诱导抗DSDNA B细胞的卵泡进入，成熟和AB产生 在充足的FAS中。总的来说，这些结果表明 T细胞帮助的可用性负责确定是否抗DSDNA B 细胞在功能上保持沉默或激活。最后，我们已经确定了 我们假设玩耍的LPR/LPR树突状细胞（DC）的独特属性 生成（自动）反应性T细胞在体内帮助的核心作用。 在这里，我们建议将这些初步发现扩展到首先确定 CD4 T细胞的性质在促进的年轻FAS缺陷小鼠中帮助 卵泡的进入，而不是抗DSDNA B细胞的末端分化，而 T细胞的需求有助于促进10周龄的自动产生生产 动物。我们将测试不同类T细胞提供T的能力 细胞帮助BALB/C抗DSDNA B细胞中Fas充足的小鼠的帮助，并改变 LPR/LPR小鼠自动产生的动力学。其次，我们将检查DC 在LPR/LPR小鼠中的功能，并确定DC中的改变程度 LPR/LPR小鼠中的表型参与自身免疫的启动或 继发于T和/或B细胞失调的继发。定义流程 将某些自反应B细胞从其耐受状态释放 自身免疫性疾病的理解和最终治疗。