PATHOGENESIS OF AUTOIMMUNE THROMBOCYTOPENIA

自身免疫性血小板减少症的发病机制

• 批准号: 6390187
• 负责人: Diane J Nugent
• 金额: $ 29.2万
• 依托单位: CHILDREN'S HOSPITAL OF ORANGE COUNTY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390187
• 关键词: B lymphocyte; CD16 molecule; CD40 molecule; antigen antibody reaction; antiidiotype antibody; autoantibody; autoimmune disorder; clinical research; enzyme linked immunosorbent assay; epitope mapping; human subject; immunoglobulin structure; interleukin 1; lymphocyte proliferation; pathologic process; phlebotomy; platelets; thrombocytopenia; tissue /cell culture

DESCRIPTION (Adapted from applicant's abstract) Idiopathic Thrombocytopenia (ITP) is an autoimmune disorder characterized by production of antiplatelet antibodies and consequent immune-mediated platelet destruction. The initial stimulus for the autoantibody response in ITP is not known, even though it is one of the most common autoimmune diseases affecting both adults and children. ITP may occur as an isolated phenomenon or in association with many conditions, for example: acquired or congenital immune dysregulation, pregnancy, viral infection like HIV or EBV, or systemic lupus erythematosus (SLE). The dominance of antiplatelet autoantibodies in such a wide variety of immune diseases suggests that there may be an alternative mechanisms to antiplatelet production as compared to other autoimmune diseases. In this grant, the applicants present a model for ITP and hypothesize that the platelet itself may act to short circuit the process of antigen specific immunoglobulin production allowing the emergence of autoantibodies which are normally restricted by a network of anti-idiotypic T and B cell clones. Ordinarily, somatic mutation and antigen selection in the B lymphocyte proceed under the strict supervision and symmetrical evolution of idiotype specific T cell clones. In their model, the platelet, mimicking a T cell, could promote polyclonal expansion of previously restricted clones without the concomitant involvement of regulatory T cells or macrophages. To test this hypothesis, the applicants will focus their efforts in following areas: SPECIFIC AIM #1: To determine the effect of ligation of CD40, membrane lg (mig) receptor, and FcRyIII on IL-1alpha and IL-1beta gene expression and production in B cells and dendritic cell/macrophages. SPECIFIC AIM #2: To determine the effect of polyclonal expansion and epitope shifts, they will use limited oligonucleotide substitutions (within the immunoglobin framework or CDR3 region) to measure changes in antigen binding using a uniquely engineered baculovirus protein expression system. Their long term goal is to identify the dysregulation which drives the production of platelet autoantibody. They believe that interruption of this process will return the immune system to a more restricted process of B cell immunoglobulin production allowing T cell regulation to further limit the emergence of autoreactive clones. (End of Abstract)

描述 （改编自申请人的摘要）特发性血小板减少症（ITP）是一种 以产生抗血小板抗体为特征的自身免疫性疾病 以及随后的免疫介导的血小板破坏。 最初的刺激 对于 ITP 中的自身抗体反应尚不清楚，尽管它是其中之一 影响成人和儿童的最常见自身免疫性疾病。 ITP 可能作为一种孤立现象发生或与许多条件相关， 例如：获得性或先天性免疫失调、怀孕、病毒 HIV 或 EBV 等感染，或系统性红斑狼疮 (SLE)。 这 抗血小板自身抗体在如此广泛的免疫中占据主导地位 疾病表明可能存在替代机制 与其他自身免疫性疾病相比，抗血小板产生。 在这个 授予，申请人提出了一个 ITP 模型并假设 血小板本身可能会短路抗原特异性的过程 免疫球蛋白的产生使得自身抗体的出现 通常受到抗独特型 T 细胞和 B 细胞克隆网络的限制。 通常，B淋巴细胞中的体细胞突变和抗原选择 在独特型的严格监督和对称进化下进行 特定的 T 细胞克隆。 在他们的模型中，血小板模仿 T 细胞， 可以促进先前限制性克隆的多克隆扩增，而无需 调节性 T 细胞或巨噬细胞的伴随参与。 测试 根据这一假设，申请人将重点在以下几个方面努力： 具体目标#1：确定 CD40、膜 lg 连接的效果 (mig) 受体和 FcRyIII 对 IL-1α 和 IL-1β 基因表达的影响 B 细胞和树突细胞/巨噬细胞中的产生。 具体目标#2：确定多克隆扩增的效果和 表位转移，他们将使用有限的寡核苷酸取代（在 免疫球蛋白框架或 CDR3 区域）来测量抗原的变化 使用独特设计的杆状病毒蛋白表达系统进行结合。 他们的长期目标是找出导致 血小板自身抗体的产生。 他们认为，中断这种情况 过程将使免疫系统返回到更受限制的 B 细胞过程 免疫球蛋白的产生允许 T 细胞调节进一步限制 自身反应性克隆的出现。 （摘要完）