PATHOGENESIS OF AUTOIMMUNE THROMBOCYTOPENIA

自身免疫性血小板减少症的发病机制

• 批准号: 2751781
• 负责人: Diane J Nugent
• 金额: $ 21.9万
• 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/2751781
• 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 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 以及随之而来的免疫介导的血小板破坏。最初的刺激措施 对于ITP的自身抗体反应尚不清楚，尽管它是 影响成人和儿童的最常见的自身免疫性疾病。ITP 可能作为一种孤立的现象出现或与许多情况相关联， 例如：后天或先天性免疫失调、怀孕、病毒感染 感染，如艾滋病毒或EB病毒，或系统性红斑狼疮(SLE)。这个 抗血小板自身抗体在如此广泛的免疫中的优势 疾病表明，可能有一种替代机制 与其他自身免疫性疾病相比，抗血小板生成。在这 Grant，申请者提出了ITP的模型，并假设 血小板本身可能使抗原特异性的过程短路。 免疫球蛋白的产生使自身抗体的产生成为可能 通常受到抗独特型T和B细胞克隆网络的限制。 正常情况下，B淋巴细胞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， 可以促进以前受限制的克隆的多克隆扩展，而无需 伴随的调节性T细胞或巨噬细胞的参与。为了测试 在这一假设下，申请者将重点在以下几个方面努力： 特异性目的1：确定CD40、Lg膜的结扎效果 (MiG)受体和FcRyIII对IL-1α和IL-1β基因表达的影响 B细胞和树突状细胞/巨噬细胞产生。 具体目的2：确定多克隆扩增和 表位转换，他们将使用有限的寡核苷酸替换(在 免疫球蛋白骨架或CDR3区)来测量抗原的变化 使用独特的工程杆状病毒蛋白表达系统进行结合。 他们的长期目标是找出推动 产生血小板自身抗体。他们认为，中断这一进程 这一过程将使免疫系统返回到受更多限制的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 出现了自体反应克隆。(摘要结束)