PATHOGENESIS OF AUTOIMMUNE THROMBOCYTOPENIA

自身免疫性血小板减少症的发病机制

• 批准号: 6527519
• 负责人: Diane J Nugent
• 金额: $ 26.16万
• 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 2004-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6527519
• 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 以及随后的免疫介导的血小板破坏。 初始刺激 对于ITP中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发生或与许多情况有关， 例如：获得性或先天性免疫失调、妊娠、病毒感染 感染如HIV或EBV，或系统性红斑狼疮（SLE）。 的 抗血小板自身抗体在如此广泛的免疫系统中占主导地位， 疾病表明，可能有一种替代机制， 抗血小板生成与其他自身免疫性疾病相比。 在这 补助金，申请人提出了一个模型，ITP和假设， 血小板本身可起到缩短抗原特异性 免疫球蛋白的产生允许自身抗体的出现， 通常受到抗独特型T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 在严格的监督和独特型的对称进化下进行 特异性T细胞克隆。 在他们的模型中，血小板模仿T细胞， 可以促进以前限制性克隆的多克隆扩增， 调节性T细胞或巨噬细胞的伴随参与。 测试 根据这一假设，申请人将集中精力在以下方面： 具体目的#1：确定CD 40、膜Ig (mig)受体和FcRyIII对IL-1 α和IL-1 β基因表达的影响， 在B细胞和树突细胞/巨噬细胞中产生。 具体目标#2：确定多克隆扩增的效果， 表位移位，它们将使用有限的寡核苷酸取代（在 免疫球蛋白框架或CDR 3区）以测量抗原 使用独特工程化的杆状病毒蛋白表达系统结合。 他们的长期目标是确定驱动细胞凋亡的调节障碍。 血小板自身抗体的产生。 他们认为，中断这一 这一过程将使免疫系统回到一个更受限制的B细胞过程， 免疫球蛋白的产生允许T细胞调节，以进一步限制免疫球蛋白的表达。 自体反应克隆的出现。 (End摘要）

项目成果

Identification of a novel regulatory element in the human interleukin 1 alpha (IL-1alpha) gene promoter.

人白细胞介素 1 α (IL-1α) 基因启动子中新型调控元件的鉴定。

• DOI: 10.1006/cyto.2002.1990
• 发表时间: 2002
• 期刊: Cytokine
• 影响因子: 3.8
• 作者: Zaldivar,Frank;Nugent,DianeJ;Imfeld,Karen;Berman,MoniqueA
• 通讯作者: Berman,MoniqueA