PATHOGENESIS OF AUTOIMMUNE THROMBOCYTOPENIA

自身免疫性血小板减少症的发病机制

基本信息

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
项目类别：
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

项目摘要

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）是自身免疫性疾病的特征是产生抗血小板抗体并因此免疫介导的血小板破坏。初始刺激因为ITP中的自身抗体响应尚不清楚，即使它是之一影响成年人和儿童的最常见自身免疫性疾病。 ITP 可能是作为孤立现象或与许多条件相关的例如：获得或先天性免疫失调，妊娠，病毒感染HIV或EBV，或全身性红斑狼疮（SLE）。这抗血小板自身抗体在如此多种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，抗血小板产生。在这个申请人授予了ITP的模型，并假设血小板本身可能作用于抗原特异性的短路免疫球蛋白产生允许出现自身抗体通常受抗IDIOTYPIC 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对称的习语演变下进行特定的T细胞克隆。在他们的模型中，血小板模仿T细胞，可以促进先前限制的克隆的多克隆扩展调节T细胞或巨噬细胞的伴随参与。测试这个假设，申请人将重点放在以下领域：特定目的＃1：确定CD40连接的影响，膜LG （MIG）IL-1Alpha和IL-1Beta基因表达上的受体和FCRYIII和在B细胞和树突细胞/巨噬细胞中产生。特定目的＃2：确定多克隆扩展的影响和表位转移，他们将使用有限的寡核苷酸取代（在内免疫球蛋白框架或CDR3区域）以测量抗原的变化使用独特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驱动的失调血小板自身抗体的产生。他们认为这中断过程将使免疫系统返回到B细胞的更限制的过程免疫球蛋白产生允许T细胞调节进一步限制自动反应性克隆的出现。（抽象的结尾）