IMMUNOLOGICAL AND GENETIC STUDIES OF THROMBOCYTOPENIAS

大多数慢性特发性血小板减少性紫癜(ITP) 产生抗血小板的免疫球蛋白抗体，这已被证明是 对增强的血小板破坏负有直接责任。基于 本病起病时，ITP可分为急性ITP和慢性ITP。 后者通常是逐渐发病的，没有先前的感染， 暗示了一种自体免疫机制。因此，慢性ITP也被称为 “自身免疫性血小板减少症”。而几种血小板抗原 被认为是疾病特异性的自身抗体已经很好地 特征是，关于罪犯抗体，就以下方面而言，人们知之甚少 它们的结构和遗传元素，以及它们的诱导和 监管。因此，这项提案的目标是将 表达的编码致病病毒的免疫球蛋白可变区(V)基因 抗血小板抗体，鉴定它们的种系对应抗体， 确定体细胞突变在致病基因产生中的作用 自身抗体，并评估自身抗体相关基因的多态性 免疫球蛋白V基因及其与诱导和临床的可能连锁 特征(如严重程度、持续时间和对各种治疗的反应) 这些疾病。具体来说，我们计划： 1)从患者体内产生抗血小板的单抗杂交瘤 自身免疫性血小板减少，并测定其免疫学特性 分泌的抗体； 2)克隆并测序上述基因中表达的Ig V基因 杂交瘤； 3)鉴定和鉴定抗血小板的种系来源 抗体；以及 4)研究选定的免疫球蛋白V基因的多态性，包括抗- 血小板抗体相关V基因与重要的生理免疫球蛋白V 患者和正常对照组的基因具有相同的种族来源。 这些研究将揭示Ig V基因在抗血小板中的作用 患者体内的抗体。疾病特异性自身抗体是否使用 一组特殊的V基因？如果是，它们是否类似于 “生理性”自身抗体在正常免疫系统中的表达 优先发生在个体发育的早期？答案将是 帮助我们了解抗血小板的诱导和调节 抗体以及静脉注射免疫球蛋白有效性的基础 自身免疫性血小板减少症患者的治疗。此外, 拟议的多态研究可能揭示某些V基因的作用 在这种自身免疫性疾病中。

Most patients with chronic idiopathic thrombocytopenic purpura (ITP) produce IgG anti-platelet antibodies, which have been shown to be directly responsible for the enhanced platelet destruction. Based on the disease onset, ITP can be divided into "acute" and "chronic" ITP. The latter often has a gradual onset with no preceding infection, suggesting an autoimmune mechanism. As such, chronic ITP is also called "autoimmune thrombocytopenia". While several platelet antigens recognized by the disease-specific autoantibodies have been well characterized, little is known about the culprit antibodies, in terms of their structures and genetic elements, as well as their induction and regulation. Therefore, the goals of this proposal are to characterize the expressed Ig variable region (V) genes that encode the pathogenic anti-platelet antibodies, identify their germline counterparts, determine the role of somatic mutations in the production of pathogenic autoantibodies, and assess the polymorphisms of the autoantibody-related Ig V genes and their possible linkage to the induction and clinical features (such as severity, duration and responses to various treatment) of the diseases. Specifically, we plan to: 1) generate monoclonal anti-platelet hybridomas from patients with autoimmune thrombocytopenia, and determine the immunological properties of the secreted antibodies; 2) clone and sequence the expressed Ig V genes in the aforementioned hybridomas; 3) identify and characterize the germline origins of the anti-platelet antibodies; and 4) study the polymorphisms of the selected Ig V genes, including anti- platelet antibody-associated V genes and physiologically important Ig V genes, in patients and normal controls matched for ethnic origins. These studies will reveal the Ig V gene usage by anti-platelet antibodies in patients. Do the disease-specific autoantibodies employ a special set of V genes? If so, are they similar to those used by the "physiological" autoantibodies in normal immune system and expressed preferentially during early ontogenic development? The answers will help us understand the induction and regulation of anti-platelet antibodies, as well as the basis of the effectiveness of intravenous Ig treatment in patients with autoimmune thrombocytopenia. In addition, the proposed polymorphism studies may reveal the role of certain V genes in this autoimmune disorder.