IMMUNOLOGICAL & GENETIC STUDIES OF THROMBOCYTOPENIAS

大多数慢性特发性血小板减少性紫癜（ITP）患者 产生IgG抗血小板抗体，这已被证明是 直接导致了血小板的破坏 基于 发病时，ITP可分为“急性”和“慢性”ITP。 后者通常是在没有先前感染的情况下逐渐发作， 说明是自身免疫机制 因此，慢性ITP也被称为 “自身免疫性血小板减少症”。 虽然几种血小板抗原 由疾病特异性自身抗体识别已经很好地 特征，对罪魁祸首抗体知之甚少，就 它们的结构和遗传因素，以及它们的诱导和 调控 因此，本提案的目标是 表达的编码致病性抗体的IG可变区（V）基因， 抗血小板抗体，识别它们的生殖细胞对应物， 确定体细胞突变在致病性 自身抗体，并评估自身抗体相关的多态性 IG V基因及其与诱导和临床的可能联系 特征（如严重程度、持续时间和对各种治疗的反应） 疾病。 具体来说，我们计划： 1)从患有以下疾病的患者产生单克隆抗血小板杂交瘤： 自身免疫性血小板减少症，并确定免疫学特性 分泌的抗体; 2)克隆并测序上述表达的IG V基因 杂交瘤; 3)鉴定和表征抗血小板药物的生殖系来源 抗体;以及 4)研究所选IG V基因的多态性，包括抗- 血小板抗体相关V基因和生理学上重要的IG V 基因，在患者和正常对照匹配的种族起源。 这些研究将揭示抗血小板药物对IG V基因的利用 患者体内的抗体 疾病特异性自身抗体 一组特殊的V基因 如果是这样，它们是否与 正常免疫系统中的“生理性”自身抗体， 在早期个体发育过程中优先发生？ 答案将 帮助我们了解抗血小板的诱导和调节 抗体，以及静脉注射IG有效性的基础 自身免疫性血小板减少症患者的治疗。 此外，本发明还提供了一种方法， 拟议的多态性研究可能揭示某些V基因的作用， 自身免疫性疾病

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.