MONOCLONAL ITP AUTOANTIBODIES--PARADIGM FOR AUTOIMMUNITY

自身免疫性疾病的研究通过关注 其中自身抗体明显有助于 致病过程 因为抗血小板抗体直接导致 疾病的表现，ITP作为一个很好的模型， 了解自身免疫的发病机制。临床上，ITP是 最常见的自身免疫性血液病 它可以发生 特异性地或在免疫系统的其他病症的情况下 如HIV感染、SLE、AIHA和CLL。 治疗直接针对 修饰体液免疫应答是最常用的，例如 如类固醇和化疗，IVIG，脾切除术， 实验上，葡萄球菌蛋白A柱。尽管取得了重大进展 在我们对ITP的理解中，一些基本问题仍然没有得到回答： 是什么导致了自我耐受性的崩溃？ 为什么ITP与 其他形式的受损体液免疫反应呢 为什么会有 这种自然史的变异性和对治疗的反应 在患者群体中？ IVIG和Rh（D）免疫球蛋白是否具有 抗原特异性机制，以及为什么对葡萄球菌A的免疫吸附 当血浆置换法无效时，色谱柱似乎有效？ 最终，可以 开发出更具体、更可靠的治疗方法？我们认为 这些临床观察结果可能是遗传的结果 这些抗原特异性自身抗体的限制。通过确定 的抗原特异性和遗传特性的谱 自身抗体库，人们可以问关于分子的问题， 致病性的基础。早期的技术不足以 确定这些关系。 我们建议利用一种强大的新的 称为Fab/噬菌体展示技术， 人血小板自身抗体，并测试这一假设。的信息 从这些研究中得出的结论将有助于深入了解 免疫库组成在自然史中起作用， ITP的治疗反应性。 这一知识对于 设计未来的实验，研究调节 自身免疫反应 对IG的更好分子理解 剧目将包括必要的第一步， 用于抗原特异性调节的新方法 诱导、基于肽的抑制剂和DNA疫苗接种， 调节性T细胞反应。 最终，所提出的方法可能是 应用于了解其他自身免疫性疾病。

The study of autoimmune disease is greatly facilitated by focusing on disorders in which the autoantibodies clearly contribute to the pathogenic process. Because anti-platelet antibodies directly lead to the manifestation of the disease, ITP serves as an excellent model for understanding the pathogenesis of autoimmunity. Clinically, ITP is the most common autoimmune hematologic disorder. It can occur idiopathically or in the context of other disorders of the immune system such as HIV infection, SLE, AIHA and CLL. Therapies aimed directly at modifying the humoral immune response are most frequently utilized, such as steroids and chemotherapy, IVIG, splenectomy and, more experimentally, Staph protein A columns. Despite significant advances in our understanding of ITP, fundamental questions remain unanswered: What causes the breakdown in self-tolerance? Why is ITP associated with those other forms of impaired humoral immune response? Why is there such variability in the natural history and responsiveness to treatment among patient groups? Does IVIG and Rh(D) immune globulin have an antigene-specific mechanism, and why does immunoadsorption on Staph A columns appear effective when plasmapheresis is not? Ultimately, can more specific and reliable forms of therapy be developed? We believe that these clinical observations may be a result of the genetic restriction of these antigen-specific autoantibodies. By determining the spectrum of antigenic specificities and genetic properties of the autoantibody repertoire, one can ask questions regarding the molecular basis for pathogenicity. Earlier technologies were insufficient to determine these relationships. We propose to utilize a powerful new technology known as Fab/phage display to rapidly clone and characterize human platelet autoantibodies and test this hypothesis. The information derived from these studies will provide insight into the role that immune repertoire composition plays in the natural history and therapeutic responsiveness of ITP. This knowledge is critical for the design for future experiments that investigate the regulation of autoimmune responses. A better molecular understanding of the Ig repertoire will comprise the essential first step for the creation of novel approaches for antigen-specific modulation such as tolerance induction, peptide-based inhibitors, and DNA vaccination that induces regulatory T-cell responses. Ultimately, the proposed approach may be applied to the understanding of other autoimmune disorders.