REGULATION OF COMPLEMENT DAMAGE BY IMMUNOGLOBULIN

这项资助研究了免疫球蛋白和补体的相互作用， 探讨了免疫球蛋白的一个重要功能是 调节激活的补体蛋白与宿主的结合 组织中 这一假设来自于对静脉注射 免疫球蛋白。 静脉注射免疫球蛋白（IVIG）用于治疗 各种自身免疫性疾病患者，包括特发性 血小板减少性紫癜与川崎 的作用机制 不明 在许多自身免疫性疾病中，体液抗体与靶结合 组织，并激活补体，导致组织破坏。 这里我们 表明IG分子作为活化的免疫球蛋白的优选受体， 补体肽，IVIG的一种作用机制是 防止补体与抗体致敏靶点结合。 机制 详细剖析了IVIG的作用机制。 我们的目标是提供一个更 更有效、更便宜和更方便的IVIG替代品。 在该模型中检查IgG亚类的功效，如 IgG和IgM免疫球蛋白片段，并还原和烷基化 抗体的 研究确定IVIG是否与IgG和IgM同时起作用 敏感目标。 具有共价结合的抗体的活性 聚乙二醇改善补体肽的受体状态， 考察 研究骨髓瘤蛋白以确定 IG的特性允许其充当有效受体。 的 IVIG是否能够降低补体与 微生物检查。 第二个相关的假设进行了探讨。 所有的免疫球蛋白分子都是一样的吗 还是一小部分IVIG起了主要作用 具有可变区的多特异性、低亲和力天然抗体， 生殖系基因构型由一组确定的B分泌 淋巴细胞CD 5阳性细胞。 这种抗体占所有抗体的20-30%。 血清免疫球蛋白，但其功能尚不清楚。 该抗体结合 对许多正常组织抗原的亲和力低。 我们建议 天然抗体用免疫球蛋白覆盖许多身体表面。 这 抗体作为活化补体肽的受体， 阻止它们与正常组织成分结合， 是由于免疫失调而形成的 如此低的亲和力 具有结合的补体肽的抗体可以从组织中分离 表面和正常组织不受损伤。 我们将比较 抗IVIG多特异性低亲和力抗体和抗IVIG抗体的活性 在阻断补体与靶标结合方面具有高亲和力。 骨髓瘤蛋白 将研究具有这些特征的集合和分离的抗体。 我们将使用多特异性靶点进行这些实验， 抗体是否结合。 此外，我们将确定是否 自身免疫性疾病患者具有多特异性IG， 在这方面。

This grant examines the interaction of immunoglobulin and complement and explores the hypothesis that an important function of immunoglobulin is to regulate the binding of activated complement proteins with host tissues. The hypothesis arises from studies of the effect of intravenous immunoglobulin. Intravenous immunoglobulin (IVIG) is used in treatment of patients with a variety of autoimmune disease, including idiopathic thrombocytopenic purpura and Kawasaki's disease. The mechanism of action is unknown. In many autoimmune disease, humoral antibody binds to target tissues, and activates complement, causing tissue destruction. Here we suggest that the Ig molecule acts as a preferred acceptor for activated complement peptides and that one mechanism of action of IVIG is to prevent complement binding to antibody sensitized targets. The mechanism by which IVIG acts is dissected in detail. The goal is to provide a more effective, less expensive and more convenient substitute for IVIG. Subclasses of IgG are examined for efficacy in this model as are fragments of IgG and IgM immunoglobulin and reduced and alkylated antibodies. Studies determine whether IVIG acts with both IgG and IgM sensitized targets. The activity of antibodies with covalently bound polyethylene glycol to improve acceptor status of complement peptides is examined. Myeloma proteins are studied to determine which structural characteristics of Ig allow it to act as an effective acceptor. The question of whether IVIG is capable of decreasing complement binding to microbes is examined. A second related hypothesis is explored. Are all IVIG molecules equal or is a fraction of IVIG responsible for most of its effect? Polyspecific, low affinity natural antibody with the variable region in the germ line gene configuration is secreted by a defined set of B lymphocytes CD5 positive cells. This antibody constitutes 20-30% of all serum immunoglobulin but its function is unknown. This antibody binds with low affinity to many normal tissue antigens. We suggest that natural antibody coats many body surfaces with immunoglobulin. This antibody acts as an acceptor for activated complement peptides, preventing their binding to normal tissue components to which antibody has been formed as a result of immune dysregulation. Such low affinity antibody with bound complement peptides can disassociate from tissue surfaces and normal tissues are not damaged. We will compare the activity of polyspecific low affinity antibody to IVIG and antibody with high affinity in blocking complement binding to targets. Myeloma protein sets and isolated antibodies with these characteristics will be studied. We will perform these experiments using targets to which the polyspecific antibody does or does not bind. In addition, we will determine whether patients with autoimmune disease have polyspecific Ig that acts normally in this respect.