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，以及 探索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 纸巾。这一假说源于对静脉注射效果的研究。 免疫球蛋白。静脉注射免疫球蛋白(IVIG)用于治疗 患有各种自身免疫性疾病的患者，包括特发性 血小板减少性紫癜和川崎病。作用机制 是未知的。在许多自身免疫性疾病中，体液抗体与靶标结合 组织，并激活补体，导致组织破坏。在这里我们 提示免疫球蛋白分子是激活的首选受体 补体多肽和IVIG作用机制之一是 防止补体与抗体致敏靶点结合。这一机制 详细剖析了IVIG的作用机制。我们的目标是提供更多 IVIG的有效、廉价和方便的替代品。 在这个模型中，我们检查了免疫球蛋白亚类的有效性。 免疫球蛋白Ig G和Ig M的片段及还原和烷化 抗体。研究确定静脉注射免疫球蛋白是否与免疫球蛋白和免疫球蛋白同时起作用 敏化目标。共价结合抗体的活性 聚乙二醇改善补体多肽受体状态的研究 检查过了。骨髓瘤蛋白的研究是为了确定哪种结构 免疫球蛋白的特性使其成为有效的接受者。这个 IVIG是否能够减少补体结合的问题 对微生物进行检测。 本文还探讨了第二个相关的假设。所有IVIG分子都相等吗 或者，静脉注射免疫球蛋白的一小部分要为其大部分效果负责？ 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 淋巴细胞CD5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。这种抗体可与 与许多正常组织抗原亲和力低。我们建议 天然抗体包被免疫球蛋白覆盖在许多身体表面。这 抗体作为激活的补体多肽的受体， 防止它们与抗体所针对的正常组织成分结合 是由于免疫失调而形成的。如此低的亲和力 结合补体多肽的抗体可以从组织中解离 表面和正常组织未受损。我们将比较 抗丙种球蛋白多特异性低亲和力抗体的活性研究 高亲和力，可阻断补体与靶的结合。骨髓瘤蛋白 具有这些特征的集合和分离抗体将被研究。 我们将使用多特定目标来执行这些实验 抗体结合或不结合。此外，我们将确定是否 自身免疫性疾病患者有多特异性免疫球蛋白正常发挥作用 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.