PATHOGENICITY OF PEMPHIGUS AND PEMPHIGOID ANTIBODIES

天疱疮和类天疱疮抗体的致病性

• 批准号: 3071305
• 负责人: GRANT J ANHALT
• 金额: $ 5.4万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-01-01 至 1991-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3071305
• 关键词: autoantibody; cell membrane; cornea; cytoplasm; cytoskeleton; endopeptidases; epidermolysis bullosa; immunoregulation; intercellular connection; keratosis; newborn animals; pemphigus; trauma; ultraviolet radiation

Over the last three years, our Laboratory has been systematically defining pathogenetic mechanisms that are operative in the autoimmune cutaneous disease pemphigus. The animal model we have developed, employing passive transfer of human autoantibodies in neonatal mice, has allowed us to define these mechanisms in vivo. It is our intention to extend these studies to define the role of plasminogen activator in the production of Lesions in vivo, to examine the potential importance of other proteinase inhibitors of various specificities to inhibit acantholysis, and to examine the possible therapeutic effect of drugs that interfere with cell surface-cytoskeleton interactions and internalization. A long-term goal is to expand the current model and attempt to produce disease in these animals by immunization with antigen. This would allow us to examine many more aspects of this complex autoimmune disease such as immune regulation by idiotypic and anti-idiotypic networks. Bullous pemphigoid (BP) is another cutaneous blistering disease in which autoantibodies are present. We have recently shown that antibodies from BP patients bind specifically in the area of the cytoplasmic attachment plaque of the epidermal basal cell hemidesmosome. We propose a series of studies to define if there are distinct populations of autoantibodies that bind to intracellular and/or extracellular BP antigens, if the different populations of antibodies are complement fixing, and if extracellular antigen is present in skin only from certain areas of the body. Once these questions are answered, we will examine the pathogenicity of these defined autoantibodies in vivo in mice and in the rabbit cornea. It is also possible that factors that permeabilize the basal cell membrane such as trauma and UV light are necessary to initiate cutaneous lesions, and these autoantibodies can then bind the cytoplasmic antigen, activate complement and propagate the lesion. This series of studies will help us understand the pathophysiology of this complex blistering disease in vivo.

在过去的三年里，我们的实验室系统地 定义在这些疾病中起作用的发病机制， 自身免疫性皮肤病天疱疮 动物模型我们 已经发展，采用被动转移人类 新生小鼠的自身抗体，使我们能够定义这些 体内机制 我们打算将这些研究扩展到 定义纤溶酶原激活剂在生产中的作用 体内病变，以检查其他 各种特异性的蛋白酶抑制剂， 棘层松解，并检查可能的治疗效果， 干扰细胞表面-细胞骨架相互作用的药物 和内在化。 一个长期目标是扩大目前的 并试图在这些动物身上制造疾病， 用抗原免疫。 这将使我们能够检查许多 这种复杂的自身免疫性疾病的更多方面， 独特型和反独特型网络的调节。 大疱性类天疱疮（BP）是另一种皮肤起泡性疾病， 哪些自身抗体存在。 我们最近的研究表明 来自BP患者的抗体特异性结合在 表皮基底细胞胞质附着斑 半桥粒 我们提出了一系列的研究，以确定是否有 是不同的自身抗体群， 细胞内和/或细胞外BP抗原，如果 抗体群是补体固定的，如果 细胞外抗原仅存在于皮肤的某些区域， 身体 一旦这些问题得到解答，我们将研究 这些定义的自身抗体在小鼠体内的致病性 和兔眼角膜中。 也有可能， 渗透基底细胞膜，如创伤和紫外线 光是启动皮肤病变所必需的，这些 然后自身抗体可以结合细胞质抗原，激活 补充并传播病变。 这一系列研究将 帮助我们了解这种复杂的水泡的病理生理学 体内疾病