PATHOGENICITY OF PEMPHIGUS AND PEMPHIGOID ANTIBODIES

在过去的三年里，我们的实验室一直在系统地 定义在人类免疫系统中起作用的致病机制 自身免疫性皮肤病天疱疮。我们的动物模型 已经开发出，使用被动转移的人 新生小鼠中的自身抗体，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 明确纤溶酶原激活物在生产中的作用 在体内的损害，以检查其他潜在的重要性 不同特异性的蛋白酶抑制剂来抑制 棘层松解术，并观察其可能的治疗效果。 干扰细胞表面-细胞骨架相互作用的药物 和内部化。一个长期目标是扩大目前的 通过建立模型并尝试在这些动物中制造疾病 用抗原进行免疫。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，如免疫 独特型和反独特型网络的调控。 大疱性类天疱疮(BP)是我国另一种皮肤水疱性疾病。 存在哪些自身抗体。我们最近已经证明， 来自BP患者的抗体特异性地结合在 表皮基底细胞的细胞质附着斑块 半桥粒。我们提出了一系列研究，以确定是否存在 是一组截然不同的自身抗体结合到 细胞内和/或细胞外BP抗原，如果不同 抗体群体是补体固定的，如果 细胞外抗原只存在于皮肤中的某些区域 身体。一旦这些问题得到回答，我们将研究 这些已明确的自身抗体在小鼠体内的致病性 在兔子的眼角膜里。也有可能是因为 渗透创伤、紫外线等基底层细胞膜 光是启动皮肤损伤所必需的，而这些 然后自身抗体可以结合胞浆抗原，激活 补充和传播病变。这一系列研究将 帮助我们了解这一复杂水泡的病理生理学 活体内的疾病。

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.