PATHOPHYSIOLOGY OF EXPERIMENTALLY INDUCED PEMPHIGUS

在过去的三年里，我们的实验室一直在系统地定义 自身免疫性皮肤的致病机制 天疱疮。我们开发的动物模型，使用被动 人类自身抗体在新生小鼠中的转移，使我们能够确定 体内的这些机制。我们打算将这些研究扩展到 明确纤溶酶原激活物在慢性阻塞性肺疾病中的作用 Vivo，用来检测其他蛋白酶的潜在重要性 抑制棘层松解的各种特异性的蛋白酶抑制剂，以及 检查干扰药物的可能的治疗效果 细胞表面-细胞骨架的相互作用和内化。长期的 目标是扩大目前的模式，并试图在这些领域制造疾病 用抗原免疫动物。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，如免疫调节 通过独特型和反独特型网络。 大疱性类天疱疮(BP)是另一种皮肤水疱性疾病， 存在自身抗体。我们最近证明了来自BP的抗体 患者特异性地结合在细胞质附着斑块的区域 属于表皮基底细胞半桥粒。我们提出了一系列研究 以确定是否有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 皮肤中的抗原只存在于身体的某些部位。一旦这些 问题已经回答了，我们将检查这些定义的致病性 小鼠体内和兔角膜中的自身抗体。它也是 可能使巴塞尔细胞膜通透性的因素，如 创伤和紫外线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，激活补体 并传播损伤。这一系列研究将帮助我们了解 这种复杂的水疱病在活体内的病理生理学。

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 had 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 proteinases by using 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 longterm 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 basel 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.