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 在自身免疫性皮肤炎中起作用的发病机制 天疱疮 我们开发的动物模型， 人类自身抗体在新生小鼠中的转移，使我们能够定义 这些机制在体内。 我们打算将这些研究扩展到 明确纤溶酶原激活剂在产生病变中的作用， 体内，检查其他蛋白酶的潜在重要性，使用 抑制棘层松解的各种特异性蛋白酶抑制剂，和 来检测药物可能的治疗效果， 细胞表面-细胞骨架相互作用和内化。 一项长期 我们的目标是扩大目前的模式，并试图在这些疾病 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）是另一种皮肤起泡疾病， 存在自身抗体。 我们最近发现来自BP的抗体 患者特异性结合在细胞质附着斑区域 表皮基底细胞半桥粒。 我们提出了一系列的研究 以确定是否存在不同的自身抗体群体， 细胞内和/或细胞外BP抗原，如果 抗体群体是补体固定的，如果是细胞外的， 抗原仅存在于身体某些区域的皮肤中。 一旦这些 问题的答案，我们将研究这些定义的致病性 小鼠和兔角膜中的体内自身抗体。 也是 有可能使巴塞尔细胞膜透化的因子， 创伤和紫外线是引发皮肤损伤所必需的， 然后自身抗体可以结合细胞质抗原，激活补体， 并扩散损伤。 这一系列的研究将帮助我们了解 这种复杂的水泡病的病理生理学。

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.