PATHOPHYSIOLOGY OF EXPERIMENTALLY INDUCED PEMPHIGUS

我们实验室已经建立了一种用于研究血管紧张素转换酶的动物模型。 自身免疫性疾病，天疱疮(NEJM 306：1189-1196)。这项研究的目的是 是为了确定这些自身抗体产生表皮的机制 小鼠受了伤。天疱疮有几个临床亚型；全部 以鳞状上皮自身抗体的存在为特征。 人们对导致这些疾病的病理生理机制知之甚少 疾病截然不同。例如，如果存在多个，则未知 细胞表面抗原与天疱疮自身抗体反应，或者如果单个 天疱疮抗原在不同个体之间可能有不同的分布。 天疱疮变异体之间的关系将通过注射研究 从这些患者的血清中提取免疫球蛋白的小鼠。几种自身免疫 伴有细胞表面受体自身抗体的疾病(肌无力 Gravis、胰岛素抵抗糖尿病等)显示出一种常见的致病因素 机制，即：一种“表面受体交联剂”由 抗体。我们的数据表明，同样的交联现象是 天疱疮自身抗体诱导组织损伤的初步研究 (注射双价天疱疮F(ab‘)2很容易引起疾病 抗体片段，但不是通过它们的单价Fab‘片段)。我们会 通过测试以下各项来澄清这些调查结果：a)在收到 注射单价天疱疮Fab‘片段，一种Fab特异性 将注射抗人类免疫球蛋白。这可能会使已经存在的 与表皮结合的Fab‘片段和诱导皮肤松解，b)能力 天疱疮FAB1片段竞争性抑制结合和诱导 通过完整的天疱疮免疫球蛋白。这些研究将清楚地定义 细胞表面交联在启动细胞损伤中的作用 活体天疱疮。天疱疮皮损皮肤检查显示 补体系统的局部激活和补体的渗透 多形核白细胞。我们将尝试定义 补体和中性粒细胞在体内疾病过程中的作用。天疱疮免疫球蛋白 将注射给a)被眼镜蛇耗尽补体的Balb/C新生儿 毒液因子和遗传C5缺陷小鼠，以及b)Balb/C新生儿 预先注射兔抗鼠中性粒细胞可使中性粒细胞耗尽 血清。我们认为，这种动物模型为我们提供了一个独特的机会 定义体内天疱疮的病理生理学，并揭示 这些自身抗体诱导细胞损伤的机制可能 常见于其他免疫性疾病。

Our laboratory has described an animal model for the study of the autoimmune disease, pemphigus (NEJM 306:1189-1196). The goal of this study is to define the mechanisms by which these autoantibodies produce epidermal injury in the mouse. There are several clinical subsets of pemphigus; all are characterized by the presence of squamous epithelial autoantibodies. Little is known about the pathophysiological mechanisms which make these diseases distinct. For example, it is unknown if there is more than one cell surface antigen reactive with pemphigus autoantibodies, or if a single pemphigus antigen may have different distributions amongst individuals. The relationship of the variants of pemphigus, will be studied by injecting mice with IgG from the sera of these patients. Several autoimmune disorders with autoantibodies against cell surface receptors (myasthenia gravis, insulin resistant diabetes, etc.) show a common pathogenic mechanism, i.e.: a "surface receptor crosslinking" induced by the antibodies. Our data suggests that the same crosslinking phenomenon is the initial step in the induction of tissue injury by pemphigus autoantibodies (disease is easily produced by injections of bivalent pemphigus F(ab')2 antibody fragments, but not by their monovalent Fab' fragments). We will clarify these findings by testing the following: a) After receiving injections of monovalent pemphigus Fab' fragments, an Fab specific anti-human immunoglobulin will be injected. This may crosslink the already epidermal-bound Fab' fragments and induce scantholysis, b) The ability of pemphigus Fab1 fragments to competitively inhibit the binding and induction of disease by intact pemphigus IgG. These studies will clearly define the role of cell surface crosslinking in the initiation of cellular injury in pemphigus in vivo. Examination of lesional skin in pemphigus demonstrates local activation of the complement system and infiltration of polymorphonuclear leucocytes. We will attempt to define the role of complement and neutrophils in the disease process in vivo. Pemphigus IgG will be injected into a) Balb/C neonates depleted of complement by cobra venom factor and genetically C5 deficient mice, and b) Balb/C neonates depleted of neutrophils by prior injection of rabbit anti-mouse neutrophil serum. We feel that this animal model provides us an unique opportunity to define the pathophysiology of pemphigus, in vivo, and to reveal whether these autoantibodies induce cellular injury by mechanisms which may be common to other immunological diseases.