PATHOPHYSIOLOGY OF EXPERIMENTALLY INDUCED PEMPHIGUS

我们的实验室已经描述了一种用于研究 自身免疫性疾病，天疱疮（NEJM 306：1189 - 1196）。 本研究的目的 是为了确定这些自身抗体产生表皮 老鼠受伤 天疱疮有几个临床亚型;所有 其特征在于存在鳞状上皮自身抗体。 人们对造成这些的病理生理机制知之甚少 疾病不同。 例如，不知道是否有多个 与天疱疮自身抗体反应的细胞表面抗原，或者如果单个 天疱疮抗原在个体中可能具有不同的分布。 天疱疮的变异之间的关系，将通过注射 用这些患者血清中的IgG感染小鼠。 几种自身免疫性 具有抗细胞表面受体的自身抗体的疾病（肌无力 重症、胰岛素抵抗性糖尿病等）显示出一种常见的致病性 机制，即： 一个"表面受体交联"诱导的 抗体的 我们的数据表明，相同的交联现象是 天疱疮自身抗体诱导组织损伤的初始步骤 （通过注射二价天疱疮F（ab '）2 抗体片段，但不是它们的单价Fab '片段）。 我们将 通过以下测试来澄清这些发现：a）在收到 注射单价天疱疮Fab '片段，Fab特异性抗体， 将注射抗人免疫球蛋白。 这可能会交联已经存在的 表皮结合的Fab B '片段并诱导溶血，B） 天疱疮Fab 1片段竞争性抑制结合和诱导 完整的天疱疮IgG抗体。 这些研究将明确界定 细胞表面交联在细胞损伤起始中的作用 体内天疱疮。 天疱疮皮损皮肤检查显示 补体系统的局部激活和 多形性白细胞 我们将尝试定义 补体和中性粒细胞在体内的疾病过程中。 天疱疮IgG a）被眼镜蛇耗尽补体的Balb/C新生儿 毒液因子和遗传性C5缺陷小鼠，和B）BalB/C新生儿 通过预先注射兔抗小鼠中性粒细胞耗竭中性粒细胞 血清的 我们认为这种动物模型为我们提供了一个独特的机会， 定义天疱疮的病理生理学，在体内，并揭示是否 这些自身抗体通过可能 与其他免疫性疾病一样。

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.