ETIOLOGY AND PATHOGENESIS OF PEMPHIGUS

我们已经证明了由患者产生的自身抗体 寻常型天疱疮和福戈-塞尔维厄姆是致病的，并对 在人类身上引发这种疾病。这就确立了真正的自身免疫 这些疾病的性质病因不明。我们已经选择了Fogo 赛尔凡因天疱疮的独特之处而研究其病因学 流行病学，即它在巴西的某些地区流行，那里有 目前登记的病例超过1万例。相比之下，天疱疮 在北美是非常罕见的。受影响的人口包括农民， 各族儿童和青壮年。这种疾病有一种引人注目的 与传染性“病原体”有强烈牵连的流行病学，由 一种昆虫媒介(一种蝇属的蝇)。 我们在这项提案中包括三个具体目标。(A)第一个目标描述 天疱疮患者自身抗体效价的检测及临床意义 来自巴西地方病和非地方病地区的控制。(B)第二项研究 将检查一种新的自身抗体系统的发病率和流行率 在两名Fogo Selovem患者的血清中发现(编号为 卡斯卡斯-42)。该自身抗体对56.5K小鼠具有高度特异性 角蛋白和装饰角质形成细胞的表面，表明它 识别这种角蛋白的胞外结构域。(C)第三个目标将 研究患者表皮和血清中的“外来抗原”以及 在由昆虫(Simulium)制成的提取物中，怀疑 福戈·塞尔维姆的病媒。 我们现在相信，对福戈·塞尔维姆的系统研究 这笔赠款将奠定基础，最终可能导致 确定这种自身免疫性疾病的病原体。如果我们 实现这一目标，它可能代表着第一项研究 确立了人类自身免疫性疾病的病因学。同样重要的是 或许，这些研究可能会为角蛋白生物学提出新的概念。我们 有证据表明某些角蛋白可能具有插入到 细胞膜(跨膜？)暴露在角质形成细胞表面的 在那里它们与邻近细胞的相似结构纠缠在一起 形成位于表皮细胞间的“外骨骼”。 并与角质形成细胞的细胞骨架相连。这 外骨骼-细胞骨架框架可以为 整个表皮。

We have demonstrated that the autoantibodies produced by patients with Pemphigus Vulgaris and Fogo Selvagem are pathogenic and are responsible for inducing the disease in humans. This has established the true autoimmune nature of these diseases of obscure etiology. We have selected Fogo Selvagem to investigate the etiology of pemphigus because of its unique epidemiology, i.e., it is endemic in certain regions of Brazil, where there are currently more than 10,000 registered cases. In comparison, pemphigus in North America is very rare. The affected population includes farmers, children and young adults of all ethnic groups. The disease has a striking epidemiology that strongly implicates an infectious "agent", transmitted by an insect vector (a fly of the genus Simulium). We include 3 Specific Aims in this Proposal. (a) The first aim describes the evaluation of the titers of pemphigus autoantibodies in patients and controls from endemic and nonendemic areas in Brazil. (b) The second study will examine the incidence and prevalence of a new autoantibody system discovered in the sera of two patients with Fogo Selvagem (designated as Cascas-42). This autoantibody is highly specific for the 56.5 K murine keratin and decorates the cell surface of keratinocytes, suggesting that it recognizes an extracellular domain of this keratin. (c) The third aim will study "foreign antigens" in the epidermis and sera of patients as well as in extracts made of the insects (Simulium) which are suspected to be vectors of Fogo Selvagem. We believe now that the systematic study of Fogo Selvagem as described in this grant will establish the foundations which may culminate in the identification of the etiological agent of this autoimmune disease. If we accomplish this goal, it would probably represent the first study that establishes an etiology for a human autoimmune disease. Equally important perhaps, these studies may present new concepts in keratin biology. We have evidence that certain keratins may have domains, inserted into the cell membrane (transmembrane?) that are exposed on the keratinocyte surface where they become entangled with similar structures of neighboring cells to form an "exoskeleton" which is located in the epidermal intercellular spaces and linked to the keratinocyte cytoskeleton. This exoskeleton-cytoskeleton framework may provide structural support to the whole epidermis.