ETIOLOGY AND PATHOGENESIS OF PEMPHIGUS

我们已经证明，由患有糖尿病的患者产生的自身抗体 寻常型天疱疮和Fogo Selvagem是致病性的， 在人类中引发疾病。 这证明了真正的自身免疫性疾病 这些疾病的病因不明的性质。 我们选择了Fogo Selvagem因其独特性而被用来探讨天疱疮的病因 流行病学，即，它是巴西某些地区的地方病， 目前已登记的案件超过10，000起。 相比之下，天疱疮 在北美非常罕见。 受影响的人口包括农民， 所有族裔群体的儿童和青年。 这种疾病具有惊人的 流行病学强烈暗示传染性“代理人”，由 一种昆虫媒介（蚋属的苍蝇）。 我们在这份提案中提出了三个具体目标。 (a)第一个目标描述了 评价患者天疱疮自身抗体滴度， 巴西流行区和非流行区的控制。 (b)第二项研究 将研究一种新的自身抗体系统的发病率和流行率， 在两名患有Fogo Selvagem的患者（指定为 卡斯卡斯-42）。 这种自身抗体对56.5 K小鼠具有高度特异性， 角蛋白和装饰角质细胞的细胞表面，这表明它 识别这种角蛋白的细胞外结构域。 (c)第三个目标将 研究患者表皮和血清中的“外来抗原”， 在昆虫（Simuelae）制成的提取物中， Fogo Selvagem的载体。 我们现在相信，系统的研究福戈塞尔瓦根所描述的， 这笔赠款将建立基础，最终可能导致 鉴定这种自身免疫性疾病的病原体。 如果我们 完成这一目标，这可能是第一个研究， 建立了人类自身免疫性疾病的病因 同样重要 这些研究可能为角蛋白生物学提供新的概念。 我们 有证据表明，某些角蛋白可能有域，插入到 细胞膜（跨膜？）暴露在角质形成细胞表面 在那里它们与相邻细胞的类似结构纠缠在一起， 形成位于表皮细胞间的“外骨骼” 空间和连接到角质细胞的细胞骨架。 这 外泌体-细胞骨架框架可以为细胞提供结构支持， 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.