ETIOLOGY AND PATHOGENESIS OF PEMPHIGUS

天疱疮的病因和发病机制

• 批准号: 3156360
• 负责人: Luis A. Diaz
• 金额: $ 6.97万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-07-01 至 1991-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3156360
• 关键词: Brazil; Simuliidae; autoantibody; autoimmune disorder; cell membrane; cytoskeleton; disease vectors; human subject; immunoglobulin G; keratin; keratinocyte; laboratory mouse; membrane activity; pathologic process; pemphigus; tritium

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.

我们已经证明了患者患者产生的自身抗体 Pemphigus dulgaris和Fogo Selvagem是致病的，负责 诱导人类疾病。 这已经建立了真正的自身免疫 这些晦涩的病因疾病的性质。 我们选择了Fogo Selvagem研究Pemphigus的病因，因为它的独特 流行病学，即，在巴西的某些地区是地方性的 目前有10,000多个注册案件。 相比之下，Pemphigus 在北美非常罕见。 受影响的人口包括农民， 所有种族的儿童和年轻人。 这种疾病有惊人的 流行病学强烈暗示着传染性的“代理人” 昆虫载体（Simulium属的飞行）。 我们在此提案中包括3个具体目标。 （a）第一个目的描述 评估患者的Pemphigus自身抗体的滴度和 来自巴西流行和非流行地区的控制。 （b）第二项研究 将检查新的自身抗体系统的发病率和患病率 在两名Fogo Selvagem患者的血清中发现（指定为 CASCAS-42）。 该自身抗体对56.5 K鼠高度特异 角蛋白并装饰角质形成细胞的细胞表面，表明它 识别该角蛋白的细胞外结构域。 （c）第三个目标 研究患者表皮和血清中的“外抗原”以及 在被昆虫（Simulium）制成的提取物中 Fogo Selvagem的向量。 我们现在相信，如前所述的Fogo Selvagem的系统研究 该赠款将建立可能在 这种自身免疫性疾病的病因学鉴定。 如果我们 实现这一目标，它可能代表了第一个研究 建立人类自身免疫性疾病的病因。 同样重要 也许，这些研究可能会介绍角蛋白生物学中的新概念。 我们 有证据表明某些角蛋白可能具有域名，插入 暴露于角质形成细胞表面的细胞膜（跨膜？） 它们与邻近细胞的相似结构纠缠到 形成一个位于表皮间间间的“外骨骼” 空间并链接到角质形成细胞细胞骨架。 这 外骨骼细胞骨架框架可以为 整个表皮。