ETIOLOGY AND PATHOGENESIS OF PEMPHIGUS

天疱疮的病因和发病机制

• 批准号: 3156353
• 负责人: Luis A. Diaz
• 金额: $ 18.51万
• 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 1996-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3156353
• 关键词: Brazil; SDS polyacrylamide gel electrophoresis; Simuliidae; antigens; autoantibody; complementary DNA; disease vectors; enzyme linked immunosorbent assay; epitope mapping; genetic library; humoral immunity; immunoglobulin G; immunoprecipitation; keratin; keratinocyte; laboratory mouse; laboratory rabbit; major histocompatibility complex; molecular chaperones; pathologic process; pemphigus; protein purification; serum; ubiquitin; western blottings

It represents a comprehensive approach to study Brazilian pemphigus foliaceus or Fogo Selvagem (FS) and describes a series of protocols aimed at uncovering the etiology of this autoimmune disease. During the previous funding period we have accumulated substantial original information which is applicable not only to understanding the pathogenesis of FS but is also relevant to other aspects of keratinocyte biology and biochemistry, i.e., we have shown that FS autoantibodies are pathogenic and restricted to the IgG4 subclass. FS autoantibodies appear to induce keratinocyte detachment by impairing the function of desmoglein 1 (a cadherin-like desmosomal glycoprotein) which is the epidermal antigen recognized by these antibodies. This proposal also describes two novel autoantibody systems in FS sera: IgG2 autoantibodies against keratin-10 and autoantibodies against a ubiquitin-carrier protein. The relevance of these autoantibodies in the etiology and pathogenesis of FS will be investigated in this proposal. Based on epidemiological data, this grant addresses the hypothesis that the humoral autoimmune response in FS is triggered and maintained by an environmental "antigenic factor(s)". FS is the ideal, and perhaps the only, human autoimmune disease in which this hypothesis could be tested since it is endemic to certain regions of Brazil, where there are currently more than 15,000 registered cases. Individuals at risk are outdoor workers living on agricultural farms. Our studies show that individuals developing FS share distinctive susceptibility HLA DR1 alleles and lack a dominant DQw2 protective gene which is present in normal people. Susceptible individuals, therefore, if exposed to unique environmental antigens, may produce antibodies which, in turn, cross-react with keratinocyte surface epitope(s) and cause acantholysis ("antigenic mimicry"?). Among a variety of etiological agents, an insect vector (a "black fly", family Simuliidae) has been suspected of precipitating the disease. Several circumstantial observations, and a recent epidemiologic case-control study (see Progress Report Section), support this hypothesis. This proposal will systematically investigate the role of black flies as a potential source of sensitizing agent that leads to autoantibody formation in FS. If successful, the information derived from these studies should be relevant to other human autoimmune diseases.

它代表了研究巴西天疱疮的综合方法 foliaceus 或 Fogo Selvagem (FS) 并描述了一系列旨在 揭示这种自身免疫性疾病的病因。 此前期间 资助期间我们积累了大量的原始资料 不仅适用于了解 FS 的发病机制，而且还适用于 与角质形成细胞生物学和生物化学的其他方面相关，即 我们已经证明 FS 自身抗体具有致病性并且仅限于 IgG4 亚类。 FS 自身抗体似乎会诱导角质形成细胞脱离 通过损害桥粒糖蛋白 1（一种钙粘蛋白样桥粒蛋白）的功能 糖蛋白），这是这些细胞识别的表皮抗原 抗体。 该提案还描述了两种新型自身抗体系统 FS 血清：抗 keratin-10 的 IgG2 自身抗体和抗 keratin-10 的自身抗体 泛素载体蛋白。 这些自身抗体的相关性 本提案将研究 FS 的病因和发病机制。 根据流行病学数据，这笔赠款提出了以下假设： FS 中的体液自身免疫反应是由 环境“抗原因子”。 FS是理想的，也许是 唯一可以检验这一假设的人类自身免疫性疾病 因为它是巴西某些地区的特有病，目前那里有 登记案件超过 15,000 起。 高危人群是户外工作者 住在农场。 我们的研究表明，个体发展 FS 具有独特的 HLA DR1 等位基因易感性，并且缺乏显性 DQw2 保护基因存在于正常人中。 易受影响的 因此，如果个体暴露于独特的环境抗原，可能会 产生抗体，进而与角质形成细胞表面发生交叉反应 表位并引起棘层松解（“抗原拟态”？）。 其中各种 病原体，昆虫媒介（“黑蝇”，Simuliidae 科） 已被怀疑诱发该疾病。 几个间接的 观察结果以及最近的一项流行病学病例对照研究（参见进展 报告部分），支持这一假设。 该提案将 系统地研究黑蝇作为潜在来源的作用 导致 FS 中自身抗体形成的致敏剂。 如果 成功的话，从这些研究中获得的信息应该是相关的 其他人类自身免疫性疾病。