ETIOLOGY AND PATHOGENESIS OF PEMPHIGUS

天疱疮的病因和发病机制

• 批准号: 3156359
• 负责人: Luis A. Diaz
• 金额: $ 21.57万
• 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/3156359
• 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.

它代表了研究巴西人的全面方法 叶子或Fogo Selvagem（FS），并描述了一系列针对的协议 揭示这种自身免疫性疾病的病因。 在上一个 资金期我们积累了大量的原始信息 不仅适用于理解FS的发病机理，还适用于 与角质形成生物学和生物化学的其他方面有关，即 我们已经表明，FS自身抗体是致病性的，并且仅限于 IgG4子类。 FS自身抗体似乎诱导角质形成细胞分离 通过损害脱木质1（钙粘蛋白样的脱发小体）的功能 糖蛋白）是这些表皮抗原 抗体。 该建议还描述了两个新型的自身抗体系统 FS血清：针对角蛋白10的IgG2自身抗体和自身抗体针对 泛素 - 载体蛋白。 这些自身抗体在 FS的病因和发病机理将在此提案中研究。 基于流行病学数据，该赠款解决了以下假设 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 仅，可以检验该假设的人类自身免疫性疾病 由于它是巴西某些地区的地方 超过15,000个注册案件。 有危险的人是户外工作人员 生活在农场。 我们的研究表明，个人正在发展 FS具有独特的敏感性HLA DR1等位基因，并且缺乏主导地位 普通人中存在的DQW2保护基因。 易受影响的 因此，如果个人接触到独特的环境抗原，则可能 产生抗体，而抗体又与角质形成细胞交叉反应 表位（S）并引起乙糖液（“抗原模仿”？）。 在各种各样 病因学剂，一种昆虫载体（“黑蝇”，simuliidae） 怀疑会导致这种疾病。 几个环境 观察结果以及最近的流行病学病例对照研究（请参阅进度 报告部分），支持此假设。 该提议将 系统地研究黑蝇作为潜在来源的作用 敏化剂，导致Fs中自身抗体形成。 如果 成功，从这些研究中得出的信息应该是相关的 到其他人类自身免疫性疾病。