ETIOLOGY AND PATHOGENESIS OF PEMPHIGUS

天疱疮的病因和发病机制

• 批准号: 2732824
• 负责人: Luis A. Diaz
• 金额: $ 24.27万
• 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 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2732824
• 关键词: B lymphocyte; Brazil; Mus musculus; Rodentias; SDS polyacrylamide gel electrophoresis; Simuliidae; T lymphocyte; autoantibody; autoimmune disorder; cats; cellular immunity; chickens; clinical research; disease /disorder etiology; disease /disorder proneness /risk; disease reservoirs; disease vectors; dogs; enzyme linked immunosorbent assay; epidemiology; epitope mapping; family genetics; gene environment interaction; histocompatibility antigens; horses; human subject; mites; molecular cloning; nucleic acid probes; pathologic process; pemphigus; polymerase chain reaction; rural area; serology /serodiagnosis

DESCRIPTION: (Adapted from the applicant's abstract) - This revised version of the renewal grant application describes a series of protocols aimed at disclosing the etiology of Brazilian pemphigus foliaceus or Fogo Selvagem (FS). FS is a human autoimmune disease mediated by pathogenic autoantibodies that are produced by immunogenetically predisposed individuals living in certain rural areas of Brazil. The epidemiology of FS points toward an, as yet unknown, environmental antigen as the trigger of the disease. The antigenic mimicry model predicts that desmoglein-1 (dsg1) harbors T and/or B cell epitopes that crossreact with the environmental agent that precipitates the disease. In the previous funding period, the investigators identified a new FS focus with a unique set of environmental, genetic, and cultural characteristics that they believe make it an ideal population on which to focus their etiologic studies. This community, the Limao Verde Reservation in central Brazil, is composed of approximately 1000 members of the Terena Indian tribe. Geographic, familial, and temporal clustering patterns have been detected among the 28 FS cases on this reservation, and the disease was found to be associated with HLA-DRB1*0404, 1402 & 1406 haplotypes (RR=14). In contrast, other Terena reservations in the region show very few or no documented FS cases. Aim 1 of this grant proposal includes a series of case control epidemiological studies designed to define further genetic and environmental risk factors of the disease. Controls from three populations will be studied: unaffected family members of FS patients, unrelated individuals from Limao Verde, and unaffected Terena Indians from a neighboring reservation. An ongoing prospective sero-epidemiological study of this population will be strengthened by an ELISA assay using recombinant dsg1. Aim 2 investigates the cellular and molecular regulatory mechanisms involved in the pathogenic autoimmune response in FS. Antigen-specific T cell clones and immortalized B cells from FS patients will be generated. This aim is supported by strong preliminary studies. Finally, Aim 3 represents a highly focused immunological investigation of potential etiologic agents of FS. The investigators' studies on salivary gland antigens from Simulium nigrimanum are based on previous data indicating that exposure to black flies is a risk factor for FS. Information obtained from these studies should be relevant in understanding the onset and development of FS and other human autoimmune diseases.

描述：（改编自申请人的摘要） - 此修订版本 续集授予应用程序的描述了一系列针对的协议 披露巴西Pemphigus叶子或Fogo Selvagem的病因 （FS）。 FS是一种由致病性介导的人类自身免疫性疾病 自身抗体是由免疫发育产生的 居住在巴西某些农村地区的个人。 FS的流行病学 指向AN，但尚不清楚的环境抗原作为触发器 疾病。 抗原模拟模型预测Desmoglein-1（DSG1） 与环境交叉反应的携带物T和/或B细胞表位 沉淀该疾病的代理。 在上一个资金期间， 调查人员确定了一种新的FS重点，并具有独特的环境， 他们认为使它成为理想的遗传和文化特征 集中于他们的病因学研究的人群。 这个社区， 巴西中部的利马佛得角保留地由大约1000 Terena印度部落的成员。 地理，家族和时间 在28个FS案例中已经检测到聚类模式 预订，发现该疾病与HLA-DRB1*0404相关， 1402和1406单倍型（RR = 14）。 相反，其他Terena保留 该地区显示很少或没有记录的FS案例。 本赠款提案的目标1包括一系列案件控制 旨在定义进一步遗传和环境的流行病学研究 疾病的危险因素。 来自三个人口的控制将是 研究：未受影响的FS患者的家庭成员，无关的个体 来自利马·佛得角（Limao Verde）和未受影响的泰雷娜（Terena Indians） 预订。 对此的持续前瞻性血清流行学研究 使用重组DSG1的ELISA测定法可以加强人口。 AIM 2研究了涉及的细胞和分子调节机制 在致病性自身免疫反应中。 抗原特异性T细胞克隆 将产生来自FS患者的永生B细胞。 这个目标是 在强大的初步研究的支持下。 最后，AIM 3代表了高度重点的免疫学调查 FS的潜在病因学剂。 研究人员关于唾液的研究 Nigrimanum的腺体抗原基于先前的数据 表明暴露于黑蝇是FS的危险因素。 从这些研究获得的信息应与理解有关 FS和其他人类自身免疫性疾病的发作和发展。