ETIOLOGY AND PATHOGENESIS OF PEMPHIGUS

描述：(改编自申请人的摘要)-此修订版 续签拨款申请的内容描述了一系列旨在 披露巴西叶状天疱疮或福戈·塞尔维姆的病原学 (FS)。FS是一种由致病因子介导的人类自身免疫性疾病 由免疫遗传易感性产生的自身抗体 居住在巴西某些农村地区的个人。小儿麻痹症的流行病学 指向一种尚不清楚的环境抗原，作为引发 这种疾病。抗原拟态模型预测桥粒芯糖蛋白-1(DSG1) 含有与环境发生交叉反应的T和/或B细胞表位 导致这种疾病的因素。在上一个资助期， 调查人员发现了一个新的FS焦点，具有一套独特的环境， 他们认为这是一种理想的遗传和文化特征 病因学研究的重点人群。这个社区，这个社区 巴西中部的利毛维德保留地，由大约1000人组成 特雷纳印第安人部落的成员。地理、家族和时间 在这28个FS病例中检测到了集群模式 保留，该疾病被发现与人类白细胞抗原DRB1*0404， 1402和1406单倍型(RR=14)。相比之下，Terena的其他预订 该地区很少或根本没有记录在案的FS病例。 这项赠款提案的目标1包括一系列病例对照 旨在进一步确定遗传和环境因素的流行病学研究 疾病的危险因素。来自三个群体的对照将是 研究：FS患者的未受影响的家庭成员，无亲属关系的个人 来自利毛维德的，以及来自邻国的未受影响的Terena印第安人 预订。一项正在进行的前瞻性血清流行病学研究 将通过使用重组DSG1的酶联免疫吸附试验加强种群。 目的2研究细胞和分子调控机制 在FS的致病性自身免疫反应中。抗原特异性T细胞克隆 并从FS患者中产生永生化的B细胞。这个目标是 有强有力的初步研究支持。 最后，目标3代表了高度集中的免疫学研究 FS的潜在致病因素。研究人员对唾液的研究 来自黑色模拟菌的腺体抗原是基于先前的数据 这表明接触黑蝇是FS的一个危险因素。 从这些研究中获得的信息应该与理解相关 FS和其他人类自身免疫性疾病的发生和发展。

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.