Etiology and Pathogenesis of Pemphigus

天疱疮的病因和发病机制

• 批准号: 6665204
• 负责人: Luis A. Diaz
• 金额: $ 33.43万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 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 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6665204
• 关键词: Brazil; T lymphocyte; autoantibody; autoimmune disorder; cellular immunity; clinical research; disease /disorder etiology; disease /disorder proneness /risk; enzyme linked immunosorbent assay; epidemiology; family genetics; gene environment interaction; genetic susceptibility; high performance liquid chromatography; histocompatibility antigens; human data; human subject; immunoglobulin G; mites; molecular cloning; pathologic process; pemphigus; rural area; serology /serodiagnosis; skin

DESCRIPTION (provided by applicant): This is competitive renewal of grant R01-AR32599, aimed at identifying the etiology of Brazilian pemphigus foliaceus or Foqo Selvagem (fs). FS is a human autoimmune disease mediated by pathogenic autoantibodies directed against desmoglein 1 (dsg1). Sensitized individuals living in certain rural areas of Brazil produce these autoantibodies. We have identified a new FS focus, with a 3% of disease-prevalence, and a unique set of environmental, genetic, and cultural characteristics. This community, the Limao Verde Reservation located in central Brazil, is composed of approximately 1100 members of the Terena Indian tribe. Geographic, familial, HLA and temporal clustering patterns have been described among the 35 cases of FS seen in this reservation. Based on our studies we predict that normal controls (pre-clinical state of FS), when exposed to certain environmental antigen(s), produce an early lgG1 anti-dsg1 response; only later, and in certain predisposed individuals, does this response become pathogenic and is mediated by lgG4 anti-dsg1 antibodies (clinical state of ES). Encouraging preliminary studies suggest that saliva from blood-feeding insects, such as kissing bugs and sand flies, may be the source of cross-reactive antigens that trigger anti-dsg1 autoantibody responses. Aims 1 and 2 include epidemiological studies designed to further define genetic and environmental risk factors associated with FS. Cohorts composed of adults and younger individuals will be followed using clinical, serological and ecological data. Serological evidence of anti-dsg1 IgG, lgG1 and lgG4 responses will be serially evaluated. The 29 FS patients that are alive will be followed, assessing the therapy as well as the environmental factors that may be linked to relapses. Aim 3 will focus on assessing the serological responses of patients with Chagas (kissing bugs) and Leishmaniasis (sand flies) to dsg1 and molecularly characterizing the salivary antigens of these blood-feeding insects. Aim 4 will test the response of FS T cells to the putative salivary antigens and Aim 5 will include studies on the frequency of FS-like disease in domestic animals. The possible existence of an "endemic pemphigus vulgaris" variant in Brazil and the evaluation of the sand fly and kissing bug species in Limao Verde are also included in this latter aim. It is likely that characteristics of the mechanism of autoimmunity for FS will be shared with other human autoimmune diseases and what we learn from ES will be applicable to the study of human autoimmunity.

描述（由申请人提供）：这是 R01-AR32599 拨款的竞争性更新，旨在确定巴西落叶型天疱疮或 Foqo Selvagem (fs) 的病因。 FS 是一种由针对桥粒芯糖蛋白 1 (dsg1) 的致病性自身抗体介导的人类自身免疫性疾病。生活在巴西某些农村地区的敏感个体会产生这些自身抗体。我们已经确定了新的 FS 焦点，其疾病患病率为 3%，并且具有一系列独特的环境、遗传和文化特征。这个社区名为 Limao Verde 保留地，位于巴西中部，由大约 1100 名特雷纳印第安部落成员组成。在该保护区发现的 35 例 FS 病例中描述了地理、家族、HLA 和时间聚类模式。根据我们的研究，我们预测正常对照（FS 的临床前状态）在暴露于某些环境抗原时会产生早期 IgG1 抗 dsg1 反应；只有后来，在某些易感个体中，这种反应才会变成致病性，并由 IgG4 抗 dsg1 抗体介导（ES 的临床状态）。令人鼓舞的初步研究表明，吸血昆虫（例如接吻虫和沙蝇）的唾液可能是触发抗 dsg1 自身抗体反应的交叉反应抗原的来源。目标 1 和 2 包括旨在进一步确定与 FS 相关的遗传和环境风险因素的流行病学研究。将使用临床、血清学和生态数据对由成年人和年轻人组成的队列进行跟踪。将连续评估抗 dsg1 IgG、IgG1 和 IgG4 反应的血清学证据。将对 29 名存活的 FS 患者进行随访，评估治疗以及可能与复发相关的环境因素。目标 3 将重点评估恰加斯病（接吻虫）和利什曼病（白蛉）患者对 dsg1 的血清学反应，并从分子角度表征这些吸血昆虫的唾液抗原。目标 4 将测试 FS T 细胞对假定唾液抗原的反应，目标 5 将包括对家畜中 FS 样疾病发生频率的研究。巴西可能存在“地方性寻常型天疱疮”变种，以及对 Limao Verde 的白蛉和接吻虫物种进行评估也包括在后一个目标中。 FS 的自身免疫机制特征很可能与其他人类自身免疫疾病相同，我们从 ES 中学到的知识将适用于人类自身免疫的研究。