Etiology and Pathogenesis of Pemphigus

描述（由申请人提供）：R01 AR 32599的竞争性更新旨在发现地方性天疱疮（PF）的病因，也称为Fogo Selvagem （FS）。器官特异性自身免疫性疾病，如FS（表皮特异性）为自身免疫研究提供了一些优势，这与抗Dsg1（粘蛋白1）自身抗体是致病性的以及自身抗原Dsg1是完全表征的事实有关。位于巴西南马托格罗索州的美洲印第安人保留区Limao Verde是美洲印第安人Terena部落1351名成员的家园（截至2006年9月10日），是FS的活跃焦点，显示出约3%的患病率。在过去的12年中，我们系统地收集了FS患者以及居住在该定居点及其周围的临床正常个体的临床和血清学数据。在LV和邻近社区的健康个体中，抗dsg1自身抗体是常见的，并且与靠近该保留区直接相关。我们还观察了11例从正常到疾病状态的临床和血清学转化。这种转变预示着从临床前阶段针对Dsg1 EC5结构域的非致病性IgG自身抗体到临床活动性疾病发病期间针对Dsg1 EC1-2结构域的致病性IgG应答。我们也报道了致病性抗体是IgG4限制性的。我们最近发现IgM抗dsg1自身抗体反应对暴露于其原生农村环境的FS患者是独特的，这一标记在其他形式的天疱疮中并不普遍。这种新的自身抗体也在早期生活在LV及其邻近农村地区的临床正常个体中检测到，而在新生儿中不存在。采用流行病学和免疫学两种方法来探讨赠款的中心假设，即环境抗原，即吸血昆虫叮咬使生活在limmao Verde的个人敏感。我们认为，这两种方式不是相互排斥的，而是相辅相成的。免疫学方法将产生新的免疫学分析和仪器，有助于识别有FS风险的个体。例如，基于对大量FS和对照中IgG亚类抗Dsg1抗体的评估，我们开发了一种“IgG4分类器/预测器”，这是高度敏感和特异性的。该仪器将血清定义为具有FS（临床前阶段）的血清学特征或健康个体的特征。使用这种新的“IgG4分类器/预测器”，我们分析了来自丽茅佛得岛3个队列的96名成员的血清，并确定了21名具有FS血清学特征的个体和75名具有健康对照特征的个体（样本收集于2005年）。这些有发展FS风险的个体将是hla型的，并且正在密切监测任何临床FS的证据。完成这个项目的目标将有利于我们了解在美国和世界各地看到的人类自身免疫性疾病。授权R01 AR32599旨在揭示巴西流行的一种人类自身免疫性皮肤病——地方性叶状天疱疮的病因。在完成本应用程序后，我们将更好地了解其他人类自身免疫性疾病，如红斑狼疮、类风湿性关节炎、甲状腺炎等。

DESCRIPTION (provided by applicant): This competitive renewal of the R01 AR 32599 is aimed at discovering the etiology of endemic pemphigus foliaceus (PF), also known as Fogo Selvagem (FS). Some of the advantages that an organ-specific autoimmune disease such as FS (which is epidermal-specific) offers to research in autoimmunity are related to the fact that anti-Dsg1 (desmoglein 1) autoantibodies are pathogenic and the self-antigen, Dsg1, is fully characterized. The Amerindian reservation of Limao Verde, located in the state of Mato Grosso do Sul, Brazil, is the home of 1,351 members of the Terena tribe of Amerindians (as of September 10, 2006), and is an active focus of FS, exhibiting a ~3 percent prevalence of disease. For the last 12 years, we have systematically collected clinical and serological data from FS patients, as well as clinically normal individuals residing in and around this settlement. Anti-Dsg1 autoantibodies in healthy individuals from LV and neighboring communities are common, and directly related to proximity to this reservation. We have also observed the clinical and serological conversion from normal to disease state in 11 individuals. This transition was heralded from non-pathogenic IgG autoantibodies targeting the EC5 domain of Dsg1 during the pre-clinical stage to a pathogenic IgG response against the Dsg1 EC1-2 domains during the onset of clinically active disease. We have also reported that the pathogenic antibodies are IgG4 restricted. We have recently found that the IgM anti-Dsg1 autoantibody response is distinctive to FS patients exposed to their native rural environment, marker that is not prevalent in other forms of pemphigus. This novel autoantibody is also detected in clinically normal individuals living in LV and its neighboring rural regions since early childhood, being absent in neonates. Two prong approaches, i.e. epidemiological and immunological are utilized to explore the central hypothesis of the grant that states that an environmental antigen(s), i.e., hematophagous insect bites sensitize individuals living in Limao Verde. We believe that both approaches are not exclusive but complementary to each other. The immunological methodologies will yield new immunological assays and instruments that will facilitate the identification of individuals at risk to develop FS. For example, based on the assessment of IgG subclass anti- Dsg1 antibodies in a large set of FS and controls we have developed an "IgG4 classifier/predictor," which is highly sensitive and specific. This instrument defines a serum as having serological features of FS (pre-clinical stage) or features of a healthy individual. Using this new "IgG4 classifier/predictor" we have analyzed the sera of 96 members of 3 cohorts from Limao Verde and have identified 21 individuals with serological features of FS and 75 with features of healthy controls (samples collected in 2005). These individual at risk to develop FS will be HLA-typed and are under close surveillance for any evidence of clinical FS. Completion of the aims of this project will benefit our understanding of human autoimmune diseases seen in the USA and around the world. Narrative: The grant R01 AR32599 is aimed at disclosing the etiology of a human autoimmune skin disease, endemic pemphigus foliaceus, which is endemic in Brazil. At the completion of this application we will have a better understanding of other human autoimmune diseases like lupus erythematosus, rheumatoid arthritis, thyroiditis, and others.