Etiology and Pathogenesis of Pemphigus

描述（由申请方提供）：R 01 AR 32599的竞争性更新旨在发现地方性落叶型天疱疮（PF）（也称为Fogo Selvagem（FS））的病因。器官特异性自身免疫性疾病如FS（表皮特异性）为自身免疫性研究提供的一些优势与抗Dsg 1（桥粒芯蛋白1）自身抗体是致病性的和自身抗原Dsg 1完全特征化的事实有关。位于巴西南南马托格罗索州的Limao Verde美洲印第安人保留区是1，351名Terena美洲印第安人部落成员的家园（截至2006年9月10日），也是FS的活跃焦点，显示出约3%的患病率。在过去的12年里，我们系统地收集了FS患者的临床和血清学数据，以及居住在该定居点及其周围的临床正常个体。来自LV和邻近社区的健康个体中的抗Dsg 1自身抗体是常见的，并且与接近该保留区直接相关。我们还观察到11例患者的临床和血清学从正常状态转变为疾病状态。这种转变预示着从临床前阶段靶向Dsg 1的EC 5结构域的非致病性IgG自身抗体到临床活动性疾病发作期间针对Dsg 1 EC 1 -2结构域的致病性IgG应答。我们还报道了致病性抗体是IgG 4限制性的。我们最近发现，IgM抗Dsg 1自身抗体反应是独特的FS患者暴露于他们的原生农村环境，标志物是不流行的其他形式的天疱疮。这种新的自身抗体也检测到临床正常的个人生活在LV及其附近的农村地区，因为幼儿期，是不存在的新生儿。两种方法，即流行病学和免疫学，被用来探讨中心假设的赠款，指出，一个环境抗原（S），即，吸血昆虫叮咬使生活在Limao Verde的个体敏感。我们认为，这两种办法不是相互排斥的，而是相互补充的。免疫学方法将产生新的免疫学检测和仪器，将有助于识别个人的风险发展FS。例如，基于在大量FS和对照组中IgG亚类抗Dsgl抗体的评估，我们开发了高度灵敏和特异的“IgG 4分类器/预测器”。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“IgG 4分类器/预测器”，我们分析了来自Limao Verde的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（2005年收集的样本）。这些有发生FS风险的个体将进行HLA分型，并密切监测任何临床FS证据。该项目目标的完成将有助于我们了解美国和世界各地的人类自身免疫性疾病。叙述：R 01 AR 32599基金旨在揭示巴西流行的人类自身免疫性皮肤病地方性落叶型天疱疮的病因。在完成本申请后，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.