Etiology and Pathogenesis of Pemphigus

天疱疮的病因和发病机制

• 批准号: 8053348
• 负责人: Luis A. Diaz
• 金额: $ 29.57万
• 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 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8053348
• 关键词: Age; Alleles; Amerindian; Antibodies; Antibody Formation; Antigens; Arthropods; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Bacterial Infections; Bedbugs; Binding; Biological Assay; Blood; Brazil; Case-Control Studies; Chagas Disease; Cities; Clinical; Cloning; Communities; Data; Data Analyses; Data Collection; Development; Disease; Dissection; Domestic Animals; Environment; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Epidemiologic Studies; Epidemiology; Epitope Mapping; Epitopes; Etiology; Evaluation; Event; Exhibits; Exposure to; Expression Library; Family; Fractionation; Funding; Future; Genetic; Grant; Home environment; Hospital Referrals; Housing; Human; IgG1; IgG4; Immune response; Immunization; Immunoglobulin G; Immunoglobulin M; Immunology; Incidence; Individual; Insect Bites; Insecta; Investigation; Japan; Leishmaniasis; Life; Link; Lupus Erythematosus; Methodology; Methods; Monitor; Mothers; Nature; Neonatal; Newborn Infant; Newly Diagnosed; Onchocerciasis; Organ; Pathogenesis; Pathogenicity; Patients; Pemphigus; Pemphigus Vulgaris; Play; Population; Populations at Risk; Prevalence; Process; Production; Progress Reports; Protocols documentation; Questionnaires; Race; Recurrence; Reporting; Research; Reservations; Rheumatoid Arthritis; Risk; Risk Factors; Role; Rural; Salivary; Salivary Glands; Salivary Proteins; Sampling; Sand Flies; Seroepidemiologic Studies; Serologic tests; Serological; Serum; Simuliidae; Site; Sorting - Cell Movement; Source; Staging; Stimulus; Testing; Thyroiditis; Time; Tribes; Update; Urban Hospitals; Validation; Virus Diseases; anti-IgG; anti-IgM; base; cDNA Expression; cell type; cohort; desmoglein 1; early childhood; feeding; follow-up; high risk; improved; instrument; member; neonate; novel; pre-clinical; response; sensitizing antigen; serological marker; sex; skin disorder; tool; vector

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.

描述（由申请人提供）：R01 AR 32599的这种竞争更新旨在发现流行的Pemphigus foliaceus（PF）的病因，也称为Fogo Selvagem（FS）。某些优势是，特异性的自身免疫性疾病（例如FS（表皮特异性）提供了自身免疫性研究的提议与抗DSG1（Desmoglein 1）自身抗体是致病性的，并且是自动抗抗体的，DSG1，DSG1，DSG1，完全表征。位于巴西Mato Grosso do Sul州利马佛得角的美洲印第安人保留地是美国阿美林人Terena Tribe的1,351名成员（截至2006年9月10日）的所在地，是FS的积极重点，是FS的一个重点，表现出约3％的疾病患者。在过去的12年中，我们已系统地收集了来自FS患者的临床和血清学数据，以及居住在该定居点内及其周围的临床正常人。来自LV和邻近社区健康个体的抗DSG1自身抗体很常见，并且与此预订的接近性直接相关。我们还观察到11个个体中从正常状态到疾病状态的临床和血清学转化。从临床前临床前阶段，针对DSG1的EC5结构域的非致病IgG自身抗体提出了这种过渡，以在临床活性疾病发作期间针对DSG1 EC1-2域的致病性IgG反应。我们还报告说，致病性抗体受IgG4受限。我们最近发现，IgM抗DSG1自身抗体反应与暴露于其本地农村环境的FS患者不同，这在其他形式的Pemphigus中并不普遍。自童年以来，在生活在LV及其邻近农村地区的临床正常个体中也发现了这种新型的自身抗体，在新生儿缺乏。两种径向方法，即流行病学和免疫学用于探索授予的核心假设，该假设指出环境抗原，即血液流传性昆虫叮咬，使生活在利马维德的人敏感。我们认为，两种方法都不是排他性的，而是彼此互补的。免疫学方法学将产生新的免疫学测定和工具，以促进识别有风险的人的FS。例如，基于对大量FS和对照组中IgG亚类抗DSG1抗体的评估，我们开发了一种“ IgG4分类器/预测指标”，该抗体高度敏感且具有特异性。该仪器将血清定义为具有FS的血清学特征（临床前阶段）或健康个体的特征。使用这种新的“ IgG4分类器/预测指标”，我们分析了Limao Verde的3个队列中96名成员的血清，并确定了21个具有FS血清学特征和75个具有健康对照特征的人（2005年收集的样品）。这些有开发FS的人将被HLA类型，并对任何临床FS的证据进行密切监视。该项目的目标的完成将有助于我们对在美国和世界各地看到的人类自身免疫性疾病的理解。叙述：赠款R01 AR32599旨在披露人类自身免疫性皮肤疾病的病因，即流行的Pemphigus foliaceus，该病因在巴西是特有的。在完成此应用时，我们将更好地了解其他人类自身免疫性疾病，例如红斑狼疮，类风湿关节炎，甲状腺炎等。