Etiology and Pathogenesis of Pemphigus

描述（由申请人提供）：这是R 01-AR 32599资助的竞争性更新，旨在确定巴西落叶型天疱疮或Foqo Selvagem（fs）的病因。FS是由针对桥粒芯糖蛋白1（dsg 1）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产生这些自身抗体。我们已经确定了一个新的FS焦点，疾病患病率为3%，以及一套独特的环境，遗传和文化特征。这个社区位于巴西中部的Limao Verde保留地，由大约1100名Terena印第安部落成员组成。在该保留地发现的35例FS病例中，描述了地理、家族、HLA和时间聚集模式。基于我们的研究，我们预测正常对照（FS的临床前状态），当暴露于某些环境抗原时，产生早期IgG 1抗dsg 1应答;仅在以后，并且在某些易感个体中，这种应答才成为致病性的并且由IgG 4抗dsg 1抗体介导（ES的临床状态）。令人鼓舞的初步研究表明，吸血昆虫的唾液，如接吻虫和白蛉，可能是触发抗dsg 1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、血清学和生态学数据对由成人和年轻个体组成的队列进行随访。将连续评价抗dsg 1 IgG、IgG 1和IgG 4应答的血清学证据。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有关的环境因素。目标3将集中于评估恰加斯病（接吻虫）和利什曼病（白蛉）患者对dsg 1的血清学反应，并对这些吸血昆虫的唾液抗原进行分子表征。目的4将测试FS T细胞对假定的唾液抗原的反应，目的5将包括对家畜FS样疾病频率的研究。巴西可能存在“地方性寻常天疱疮”变种，以及对Limao Verde的白蛉和吻虫物种进行评价也包括在后一个目标中。FS的自身免疫机制可能与其他人类自身免疫性疾病具有相同的特点，我们从ES中所学到的知识将适用于人类自身免疫性疾病的研究。

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.