The IgE Antibody Response to Dsg1 and Environmental Antigens in Endemic Pemphigus Foliaceus

 描述（由申请人提供）：在本项目中，我们试图了解 IgE 对环境抗原的反应在地方性落叶型天疱疮 (PF)、Fogo Selvagem (FS) 发展中的病因学作用。落叶型天疱疮代表自身免疫性水疱疾病，表现出针对桥粒芯蛋白 1 (Dsg1)（一种桥粒细胞粘附分子）的致病性 IgG4 自身抗体。有趣的是，众所周知，在慢性过敏原刺激或过敏性疾病的免疫治疗过程中，IgE 和 IgG4 抗体会依次出现。我们对 FS 中 IgE 抗体反应的最新研究提供了证据，表明地方性落叶型天疱疮中 IgG4 抗体的发展与对环境抗原的 IgE 反应有关。该证据包括但不限于： 1) 昆虫叮咬是 FS 的危险因素。 2) 利什曼病和白桦茸病在 FS 流行地区集中，白蛉、红蝽、黑蝇等这些疾病的媒介也很流行。利什曼病和恰加斯病患者的抗 Dsg1 抗体水平较高。 3) 已知昆虫叮咬会诱发 IgE 反应。 4) FS患者中存在显着较高水平的IgE抗体，这些IgE抗体的水平与FS中的IgG4抗体的水平显着相关。 5) FS 患者的单克隆自身抗体与 LJM11 发生交叉反应，LJM11 是白蛉唾液腺抗原中最具免疫原性的成分，也是人类暴露于白蛉叮咬的标记。我们假设 FS 流行地区遗传易感个体的慢性环境抗原刺激会触发初始 IgE 反应，从而导致 FS 易感个体随后出现自身抗体和临床 FS。为了检验我们的假设，本次调查提出了三个目标。 1) 本次研究的首要目标是关注 FS 患者 IgE 的发展。我们将确定针对环境抗原 LJM11 自身抗原的 IgE 抗体与 FS 中的 Dsg1 之间是否存在关联。 2) 在第二个目标中，将调查临床 FS 发病前（FS 前）个体和生活在 FS 流行地区的正常个体中 IgE 抗体的发展。我们将确定 IgE 反应是否由环境抗原 LJM11 触发，从而导致自身抗体的产生。这将回答 FS 易感个体中的抗 Dsg1 IgE 自身抗体是否源自对环境抗原的 IgE 反应这一关键问题。 3）第三个目标，我们将鉴定那些IgE克隆相关的IgG4自身抗体并确定其发展机制。我们还将在体内和体外研究这些IgG4自身抗体的致病性，以确定这些IgE克隆相关的IgG4自身抗体是否参与FS的发病机制。这项研究的成功完成将揭示遗传性 FS 易感个体中自身抗体产生的病因机制。此外，我们对 FS 发病前 IgE 抗体形成机制的研究可能证实，IgE 抗体的存在是个体有发生 FS 风险的早期迹象，从而为我们提供了更多信息。 具有 FS 和/或其他 IgG4 相关疾病的有价值的疾病标志物。

 DESCRIPTION (provided by applicant): In this project we seek to understand the etiological role of IgE response to environmental antigens in development of an endemic pemphigus foliaceus (PF), Fogo Selvagem (FS). Pemphigus foliaceus represents autoimmune blistering diseases exhibiting pathogenic IgG4 autoantibodies against desmogleins 1 (Dsg1), a desmosomal cell adhesion molecule. Interestingly, there is a well-known sequential development of IgE and IgG4 antibody development during chronic allergen stimulation or during the immunotherapy of allergic diseases. Our latest investigations into IgE antibody response in FS provide evidence that the development of IgG4 antibodies in endemic pemphigus foliaceus is linked to the IgE response to environmental antigens. This evidence includes, but is not limited to: 1) Insect bite is a risk factor for FS. 2) Leishmaniasis and Chaga disease are clustered in FS endemic regions and the vectors for these diseases, such as sand flies, reduviid bugs, and black flies, are also prevalent. Patients with Leishmaniasis and Chagas disease have high levels of anti-Dsg1 antibodies. 3) Insect bites are known to induce IgE response. 4) Significant higher levels of IgE antibodies are present in FS patients, the levels of these IgE antibodies significantly correlating with that of IgG4 antibodies in FS. 5) Monoclonal autoantibodies from FS patients cross-react with LJM11, the most immunogenic component of sand fly salivary gland antigens and a marker for human exposer to sand fly bites. We hypothesize that chronic environmental antigen stimulation in genetic susceptible individuals in FS endemic regions triggers the initial IgE response which leads to the subsequent development of autoantibodies and clinical FS in FS susceptible individuals. Three aims are proposed in this investigation in order to test our hypothesis. 1) The first aim of this investigaton will focus on the IgE development in FS patients. We will identify whether there is an association between IgE antibodies directed against environmental antigen LJM11 autoantigen and Dsg1 in FS. 2) In the second aim IgE antibodies development in individuals before their onset of clinical FS (pre-FS) and normal individuals living in FS endemic regions will be investigated. We will determine whether the IgE response is triggered by environmental antigen LJM11, which would then lead to autoantibody development. This will answer the critical question as to whether anti-Dsg1 IgE autoantibodies in FS susceptible individuals are originated from IgE response to environmental antigen. 3) In the third aim, we will identify those IgE clonal related IgG4 autoantibodies and determine the mechanism of their development. We will also investigate the pathogenicity of these IgG4 autoantibodies in vivo and in vitro to determine whether those IgE clonal related IgG4 autoantibodies participate in the pathogenesis in FS. The successful completion of this investigation will reveal the etiological mechanism of autoantibody development in genetically FS susceptible individuals. In addition, our studies of the mechanism of IgE antibody development before the onset of FS may substantiate that the presence of IgE antibodies is an early indication that an individual is at risk of developing FS, thus providing us with a valuable disease marker for FS and/or other IgG4-related diseases.