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

 描述(由申请人提供)：在这个项目中，我们试图了解IgE对环境抗原的反应在地方性叶状天疱疮(PF)发展中的病因学作用。叶型天疱疮是一种自身免疫性水疱性疾病，表现出针对桥粒细胞黏附分子桥粒蛋白1(DSG1)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期间，IgE和IgG4抗体的发展是连续发展的。我们对FS中IgE抗体反应的最新研究提供了证据，表明地方性叶状天疱疮中IgG4抗体的产生与IgE对环境抗原的反应有关。这一证据包括但不限于：1)昆虫叮咬是FS的危险因素。2)利什曼病和恰加病在FS流行地区呈聚集性分布，传播媒介如沙蝇、残存线虫和黑蝇也很流行。利什曼病和恰加斯病患者的抗DSG1抗体水平较高。3)昆虫叮咬可诱发免疫球蛋白E反应。4)FS患者血清中的IgE抗体水平明显高于对照组，且与IgG4抗体水平呈显著正相关。5)来自FS患者的单抗与LJM11发生交叉反应，LJM11是沙蝇唾液腺抗原中免疫原性最强的成分，也是人类暴露于沙蝇叮咬的标志。我们假设，在FS流行区的遗传易感人群中，慢性环境抗原刺激触发了初始的IgE反应，从而导致FS易感人群的自身抗体和临床FS的后续发展。为了验证我们的假设，本研究提出了三个目标。1)本研究的第一个目的是研究FS患者的IgE发育情况。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(前FS)患者和生活在FS流行区的正常人的IgE抗体的发展情况。我们将确定IgE反应是否由环境抗原LJM11触发，这将导致自身抗体的产生。这将回答一个关键的问题，即FS易感人群中的抗DSG1 IgE自身抗体是否源于对环境抗原的IgE反应。3)在第三个目标中，我们将鉴定与IgE克隆性相关的IgG4自身抗体，并确定它们的形成机制。我们还将研究这些IgG4自身抗体在体内和体外的致病性，以确定这些与IgE克隆性相关的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易感FS个体中自身抗体产生的病因学机制。此外，我们在FS发病前对IgE抗体形成机制的研究可能证实，IgE抗体的存在是个体有患FS风险的早期迹象，从而为我们提供了 具有FS和/或其他IgG4相关疾病的有价值的疾病标记物。

 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.