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

地方性落叶型天疱疮中 IgE 抗体对 Dsg1 和环境抗原的反应

• 批准号: 9303192
• 负责人: Ye Qian
• 金额: $ 33.44万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9303192
• 关键词: Allergens; Allergic; Allergic Disease; Antibodies; Antibody Response; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Bite; Brazil; Bulla; Cell Adhesion Molecules; Chagas Disease; Chronic; Clinical; Development; Disease; Disease Clusterings; Disease Marker; Disease Vectors; Disease model; Dose; Environmental Risk Factor; Etiology; Evolution; Exhibits; Exposure to; Genetic; Genetic Predisposition to Disease; Heterogeneity; Human; IgE; IgG4; Immune response; Immunotherapy; In Vitro; Individual; Insect Bites; Intervention; Investigation; Lead; Leishmaniasis; Link; Modeling; Mucous Membrane; Nature; Onchocerciasis; Outcome; Pathogenesis; Pathogenicity; Patients; Pemphigus; Relapse; Risk; Risk Factors; Role; Salivary Glands; Sand Flies; Simuliidae; Skin; Systems Analysis; Testing; Time; anti-IgE; autoreactivity; cross reactivity; desmoglein 1; epidemiology study; exposure route; genetic analysis; immunogenic; in vivo; public health relevance; response; skin disorder; vector

 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.

 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）发展中的病因作用。落叶型天疱疮代表自身免疫性起泡疾病，其表现出针对桥粒糖蛋白1（Dsg 1）（一种桥粒细胞粘附分子）的致病性IgG 4自身抗体。有趣的是，在慢性过敏原刺激期间或在过敏性疾病的免疫治疗期间，存在众所周知的IgE和IgG 4抗体发展的顺序发展。我们最新的调查IgE抗体反应FS提供的证据表明，地方性落叶型天疱疮的IgG 4抗体的发展与环境抗原的IgE反应。这些证据包括但不限于：1）昆虫叮咬是FS的风险因素。2)利什曼病和恰加病聚集在FS地方病地区，这些疾病的媒介，如白蛉、红蝽和黑蝇也很流行。利什曼病和恰加斯病患者具有高水平的抗Dsg 1抗体。3)已知昆虫叮咬可诱导IgE反应。4)FS患者中存在显著较高水平的IgE抗体，这些IgE抗体的水平与FS中IgG 4抗体的水平显著相关。5)来自FS患者的单克隆自身抗体与LJM 11交叉反应，LJM 11是白蛉唾液腺抗原中最具免疫原性的成分，也是白蛉叮咬后人类免疫缺陷的标志物。我们假设，慢性环境抗原刺激遗传易感个体在FS流行地区触发初始IgE反应，导致随后的发展自身抗体和临床FS FS FS易感个体。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将集中在FS患者的IgE发展。我们将确定是否有针对环境抗原LJM 11自身抗原和Dsg 1在FS的IgE抗体之间的关联。2)在第二个目标，IgE抗体的发展在个人发病前的临床FS（FS前）和正常人生活在FS流行地区将进行调查。我们将确定IgE反应是否由环境抗原LJM 11触发，然后导致自身抗体的发展。这将回答关键的问题，是否抗Dsg 1 IgE自身抗体在FS易感个体起源于IgE反应的环境抗原。3)在第三个目标中，我们将鉴定那些IgE克隆相关的IgG 4自身抗体，并确定其产生的机制。我们还将在体内和体外研究这些IgG 4自身抗体的致病性，以确定这些IgE克隆相关的IgG 4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FS易感个体自身抗体发展的病因机制。此外，我们对FS发病前IgE抗体产生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 具有FS和/或其他IgG 4相关疾病的有价值的疾病标志物。