Interactions of lgC4 & lgE anti-Dsg1 Autoantibodies in Endemic Pemphigus Foliaceu

描述（由申请人提供）：P.I.最近进入了皮肤自身免疫的研究领域。他的职业发展计划旨在确保该领域的高级培训，并使他在导师L.A.博士的指导下成为一名独立研究者。迪亚兹是国际公认的皮肤病领域的领导者。为了加强培训，该计划已经招募了一个咨询委员会的专业知识，该委员会由在皮肤生物学，自身免疫和过敏以及生物统计学领域具有专业知识的知名研究人员组成，以提供科学和职业建议。私家侦探一直在研究地方性[Fogo Selvagem（FS）]和非地方性落叶型天疱疮（PF）和寻常型天疱疮（PV）中自身抗体产生的机制。他专注于在这些患者中发现的致病性抗桥粒芯糖蛋白1（Dsg 1）自身抗体的启动和发展。该研究旨在探索FS中自身反应性IgE抗体和致病性IgG4自身抗体的相互作用。我们实验室的最近工作表明，与健康对照相比，FS患者具有显著更高水平的抗Dsgl IgE抗体。我们假设FS中的IgG 4和IgE抗Dsgl自身抗体应答由相同的环境抗原（“过敏原”）触发。候选人的近期研究计划是提供证据证明FS中的IgE和IgG 4自身抗体反应与疾病的发病机制相关。目的1将集中于FS患者和来自FS流行区的健康个体中IgE和IgG 4抗Dsgl应答的相互作用。在目的2中，我们将产生抗Dsgl IgE单克隆抗体以研究它们的V基因使用，并通过它们的“克隆特征”分析在相同FS患者中抗Dsgl IgG4和IgE自身抗体之间是否存在任何遗传关系。在目的3中，我们将通过被动转移小鼠模型确定抗Dsgl IgE抗体的病原体城市。本课题的成功完成将有助于我们对FS的病因和发病机制以及其他人类皮肤疾病的研究。此外，该K01奖将促进申请人的职业发展，并帮助他实现研究独立。

DESCRIPTION (provided by applicant): The P.I. has recently entered the research field of cutaneous autoimmunity. His career development plan is designed to secure advanced training in this field and prepare him to become an independent investigator under the guidance of his mentor, Dr. L.A. Diaz, who is internationally recognized as a leader in the field of skin diseases. To enhance the training, the program has enlisted the expertise of an advisory committee that consists of established investigators with expertise in the field of cutaneous biology, autoimmunity and allergy, and biostatistics for the scientific and career advice. The P.I. have been studying the mechanism of the development of auto antibodies in endemic [Fogo Selvagem (FS)] and non-endemic pemphigus foliaceus (PF) and pemphigus vulgaris (PV). He is focusing on the initiation and development of pathogenic anti- desmoglein 1 (Dsg1) auto antibodies that are found in these patients. This grant explores the interaction of self-reactive IgE antibodies and pathogenic lgG4 auto antibodies in FS. Recent work in our laboratory demonstrated that FS patients have significantly higher levels of anti-Dsgl IgE antibodies compared to healthy controls. We hypothesize that the lgG4 and IgE anti-Dsgl autoantibody responses in FS are triggered by the same environmental antigen ("allergen"). The candidate's immediate research plan is to provide evidence that the IgE and lgG4 autoantibody response in FS is relevant to the pathogenesis of the disease. Aim 1 will focus on the interactions of IgE and lgG4 anti-Dsgl response in FS patients and healthy individuals from endemic areas of FS. In Aim 2, we will generate anti-Dsgl IgE monoclonal antibodies to study their V gene usage, and analyze whether there is any genetic relationship between anti-Dsgl lgG4 and IgE auto antibodies in the same FS patients through their "clonal signature". In Aim 3, we will determine the pathogen city of anti-Dsgl IgE antibodies by the passive transfer mouse model. The successful conclusion of this project will shed light on our understanding of the mechanism of etiology and pathogenesis of FS, as well as other human cutaneous diseases. Additionally, this K01 Award will promote the career advancement of the applicant and help him to achieve research independence.