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

描述（由申请人提供）：该pi最近进入皮肤自身免疫的研究领域。他的职业发展计划旨在确保在该领域的高级培训，并准备在他的导师L.A. Diaz博士的指导下成为一名独立调查员，L.A. Diaz博士是国际公认的皮肤病领域的领导者。为了加强培训，该项目征集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调查人员组成，为科学和职业提供建议。ppi一直在研究地方性[foo Selvagem (FS)]和非地方性天疱疮（PF）和寻常型天疱疮（PV）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粘粒蛋白1 （Dsg1）自身抗体的起始和发展。本基金旨在探索FS中自身反应性IgE抗体和致病性lgG4自身抗体的相互作用。我们实验室最近的工作表明，与健康对照相比，FS患者的抗dsgl IgE抗体水平明显较高。我们假设FS中的lgG4和IgE抗dsgl自身抗体反应是由相同的环境抗原（“过敏原”）触发的。候选人近期的研究计划是提供证据，证明FS中的IgE和lgG4自身抗体反应与疾病的发病机制有关。目的1将重点关注FS患者和来自FS流行地区的健康个体中IgE和lgG4抗dsgl反应的相互作用。在Aim 2中，我们将生成抗dsgl IgE单克隆抗体，研究其V基因使用情况，并通过“克隆标记”分析同一FS患者的抗dsgl lgG4和IgE自身抗体之间是否存在遗传关系。在第三阶段，我们将通过被动转移小鼠模型确定抗dsgl IgE抗体的病原城市。本项目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认识。此外，这个K01奖将促进申请人的职业发展，帮助他实现研究的独立性。

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.