Characterizing the IgG1 Memory B cells that are precursors of pathogenic IgE

项目概要： 在美国，IgE 介导的食物过敏影响着大约三分之一的儿童，并且这种情况持续增长 近几十年来盛行。对于许多人来说，目前的免疫疗法无效，这使其成为终生的治疗方法 严重损害生活质量的疾病。尽管 IgE 对食物的病理生理学至关重要 过敏，维持高亲和力（致病性）IgE 的机制尚不清楚。以前的工作 我们实验室的研究表明，小鼠的 IgE 记忆包含在抗原特异性群体中 IgG 记忆 B 细胞 (MBC)，可进行类别转换至 IgE。然而，针对广泛的战略 表达 IgG 的细胞亚群用于治疗食物过敏，由于需要保留保护性而变得复杂 对病原体的免疫力。因此，识别具有这种能力的特定 IgG MBC 非常重要 产生高亲和力 IgE 反应。该提案旨在利用花生过敏的小鼠模型来 鉴定可区分 IgG MBC 亚群的免疫表型标记物，并能够产生高 亲和力 IgE 浆细胞 (PC)。此外，该应用将解决这种细胞命运的可塑性和 IgG MBC 分化为 IgE PC 所需的外部信号。最终，我们想要 了解 IgG MBC 怎样才能成为产生致病性 IgE 的浆细胞并揭示 可以接受治疗干预的目标，以改善患者的生活质量 患有食物过敏。

PROJECT SUMMARY: IgE-mediated food allergy affects approximately 1 in 13 children in the USA and has continued to grow in prevalence in recent decades. For many, current immunotherapies are ineffective, making this is a lifelong disease with significant impairment in quality of life. Although IgE is central to the pathophysiology of food allergy, the mechanisms maintaining high affinity (pathogenic) IgE are not well understood. Previous work from our laboratory has shown that IgE memory in mice is contained within a population of antigen-specific IgG memory B cells (MBC) that can undergo class switching to IgE. However, strategies targeting a broad subset of IgG-expressing cells for treatment of food allergy is complicated by the need to retain protective immunity against pathogens. Therefore, it is important to identify the specific IgG MBC that have the ability to generate high affinity IgE responses. This proposal seeks to use mouse models of peanut allergy to identify immunophenotypic markers that can distinguish IgG MBC subsets with the ability to produce high affinity IgE plasma cells (PC). In addition, this application will address the plasticity of this cell fate and the external signals that are required for IgG MBC differentiation into IgE PC. Ultimately, we want to understand what it takes for an IgG MBC to become a pathogenic-IgE producing plasma cell and reveal targets that could be amenable to therapeutic intervention to improve the quality of life of patients who suffer from food allergies.