Regulation of self-reactive B cells in human and mice

几个耐受性检查点控制自我反应性B细胞的发育和活化。由于遗传易感性和环境因素导致的耐受性丧失导致产生自身抗体的浆细胞和自身免疫性疾病如系统性红斑狼疮（SLE）的发展。然而，在SLE的发展过程中不能调节自身反应性B细胞的耐受检查点仍然缺乏研究。拟议的研究项目的目标是定义控制天真的公差检查点在健康人（I）和小鼠（II）中，在抗原介导的活化后以及在向记忆细胞和浆细胞分化的过渡期，外周中的（自身反应性）B细胞，并确定在SLE患者中，在抗原介导的B细胞分化的晚期阶段，自身耐受性在何处和何时被破坏（I）和狼疮小鼠模型（II）。人类材料的研究对于了解疾病至关重要，但仅限于描述性分析。因此，小鼠模型提供了重要的工具，以解决机制的问题。我们建议将详细的小鼠分析与患者和健康人的单个B细胞表征紧密联系起来。这两种系统的结合将使我们能够解决更具体的问题，分子基础以及环境因素对人类SLE发展的影响，并将开辟新的方向，为免疫学方法的发展，以阻止疾病的未来。

Several tolerance checkpoints control the development and activation of selfreactive B cells. Loss of tolerance due to genetic susceptibility and environmental factors is responsible for the generation of autoantibody producing plasma cells and the development of autoimmune diseases like Systemic Lupus Erythematodes (SLE). However, the tolerance checkpoints, which fail to regulate self-reactive B cells during the development of SLE are still poorly investigated. The goal of the proposed research project is to define tolerance checkpoints that control naive (self-reactive) B cells in the periphery after antigen-mediated activation and at the transition to differentiation into memory and plasma cells in healthy human (I) and mice (II) and to determine where and when during the late stages of antigen-mediated B cell differentiation self-tolerance is broken in patients with SLE (I) and lupus mouse models (II). Studies with human material are essential to understanding disease but are limited to largely descriptive analyses. Therefore, mouse models provide important tools to address mechanistic questions. We propose to closely link detailed mouse analyses and single B cell characterization of patients and healthy humans. Combination of both systems will allow us to address more specific questions regarding the molecular basis as well as the influence of environmental factors for the development of SLE in humans and will open new directions for the development of immunological approaches to block the disease in the future.