Regulation of self-reactive B cells in human and mice

几个耐受检查点控制着自我反应性B细胞的发育和激活。由于遗传易感性和环境因素导致的耐受性丧失是产生自身抗体的浆细胞和系统性红斑狼疮（SLE）等自身免疫性疾病的原因。然而，在SLE的发展过程中，耐受检查点不能调节自身反应性B细胞，但对其的研究仍然很少。提出了研究项目的目的是定义公差控制天真的检查点(反应)B细胞在外围antigen-mediated激活和分化的过渡到内存和浆细胞在健康老鼠人类(I)和(II)并确定何时何地antigen-mediated B细胞分化晚期期间自我耐受性坏了系统性红斑狼疮患者(我)和狼疮小鼠模型(II)。对人体材料的研究对了解疾病至关重要，但主要限于描述性分析。因此，小鼠模型为解决机制问题提供了重要的工具。我们建议将详细的小鼠分析与患者和健康人的单个B细胞特征密切联系起来。这两种系统的结合将使我们能够解决关于分子基础以及环境因素对人类SLE发展的影响的更具体的问题，并将为未来开发免疫方法来阻断疾病开辟新的方向。

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.