Regulation of self-reactive B cells in human and mice

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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.