Amsterdam UMC, University of Amsterdam, Department of Rheumatology & Clinical Immunology, Amsterdam Infection & Immunity Institute, Amsterdam, the Netherlands; Amsterdam UMC, University of Amsterdam, Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam, the Netherlands; Amsterdam Rheumatology & Immunology Center (ARC), Amsterdam UMC, the Netherlands.
Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam, the Netherlands.
J Autoimmun. 2019 Jul;101:131-144. doi: 10.1016/j.jaut.2019.04.011. Epub 2019 Apr 30.
During T cell-dependent (TD) germinal center (GC) responses, naïve B cells are instructed to differentiate towards GC B cells (GCBC), high-affinity long-lived plasma cells (LLPC) or memory B cells (Bmem). Alterations in the B cell-fate choice could contribute to immune dysregulation leading to the loss of self-tolerance and the initiation of autoimmune disease. Here we show that mRNA levels of the transcription regulator BOB.1 are increased in the lymph node compartment of patients with rheumatoid arthritis (RA), a prototypical autoimmune disease caused by the loss of immunological tolerance. Investigating to what extent levels of BOB.1 impact B cells during TD immune responses we found that BOB.1 has a crucial role in determining the B cell-fate decision. High BOB.1 levels promote the generation of cells with phenotypic and functional characteristics of Bmem. Mechanistically, overexpression of BOB.1 drives ABF1 and suppresses BCL6, favouring Bmem over LLPC or recycling GCBC. Low levels of BOB.1 are sufficient for LLPC but not for Bmem differentiation. Our findings demonstrate a novel role for BOB.1 in B cells during TD GC responses and suggest that its dysregulation may contribute to the pathogenesis of RA by disturbing the B cell-fate determination.
在 T 细胞依赖的（TD）生发中心（GC）反应中，幼稚 B 细胞被指示分化为 GC B 细胞（GCBC）、高亲和力长寿命浆细胞（LLPC）或记忆 B 细胞（Bmem）。B 细胞命运选择的改变可能导致免疫失调，导致自身耐受的丧失和自身免疫性疾病的发生。在这里，我们表明，转录调节剂 BOB.1 的 mRNA 水平在类风湿关节炎（RA）患者的淋巴结区增加，RA 是一种由免疫耐受丧失引起的典型自身免疫性疾病。研究 BOB.1 的水平在 TD 免疫反应中对 B 细胞的影响程度，我们发现 BOB.1 在决定 B 细胞命运决策中起着至关重要的作用。高 BOB.1 水平促进具有 Bmem 表型和功能特征的细胞的产生。从机制上讲，BOB.1 的过表达驱动 ABF1 并抑制 BCL6，有利于 Bmem 而不是 LLPC 或循环 GCBC。低水平的 BOB.1 足以促进 LLPC，但不足以促进 Bmem 分化。我们的研究结果表明，BOB.1 在 TD GC 反应中的 B 细胞中具有新的作用，并表明其失调可能通过干扰 B 细胞命运决定，导致 RA 的发病机制。
