van den Broek T, Oleinika K, Rahmayanti S, Castrillon C, van der Poel C E, Carroll M C
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston; MA 02115, USA.
bioRxiv. 2023 Jun 1:2023.05.30.542805. doi: 10.1101/2023.05.30.542805.
In autoreactive germinal centers (GC) initiated by a single rogue B cell clone, wild-type B cells expand and give rise to clones that target other autoantigens, known as epitope spreading. The chronic, progressive nature of epitope spreading calls for early interventions, but the kinetics and molecular requirements for wild-type B cell invasion and participation in GC remain largely unknown. With parabiosis and adoptive transfer approaches in a murine model of systemic lupus erythematosus, we demonstrate that wild-type B cells join existing GCs rapidly, clonally expand, persist, and contribute to autoantibody production and diversification. The invasion of autoreactive GCs required TLR7, B cell receptor specificity, antigen presentation, and type I interferon signaling. The adoptive transfer model provides a novel tool for identifying early events in the breaking of B cell tolerance in autoimmunity.
在由单个异常B细胞克隆引发的自身反应性生发中心（GC）中，野生型B细胞会扩增并产生靶向其他自身抗原的克隆，这被称为表位扩展。表位扩展的慢性、进行性特征需要早期干预，但野生型B细胞侵入和参与GC的动力学及分子要求在很大程度上仍不清楚。通过联体生活和过继转移方法，在系统性红斑狼疮小鼠模型中，我们证明野生型B细胞能迅速加入现有的GC，进行克隆性扩增、持续存在，并促进自身抗体的产生和多样化。自身反应性GC的侵入需要Toll样受体7（TLR7）、B细胞受体特异性、抗原呈递和I型干扰素信号传导。过继转移模型为识别自身免疫中B细胞耐受性破坏的早期事件提供了一种新工具。
