B cells expressing the transcription factor T-bet are found to have a protective role in viral infections, but are also considered major players in the onset of different types of autoimmune diseases. Currently, the exact mechanisms driving such ‘atypical’ memory B cells to contribute to protective immunity or autoimmunity are unclear. In addition to general autoimmune-related factors including sex and age, the ways T-bet⁺ B cells instigate autoimmune diseases may be determined by the close interplay between genetic risk variants and Epstein–Barr virus (EBV). The impact of EBV on T-bet⁺ B cells likely relies on the type of risk variants associated with each autoimmune disease, which may affect their differentiation, migratory routes and effector function. In this hypothesis-driven review, we discuss the lines of evidence pointing to such genetic and/or EBV-mediated influence on T-bet⁺ B cells in a range of autoimmune diseases, including systemic lupus erythematosus (SLE) and multiple sclerosis (MS). We provide examples of how genetic risk variants can be linked to certain signaling pathways and are differentially affected by EBV to shape T-bet⁺ B-cells. Finally, we propose options to improve current treatment of B cell-related autoimmune diseases by more selective targeting of pathways that are critical for pathogenic T-bet⁺ B-cell formation.

人们发现表达转录因子 T-bet 的 B 细胞在病毒感染中具有保护作用，但也被认为是不同类型自身免疫性疾病发病的主要参与者。目前，驱动这种“非典型”记忆 B 细胞促进保护性免疫或自身免疫的确切机制尚不清楚。除了性别和年龄等一般自身免疫相关因素外，T-bet ⁺ B 细胞引发自身免疫性疾病的方式可能是由遗传风险变异和 Epstein-Barr 病毒 (EBV) 之间的密切相互作用决定的。^{EBV 对 T-bet +} B 细胞的影响可能取决于与每种自身免疫性疾病相关的风险变异类型，这可能会影响它们的分化、迁移途径和效应器功能。在这篇以假设为驱动的综述中，我们讨论了一系列证据，这些证据表明遗传和/或 EBV 介导的对一系列自身免疫性疾病中T-bet ⁺ B 细胞的影响，包括系统性红斑狼疮 (SLE) 和多发性硬化症 (MS) ）。我们提供了一些例子，说明遗传风险变异如何与某些信号通路联系起来，并如何受到 EBV 的不同影响来塑造 T-bet ⁺ B 细胞。最后，我们提出了通过更有选择性地靶向对致病性 T-bet ⁺ B细胞形成至关重要的途径来改善当前 B 细胞相关自身免疫性疾病的治疗的方案。