B cell targeting therapies are effective in various autoimmune diseases, among others rheumatoid arthritis, pemphigus vulgaris, and systemic lupus erythematosus. Given these successes, it is evident that B cells are central orchestrators in the processes leading to the signs and symptoms hallmarking many human autoimmune diseases. The pathways provoking the generation of such autoreactive B cells or mechanisms preventing their induction in health are, however, poorly explored. Nevertheless, such information is crucial for the development of preventative/curative interventions aiming to permanently deplete‐ or prohibit the emergence of autoreactive B cells. Hence, this review will focus on how B cell tolerance might be breached, and which checkpoints are at play preventing the arousal of autoreactive B cells in human. Especially antigen presentation by follicular dendritic cells, somatic hypermutation, and cross‐reactivity to the microbiome/environment could operate as actors playing pivotal roles in the induction of B cell‐mediated humoral autoimmunity. Moreover, we highlight the human autoimmune disease rheumatoid arthritis as a prototype where autoreactive B cells combine several mechanisms to overcome peripheral B cell checkpoints.

中文翻译：

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控制人类自身免疫性疾病中B细胞介导的自身免疫性的检查点

B细胞靶向疗法可有效治疗各种自身免疫性疾病，尤其是类风湿关节炎，寻常型天疱疮和系统性红斑狼疮。有了这些成功，很明显，B细胞在导致许多人类自身免疫性疾病的体征和症状的过程中是关键的协调者。然而，很少探索引起这种自身反应性B细胞生成的途径或阻止其在健康中被诱导的机制。然而，这些信息对于开发旨在永久耗尽或禁止自身反应性B细胞出现的预防/治疗措施至关重要。因此，本综述将重点关注如何突破B细胞耐受性，以及哪些检查点在起作用，从而防止了人类自身反应性B细胞的唤醒。尤其是卵泡树突状细胞的抗原呈递，体细胞超突变以及与微生物组/环境的交叉反应性，可能在诱导B细胞介导的体液自身免疫中起关键作用。此外，我们突出了人类自身免疫性疾病类风湿关节炎的原型，其中自身反应性B细胞结合了多种机制来克服外周B细胞检查点。