Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
Eur J Immunol. 2020 Dec;50(12):1885-1894. doi: 10.1002/eji.202048820. Epub 2020 Dec 2.
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.
B 细胞靶向治疗在多种自身免疫性疾病中有效，包括类风湿关节炎、寻常型天疱疮和系统性红斑狼疮等。鉴于这些成功，显然 B 细胞是导致许多人类自身免疫性疾病的特征性体征和症状的核心协调者。然而，引发此类自身反应性 B 细胞的途径或在健康状态下阻止其诱导的机制仍未得到充分探索。然而，此类信息对于开发旨在永久性耗尽或阻止自身反应性 B 细胞出现的预防/治疗干预措施至关重要。因此，本综述将重点关注 B 细胞耐受如何被打破，以及哪些检查点在防止人类自身反应性 B 细胞出现中发挥作用。特别是滤泡树突状细胞的抗原呈递、体细胞高频突变和对微生物组/环境的交叉反应可能作为在诱导 B 细胞介导的体液自身免疫中起关键作用的因素发挥作用。此外，我们强调人类自身免疫性疾病类风湿关节炎作为一个原型，其中自身反应性 B 细胞结合几种机制来克服外周 B 细胞检查点。
