Ashworth Laboratories, School of Biological Sciences, Institute of Immunology and Infection Research, The University of Edinburgh, Edinburgh, United Kingdom.
MRC/University of Edinburgh Centre for Inflammation Research, The Queen's Medical Research Institute, Edinburgh, United Kingdom.
Front Immunol. 2020 Mar 20;11:395. doi: 10.3389/fimmu.2020.00395. eCollection 2020.
B cells are critical for promoting autoimmunity and the success of B cell depletion therapy in rheumatoid arthritis (RA) confirms their importance in driving chronic inflammation. Whilst disease specific autoantibodies are useful diagnostically, our understanding of the pathogenic B cell repertoire remains unclear. Defining it would lead to novel insights and curative treatments. To address this, we have undertaken the largest study to date of over 150 RA patients, utilizing next generation sequencing (NGS) to analyze up to 200,000 BCR sequences per patient. The full-length antigen-binding variable region of the heavy chain (IgGHV) of the IgG B cell receptor (BCR) were sequenced. Surprisingly, RA patients do not express particular clonal expansions of B cells at diagnosis. Rather they express a polyclonal IgG repertoire with a significant increase in BCRs that have barely mutated away from the germline sequence. This pattern remains even after commencing disease modifying therapy. These hypomutated BCRs are expressed by TNF-alpha secreting IgGCD27 B cells, that are expanded in RA peripheral blood and enriched in the rheumatoid synovium. A similar B cell repertoire is expressed by patients with Sjögren's syndrome. A rate limiting step in the initiation of autoimmunity is the activation of B cells and this data reveals that a sizeable component of the human autoimmune B cell repertoire consists of polyclonal, hypomutated IgG B cells, that may play a critical role in driving chronic inflammation.
B 细胞对于促进自身免疫和类风湿关节炎（RA）中 B 细胞耗竭疗法的成功至关重要，这证实了它们在驱动慢性炎症中的重要性。虽然疾病特异性自身抗体在诊断上很有用，但我们对致病性 B 细胞库的理解仍不清楚。定义它将导致新的见解和治疗方法。为了解决这个问题，我们对 150 多名 RA 患者进行了迄今为止最大规模的研究，利用下一代测序（NGS）对每个患者分析多达 200,000 个 BCR 序列。对 IgG B 细胞受体（BCR）的重链（IgGHV）全长抗原结合可变区进行了测序。令人惊讶的是，RA 患者在诊断时并没有表达特定的 B 细胞克隆扩增。相反，他们表达了一个多克隆 IgG 库，其中与种系序列相差无几的 BCR 数量显著增加。即使在开始使用疾病修正治疗后，这种模式仍然存在。这些低突变的 BCR 由 TNF-α分泌的 IgGCD27 B 细胞表达，这些细胞在 RA 外周血中扩增，并在类风湿滑膜中富集。干燥综合征患者也表达类似的 B 细胞库。自身免疫的启动的一个限速步骤是 B 细胞的激活，这一数据表明，人类自身免疫 B 细胞库的一个相当大的组成部分由多克隆、低突变的 IgG B 细胞组成，这些细胞可能在驱动慢性炎症中发挥关键作用。
