Institute of Immunology, Rikshospitalet, Oslo University Hospital, Sognsvannsveien 20, Oslo, Norway.
Autoimmun Rev. 2011 Nov;11(1):28-34. doi: 10.1016/j.autrev.2011.06.010. Epub 2011 Jul 14.
Rheumatoid arthritis (RA) is a chronic, autoimmune disease that affects primarily the joints and without proper treatment results in their progressive destruction. In addition to T-cells, B-cells play a central role in the pathogenesis of this disease. The synovial tissue is an active site of B-cell accumulation, plasma cell differentiation and in situ antibody-production in RA. As part of the complex role of B-cells in the joints and synovial membrane of RA patients, B cells secrete chemokines and cytokines and may function as antigen presenting cells. The multifaceted pathogenic function of B-cells identifies them as excellent targets for immunosuppressive therapy. B-cell targeting involves a wide spectrum of molecules, for example the B-cell antigen CD20 that allows specific and effective B-cell depletion. Another target, CD79, expressed by B-cell and plasma cell precursors is an obvious candidate that induces apoptosis as well as inhibition of B-cell receptor (BCR) activation and possibly depletion of ectopic germinal centers (GC). Inhibition of B-cell co-stimulatory molecules such as CD40, CD80/86 and ICOS, can lead to diminished B-cell activation. Moreover, anti-chemokine and anti-cytokine therapies can be efficacious in RA by the disruption of B-cell activation and autoantibody production, B-cell synovial migration and ectopic GC formation. Finally, targeting the signal transduction pathways required for proximal BCR signaling has also been found efficacious in early clinical trials in RA. Even so, some B cells inhibit immune responses, these regulatory B cells may play a part in immune regulation in patients and it is unclear what effects B cell depletion strategies have in terms of such B cell subsets. This review discusses current strategies of targeting B-cells as therapeutic candidates in the management of RA. Better insights into the pathogenic role of B-cells provide efficacious opportunities to improve both therapy and prognosis of patients with RA.
类风湿关节炎（RA）是一种慢性自身免疫性疾病，主要影响关节，如果不进行适当治疗，会导致关节逐渐破坏。除 T 细胞外，B 细胞在这种疾病的发病机制中也起着核心作用。滑膜组织是 B 细胞聚集、浆细胞分化和 RA 原位抗体产生的活性部位。作为 B 细胞在 RA 患者关节和滑膜中的复杂作用的一部分，B 细胞分泌趋化因子和细胞因子，并可能作为抗原提呈细胞发挥作用。B 细胞的多方面致病功能将其确定为免疫抑制治疗的理想靶点。B 细胞靶向涉及广泛的分子，例如 B 细胞抗原 CD20，可实现特异性和有效 B 细胞耗竭。另一个靶标，即 B 细胞和浆细胞前体表达的 CD79，是诱导凋亡以及抑制 B 细胞受体（BCR）激活和可能耗竭异位生发中心（GC）的明显候选物。抑制 B 细胞共刺激分子，如 CD40、CD80/86 和 ICOS，可导致 B 细胞激活减少。此外，通过破坏 B 细胞激活和自身抗体产生、B 细胞滑膜迁移和异位 GC 形成，抗趋化因子和抗细胞因子疗法在 RA 中可能有效。最后，针对 BCR 信号转导所需的信号转导途径的靶向治疗在 RA 的早期临床试验中也被证明是有效的。即便如此，一些 B 细胞抑制免疫反应，这些调节性 B 细胞可能在患者的免疫调节中发挥作用，并且尚不清楚 B 细胞耗竭策略对这些 B 细胞亚群有何影响。本文综述了靶向 B 细胞作为 RA 治疗靶点的当前策略。对 B 细胞致病作用的更好了解为改善 RA 患者的治疗和预后提供了有效的机会。
