A role for B cells in autoimmune diseases is now clearly established both in mouse models and humans by successful treatment of multiple sclerosis and rheumatoid arthritis with anti-CD20 monoclonal antibodies that eliminate B cells. However, the underlying mechanisms by which B cells promote the development of autoimmune diseases remain poorly understood. Here, we review evidence that patients with autoimmune disease suffer from defects in early B-cell tolerance checkpoints and therefore fail to counterselect developing autoreactive B cells. These B-cell tolerance defects are primary to autoimmune diseases and may result from altered B-cell receptor signaling and dysregulated T-cell/regulatory T-cell compartment. As a consequence, large numbers of autoreactive naive B cells accumulate in the blood of patients with autoimmune diseases and may promote autoimmunity through the presentation of self-antigen to T cells. In addition, new evidence suggests that this reservoir of autoreactive naive B cells contains clones that may develop into CD27- CD21-/lo B cells associated with increased disease severity and plasma cells secreting potentially pathogenic autoantibodies after the acquisition of somatic hypermutations that improve affinity for self-antigens.

中文翻译：

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B细胞耐受性检查点受损促进自身免疫性疾病和致病性自身抗体的发展。

通过用消除 B 细胞的抗 CD20 单克隆抗体成功治疗多发性硬化症和类风湿性关节炎，B 细胞在自身免疫性疾病中的作用现已在小鼠模型和人类中得到明确证实。然而，B细胞促进自身免疫性疾病发展的潜在机制仍然知之甚少。在这里，我们回顾了自身免疫性疾病患者在早期 B 细胞耐受性检查点存在缺陷的证据，因此无法反选择发育中的自身反应性 B 细胞。这些 B 细胞耐受缺陷是自身免疫性疾病的原发性，可能是由于 B 细胞受体信号传导改变和 T 细胞/调节性 T 细胞区室失调所致。作为结果，大量自身反应性幼稚 B 细胞积聚在自身免疫性疾病患者的血液中，并可能通过向 T 细胞呈递自身抗原来促进自身免疫。此外，新的证据表明，这种自身反应性幼稚 B 细胞库包含可能发育成 CD27-CD21-/lo B 细胞的克隆，这些细胞与疾病严重程度增加和浆细胞在获得体细胞高突变后分泌潜在的致病性自身抗体相关，从而提高对自身抗原。