The presence of disease-specific autoantibody responses and the efficacy of B cell-targeting therapies in rheumatoid arthritis (RA) indicate a pivotal role for B cells in disease pathogenesis. Important advances have shaped our understanding of the involvement of autoantibodies and autoreactive B cells in the disease process. In RA, autoantibodies target antigens with a variety of post-translational modifications such as carbamylation, acetylation and citrullination. B cell responses against citrullinated antigens generate anti-citrullinated protein antibodies (ACPAs), which are themselves modified in the variable domains by abundant N-linked glycans. Insights into the induction of autoreactive B cells against antigens with post-translational modifications and the development of autoantibody features such as isotype usage, epitope recognition, avidity and glycosylation reveal their relationship to particular RA risk factors and clinical phenotypes. Glycosylation of the ACPA variable domain, for example, seems to predict RA onset in ACPA⁺ healthy individuals, possibly because it affects B cell receptor signalling. Moreover, ACPA-expressing B cells show dynamic phenotypic changes and develop a continuously proliferative and activated phenotype that can persist in patients who are in drug-induced clinical remission. Together, these findings can be integrated into a conceptual framework of immunological autoreactivity in RA, delineating how it develops and persists and why disease activity recurs when therapy is tapered or stopped.

疾病特异性自身抗体反应的存在和 B 细胞靶向疗法在类风湿性关节炎 (RA) 中的疗效表明 B 细胞在疾病发病机制中的关键作用。重要的进展塑造了我们对自身抗体和自身反应性 B 细胞参与疾病过程的理解。在 RA 中，自身抗体靶向具有多种翻译后修饰的抗原，例如氨基甲酰化、乙酰化和瓜氨酸化。B 细胞对瓜氨酸化抗原的反应产生抗瓜氨酸化蛋白抗体 (ACPA)，这些抗体本身在可变域中被丰富的 N-连接聚糖修饰。深入了解具有翻译后修饰的抗原诱导自身反应性 B 细胞以及同种型使用、表位识别等自身抗体特征的发展，亲合力和糖基化揭示了它们与特定 RA 危险因素和临床表型的关系。例如，ACPA 可变域的糖基化似乎可以预测 ACPA 中的 RA 发作⁺健康个体，可能是因为它影响 B 细胞受体信号。此外，表达 ACPA 的 B 细胞表现出动态的表型变化，并发展出一种持续增殖和激活的表型，这种表型可以在处于药物诱导的临床缓解期的患者中持续存在。总之，这些发现可以整合到 RA 免疫自身反应性的概念框架中，描述它是如何发展和持续的，以及为什么在治疗逐渐减少或停止时疾病活动会复发。