Since entering the stage 25 years ago as a highly specific serological biomarker for rheumatoid arthritis, anti-citrullinated protein antibodies (ACPAs) have been a topic of extensive research. This hallmark B cell response arises years before disease onset, displays interpatient autoantigen variability, and is associated with poor clinical outcomes. Technological and scientific advances have revealed broad clonal diversity and intriguing features including high levels of somatic hypermutation, variable-domain N-linked glycosylation, hapten-like peptide interactions, and clone-specific multireactivity to citrullinated, carbamylated and acetylated epitopes. ACPAs have been found in different isotypes and subclasses, in both circulation and tissue, and are secreted by both plasmablasts and long-lived plasma cells. Notably, although some disease-promoting features have been reported, results now demonstrate that certain monoclonal ACPAs therapeutically block arthritis and inflammation in mouse models. A wealth of functional studies using patient-derived polyclonal and monoclonal antibodies have provided evidence for pathogenic and protective effects of ACPAs in the context of arthritis. To understand the roles of ACPAs, one needs to consider their immunological properties by incorporating different facets such as rheumatoid arthritis B cell biology, environmental triggers and chronic antigen exposure. The emerging picture points to a complex role of citrulline-reactive autoantibodies, in which the diversity and dynamics of antibody clones could determine clinical progression and manifestations.

自从 25 年前作为类风湿性关节炎的高度特异性血清学生物标志物进入阶段以来，抗瓜氨酸蛋白抗体 (ACPA) 一直是广泛研究的主题。这种标志性 B 细胞反应在疾病发作前数年出现，显示患者间自身抗原变异性，并与不良的临床结果相关。技术和科学进步揭示了广泛的克隆多样性和有趣的特征，包括高水平的体细胞超突变、可变域 N 连接糖基化、半抗原样肽相互作用以及对瓜氨酸、氨甲酰化和乙酰化表位的克隆特异性多反应性。 ACPA 已在循环和组织中的不同同种型和亚类中被发现，并由浆母细胞和长寿命浆细胞分泌。值得注意的是，尽管已经报道了一些促进疾病的特征，但现在的结果表明，某些单克隆 ACPA 可以治疗小鼠模型中的关节炎和炎症。使用患者来源的多克隆和单克隆抗体进行的大量功能研究为 ACPA 在关节炎中的致病和保护作用提供了证据。为了了解 ACPA 的作用，我们需要结合类风湿性关节炎 B 细胞生物学、环境触发因素和慢性抗原暴露等不同方面来考虑其免疫学特性。新的情况表明瓜氨酸反应性自身抗体的复杂作用，其中抗体克隆的多样性和动态可以决定临床进展和表现。