Department of Medicine, Division of Rheumatology, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Nat Rev Rheumatol. 2024 Jul;20(7):399-416. doi: 10.1038/s41584-024-01124-6. Epub 2024 Jun 10.
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 25 年前作为类风湿关节炎的高度特异性血清学生物标志物进入临床阶段以来，抗瓜氨酸化蛋白抗体（ACPA）一直是广泛研究的课题。这种标志性的 B 细胞反应早在疾病发作前多年就出现了，具有患者间自身抗原变异性，并与不良临床结局相关。技术和科学的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针对瓜氨酸化、氨甲酰化和乙酰化表位的克隆特异性多反应性。ACPA 存在于不同的同种型和亚类中，在循环和组织中均有发现，并由浆母细胞和长寿浆细胞分泌。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 在小鼠模型中具有治疗性阻断关节炎和炎症的作用。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 在关节炎背景下的致病性和保护作用提供了证据。为了了解 ACPA 的作用，需要通过纳入类风湿关节炎 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。新出现的情况表明，瓜氨酸反应性自身抗体具有复杂的作用，抗体克隆的多样性和动态性可能决定临床进展和表现。
