The immune response to citrullinated antigens is found almost exclusively in patients with rheumatoid arthritis (RA). It is a dynamic response that expands before the onset of disease and generates antibodies (anti-citrullinated protein antibodies (ACPAs)) that are extensively glycosylated in the variable domain. This feature of ACPAs is remarkable and warrants detailed investigation, as it can offer insights into the earliest immunologic mechanisms that lead up to the development of RA. The acquisition of variable domain glycans, in fact, could enable ACPA-expressing B cells to breach tolerance. Although the underlying mechanisms are still elusive, data to support this concept are emerging, owing to the reliable identification and isolation of citrullinated antigen-directed B cells from patients with RA. This technological proficiency also allows for the generation of an increasing number of well-defined monoclonal ACPAs, and provides the opportunity to test and define the mechanisms by which the citrullinated antigen-directed B cell response contributes to the onset and persistence of inflammation. Together with a revised perception of the HLA-risk effect and novel insights into how T cells can govern antibody effector functions, these developments shape an increasingly clear picture of the B cell response to citrullinated antigens in the development of RA.

对瓜氨酸化抗原的免疫应答几乎仅在类风湿关节炎（RA）患者中发现。它是一种动态反应，会在疾病发作之前扩展并产生在可变域中广泛糖基化的抗体（抗瓜氨酸化蛋白抗体（ACPA））。ACPAs的这一功能非常出色，值得进一步研究，因为它可以洞悉导致RA发展的最早的免疫学机制。实际上，获得可变域聚糖可以使表达ACPA的B细胞突破耐受性。尽管潜在的机制仍然难以捉摸，但由于可靠地从RA患者中鉴定和分离了瓜氨酸化抗原导向的B细胞，正在出现支持该概念的数据。这种技术水平还允许生成越来越多的明确定义的单克隆ACPA，并提供了机会来测试和定义瓜氨酸化抗原指导的B细胞应答助长炎症发作和持久性的机制。结合对HLA风险作用的修订认识以及对T细胞如何调控抗体效应子功能的新颖见解，这些发展形成了RA发展过程中B细胞对瓜氨酸化抗原反应的越来越清晰的图景。