Juvenile idiopathic arthritis (JIA) encompasses all forms of chronic idiopathic arthritis that arise before age 16. Previous studies have found JIA to be associated with lower Fc galactosylation of circulating IgG, but the overall spectrum of glycan changes and the net impact on IgG function are unknown. Using ultra performance liquid chromatography (UPLC), we compared IgG glycosylation in 54 subjects with recent-onset untreated JIA with 98 healthy pediatric controls, paired to biophysical profiling of affinity for 20 IgG receptors using a high-throughput multiplexed microsphere assay. Patients with JIA exhibited an increase in hypogalactosylated and hyposialylated IgG glycans, but no change in fucosylation or bisection, together with alteration in the spectrum of IgG ligand binding. Supervised machine learning demonstrated a robust capacity to discriminate JIA subjects from controls using either glycosylation or binding data. The binding signature was driven predominantly by enhanced affinity for Fc receptor like protein 5 (FcRL5), a noncanonical Fc receptor expressed on B cells. Affinity for FcRL5 correlated inversely with galactosylation and sialylation, a relationship confirmed through enzymatic manipulation. These results demonstrate the capacity of combined structural and biophysical IgG phenotyping to define the overall functional impact of IgG glycan changes and implicate FcRL5 as a potential cellular sensor of IgG glycosylation.

中文翻译：

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高通量表征 IgG Fc 聚糖异常对幼年特发性关节炎的功能影响


幼年特发性关节炎 (JIA) 涵盖 16 岁之前出现的所有形式的慢性特发性关节炎。之前的研究发现 JIA 与循环 IgG 的 Fc 半乳糖基化较低有关，但聚糖变化的总体范围和对 IgG 功能的净影响是未知。使用超高效液相色谱 (UPLC)，我们比较了 54 名新近发病且未经治疗的 JIA 受试者与 98 名健康儿科对照者的 IgG 糖基化，并使用高通量多重微球测定法对 20 种 IgG 受体的亲和力进行了生物物理分析。 JIA 患者表现出低半乳糖基化和低唾液酸化 IgG 聚糖增加，但岩藻糖基化或二等分没有变化，同时 IgG 配体结合谱也没有变化。监督机器学习展示了使用糖基化或结合数据区分 JIA 受试者和对照组的强大能力。结合特征主要是由 Fc 受体样蛋白 5 (FcRL5) 的亲和力增强驱动的，FcRL5 是 B 细胞上表达的一种非典型 Fc 受体。 FcRL5 的亲和力与半乳糖基化和唾液酸化成反比，这种关系通过酶促操作得到证实。这些结果证明了结合结构和生物物理 IgG 表型分析来定义 IgG 聚糖变化的整体功能影响的能力，并暗示 FcRL5 作为 IgG 糖基化的潜在细胞传感器。