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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IgG Fc聚糖异常对青少年特发性关节炎的功能影响的高通量表征

少年特发性关节炎（JIA）涵盖了16岁之前出现的所有形式的慢性特发性关节炎。先前的研究发现JIA与循环IgG的较低Fc半乳糖基化相关，但是聚糖变化的整体范围以及对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98名健康儿科对照的54例新近发生的未经治疗的JIA患者的IgG糖基化，并使用高通量多重微球分析对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聚糖的增加，但岩藻糖基化或二等分没有变化，并且IgG配体结合的光谱发生了变化。有监督的机器学习证明了使用糖基化或结合数据将JIA受试者与对照区分开的强大能力。结合签名主要是通过增强对Fc受体样蛋白5（FcRL5）（在B细胞上表达的非规范Fc受体）的亲和力来驱动的。FcRL5的亲和力与半乳糖基化和唾液酸化呈负相关，这种关系已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表型的能力，以定义IgG聚糖变化的整体功能影响，并暗示FcRL5作为IgG糖基化的潜在细胞传感器。在B细胞上表达的非经典Fc受体。FcRL5的亲和力与半乳糖基化和唾液酸化呈负相关，这种关系已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表型的能力，以定义IgG聚糖变化的整体功能影响，并暗示FcRL5作为IgG糖基化的潜在细胞传感器。在B细胞上表达的非经典Fc受体。FcRL5的亲和力与半乳糖基化和唾液酸化呈负相关，这种关系已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表型的能力，以定义IgG聚糖变化的整体功能影响，并暗示FcRL5作为IgG糖基化的潜在细胞传感器。