Serum N-Glycan Signatures as Potential Biomarkers for the Detection and Monitoring of IgG4-Related Disease.

IgG4-related disease (IgG4-RD) is a rare disease characterized by lymphoplasmatic infiltration and fibrosis in multiple organs, often accompanied by elevated serum levels of IgG4. Considerable efforts have been devoted to the diagnosis of IgG4-related diseases, but its etiology and pathogenesis remain poorly understood. The total serum N-glycome profile can reflect disease phenotypes with specific serum N-glycans serving as potential biomarkers for diagnosis and prognosis. However, the serum N-glycome profile in IgG4-RD has yet to be characterized. In this study, two high-throughput orthogonal strategies, matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and lectin-based enzyme-linked immunosorbent assay (ELISA), were employed to analyze serum N-glycome in IgG4-RD and patients undergoing different therapeutic treatments. It was observed that IgG4-RD is associated with a decreased level of galactosylation and an increased level of sialylation. These alterations were further validated through an independent validation set and a lectin-based ELISA assay. Importantly, longitudinal analysis showed a good response of total galactosylation and monosialylated N-glycan (H4N3S1) to drug therapy. Additionally, altered serum N-glycosylation was associated with the routine prognostic indicators for IgG4-RD, including response index (RI), and the levels of IgG4 and IgE. Our study demonstrated the crucial role of N-glycosylation in IgG4-RD, providing new insight into its etiology and pathogenesis.