Author Identifier
Zhixian Chen: http://orcid.org/0000-0002-2970-3346
Date of Award
2026
Keywords
Immunoglobulin G, glycosylation, Sjögren disease, biomarker, Mendelian randomization
Document Type
Thesis - ECU Access Only
Publisher
Edith Cowan University
Degree Name
Doctor of Philosophy
School
School of Medical and Health Sciences
First Supervisor
Wei Wang
Second Supervisor
Ling Lin
Third Supervisor
Manshu Song
Fourth Supervisor
Christopher Abbiss
Abstract
Sjögren disease (SjD) is a systemic autoimmune disease characterized by exocrine gland dysfunction that can occur alone as primary SjD or in association with other autoimmune disorders. Due to clinical overlap with diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), accurate diagnosis and disease monitoring remain challenging. Immunoglobulin G (IgG) N-glycosylation, a key regulator of immune responses, exhibits disease-specific changes in autoimmune disorders, suggesting potential as a biomarker for SjD. This PhD project aimed to investigate the association between IgG N-glycosylation and SjD, and to explore its clinical utility through integrative approaches combining glycomic, immunological, and genetic data.
First, a comprehensive review summarized the structure and immunological role of IgG N-glycosylation and synthesized current evidence linking it to SjD pathogenesis and biomarker potential. Second, a focused review examined the interaction between cytokines and IgG N-glycosylation across inflammatory conditions to provide mechanistic insights. Third, a case-control study evaluated IgG N-glycan features as biomarkers for diagnosing SjD and assessing disease activity. Finally, a Mendelian randomization (MR) analysis was conducted using public genome-wide association summary statistics to explore the causal relationship between IgG glycosylation and SjD.
In the case-control study, patients with SjD, RA, and SLE all exhibited reduced IgG galactosylation and increased bisecting N-acetylglucosamine (GlcNAc), with SjD showing the lowest sialylation and highest bisecting GlcNAc levels. They also shared elevated ultra-performance liquid chromatography (UPLC) chromatographic glycan peaks GP1 (FA1) and reduced GP9 (FA2[3]G1). Compared with RA, SjD was characterized by elevated GP3 (A2B), GP8 (FA2[6]G1) and reduced GP23 (FA2G2S2) with adjusted odds ratios (AORs) of 4.27, 3.53 and 0.07, respectively. Elevated GP11 (FA2[3]BG1) distinguished SjD from SLE (AOR 11.99). These glycan traits demonstrated superior diagnostic performance to conventional autoantibodies in receiver operating characteristic (ROC) analysis. In SjD, reduced galactosylation was associated with higher disease activity, with GP5 (M5) and GP14 (FA2G2) showing stronger correlations than erythrocyte sedimentation rate or serum IgG. Glycan changes also correlated with plasma levels of B cell activating factor and interferon-α. In the MR analysis, no strong evidence supported a causal effect of IgG N-glycosylation on SjD. However, SjD exhibited a significant negative causal effect on the IgG glycan trait IGP8 (i.e., GP9, FA2[3]G1; IGP8 refers to the Edinburgh identifier corresponding to GP9 in the Zagreb nomenclature) (β = -0.08, 95% CI: -0.13 to -0.04, FDR-adjusted P = 0.009) and IGP33 (a derived glycan trait representing monosialylated, fucosylated structures) (β = -0.09, 95% CI: -0.14 to -0.05, FDR-adjusted P = 0.003) based on meta analyzed inverse-variance weighted estimates. These results were robust across sensitivity analyses, with no evidence of pleiotropy, heterogeneity, or outliers.
In summary, serum IgG N-glycosylation profiles show potential for diagnosing SjD and differentiating it from RA and SLE, as well as for assessing disease activity. While no strong causal link was found between IgG N-glycosylation and SjD risk, SjD may influence specific glycan traits, reflecting downstream immune dysregulation. These findings support the utility of IgG glycosylation as a biomarker for disease monitoring rather than as a causal factor. Further studies are needed to validate these results and explore clinical applications.
Access Note
Access to this thesis is embargoed until 30th May 2031
Recommended Citation
Chen, Z. (2026). Investigating the role of IgG N-glycosylation in diagnosis, disease activity, and causal inference of Sjögren disease. Edith Cowan University. https://doi.org/10.25958/37w6-pa37