Author Identifier

Xiaojia Xu: http://orcid.org/0000-0003-2621-1618

Date of Award

2025

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

Xingang Li

Abstract

Axial spondyloarthritis (axSpA) is a chronic inflammatory rheumatic disease with challenges in diagnosis and disease activity assessment. Alterations in immunoglobulin G (IgG) N-glycosylation have been implicated in several inflammatory and autoimmune diseases. However, their role in axSpA remains unclear. This PhD project aimed to investigate the association of IgG N-glycosylation in axSpA, and explored the role of IgG N-glycosylation in the pathogenesis and disease activity of axSpA, with reference to inflammatory cytokines and also radiographic sacroiliitis to provide novel insights into disease development and improve diagnostic and disease activity assessment strategies.

Firstly, a systematic review was conducted to summarize the structure and function of IgG N-glycosylation, and synthesize the existing knowledge on its relationship with the development and prognosis of axSpA. Subsequently, a clinic-based case-control study was performed to compare IgG N-glycan profiles among axSpA, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), osteoarthritis (OA), gout and healthy controls. Additionally, the relationship between IgG N-glycosylation, disease activity indicators and inflammatory cytokines were examined in axSpA. Furthermore, a subgroup analysis was performed to assess glycosylation changes in different disease stages of axSpA, including early and non-early axSpA.

The results demonstrated that patients with axSpA exhibited significantly reduced IgG galactosylation and sialylation compared to those of healthy controls, while IgG fucosylation levels were elevated compared to other four studied rheumatic diseases. Among the identified IgG N-glycans, two asialylated IgG N-glycans (FA2 and FA2[3]G1) were associated with axSpA, with adjusted odds ratios (AORs) of 5.62 (95% CI: 3.41-9.24) and 0.33 (95% CI: 0.22-0.50), respectively. These glycans exhibited outstanding performance in distinguishing axSpA from healthy controls, with an area under the curve (AUC) of 0.869 (95%CI: 0.820-0.909). Notably, decreased FA2BG2S2 was a unique IgG N-glycan differentiating axSpA from the other four types of rheumatic diseases. Furthermore, FA2 displayed a positive association with disease activity indicators (ASDAS-CRP, SPARCC-SIJ and SPARCC-spine) in axSpA. IgG N-glycans, particularly FA2 [3]G1, FA2BG2S2 and FA2, demonstrated canonical correlation with inflammatory cytokines, including interleukin-23 and tumor necrosis factor α, in axSpA patients. In the subgroup analysis, two asialylated IgG N-glycans (FA2[3]G1 and FA2G2) were negatively associated with both early and non-early axSpA, with AORs of 0.24 (95% CI: 0.12-0.46) and 0.23 (95% CI: 0.11-0.46) for early axSpA, and 0.36 (95% CI: 0.21-0.61) and 0.12 (95% CI: 0.06-0.24) for non-early axSpA, respectively. These two glycans exhibited strong diagnostic performance, distinguishing patients with early axSpA (AUC=0.825, 95%CI: 0.758-0.879) and non-early axSpA (AUC=0.880, 95%CI: 0.828-0.921) from healthy controls. Additionally, FA2[3]G1 exhibited positive correlations with radiographic sacroiliitis in both early and non-early axSpA patients.

In summary, this PhD project identified that altered IgG N-glycosylation is a distinctive feature of axSpA and varies across disease stages. Specific IgG N-glycans, particularly FA2[3]G1, FA2G2, and FA2, may serve as novel biomarkers for axSpA diagnosis and disease activity assessment. These findings provide new insights into the role of IgG N-glycosylation in the onset of axSpA and highlight its potential in improving early diagnosis and disease progress monitoring.

DOI

10.25958/r6g1-f172

Access Note

Access to this thesis is embargoed until 12th August 2030

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Available for download on Monday, August 12, 2030

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