Specific IgG glycosylation differences precede relapse in PR3-ANCA associated vasculitis patients with and without ANCA rise

Frontiers in Immunology, vol. 14, pp. 1214945

Abstract

Introduction Immunoglobulin G (IgG) contains a conserved N-glycan in the fragment crystallizable (Fc), modulating its structure and effector functions. In anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) alterations of IgG Fc-glycosylation have been observed to correlate with the disease course. Here, we examined longitudinal changes in N-linked Fc glycans of IgG in an AAV patient cohort and their relationship with disease flares. Methods Using liquid chromatography coupled with mass spectrometry, we analysed IgG Fc-glycosylation in 410 longitudinal samples from 96 individuals with AAV. Results Analysis of the cross-sectional differences as well as longitudinal changes demonstrated that IgGs of relapsing PR3-ANCA patients have higher ΔFc-bisection at diagnosis (P = 0.004) and exhibit a decrease in Fc-sialylation prior to the relapse (P = 0.0004), discriminating them from non-relapsing patients. Most importantly, PR3-ANCA patients who experienced an ANCA rise and relapsed shortly thereafter, exhibit lower IgG Fc-fucosylation levels compared to non-relapsing patients already 9 months before relapse (P = 0.02). Discussion Our data indicate that IgG Fc-bisection correlates with long-term treatment outcome, while lower IgG Fc-fucosylation and sialylation associate with impending relapse. Overall, our study replicated the previously published reduction in total IgG Fc-sialylation at the time of relapse, but showed additionally that its onset precedes relapse. Furthermore, our findings on IgG fucosylation and bisection are entirely new. All these IgG Fc-glycosylation features may have the potential to predict a relapse either independently or in combination with known risk factors, such as a rise in ANCA titre.

Authors 6

1. Iwona Wójcik Aachen Center for Proteomics and Metabolomics

   Leiden University Medical Center · Genos (Croatia)

   Affiliation as printed

   Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, Netherlands

   Glycoscience Research Laboratory, Genos Ltd., Zagreb, Croatia

2. Manfred Wuhrer Aachen Center for Proteomics and Metabolomics

   Leiden University Medical Center

   Affiliation as printed

   Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, Netherlands

3. Peter Heeringa

   University Medical Center Groningen

   Affiliation as printed

   Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, Netherlands

4. Coen A. Stegeman

   University Medical Center Groningen

   Affiliation as printed

   Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, Groningen, Netherlands

5. Abraham Rutgers corresponding

   University Medical Center Groningen

   Affiliation as printed

   Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, Groningen, Netherlands

6. David Falck corresponding Aachen Center for Proteomics and Metabolomics

   Leiden University Medical Center

   Affiliation as printed

   Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, Netherlands