Does Immunoglobulin G Glycosylation Have Potential to Predict Relapse in Patients with ANCA Associated Vasculitis?

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Does Immunoglobulin G Glycosylation Have Potential to Predict Relapse in Patients with ANCA Associated Vasculitis?

Iwona Wójcik 1 , David Falck 1 , Bas Cornelis Jansen 1 , Minke Huitema 2 , Bram Rutgers 2 , Peter Heeringa 3 , Manfred Wuhrer 1

1 Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands, 2 Faculty of Medical Sciences, Division of Rheumatology and Clinical Immunology, University of Groningen, Groningen, The Netherlands, 3 Faculty of Medical Sciences, Division of Pathology and Medical Biology, University of Groningen, Groningen, The Netherlands

Introduction The function of human IgGs is modified by N-glycans attached to the conserved Asn297 residue of the crystallizable fragment (Fc). These N-glycans are mainly complex, biantennary structures that vary with respect to the degree of core fucosylation, sialylation and galactosylation [1]. The glycosylation pattern is stable within a healthy individual, but it can change remarkably with various autoimmune diseases, including anti-neutrophil cytoplasmic antibody (ANCA) – associated vasculitis (AAV) [2]. AAV is characterized by the presence of antigen-specific IgG against proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO). In PR3-ANCA positive patients it was previously reported that low levels of Fc domain galactosylation and sialylation on total IgG predict AAV remission [3]. However, the previous study was limited to PR3-ANCA positive patients and only two different time points – an ANCA rise and relapse/remission. In order to examine the diagnostic value, the glycosylation changes at different time points after treatment and before relapse in both serological groups (MPO- and PR3-ANCA) were investigated in this longitudinal study.

Methods Total serum IgG was affinity-purified from a longitudinal cohort of 107 patients with AAV, of which 82 patients relapsed and 25 patients stayed in remission. IgG was trypsin cleaved, separated and subjected to mass spectrometry analysis (LC-ESI-MS). The obtained spectra were automatically aligned, calibrated and quantified using the LaCyTools software. Subsequently, several glycosylation features were calculated from the quantified glycoforms, including: galactosylation, sialylation, fucosylation and bisection.

Results In relapsing MPO-ANCA patients the level of galactosylation on total IgG1 significantly increased upon treatment in the first three months after diagnosis (from 37.0% to 44.5%; p = 0.024), while this glycosylation trait remains stable in non-relapsing patients. Moreover, the same significant galactosylation change was observed between relapse and three months after relapse in the MPO-ANCA patient group (from 41.8% to 47.1%; p = 0.034). IgG1 Fc galactosylation changes after treatment were associated with relapse in MPO-ANCA but not in PR3-ANCA patients.

Conclusions In relapsing MPO-ANCA patients the implementation of treatment after both periods of symptom manifestation, namely diagnosis and relapse, resulted in the increase of galactosylation on IgG1. Therefore, it appears that these patients gain a more anti-inflammatory phenotype upon the treatment. This change in phenotype was not observed in non-relapsing MPO-ANCA patients. However, further analysis of the differences between the patients groups, especially with regard to treatment and disease severity is required.

This project has received funding from the GlySign – European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 722095.

Pucić M, et al. High throughput isolation and glycosylation analysis of IgG-variability and heritability of the IgG glycome in three isolated human populations. Mol Cell Proteomics. 2011

Lurati-Ruiz F, Spertini F. Predictive value of antineutrophil cytoplasmic antibodies in small-vessel vasculitis. J Rheumatol. 2005

Kemna MJ, et al. Galactosylation and Sialylation Levels of IgG Predict Relapse in Patients With PR3-ANCA Associated Vasculitis. EBioMedicine. 2017

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