TY - JOUR
T1 - O- and N-Glycosylation of Serum Immunoglobulin A is Associated with IgA Nephropathy and Glomerular Function
AU - Dotz, Viktoria
AU - Visconti, Alessia
AU - Lomax-Browne, Hannah
AU - Florent, Clerc
AU - Hipgrave Ederveen, Agnes
AU - Medjeral-Thomas, Nicholas
AU - Cook, H Terence
AU - Pickering, Matthew
AU - Wuhrer, Manfred
AU - Falchi, Mario
N1 - Funding Information:
This work was supported by funding from Medical Research Council grant MR/K01353X/2. M. C. Pickering is a Wellcome Trust Senior Fellow in Clinical Science under grant 212252/Z/18/Z.
Funding Information:
H.T. Cook reports consultancy agreements with Alexion Pharmaceuticals, Apellis Pharmaceuticals, and Novartis and honoraria from Alexion Pharmaceuticals. V. Dotz is employed by Janssen Vaccines (a Johnson & Johnson company). M. C. Pickering reports consultancy agreements with Achillion Pharmaceuticals as a scientific advisor, Alexion Pharmaceuticals for scientific advisory board attendance, the ChemoCentryx Sciviaentific Advisory Board (meeting on May 7th, 2016) as an invited speaker, Gyroscope for scientific board membership, and Ra Pharma for scientific advisory board attendance; research funding from Achillion for the C3 Glomerulopathy Natural History Study, Alexion for preclinical studies in animal models, Lab-oratoires Franc¸ais de Fractionnement et des Biotechnologies for preclinical studies in animal models, and Ra Pharma for complement C9 in lupus nephritis; honoraria from Gyroscope as advisory board fees; and scientific advisor or membership with Gyroscope Pharma via the advisory board. M. Falchi reports research funding from Sanofi for the identification of multi-disease drug targets through systems-immunology dissection of immune ageing. All remaining authors have nothing to disclose.
Publisher Copyright:
Copyright ß 2021 by the American Society of Nephrology
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/10
Y1 - 2021/10
N2 - Background IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide and is a leading cause of renal failure. The disease mechanisms are not completely understood, but a higher abundance of galactose-deficient IgA is recognized to play a crucial role in IgAN pathogenesis. Although both types of human IgA (IgA1 and IgA2) have several N-glycans as post-translational modification, only IgA1 features extensive hinge-region O-glycosylation. IgA1 galactose deficiency on the O-glycans is commonly detected by a lectin-based method. To date, limited detail is known about IgA O- and N-glycosylation in IgAN. Methods To gain insights into the complex O- and N-glycosylation of serum IgA1 and IgA2 in IgAN, we used liquid chromatography-mass spectrometry (LC-MS) for the analysis of tryptic glycopeptides of serum IgA from 83 patients with IgAN and 244 age- and sex-matched healthy controls. Results Multiple structural features of N-glycosylation of IgA1 and IgA2 were associated with IgAN and glomerular function in our cross-sectional study. These features included differences in galactosylation, sialylation, bisection, fucosylation, and N-glycan complexity. Moreover, IgA1 O-glycan sialylation was associated with both the disease and glomerular function. Finally, glycopeptides were a better predictor of IgAN and glomerular function than galactose-deficient IgA1 levels measured by lectin-based ELISA. Conclusions Our high-resolution data suggest that IgA O- and N-glycopeptides are promising targets for future investigations on the pathophysiology of IgAN and as potential noninvasive biomarkers for disease prediction and deteriorating kidney function.
AB - Background IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide and is a leading cause of renal failure. The disease mechanisms are not completely understood, but a higher abundance of galactose-deficient IgA is recognized to play a crucial role in IgAN pathogenesis. Although both types of human IgA (IgA1 and IgA2) have several N-glycans as post-translational modification, only IgA1 features extensive hinge-region O-glycosylation. IgA1 galactose deficiency on the O-glycans is commonly detected by a lectin-based method. To date, limited detail is known about IgA O- and N-glycosylation in IgAN. Methods To gain insights into the complex O- and N-glycosylation of serum IgA1 and IgA2 in IgAN, we used liquid chromatography-mass spectrometry (LC-MS) for the analysis of tryptic glycopeptides of serum IgA from 83 patients with IgAN and 244 age- and sex-matched healthy controls. Results Multiple structural features of N-glycosylation of IgA1 and IgA2 were associated with IgAN and glomerular function in our cross-sectional study. These features included differences in galactosylation, sialylation, bisection, fucosylation, and N-glycan complexity. Moreover, IgA1 O-glycan sialylation was associated with both the disease and glomerular function. Finally, glycopeptides were a better predictor of IgAN and glomerular function than galactose-deficient IgA1 levels measured by lectin-based ELISA. Conclusions Our high-resolution data suggest that IgA O- and N-glycopeptides are promising targets for future investigations on the pathophysiology of IgAN and as potential noninvasive biomarkers for disease prediction and deteriorating kidney function.
UR - http://www.scopus.com/inward/record.url?scp=85116002718&partnerID=8YFLogxK
U2 - 10.1681/ASN.2020081208
DO - 10.1681/ASN.2020081208
M3 - Article
C2 - 34127537
SN - 1046-6673
VL - 32
SP - 2455
EP - 2465
JO - Journal of the American Society of Nephrology : JASN
JF - Journal of the American Society of Nephrology : JASN
IS - 10
ER -
