Glycosylation Alterations in Multiple Sclerosis Show Increased Proinflammatory Potential.

Ana Cvetko,James F Wilson,Olga Gornik,Gordan Lauc,Tamara Štambuk,Domagoj Kifer,Elizabeth Visser,Lucija Klarić

doi:10.3390/biomedicines8100410

Abstract

Multiple sclerosis (MS) is an inflammatory autoimmune disorder affecting the central nervous system (CNS), with unresolved aetiology. Previous studies have implicated N-glycosylation, a highly regulated enzymatic attachment of complex sugars to targeted proteins, in MS pathogenesis. We investigated individual variation in N-glycosylation of the total plasma proteome and of IgG in MS. Both plasma protein and IgG N-glycans were chromatographically profiled and quantified in 83 MS cases and 88 age- and sex-matched controls. Comparing levels of glycosylation features between MS cases and controls revealed that core fucosylation (p = 6.96 × 10−3) and abundance of high-mannose structures (p = 1.48 × 10−2) were the most prominently altered IgG glycosylation traits. Significant changes in plasma protein N-glycome composition were observed for antennary fucosylated, tri- and tetrasialylated, tri- and tetragalactosylated, high-branched N-glycans (p-value range 1.66 × 10−2–4.28 × 10−2). Classification performance of N-glycans was examined by ROC curve analysis, resulting in an AUC of 0.852 for the total plasma N-glycome and 0.798 for IgG N-glycome prediction models. Our results indicate that multiple aspects of protein glycosylation are altered in MS, showing increased proinflammatory potential. N-glycan alterations showed substantial value in classification of the disease status, nonetheless, additional studies are warranted to explore their exact role in MS development and utility as biomarkers.

Highlights

Multiple sclerosis (MS) is a disease affecting the central nervous system (CNS), and is characterized by inflammation and demyelination that eventually lead to axon degeneration and physical disability [1].It affects women three times more often than men [2], with an average age of onset around 30 years [3,4].MS prevalence has been rising across North America and Europe in the past decades, where persistent geographical risk gradients have been documented, displaying its unusually high prevalence in Scotland, in particular, on the Northern Isles of Orkney and Shetland [5,6]
Comparison of multiple sclerosis subjects against their age, sexand ancestry-matched controls showed that four out of 24 directly measured IgG N-glycan traits were significantly different between the groups (Table 2)
One significantly changed glycan was of oligomannose type, while all the others were complex N-glycans

Summary

Introduction

Multiple sclerosis (MS) is a disease affecting the central nervous system (CNS), and is characterized by inflammation and demyelination that eventually lead to axon degeneration and physical disability [1].It affects women three times more often than men [2], with an average age of onset around 30 years [3,4].MS prevalence has been rising across North America and Europe in the past decades, where persistent geographical risk gradients have been documented, displaying its unusually high prevalence in Scotland, in particular, on the Northern Isles of Orkney and Shetland [5,6]. Multiple sclerosis (MS) is a disease affecting the central nervous system (CNS), and is characterized by inflammation and demyelination that eventually lead to axon degeneration and physical disability [1]. Additional evidence, proving that an interplay between genetics, immunity and environment is determining MS predisposition, has been provided in recent large genome wide association studies (GWAS). These studies identified hits in multiple loci containing genes coding for various molecules involved in immune processes and environmental risk factors, such as enzymes involved in vitamin D metabolism [10,11]

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