Glycosylation Alterations in Multiple Sclerosis Show Increased Proinflammatory Potential

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.

Extracellular matrix protein N-glycosylation mediates immune self-tolerance inDrosophila melanogaster

“…Like the tuSz 1 mutant, the αM-II mouse phenotype arises due to alterations in protein N-glycosylation in nonimmune tissues and is mediated by innate immune cells (115). Altered patterns of protein N-glycosylation are also observed in additional mouse models of autoimmune disease (117,118) and have been linked to autoimmune disease in human patients (119)(120)(121)(122)(123).…”

N‐glycan profiling alterations of serum and immunoglobulin G in immune thrombocytopenia

“…It has been reported that a variety of autoimmune and inflammatory diseases such as autoimmune hemolytic anemia, systemic lupus erythematosus, inflammatory bowel disease, and rheumatoid arthritis have skewed IgG glycosylation pattern, 6‐9 and in some diseases, the skewed IgG glycosylation is associated with disease severity and treatment response 10,11 . In addition to IgG, the altered glycosylation pattern of total serum proteins, which is considered reflecting the physiological and pathological state of the body, is also associated with autoimmune and inflammatory diseases 12 12‐16 …”

Accelerated biological aging in people with Down syndrome with full and segmental trisomy 21 begins in childhood as revealed by immunoglobulin G glycosylation

“…The basic characteristics of the cohorts are given in Table 1. IgG glycosylation was analysed using a well-established reliable liquid chromatography method for IgG N-glycan analysis with con rmed reproducibility and robustness 30,31 , and which has already been successfully employed to detect signi cant changes in glycosylation in many different diseases (such as COVID-19 32 , thyroid disease 33 , multiple sclerosis 34 , rheumatoid arthritis 35 , cardiovascular disease 36 and systemic lupus erythematosus 37 ). IgG glycans were separated into 24 chromatographic peaks (GP1-GP24) and glycans corresponding to each individual peak are shown in Figure 1.…”