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1
Hanić, Maja, Frano Vučković, Helena Deriš, Claire Bewshea, Simeng Lin, James R. Goodhand, Tariq Ahmad, Irena Trbojević-Akmačić, Nicholas A. Kennedy, and Gordan Lauc. "Anti-TNF Biologicals Enhance the Anti-Inflammatory Properties of IgG N-Glycome in Crohn’s Disease." Biomolecules 13, no. 6 (June 7, 2023): 954. http://dx.doi.org/10.3390/biom13060954.
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Crohn’s disease (CD) is a chronic inflammation of the digestive tract that significantly impairs patients’ quality of life and well-being. Anti-TNF biologicals revolutionised the treatment of CD, yet many patients do not adequately respond to such therapy. Previous studies have demonstrated a pro-inflammatory pattern in the composition of CD patients’ immunoglobulin G (IgG) N-glycome compared to healthy individuals. Here, we utilised the high-throughput UHPLC method for N-glycan analysis to explore the longitudinal effect of the anti-TNF drugs infliximab and adalimumab on N-glycome composition of total serum IgG in 198 patients, as well as the predictive potential of IgG N-glycans at baseline to detect primary non-responders to anti-TNF therapy in 1315 patients. We discovered a significant decrease in IgG agalactosylation and an increase in monogalactosylation, digalactosylation and sialylation during the 14 weeks of anti-TNF treatment, regardless of therapy response, all of which suggested a diminished inflammatory environment in CD patients treated with anti-TNF therapy. Furthermore, we observed that IgG N-glycome might contain certain information regarding the anti-TNF therapy outcome before initiating the treatment. However, it is impossible to predict future primary non-responders to anti-TNF therapy based solely on IgG N-glycome composition at baseline.
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Font, Guillaume, Marie-Laure Walet-Balieu, Marie Petit, Carole Burel, Maud Maho-Vaillant, Vivien Hébert, Philippe Chan, et al. "IgG N-Glycosylation from Patients with Pemphigus Treated with Rituximab." Biomedicines 10, no. 8 (July 22, 2022): 1774. http://dx.doi.org/10.3390/biomedicines10081774.
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Pemphigus is a life-threatening auto-immune blistering disease of the skin and mucous membrane that is caused by the production of auto-antibodies (auto-Abs) directed against adhesion proteins: desmoglein 1 and 3. We demonstrated in the “Ritux3” trial, the high efficacy of rituximab, an anti-CD20 recombinant monoclonal antibody, as the first-line treatment for pemphigus. However, 25% of patients relapsed during the six-month period after rituximab treatment. These early relapses were associated with a lower decrease in anti-desmoglein auto-Abs after the initial cycle of rituximab. The N-glycosylation of immunoglobulin-G (IgG) can affect their affinity for Fc receptors and their serum half-life. We hypothesized that the extended half-life of Abs could be related to modifications of IgG N-glycans. The IgG N-glycome from pemphigus patients and its evolution under rituximab treatment were analyzed. Pemphigus patients presented a different IgG N-glycome than healthy donors, with less galactosylated, sialylated N-glycans, as well as a lower level of N-glycans bearing an additional N-acetylglucosamine. IgG N-glycome from patients who achieved clinical remission was not different to the one observed at baseline. Moreover, our study did not identify the N-glycans profile as discriminating between relapsing and non-relapsing patients. We report that pemphigus patients present a specific IgG N-glycome. The changes observed in these patients could be a biomarker of autoimmunity susceptibility rather than a sign of inflammation.
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Radovani, Barbara, Frano Vučković, Aldo P. Maggioni, Ele Ferrannini, Gordan Lauc, and Ivan Gudelj. "IgG N-Glycosylation Is Altered in Coronary Artery Disease." Biomolecules 13, no. 2 (February 16, 2023): 375. http://dx.doi.org/10.3390/biom13020375.
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Coronary artery disease (CAD) is the most common cardiovascular disease (CVD), and previous studies have shown a significant association between N-glycosylation, a highly regulated posttranslational modification, and the development of atherosclerotic plaques. Our aim was to determine whether the N-glycome of immunoglobulin G (IgG) is associated with CAD, as N-glycans are known to alter the effector functions of IgG, which may enhance the inflammatory response in CAD. Therefore, in this study, we isolated IgG from subjects with coronary atherosclerosis (CAD+) and from subjects with clean coronaries (CAD−). The purified IgGs were denatured and enzymatically deglycosylated, and the released and fluorescently labelled N-glycans were analysed by ultra-high performance liquid chromatography based on hydrophilic interactions with fluorescence detection (HILIC-UHPLC-FLR). Sex-stratified analysis of 316 CAD− and 156 CAD+ cases revealed differences in IgG N-glycome composition. The most notable differences were observed in women, where the presence of sialylated N-glycan structures was negatively associated with CAD. The obtained chromatograms provide insight into the IgG N-glycome composition in CAD as well as the biomarker potential of IgG N-glycans in CAD.
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Cvetko, Ana, Domagoj Kifer, Olga Gornik, Lucija Klarić, Elizabeth Visser, Gordan Lauc, James F. Wilson, and Tamara Štambuk. "Glycosylation Alterations in Multiple Sclerosis Show Increased Proinflammatory Potential." Biomedicines 8, no. 10 (October 13, 2020): 410. http://dx.doi.org/10.3390/biomedicines8100410.
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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.
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Meng, Xiaoni, Manshu Song, Marija Vilaj, Jerko Štambuk, Mamatyusupu Dolikun, Jie Zhang, Di Liu, et al. "Glycosylation of IgG Associates with Hypertension and Type 2 Diabetes Mellitus Comorbidity in the Chinese Muslim Ethnic Minorities and the Han Chinese." Journal of Personalized Medicine 11, no. 7 (June 29, 2021): 614. http://dx.doi.org/10.3390/jpm11070614.
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Objectives: Hypertension and type 2 diabetes mellitus comorbidity (HDC) is common, which confers a higher risk of cardiovascular disease than the presence of either condition alone. Describing the underlying glycomic changes of immunoglobulin G (IgG) that predispose individuals to HDC may help develop novel protective immune-targeted and anti-inflammatory therapies. Therefore, we investigated glycosylation changes of IgG associated with HDC. Methods: The IgG N-glycan profiles of 883 plasma samples from the three northwestern Chinese Muslim ethnic minorities and the Han Chinese were analyzed by ultra-performance liquid chromatography instrument. Results: We found that 12 and six IgG N-glycan traits showed significant associations with HDC in the Chinese Muslim ethnic minorities and the Han Chinese, respectively, after adjustment for potential confounders and false discovery rate. Adding the IgG N-glycan traits to the baseline models, the area under the receiver operating characteristic curves (AUCs) of the combined models differentiating HDC from hypertension (HTN), type 2 diabetes mellitus (T2DM), and healthy individuals were 0.717, 0.747, and 0.786 in the pooled samples of Chinese Muslim ethnic minorities, and 0.828, 0.689, and 0.901 in the Han Chinese, respectively, showing improved discriminating performance than both the baseline models and the glycan-based models. Conclusion: Altered IgG N-glycan profiles were shown to associate with HDC, suggesting the involvement of inflammatory processes of IgG glycosylation. The alterations of IgG N-glycome, illustrated here for the first time in HDC, demonstrate a biomarker potential, which may shed light on future studies investigating their potential for monitoring or preventing the progression from HTN or T2DM towards HDC.
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Blomme, Bram, Christophe Van Steenkiste, Paola Grassi, Stuart M. Haslam, Anne Dell, Nico Callewaert, and Hans Van Vlierberghe. "Alterations of serum protein N-glycosylation in two mouse models of chronic liver disease are hepatocyte and not B cell driven." American Journal of Physiology-Gastrointestinal and Liver Physiology 300, no. 5 (May 2011): G833—G842. http://dx.doi.org/10.1152/ajpgi.00228.2010.
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N-glycosylation of immunoglobulin G (IgG) has an important impact on the modification of the total serum N-glycome in chronic liver patients. Our aim was to determine the role and magnitude of the alterations in which hepatocytes and B cells are involved in two mouse models of chronic liver disease. Common bile duct ligation (CBDL) and subcutaneous injections with CCl4 were induced in B cell-deficient and wild-type (WT) mice. IgG depletion was performed with beads covered with protein A/G and the depletions were evaluated by SDS-PAGE and Western blot analysis. N-glycan analysis was performed by improved DSA-FACE technology. Structural analysis of the mouse serum N-glycans was performed by exoglycosidase digests and MALDI-TOF mass spectrometry of permethylated glycans. The alterations seen in B cell-deficient mice closely resembled the alterations in WT mice, in both the CBDL and the CCl4 models. N-glycan analysis of the IgG fraction in both mouse models revealed different changes compared with humans. Overall, the impact of IgG glycosylation on total serum glycosylation was marginal. Interestingly, the amount of fibrosis present in CBDL B cell-deficient mice was significantly increased compared with CBDL WT mice, whereas the opposite was true for the CCl4 model as determined by Sirius red staining. However, this had no major effect on the alteration of N-glycosylation of serum proteins. Alterations of total serum N-glycome in mouse models of chronic liver disease are hepatocyte-driven. Undergalactosylation of IgG is not present in mouse models of chronic liver disease.
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Pučić, Maja, Ana Mužinić, Mislav Novokmet, Marijana Škledar, Nela Pivac, Gordan Lauc, and Olga Gornik. "Changes in plasma and IgG N-glycome during childhood and adolescence." Glycobiology 22, no. 7 (March 16, 2012): 975–82. http://dx.doi.org/10.1093/glycob/cws062.
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Simunovic, Jelena, Marija Vilaj, Irena Trbojevic-Akmacic, Ana Momcilovic, Frano Vuckovic, Ivan Gudelj, Julija Juric, Natali Nakic, Gordan Lauc, and Marija Pezer. "Comprehensive N-glycosylation analysis of immunoglobulin G from dried blood spots." Glycobiology 29, no. 12 (May 30, 2019): 817–21. http://dx.doi.org/10.1093/glycob/cwz061.
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Abstract Immunoglobulin G (IgG) glycans are emerging as a new putative biomarker for biological age and different diseases, requiring a robust workflow for IgG glycome analysis, ideally beginning with a simple and undemanding sampling procedure. Here, we report the first comprehensive study on total N-glycans of IgG isolated from dried blood spots (DBSs), which was performed in a high-throughput mode. We compared the IgG N-glycan profiles originating from DBS with those originating from plasma, compared different media for DBS collection, evaluated analytical variation and assessed IgG N-glycan profile stability for different storage conditions. In conclusion, we show that DBSs are a good and stable source material for a robust IgG N-glycan analysis by ultra-performance liquid chromatography, suitable for blood sampling in conditions where no trained personnel and necessary laboratory equipment are available.
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Singh, Sunny S., Ralph Heijmans, Claudia K. E. Meulen, Aloysius G. Lieverse, Olga Gornik, Eric J. G. Sijbrands, Gordan Lauc, and Mandy van Hoek. "Association of the IgG N-glycome with the course of kidney function in type 2 diabetes." BMJ Open Diabetes Research & Care 8, no. 1 (April 2020): e001026. http://dx.doi.org/10.1136/bmjdrc-2019-001026.
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IntroductionInflammatory processes are thought to be involved in kidney function decline in individuals with type 2 diabetes. Glycosylation of immunoglobulin G (IgG) is an important post-translation process affecting the inflammatory potential of IgG. We investigated the prospective relationship between IgG N-glycosylation patterns and kidney function in type 2 diabetes.Research design and methodsIn the DiaGene study, an all-lines-of-care case–control study (n=1886) with mean prospective follow-up of 7.0 years, the association between 58 IgG N-glycan profiles and estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR) per year and during total follow-up was analyzed. Models were adjusted for clinical variables and multiple comparisons.ResultsEleven traits were significantly associated with eGFR change per year. Bisecting GlcNAc in fucosylated and fucosylated disialylated structures and monosialylation of fucosylated digalactosylated structures were associated with a faster decrease of eGFR. Fucosylation of neutral and monogalactosylated structures was associated with less eGFR decline per year. No significant associations between IgG glycans and ACR were found.ConclusionsIn type 2 diabetes, we found IgG N-glycosylation patterns associated with a faster decline of kidney function, reflecting a pro-inflammatory state of IgG. eGFR, but not ACR, was associated with IgG glycans, which suggests these associations may represent renal macroangiopathy rather than microvascular disease.
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Plećaš, Doris, Nikol Mraz, Anne Marie Patanaude, Tea Pribić, Ivana Pavlinac Dodig, Renata Pecotić, Gordan Lauc, Ozren Polašek, and Zoran Đogaš. "Not-So-Sweet Dreams: Plasma and IgG N-Glycome in the Severe Form of the Obstructive Sleep Apnea." Biomolecules 13, no. 6 (May 23, 2023): 880. http://dx.doi.org/10.3390/biom13060880.
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Obstructive sleep apnea (OSA) is a prevalent disease associated with increased risk for cardiovascular and metabolic diseases and shortened lifespan. The aim of this study was to explore the possibility of using N-glycome as a biomarker for the severe form of OSA. Seventy subjects who underwent a whole-night polysomnography/polygraphy and had apnea–hypopnea index (AHI) over 30 were compared to 23 controls (AHI under 5). Plasma samples were used to extract 39 glycan peaks using ultra-high-performance liquid chromatography (UPLC) and 27 IgG peaks using capillary gel electrophoresis (CGE). We also measured glycan age, a molecular proxy for biological aging. Three plasma and one IgG peaks were significant in a multivariate model controlling for the effects of age, sex, and body mass index. These included decreased GP24 (disialylated triantennary glycans as major structure) and GP28 (trigalactosylated, triantennary, disialylated, and trisialylated glycans), and increased GP32 (trisialylated triantennary glycan). Only one IgG glycan peak was significantly increased (P26), which contains biantennary digalactosylated glycans with core fucose. Patients with severe OSA exhibited accelerated biological aging, with a median of 6.9 years more than their chronological age (p < 0.001). Plasma N-glycome can be used as a biomarker for severe OSA.
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Štambuk, Tamara, Domagoj Kifer, Lea Smirčić-Duvnjak, Marijana Vučić Lovrenčić, and Olga Gornik. "Associations between plasma protein, IgG and IgA N-glycosylation and metabolic health markers in pregnancy and gestational diabetes." PLOS ONE 18, no. 4 (April 20, 2023): e0284838. http://dx.doi.org/10.1371/journal.pone.0284838.
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Background Monitoring human circulating N-glycome could provide valuable insight into an individual’s metabolic status. Therefore, we examined if aberrant carbohydrate metabolism in gestational diabetes mellitus (GDM) associates with alterations in plasma protein, immunoglobulin G (IgG) and immunoglobulin A (IgA) N-glycosylation. Methods Plasma protein, IgG and IgA N-glycans were enzymatically released, purified and chromatographically profiled in 48 pregnant women with normal glucose tolerance and 41 pregnant women with GDM, all sampled at 24–28 weeks of gestation. Linear mixed models adjusting for age and multiple testing (FDR<0.05) were used to investigate the associations between glycosylation features, metabolic markers and GDM status. Results Fasting insulin exhibited significant associations to numerous glycan traits, including plasma protein galactosylation, sialylation, branching, core fucosylation and bisection, to IgG core fucosylated, bisected (FA2B) and afucosylated disialylated (A2G2S2) glycan and to IgA trisialylated triantennary (A3G3S3) glycan (padj range: 4.37x10-05–4.94x10-02). Insulin resistance markers HOMA2-IR and HOMA2-%B were mostly associated to the same glycan structures as fasting insulin. Both markers showed positive association with high-branched plasma glycans (padj = 1.12x10-02 and 2.03x10-03) and negative association with low-branched plasma glycans (padj = 1.21x10-02 and 2.05x10-03). Additionally, HOMA2-%B index was significantly correlated with glycosylation features describing IgG sialylation. Multiple plasma protein IgG and IgA glycans showed significant associations with total cholesterol and triglyceride levels. None of the tested glycan traits showed a significant difference between GDM and normoglycemic pregnancies. Conclusion Markers of glucose homeostasis and lipid metabolism in pregnancy show extensive associations to various N-glycosylation features. However, plasma protein, IgG and IgA N-glycans were not able to differentiate pregnant women with and without GDM, possibly due to numerous physiological changes accompanying pregnancy, which confound the impact of GDM on protein glycosylation.
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Liu, Si, Liming Cheng, Yang Fu, Bi-Feng Liu, and Xin Liu. "Characterization of IgG N-glycome profile in colorectal cancer progression by MALDI-TOF-MS." Journal of Proteomics 181 (June 2018): 225–37. http://dx.doi.org/10.1016/j.jprot.2018.04.026.
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Šimunić-Briški, Nina, Robert Zekić, Vedran Dukarić, Mateja Očić, Azra Frkatović-Hodžić, Helena Deriš, Gordan Lauc, and Damir Knjaz. "Physical Exercise Induces Significant Changes in Immunoglobulin G N-Glycan Composition in a Previously Inactive, Overweight Population." Biomolecules 13, no. 5 (April 27, 2023): 762. http://dx.doi.org/10.3390/biom13050762.
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Regular exercise improves health, modulating the immune system and impacting inflammatory status. Immunoglobulin G (IgG) N-glycosylation reflects changes in inflammatory status; thus, we investigated the impact of regular exercise on overall inflammatory status by monitoring IgG N-glycosylation in a previously inactive, middle-aged, overweight and obese population (50.30 ± 9.23 years, BMI 30.57 ± 4.81). Study participants (N = 397) underwent one of three different exercise programs lasting three months with blood samples collected at baseline and at the end of intervention. After chromatographically profiling IgG N-glycans, linear mixed models with age and sex adjustment were used to investigate exercise effects on IgG glycosylation. Exercise intervention induced significant changes in IgG N-glycome composition. We observed an increase in agalactosylated, monogalctosylated, asialylated and core-fucosylated N-glycans (padj = 1.00 × 10−4, 2.41 × 10−25, 1.51 × 10−21 and 3.38 × 10−30, respectively) and a decrease in digalactosylated, mono- and di-sialylated N-glycans (padj = 4.93 × 10−12, 7.61 × 10−9 and 1.09 × 10−28, respectively). We also observed a significant increase in GP9 (glycan structure FA2[3]G1, β = 0.126, padj = 2.05 × 10−16), previously reported to have a protective cardiovascular role in women, highlighting the importance of regular exercise for cardiovascular health. Other alterations in IgG N-glycosylation reflect an increased pro-inflammatory IgG potential, expected in a previously inactive and overweight population, where metabolic remodeling is in the early stages due to exercise introduction.
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Mayboroda, Oleg A., Guinevere S. M. Lageveen-Kammeijer, Manfred Wuhrer, and Radboud J. E. M. Dolhain. "An Integrated Glycosylation Signature of Rheumatoid Arthritis." Biomolecules 13, no. 7 (July 12, 2023): 1106. http://dx.doi.org/10.3390/biom13071106.
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Rheumatoid arthritis (RA) Is a highly prevalent autoimmune disease that affects the joints but also various other organs. The disease is characterized by autoantibodies that are often already observed pre-disease. Since the 1980s, it has been known that antibody glycosylation is different in RA as compared to control individuals. While the literature on glycosylation changes in RA is dominated by reports on serum or plasma immunoglobulin G (IgG), our recent studies have indicated that the glycosylation changes observed for immunoglobulin A (IgA) and total serum N-glycome (TSNG) may be similarly prominent, and useful in differentiating between the RA patients and controls, or as a proxy of the disease activity. In this study, we integrated and compared the RA glycosylation signatures of IgG, IgA and TSNG, all determined in the pregnancy-induced amelioration of rheumatoid arthritis (PARA) cohort. We assessed the association of the altered glycosylation patterns with the disease, autoantibody positivity and disease activity. Our analyses indicated a common, composite glycosylation signature of RA that was independent of the autoantibody status.
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Flevaris, Konstantinos, and Cleo Kontoravdi. "Immunoglobulin G N-glycan Biomarkers for Autoimmune Diseases: Current State and a Glycoinformatics Perspective." International Journal of Molecular Sciences 23, no. 9 (May 6, 2022): 5180. http://dx.doi.org/10.3390/ijms23095180.
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The effective treatment of autoimmune disorders can greatly benefit from disease-specific biomarkers that are functionally involved in immune system regulation and can be collected through minimally invasive procedures. In this regard, human serum IgG N-glycans are promising for uncovering disease predisposition and monitoring progression, and for the identification of specific molecular targets for advanced therapies. In particular, the IgG N-glycome in diseased tissues is considered to be disease-dependent; thus, specific glycan structures may be involved in the pathophysiology of autoimmune diseases. This study provides a critical overview of the literature on human IgG N-glycomics, with a focus on the identification of disease-specific glycan alterations. In order to expedite the establishment of clinically-relevant N-glycan biomarkers, the employment of advanced computational tools for the interpretation of clinical data and their relationship with the underlying molecular mechanisms may be critical. Glycoinformatics tools, including artificial intelligence and systems glycobiology approaches, are reviewed for their potential to provide insight into patient stratification and disease etiology. Challenges in the integration of such glycoinformatics approaches in N-glycan biomarker research are critically discussed.
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Greto, Valentina L., Ana Cvetko, Tamara Štambuk, Niall J. Dempster, Domagoj Kifer, Helena Deriš, Ana Cindrić, et al. "Extensive weight loss reduces glycan age by altering IgG N-glycosylation." International Journal of Obesity 45, no. 7 (May 3, 2021): 1521–31. http://dx.doi.org/10.1038/s41366-021-00816-3.
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Abstract Background Obesity, a major global health problem, is associated with increased cardiometabolic morbidity and mortality. Protein glycosylation is a frequent posttranslational modification, highly responsive to inflammation and ageing. The prospect of biological age reduction, by changing glycosylation patterns through metabolic intervention, opens many possibilities. We have investigated whether weight loss interventions affect inflammation- and ageing-associated IgG glycosylation changes, in a longitudinal cohort of bariatric surgery patients. To support potential findings, BMI-related glycosylation changes were monitored in a longitudinal twins cohort. Methods IgG N-glycans were chromatographically profiled in 37 obese patients, subjected to low-calorie diet, followed by bariatric surgery, across multiple timepoints. Similarly, plasma-derived IgG N-glycan traits were longitudinally monitored in 1680 participants from the TwinsUK cohort. Results Low-calorie diet induced a marked decrease in the levels of IgG N-glycans with bisecting GlcNAc, whose higher levels are usually associated with ageing and inflammatory conditions. Bariatric surgery resulted in extensive alterations of the IgG N-glycome that accompanied progressive weight loss during 1-year follow-up. We observed a significant increase in digalactosylated and sialylated glycans, and a substantial decrease in agalactosylated and core fucosylated IgG N-glycans (adjusted p value range 7.38 × 10−04–3.94 × 10−02). This IgG N-glycan profile is known to be associated with a younger biological age and reflects an enhanced anti-inflammatory IgG potential. Loss of BMI over a 20 year period in the TwinsUK cohort validated a weight loss-associated agalactosylation decrease (adjusted p value 1.79 × 10−02) and an increase in digalactosylation (adjusted p value 5.85 × 10−06). Conclusions Altogether, these findings highlight that weight loss substantially affects IgG N-glycosylation, resulting in reduced glycan and biological age.
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Suhre, Karsten, Irena Trbojević-Akmačić, Ivo Ugrina, Dennis Mook-Kanamori, Tim Spector, Johannes Graumann, Gordan Lauc, and Mario Falchi. "Fine-Mapping of the Human Blood Plasma N-Glycome onto Its Proteome." Metabolites 9, no. 7 (June 26, 2019): 122. http://dx.doi.org/10.3390/metabo9070122.
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Most human proteins are glycosylated. Attachment of complex oligosaccharides to the polypeptide part of these proteins is an integral part of their structure and function and plays a central role in many complex disorders. One approach towards deciphering this human glycan code is to study natural variation in experimentally well characterized samples and cohorts. High-throughput capable large-scale methods that allow for the comprehensive determination of blood circulating proteins and their glycans have been recently developed, but so far, no study has investigated the link between both traits. Here we map for the first time the blood plasma proteome to its matching N-glycome by correlating the levels of 1116 blood circulating proteins with 113 N-glycan traits, determined in 344 samples from individuals of Arab, South-Asian, and Filipino descent, and then replicate our findings in 46 subjects of European ancestry. We report protein-specific N-glycosylation patterns, including a correlation of core fucosylated structures with immunoglobulin G (IgG) levels, and of trisialylated, trigalactosylated, and triantennary structures with heparin cofactor 2 (SERPIND2). Our study reveals a detailed picture of protein N-glycosylation and suggests new avenues for the investigation of its role and function in the associated complex disorders.
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Mehta, Anand, and Timothy M. Block. "Fucosylated Glycoproteins as Markers of Liver Disease." Disease Markers 25, no. 4-5 (2008): 259–65. http://dx.doi.org/10.1155/2008/264594.
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Changes in N-linked glycosylation are known to occur during the development of various diseases. For example, increased branching of oligosaccharides has been associated with cancer metastasis and has been correlated to tumor progression in human cancers of the breast, colon and melanomas. Increases in core fucosylation have also been associated with the development of hepatocellular carcinoma (HCC). Recently, changes in both the total serum glycome and the glycosylation of specific IgG molecules have been observed in people with liver fibrosis and cirrhosis. The mechanisms by which changes in glycosylation are observed and their use as biomarkers of disease will be discussed.
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Plavša, Branimir, Janko Szavits-Nossan, Aleksandar Blivajs, Borna Rapčan, Barbara Radovani, Igor Šesto, Krešimir Štambuk, et al. "The N-Glycosylation of Total Plasma Proteins and IgG in Atrial Fibrillation." Biomolecules 13, no. 4 (March 28, 2023): 605. http://dx.doi.org/10.3390/biom13040605.
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Atrial fibrillation is a disease with a complex pathophysiology, whose occurrence and persistence are caused not only by aberrant electrical signaling in the heart, but by the development of a susceptible heart substrate. These changes, such as the accumulation of adipose tissue and interstitial fibrosis, are characterized by the presence of inflammation. N-glycans have shown great promise as biomarkers in different diseases, specifically those involving inflammatory changes. To assess the changes in the N-glycosylation of the plasma proteins and IgG in atrial fibrillation, we analyzed the N-glycosylation of 172 patients with atrial fibrillation, before and six months after a pulmonary vein isolation procedure, with 54 cardiovascularly healthy controls. An analysis was performed using ultra-high-performance liquid chromatography. We found one oligomannose N-glycan structure from the plasma N-glycome and six IgG N-glycans, mainly revolving around the presence of bisecting N-acetylglucosamine, that were significantly different between the case and control groups. In addition, four plasma N-glycans, mostly oligomannose structures and a derived trait that was related to them, were found to be different in the patients who experienced an atrial fibrillation recurrence during the six-month follow-up. IgG N-glycosylation was extensively associated with the CHA2DS2-VASc score, confirming its previously reported associations with the conditions that make up the score. This is the first study looking at the N-glycosylation patterns in atrial fibrillation and warrants further investigation into the prospect of glycans as biomarkers for atrial fibrillation.
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Meulen, C., S. Singh, A. Lieverse, O. Gornik, E. Sijbrands, G. Lauc, and M. van Hoek. "The Association Of The Igg N-Glycome With The Course Of Kidney Function In Type 2 Diabetes Mellitus." Atherosclerosis 287 (August 2019): e117. http://dx.doi.org/10.1016/j.atherosclerosis.2019.06.339.
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Han, Jing, Yiqing Pan, Yong Gu, Xiaoyan Xu, Ran Zhao, Jichen Sha, Rongrong Zhang, Jianxin Gu, and Shifang Ren. "Profiling of IgG N-glycome during mouse aging: Fucosylated diantennary glycans containing one Neu5Gc-linked LacNAc are associated with age." Journal of Proteomics 229 (October 2020): 103966. http://dx.doi.org/10.1016/j.jprot.2020.103966.
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Ho, Cheng-Hsun, Rong-Nan Chien, Pin-Nan Cheng, Cheng-Kun Liu, Chih-Sheng Su, I.-Chin Wu, Wen-Chun Liu, Shu-Hui Chen, and Ting-Tsung Chang. "Association of serum IgG N-glycome and transforming growth factor-β1 with hepatitis B virus e antigen seroconversion during entecavir therapy." Antiviral Research 111 (November 2014): 121–28. http://dx.doi.org/10.1016/j.antiviral.2014.09.011.
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Klobučar, Marko, Sanja Dević Pavlić, Iris Car, Neda Smiljan Severinski, Tamara Tramišak Milaković, Anđelka Radojčić Badovinac, and Sandra Kraljević Pavelić. "Mass spectrometry-based glycomic profiling of the total IgG and total proteome N-glycomes isolated from follicular fluid." Biomolecular Concepts 11, no. 1 (October 25, 2020): 153–71. http://dx.doi.org/10.1515/bmc-2020-0015.
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AbstractCouples with infertility issues have been assisted by in vitro fertilization reproduction technologies with high success rates of 50-80%. However, complications associated with ovarian stimulation remain, such as ovarian hyperstimulation. Oocyte quality is a significant factor impacting the outcome of in vitro fertilization procedures, but other processes are also critical for fertilization success. Increasing evidence points to aberrant inflammation as one of these critical processes reflected in molecular changes, including glycosylation of proteins. Here we report results from a MALDI-TOF-MS-based glycomic profiling of the total IgG and total proteome N-glycomes isolated from the follicular fluid obtained from patients undergoing fertilization through either (1) assisted reproduction by modified natural cycle or (2) controlled ovarian stimulation (GnRH antagonist, GnRH Ant) protocols. Significant inflammatory-related differences between analyzed N-glycomes were observed from samples and correlated with the ovarian stimulation protocol used in patients.
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Chang, Ting-Tsung, Hung-Wen Tsai, and Cheng-Hsun Ho. "Fucosyl-Agalactosyl IgG1 Induces Cholangiocarcinoma Metastasis and Early Recurrence by Activating Tumor-Associated Macrophage." Cancers 10, no. 11 (November 21, 2018): 460. http://dx.doi.org/10.3390/cancers10110460.
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Concern over roles of serum IgG agalactosylation in chronic inflammatory diseases has been mounting for years but less touched in cancers. The present study addressed the underlying role of agalactosylated IgG beyond tumorigenesis. Liquid-chromatography-tandem mass spectrometry was leveraged for the analysis of IgG1 and IgG2 N-glycomes. We found that a high percentage of serum fucosyl-agalactosyl IgG1 (IgG1-G0F) in patients with cholangiocarcinoma was associated with poor tumor differentiation and tumor metastasis. Results from Kaplan–Meier analyses and a stepwise Cox regression analysis showed that patients with serum IgG1-G0F ≥40% were highly correlated with poor recurrence-free survivals and overall survivals. Interestingly, patients with cholangiocarcinoma whose serum IgG1-G0F ≥40% had more CD163+ tumor-associated macrophages in cancerous tissues than adjacent non-cancerous counterparts. In vitro assays revealed that agalactosylated IgG upregulated tumor-associated macrophage markers CD163 and CD204 in human U-937 cells and peripheral macrophages. Moreover, a positive and a negative feedback loop of transforming growth factor-β1 and interferon-γ, respectively, on IgG agalactosylation was identified using hybridoma cells and verified in sera of the patients. In conclusion, agalactosylated IgG activates tumor-associated macrophages, thereby promoting tumor metastasis and recurrence of cholangiocarcinoma.
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Haslund-Gourley, Benjamin S., Brian Wigdahl, and Mary Ann Comunale. "IgG N-glycan Signatures as Potential Diagnostic and Prognostic Biomarkers." Diagnostics 13, no. 6 (March 7, 2023): 1016. http://dx.doi.org/10.3390/diagnostics13061016.
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IgG N-glycans are an emerging source of disease-specific biomarkers. Over the last decade, the continued development of glycomic databases and the evolution of glyco-analytic methods have resulted in increased throughput, resolution, and sensitivity. IgG N-glycans promote adaptive immune responses through antibody-dependent cellular cytotoxicity (ADCC) and complement activation to combat infection or cancer and promote autoimmunity. In addition to the functional assays, researchers are examining the ability of protein-specific glycosylation to serve as biomarkers of disease. This literature review demonstrates that IgG N-glycans can discriminate between healthy controls, autoimmune disease, infectious disease, and cancer with high sensitivity. The literature also indicates that the IgG glycosylation patterns vary across disease state, thereby supporting their role as specific biomarkers. In addition, IgG N-glycans can be collected longitudinally from patients to track treatment responses or predict disease reoccurrence. This review focuses on IgG N-glycan profiles applied as diagnostics, cohort discriminators, and prognostics. Recent successes, remaining challenges, and upcoming approaches are critically discussed.
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Tudor, Lucija, Gordana Nedic Erjavec, Matea Nikolac Perkovic, Marcela Konjevod, Dubravka Svob Strac, Suzana Uzun, Oliver Kozumplik, Tanja Jovanovic, Gordan Lauc, and Nela Pivac. "N-glycomic Profile in Combat Related Post-Traumatic Stress Disorder." Biomolecules 9, no. 12 (December 6, 2019): 834. http://dx.doi.org/10.3390/biom9120834.
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Post-traumatic stress disorder (PTSD) develops in a portion of individuals exposed to extreme trauma. Glycosylation is a post-translational modification that affects protein functions and is altered in various pathophysiological states and aging. There are still no validated biomarkers of PTSD. The aim of this study was to evaluate the N-glycomic profile in 543 male Caucasian individuals (299 veterans with PTSD and 244 control subjects). The study included discovery (N = 233) and replication (N = 310) cohort. Hydrophilic interaction HPLC and ultra-performance liquid chromatography were used to separate and detect 39 plasma and 24 IgG N-glycan species, respectively. All results were corrected for the effects of age and multiple testing. Significant results included only significantly altered N-glycans in cases/controls in both cohorts, in the same direction. Results showed that six plasma N-glycans (four increased and two decreased) were altered in PTSD vs. controls in both cohorts, but IgG N-glycans were similar between groups. The severity of PTSD was not associated with different plasma N-glycans. This is the first study detecting alterations in plasma N-glycans in PTSD. These N-glycans are also associated with other neuropsychiatric disorders and inflammation, suggesting possible shared glycosylation mechanisms.
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Hipgrave Ederveen, Agnes L., Noortje de Haan, Melissa Baerenfaenger, Dirk J. Lefeber, and Manfred Wuhrer. "Dissecting Total Plasma and Protein-Specific Glycosylation Profiles in Congenital Disorders of Glycosylation." International Journal of Molecular Sciences 21, no. 20 (October 15, 2020): 7635. http://dx.doi.org/10.3390/ijms21207635.
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Protein N-glycosylation is a multifactorial process involved in many biological processes. A broad range of congenital disorders of glycosylation (CDGs) have been described that feature defects in protein N-glycan biosynthesis. Here, we present insights into the disrupted N-glycosylation of various CDG patients exhibiting defects in the transport of nucleotide sugars, Golgi glycosylation or Golgi trafficking. We studied enzymatically released N-glycans of total plasma proteins and affinity purified immunoglobulin G (IgG) from patients and healthy controls using mass spectrometry (MS). The applied method allowed the differentiation of sialic acid linkage isomers via their derivatization. Furthermore, protein-specific glycan profiles were quantified for transferrin and IgG Fc using electrospray ionization MS of intact proteins and glycopeptides, respectively. Next to the previously described glycomic effects, we report unprecedented sialic linkage-specific effects. Defects in proteins involved in Golgi trafficking (COG5-CDG) and CMP-sialic acid transport (SLC35A1-CDG) resulted in lower levels of sialylated structures on plasma proteins as compared to healthy controls. Findings for these specific CDGs include a more pronounced effect for α2,3-sialylation than for α2,6-sialylation. The diverse abnormalities in glycomic features described in this study reflect the broad range of biological mechanisms that influence protein glycosylation.
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Stevenson, Taylor C., Colette Cywes-Bentley, Tyler D. Moeller, Kevin B. Weyant, David Putnam, Yung-Fu Chang, Bradley D. Jones, Gerald B. Pier, and Matthew P. DeLisa. "Immunization with outer membrane vesicles displaying conserved surface polysaccharide antigen elicits broadly antimicrobial antibodies." Proceedings of the National Academy of Sciences 115, no. 14 (March 19, 2018): E3106—E3115. http://dx.doi.org/10.1073/pnas.1718341115.
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Many microbial pathogens produce a β-(1→6)–linked poly-N-acetyl-d-glucosamine (PNAG) surface capsule, including bacterial, fungal, and protozoan cells. Broadly protective immune responses to this single conserved polysaccharide antigen in animals are possible but only when a deacetylated poly-N-acetyl-d-glucosamine (dPNAG; <30% acetate) glycoform is administered as a conjugate to a carrier protein. Unfortunately, conventional methods for natural extraction or chemical synthesis of dPNAG and its subsequent conjugation to protein carriers can be technically demanding and expensive. Here, we describe an alternative strategy for creating broadly protective vaccine candidates that involved coordinating recombinant poly-N-acetyl-d-glucosamine (rPNAG) biosynthesis with outer membrane vesicle (OMV) formation in laboratory strains ofEscherichia coli. The glycosylated outer membrane vesicles (glycOMVs) released by these engineered bacteria were decorated with the PNAG glycopolymer and induced high titers of PNAG-specific IgG antibodies after immunization in mice. When aStaphylococcus aureusenzyme responsible for PNAG deacetylation was additionally expressed in these cells, glycOMVs were generated that elicited antibodies to both highly acetylated PNAG (∼95–100% acetate) and a chemically deacetylated dPNAG derivative (∼15% acetate). These antibodies mediated efficient in vitro killing of two distinct PNAG-positive bacterial species, namelyS. aureusandFrancisella tularensissubsp.holarctica, and mice immunized with PNAG-containing glycOMVs developed protective immunity against these unrelated pathogens. Collectively, our results reveal the potential of glycOMVs for targeting this conserved polysaccharide antigen and engendering protective immunity against the broad range of pathogens that produce surface PNAG.
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Ruhaak, L. Renee, Cynthia Williams, Anne Fenton, Lauren Nagy, Qiuting Hong, Satya Dandekar, and Carlito Lebrilla. "Aberrant glycosylation of plasma proteins in HIV-infected patients (P6361)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 216.5. http://dx.doi.org/10.4049/jimmunol.190.supp.216.5.
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Abstract Background: Glycosylation is one of the most abundant post-translational modifications, and is involved in protein structure formation and protein-protein interactions. Aberrant glycosylation profiles are often observed on plasma proteins from patients with inflammatory diseases. Increased levels of non-galactosylated glycans have been reported on serum IgGs of HIV-infected patients. We investigated the effects of HIV infection on protein glycosylation by N-glycomic profiling of plasma and plasma IgG. Methods: We obtained plasma samples of 22 HIV infected patients (11 therapy-naïve, 11 receiving anti-retroviral therapy) and 11 HIV-negative controls. First, a nano-LC-TOF-MS strategy was employed for the evaluation of plasma N-glycan profiles in each of the samples. Then, a UPLC-QQQ-MS method was used to evaluate the IgG specific glycosylation patterns. N-glycan peak integrals were used for biostatistical analysis. Results and conclusion: Several neutral, fucosylated and sialylated glycan compositions as well as high mannose type glycans in plasma samples were significantly altered in therapy-naïve HIV infected patients compared to controls. Moreover, galactose-deficient glycans were increased on the IgG in these patients, independent of IgG subclass. Interestingly, these effects were largely reduced in HIV infected patients receiving therapy. These results suggest an important role for protein glycosylation in immune dysfunction that is driven by active HIV infection.
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Mittermayr, Stefan, Jonathan Bones, Giao N. Le, and Peter O'Gorman. "N-Glycan Analysis of Polyclonal IgG from Patients with Multiple Myeloma Enables Classification of Stage Specific Pathologies." Blood 126, no. 23 (December 3, 2015): 1761. http://dx.doi.org/10.1182/blood.v126.23.1761.1761.
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Abstract Background Multiple myeloma (MM) is an incurable plasma cell malignancy, with eventual disease refractory and relapse. Its benign precursor, monoclonal gammopathy of undetermined significance (MGUS), has an annual transformation rate of 1%, while that of the asymptomatic smouldering myeloma (SMM) is 10%. The pathognomonic feature is the presence abnormal monoclonal immunoglobulin, of which immunoglobulin G (IgG) paraprotein is the most common. All subclasses of Igs are post-translationally modified by the addition of N-glycans, reportedly influencing structure, stability, and biological function. Previous studies in MM IgG had suggested an increase in the glycosylation of the antigen-binding fragment (Fab), and an overall elevation of sialylation. Using glycomic platforms, we aimed to investigate and characterise the IgG N-glycosylation profiles across the myeloma disease spectrum. Methods Polyclonal IgG was extracted from sera of patients with MM, SMM, MGUS, and age-matched control, using Protein G affinity chromatography. The quantity of extracted IgG was determined using the Bradford assay. N-glycans were enzymatically liberated from a normalised quantity of purified IgG, fluorescently labelled and profiled using hydrophilic interaction ultra-performance liquid chromatography. A combination of exoglycosidase digestions and mass spectrometry were used to elucidate the glycan structures with full linkage and positional specificity. Localisation analyses were performed to determine the distribution of N-glycans at asparagine 297 in the Fc region of the antibody and those present at any additional glycosylation sites present in the Fab region using a combination of enzymatic digestion using the commercially available IdeS enzyme and chemical reduction followed by SDS-PAGE separation of the resulting protein fragments and subsequent in-gel digestion of the N-glycans. Non-supervised principal component analysis (PCA) was employed to detect distinguishable chromatographic features among the studied groups. Longitudinal analyses of samples from individual patients collected during multiple clinical assessments were also performed. Results N-glycan analysis of polyclonal IgG showed unique N-glycan peaks with statistically significant chromatogram variation across the 4 studied groups. PCA identified specific patterns of glycosylation present in the glycan profiles, thus demonstrating the ability to distinguish between MGUS, SMM, MM and control. Sialylated biantennary N-glycans and N-glycans containing bisecting GlcNAc residues contributed most to the PCA separation. Further characterisation of the glycans using sialic acid linkage specific derivatisation and LC-MS analysis confirmed that sialic acids were present in an α2-6 linked configuration. Localisation analysis revealed N-glycans present in the Fc region of the extracted polyclonal antibodies consisted of the standard biantennary type glycans with core fucosylation, variable degrees of galactosylation and low levels of sialylation. Such oligosaccharide structures suggest that the Fc regions of polyclonal IgG present in patients with varying stages of plasma cell disorder maintain a correct orientation to facilitate interaction with Fcγ receptors. Sialylated biantennary N-glycans, identified during global polyclonal IgG glycosylation profiling, were found to be located predominantly in the Fab region of the antibody. The formation of these larger highly sialylated N-glycan structures is likely due to the removal of steric hindrance resulting in more facilitated access by the associated glycosyltransferases required for oligosaccharide biosynthesis. The presence of these charged oligosaccharide structures, with their inherent structural dynamics, are likely to affect the ability of the antibody to recognise antigen and form an immune complex. Conclusions Glycan analysis of polyclonal IgG extracted from the sera of patients with varying stages of myeloma progression is reported. Differential glycosylation on polyclonal IgG was observed between the patients with MGUS, SMM, and MM, with alterations in the levels of sialylated biantennary structures and glycans bearing bisecting GlcNAc residues capable of distinguishing between the patient groups in the spectrum of plasma cell disorders. Disclosures No relevant conflicts of interest to declare.
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Kianičková, Kristína, Lucia Pažitná, Paras H. Kundalia, Zuzana Pakanová, Marek Nemčovič, Peter Baráth, Eva Katrlíková, Ján Šuba, Jana Trebatická, and Jaroslav Katrlík. "Alterations in the Glycan Composition of Serum Glycoproteins in Attention-Deficit Hyperactivity Disorder." International Journal of Molecular Sciences 24, no. 10 (May 14, 2023): 8745. http://dx.doi.org/10.3390/ijms24108745.
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Changes in protein glycosylation are associated with most biological processes, and the importance of glycomic analysis in the research of disorders is constantly increasing, including in the neurodevelopmental field. We glycoprofiled sera in 10 children with attention-deficit hyperactivity disorder (ADHD) and 10 matching healthy controls for 3 types of samples: whole serum, sera after depletion of abundant proteins (albumin and IgG), and isolated IgG. The analytical methods used were a lectin-based glycoprotein microarray enabling high-throughput glycan analysis and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) as a standard method for the identification of glycan structures. For microarray analysis, the samples printed on microarray slides were incubated with biotinylated lectins and detected using the fluorescent conjugate of streptavidin by a microarray scanner. In the ADHD patient samples, we found increased antennary fucosylation, decreased di-/triantennary N-glycans with bisecting N-acetylglucosamine (GlcNAc), and decreased α2-3 sialylation. The results obtained by both independent methods were consistent. The study’s sample size and design do not allow far-reaching conclusions to be drawn. In any case, there is a strong demand for a better and more comprehensive diagnosis of ADHD, and the obtained results emphasize that the presented approach brings new horizons to studying functional associations of glycan alterations in ADHD.
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Sénard, T., I. Flouri, F. Vučković, G. Papadaki, P. Goutakoli, A. Banos, M. Pučić-Baković, et al. "AB0090 BASELINE IgG-Fc N-GLYCOSYLATION PROFILE IS ASSOCIATED WITH LONG-TERM OUTCOME IN A COHORT OF EARLY INFLAMMATORY ARTHRITIS PATIENTS." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 1176.2–1177. http://dx.doi.org/10.1136/annrheumdis-2022-eular.4480.
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BackgroundRheumatoid arthritis (RA) is a systemic autoimmune disease which causes chronic joint inflammation and functional limitation1,2. The diagnosis of rheumatoid arthritis (RA) is mainly based on clinical data and RA specific autoantibodies, while the prediction of long-term prognosis from disease outset is not clinically reliable3,4. The importance of immunoglobulin G (IgG) and its Fc N-glycosylation in inflammation of RA has been described, with changes in the glycosylation profiles observed years before the diagnosis of RA5.ObjectivesWe herein sought to assess the value of total serum IgG Fc N-glycosylation as a diagnostic and prognostic biomarker in patients with early inflammatory arthritis (EIA). Specifically, we aim to assess whether IgG N-glycoform levels may predict the diagnosis of RA or undifferentiated arthritis (UA) and the long-term disease‘s outcome in patients with EIA arthritis patients naïve to treatment.MethodsThe “Early Arthritis Clinic” of the University Hospital of Heraklion is a prospective cohort of patients with inflammatory arthritis. For the present study, we selected a group of patients naïve to any immunosuppressive treatments with available serum at baseline evaluation (n=118). At baseline, demographics, RA clinical characteristics (DAS28, HAQ-DI) and laboratory tests [autoantibodies (RF and/or ACPA)], were also recorded. The patients were prospectively followed for two years, with clinical, laboratory and disease-related treatments documented. A diagnosis of RA or UA was based on established classification criteria6. In order to assess long-term prognosis we formulated a combined “index” of favourable outcome if the patients fulfilled all the following at 24 months of follow-up: remission or low disease activity (based on DAS28 < 3.2) and normal functionality (based on HAQ ≤ 0.25) while on treatment with csDMARDs and never use bDMARDs. We applied a state-of-the-art liquid chromatography - mass spectrometry (LC-MS) based workflow for analysis of subclass-specific IgG Fc N-glycosylation at the baseline7.ResultsWe studied 118 EIA patients [age (mean, SD) (53, 15.6) years, females (80.5%), symptoms duration (53.8, 8.7) years, ACPA positive (16%), DAS28 (4.8, 0.14)]. During the 2 years of follow-up, 60% of the patients were diagnosed with RA and 40% with UA. Although patients with UA had higher relative abundances of galactosylated and sialylated N-glycoforms (H4N4F1, H5N4F1 and H5N4F1S1) in all IgG subclasses at baseline compared to RA patients, differences were not statistically important. Interestingly, we observed a significant association between high levels of IgG2/3 galactosylation for H5N4F1 [effect 0.63, adjusted p=0.036)] and H3N4F1 [effect -0.55122, adjusted p=0.0496) and favorable outcome after two years of treatment.ConclusionIn our cohort of EIA we found IgG2/3 Fc N-glycoforms to be associated with a favorable prognosis after 2 years of follow-up. Should the present data be confirmed in a larger cohort could be of clinical value. Since currently available prognostic tools have significant limitations, further research should aim to the development of a predictive tool of high specificity and sensitivity based on the combination of clinical, serological data and novel biomarkers.References[1]Smolen JS, et al. Lancet (2016) 388(10055):2023-38. doi: 10.1016/S0140-6736(16)30173-8[2]Firestein GS, McInnes IB. Immunity (2017) 46(2):183-96. doi: 10.1016/j.immuni.2017.02.006.[3]Scott DL, et al.J. Lancet (2010) 376(9746):1094-108. doi: Doi 10.1016/S0140-6736(10)60826-4.[4]Weyand CM, Goronzy JJ. Nat Immunol (2021) 22(1):10-8. doi: 10.1038/s41590-020-00816-x.[5]Ligier S, et al. Br J Rheumatol (1998) 37(12):1307-14. doi: 10.1093/rheumatology/37.12.1307.[6]Aletaha D, et al. Ann Rheum Dis (2010) 69(9):1580-8. doi: 10.1136/ard.2010.138461.[7]De Leoz MLA, et al. Molecular & Cellular Proteomics (2020) 19(1):11-30. doi: 10.1074/mcp.RA119.001677.AcknowledgementsThis research was funded by the GlySign and SYSCID – European Union’s Horizon 2020 research and innovation programs under the Marie Skłodowska-Curie, grant numbers 722095 and 733100, respectively.Disclosure of InterestsThomas Sénard: None declared, Irini Flouri: None declared, Frano Vučković Employee of: Genos Ltd, Garyfalia Papadaki: None declared, Panagiota Goutakoli: None declared, Aggelos Banos: None declared, Maja Pučić-Baković Employee of: Genos Ltd, Marija Pezer Employee of: Genos Ltd, George Bertsias: None declared, Gordan Lauc Shareholder of: Genos Ltd, a private research organization that specializes in high-throughput glycomic analyses and has several patents in this field., Prodromos Sidiropoulos: None declared
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Deriš, Helena, Petra Tominac, Frano Vučković, Nina Briški, Arne Astrup, Ellen E. Blaak, Gordan Lauc, and Ivan Gudelj. "Effects of low-calorie and different weight-maintenance diets on IgG glycome composition." Frontiers in Immunology 13 (September 21, 2022). http://dx.doi.org/10.3389/fimmu.2022.995186.
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Obesity-induced inflammation activates the adaptive immune system by altering immunoglobulin G (IgG) glycosylation in a way to produce more proinflammatory antibodies. The IgG glycome has already been well studied, and its alterations are correlated with a high body mass index (BMI) and central adiposity. Still, the IgG N-glycome susceptibility to different dietary regimes for weight control after the initial weight loss has not been studied. To explore changes in IgG glycosylation induced by weight loss and subsequent weight-maintenance diets, we analyzed 1,850 IgG glycomes from subjects in a dietary intervention Diogenes study. In this study, participants followed a low-calorie diet (LCD) providing 800 kcal/d for 8 weeks, followed by one of five weight-maintenance diets over a 6-month period. The most significant alteration of the IgG N-glycome was present 8 weeks after the subjects underwent an LCD, a statistically significant decrease of agalactosylated and the increase of sialylated N glycans. In the follow-up period, the increase in glycans with bisecting GlcNAc and the decrease in sialylated glycans were observed. Those changes were present regardless of the diet type, and we did not observe significant changes between different diets. However, it should be noted that in all five diet groups, there were individuals who prominently altered their IgG glycome composition in either proinflammatory or anti-inflammatory directions.
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Zhang, Ze-Jian, Hui-Fang Wang, Tian-Yu Lian, Yu-Ping Zhou, Xi-Qi Xu, Fan Guo, Yun-Peng Wei, et al. "Human Plasma IgG N -Glycome Profiles Reveal a Proinflammatory Phenotype in Chronic Thromboembolic Pulmonary Hypertension." Hypertension, July 14, 2023. http://dx.doi.org/10.1161/hypertensionaha.123.21408.
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BACKGROUND: The pathological mechanism of chronic thromboembolic pulmonary hypertension (CTEPH) is not fully understood, and inflammation has been reported to be one of its etiological factors. IgG regulates systemic inflammatory homeostasis, primarily through its N -glycans. Little is known about IgG N -glycosylation in CTEPH. We aimed to map the IgG N -glycome of chronic thromboembolic pulmonary hypertension to provide new insights into its pathogenesis and discover novel markers and therapies. METHODS: We characterized the plasma IgG N -glycome of patients with chronic thromboembolic pulmonary hypertension in a discovery cohort and validated our results in an independent validation cohort using matrix-assisted laser desorption/ionization time of flight mass spectrometry. Thereafter, we correlated IgG N -glycans with clinical parameters and circulating inflammatory cytokines in patients with CTEPH. Furthermore, we determined IgG N -glycan quantitative trait loci in chronic thromboembolic pulmonary hypertension to reveal partial mechanisms underlying glycan changes. RESULTS: Decreased IgG galactosylation representing a proinflammatory phenotype was found in CTEPH. The distribution of IgG galactosylation showed a strong association with NT-proBNP (N-terminal pro-B-type natriuretic peptide) in CTEPH. In line with the glycomic findings, IgG pro-/anti-inflammatory N -glycans correlated well with a series of inflammatory markers and gene loci that have been reported to be involved in the regulation of these glycans or inflammatory immune responses. CONCLUSIONS: This is the first study to reveal the full signature of the IgG N -glycome of a proinflammatory phenotype and the genes involved in its regulation in CTEPH. Plasma IgG galactosylation may be useful for evaluating the inflammatory state in patients with CTEPH; however, this requires further validation. This study improves our understanding of the mechanisms underlying chronic thromboembolic pulmonary hypertension inflammation from the perspective of glycomics.
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Zaytseva, Olga O., Sodbo Zh Sharapov, Marcus Perola, Tonu Esko, Arianna Landini, Caroline Hayward, James F. Wilson, et al. "Investigation of the causal relationships between human IgG N-glycosylation and 12 common diseases associated with changes in the IgG N-glycome." Human Molecular Genetics, November 15, 2021. http://dx.doi.org/10.1093/hmg/ddab335.
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Abstract Changes in the N-glycosylation of immunoglobulin G (IgG) are often observed in pathological states, such as autoimmune, inflammatory, neurodegenerative, cardiovascular diseases and some types of cancer. However, in most cases, it is not clear if the disease onset causes these changes, or if the changes in IgG N-glycosylation are among the risk factors for the diseases. The aim of this study was to investigate the casual relationships between IgG N-glycosylation traits and 12 diseases, in which the alterations of IgG N-glycome were previously reported, using two sample Mendelian randomization (MR) approach. We have performed two sample MR using publicly available summary statistics of genome-wide association studies of IgG N-glycosylation and disease risks. Our results indicate positive causal effect of systemic lupus erythematosus (SLE) on the abundance of N-glycans with bisecting N-acetylglucosamine in the total IgG N-glycome. Therefore, we suggest regarding this IgG glycosylation trait as a biomarker of SLE. We also emphasize the need for more powerful GWAS studies of IgG N-glycosylation to further elucidate the causal effect of IgG N-glycome on the diseases.
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Devi. Pavlić, S., M. Klobučar, N. Smilja. Severinski, and A. Radojči. Badovinac. "P–591 Mass spectrometry-based glycomic profiling of the follicular fluid total immunoglobulin G and proteome N-glycomes reveals deregulated inflammatory processes associated with specific controlled ovarian stimulation protocols." Human Reproduction 36, Supplement_1 (July 1, 2021). http://dx.doi.org/10.1093/humrep/deab130.590.
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Abstract Study question Is there a significant inflammatory-related difference between analyzed follicular fluid (FF) glycome profiles regarding the ovarian stimulation protocol used in patients? Summary answer Observed differences between analyzed glycome profiles from patients that underwent different controlled ovarian stimulation (COS) protocols point to deregulated inflammatory processes associated with specific COS. What is known already Successful physiological folliculogenesis and ovulation require an adequate inflammatory response. On the other hand, COS application in ART relies on induced hormonal activation of systemic inflammatory processes. Several studies have confirmed a rise in inflammatory cytokines, CRP, and other markers of inflammation in patients subjected to different COS protocols, pointing to an enhanced inflammatory response during ovulation stimulation. Glycoproteins and glycans have an indisputable role in immune response modulation: proper glycosylation of glycoproteins plays a pivotal role in the regulation of normal physiological processes, and aberrant glycosylation of glycoproteins has been associated with various pathological states, including inflammation. Study design, size, duration Study design: Cross sectional – FFs from patients that underwent ART in modified natural cycle (MNC group) versus FFs from patients that underwent ART under GnRH antagonist COS (COS group). Size: 20 FFs from 20 patients undergoing ART. Duration: One year. Sampling procedure: Each FF was aspirated from the dominant follicle. In the COS group, only the fluid from the first aspirated follicle of each patient was collected. Participants/materials, setting, methods Study included 20 FF samples from 20 patients divided into two groups according to the applied ovarian stimulation protocol: MNC group (n = 10) and COS group (n = 10). The immunoglobulin G (IgG) was isolated from FF samples by immunoaffinity chromatography. The N-linked glycans derived from IgG molecule and the remaining FF total proteomes were enzymatically cleaved and subjected to derivatization procedure. N-glycomes of FF-isolated IgG and total proteomes were analyzed separately by MALDI-TOF-MS. Main results and the role of chance FF IgG N-glycome profiling The MALDI-TOF-MS based comparative analysis of the individual glycan relative abundances, revealed several significantly deregulated glycoforms between analyzed groups whose levels were significantly elevated (p˂0.05) in the COS vs. MNC group. Furthermore, additional low abundant N-glycan species were also found to be deregulated between the analyzed groups: two monogalactolysed and monosialylated N-glycan compositions were only identified in the COS group. The comparative analysis of FF IgG N-glycome features revealed statistically relevant differences in the levels of two derived traits: galactosylation and bigalactosylation levels of the FF IgG N-glycome, both significantly downregulated (p˂0.05) in the MNC vs. COS profile. Comparative analysis of FF total proteome N-glycome The majority of identified glycan compositions were complex type N-glycans representing more than 98% of the total N-glycome profiles in both analyzed groups. The comparative analysis of individual glycan relative abundances revealed relevant differences in regulation of ten N-glycan species between the two analyzed profiles. In the MNC group, six N-glycan species showed significantly increased abundances (p˂0.05) compared with the COS group. Moreover, two compositions were exclusively identified in the MNC group, while two compositions were identified only in the COS group. Limitations, reasons for caution Since this preliminary study was conducted on relatively small sample size, all results should be verified on a larger sample set. Moreover, focused glycosylation analysis of a panel of individual FF acute phase blood serum derived proteins and immunoglobulins, might additionally clarify the inflammatory mechanisms underlying different ART stimulation protocols. Wider implications of the findings: While glycome profiling of human FFs was conducted for the first time, previous evidence supports the shown association of aberrant inflammation in diverse ART stimulation protocols and in development of various pathological states (i.e. OHSS). Obtained results are in line with previous similar studies performed in the human plasma. Trial registration number uniri-biomed–18–161 1310
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Zhang, Zejian, Jianqiang Wu, Peng Liu, Lin Kang, and Xiequn Xu. "Diagnostic Potential of Plasma IgG N-glycans in Discriminating Thyroid Cancer from Benign Thyroid Nodules and Healthy Controls." Frontiers in Oncology 11 (August 12, 2021). http://dx.doi.org/10.3389/fonc.2021.658223.
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BackgroundNovel biomarkers are urgently needed to distinguish between benign and malignant thyroid nodules and detect thyroid cancer in the early stage. The associations between serum IgG N-glycosylation and thyroid cancer risk have been revealed. We aimed to explore the potential of IgG N-glycan traits as biomarkers in the differential diagnosis of thyroid cancer.MethodsPlasma IgG N-glycome analysis was applied to a discovery cohort followed by independent validation. IgG N-glycan profiles were obtained using a robust quantitative strategy based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. IgG N-glycans were relatively quantified, and classification performance was evaluated based on directly detected and derived glycan traits.ResultsFour directly detected glycans were significantly changed in thyroid cancer patients compared to that in non-cancer controls. Derived glycan traits and a classification glycol-panel were generated based on the directly detected glycan traits. In the discovery cohort, derived trait BN (bisecting type neutral N-glycans) and the glyco-panel showed potential in distinguishing between thyroid cancer and non-cancer controls with AUCs of 0.920 and 0.917, respectively. The diagnostic potential was further validated. Derived trait BN and the glycol-panel displayed “accurate” performance (AUC>0.8) in discriminating thyroid cancer from benign thyroid nodules and healthy controls in the validation cohort. Meanwhile, derived trait BN and the glycol-panel also showed diagnostic potential in detecting early-stage thyroid cancer.ConclusionsIgG N-glycome analysis revealed N-glycomic differences that allow classification of thyroid cancer from non-cancer controls. Our results suggested that derived trait BN and the classification glyco-panel rather than single N-glycans may serve as candidate biomarkers for further validation.
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Hou, Haifeng, Huan Yang, Pengcheng Liu, Changwu Huang, Meng Wang, Yuejin Li, Mingsong Zhu, et al. "Profile of Immunoglobulin G N-Glycome in COVID-19 Patients: A Case-Control Study." Frontiers in Immunology 12 (September 23, 2021). http://dx.doi.org/10.3389/fimmu.2021.748566.
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Coronavirus disease 2019 (COVID-19) remains a major health challenge globally. Previous studies have suggested that changes in the glycosylation of IgG are closely associated with the severity of COVID-19. This study aimed to compare the profiles of IgG N-glycome between COVID-19 patients and healthy controls. A case-control study was conducted, in which 104 COVID-19 patients and 104 age- and sex-matched healthy individuals were recruited. Serum IgG N-glycome composition was analyzed by hydrophilic interaction liquid chromatography with the ultra-high-performance liquid chromatography (HILIC-UPLC) approach. COVID-19 patients have a decreased level of IgG fucosylation, which upregulates antibody-dependent cell cytotoxicity (ADCC) in acute immune responses. In severe cases, a low level of IgG sialylation contributes to the ADCC-regulated enhancement of inflammatory cytokines. The decreases in sialylation and galactosylation play a role in COVID-19 pathogenesis via the activation of the lectin-initiated alternative complement pathway. IgG N-glycosylation underlines the complex clinical phenotypes of SARS-CoV-2 infection.
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Siekman, Sterre L., Tamas Pongracz, Wenjun Wang, Jan Nouta, Peter G. Kremsner, Pedro Vieira da Silva-Neto, Meral Esen, et al. "The IgG glycome of SARS-CoV-2 infected individuals reflects disease course and severity." Frontiers in Immunology 13 (October 18, 2022). http://dx.doi.org/10.3389/fimmu.2022.993354.
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Immunoglobulin G (IgG) antibodies play an important role in the immune response against viruses such as SARS-CoV-2. As the effector functions of IgG are modulated by N-glycosylation of the Fc region, the structure and possible function of the IgG N-glycome has been under investigation in relation to divergent COVID-19 disease courses. Through LC-MS analysis we studied both total IgG1 and spike protein-specific IgG1 Fc glycosylation of 129 German and 163 Brazilian COVID-19 patients representing diverse patient populations. We found that hospitalized COVID-19 patients displayed decreased levels of total IgG1 bisection and galactosylation and lowered anti-S IgG1 fucosylation and bisection as compared to mild outpatients. Anti-S IgG1 glycosylation was dynamic over the disease course and both anti-S and total IgG1 glycosylation were correlated to inflammatory markers. Further research is needed to dissect the possible role of altered IgG glycosylation profiles in (dys)regulating the immune response in COVID-19.
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Kovacs, Z., B. Adamczyk, F. Reidy, F. M. McAuliffe, P. M. Rudd, M. Wingfield, L. Glover, and R. Saldova. "P–340 Novel non-invasive diagnostic options for endometriosis - based on glycome analysis." Human Reproduction 36, Supplement_1 (July 1, 2021). http://dx.doi.org/10.1093/humrep/deab130.339.
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Abstract Study question Could glycosylation changes on serum and/or urine glycoproteins be suitable biomarkers for the non-invasive diagnosis of endometriosis? Summary answer The glycosylation pattern on serum and urine glycoproteins differed significantly in endometriosis patients compared to controls, suggesting a novel role as biomarkers of the disease. What is known already There is little published on endometriosis and glycosylation, and most of the studies are conducted with tissue or peritoneal fluid samples, collected by invasive means. An Iraqi study draws attention to the importance of serum sialylation, which is dramatically changed in endometriosis patients after zoladex therapy, indicating that changes in serum sialylation may be a new biomarker of the disease. While glycosylation of urine in endometriosis has not been studied so far, in a study of endometrial cancer, the urinary level of two glycoproteins was significantly increased in the patients compared to the control group. Study design, size, duration This was a prospective study. In this basic research project, serum and urine samples were collected for glycome analysis in women with and without endometriosis, as diagnosed at laparoscopy. Glycated haemoglobin (HbA1c), fasting glucose levels as well as hormone levels were also collected from the patients to link our glycomic findings with metabolic and hormone profiles. The study was approved by the Research and Ethics Committee of the National Maternity Hospital, Dublin (EC19.2018). Participants/materials, setting, methods Samples from 24 cases of endometriosis (patients without previous anti-inflammatory or hormonal therapy, endometriosis was confirmed by laparoscopy) and 27 control patients (patients without endometriosis) were processed to analyse N-glycans (total serum), urine glycoproteins, and IgG. The pre-processed, PNGase F-digested serum and urine samples were labelled with fluorescent tag and then analysed by mass spectrometry, ultra-performance liquid chromatography (UPLC) in combination with exoglycosidase digestions and Glycostore (https://glycostore.org/). Main results and the role of chance Glycosylation on total serum and urine glycoproteins and IgG was investigated and differed in endometriosis compared to controls. The N-glycome from the total glycoproteins in serum and urine was also different. The proportion of the galactosylation and sialylation differed between urine and serum IgG and these alterations have an impact on the IgG function. Our preliminary data indicate, that there is an increase in alpha 2–3 sialylation, galactosylation, and fucosylation on urine glycans from endometriosis patients compared to the control pool. Urine is a good source of biomarkers as it can be collected non-invasively. Our group is the first to have developed a protocol for the recovery of N-glycans in urine and to have identified the total N-glycome in urine. The urine N-glycome contains mostly complex N-glycans and also some oligomannosylated and hybrid glycans. Our results may lead to non-invasive biomarkers for the diagnosis of endometriosis and the monitoring of the disease. Limitations, reasons for caution The number of participants involved in this basic research is low but this is a pilot study. A larger, validation study, is warranted in the future. Furthermore, the follow-up of treated patients also would be an interesting field of research. Wider implications of the findings: Glycomics may be a potent source of biomarkers of endometriosis, with a number of glyco-biomarkers already approved by the FDA. Endometriosis-associated glycomic profiles from serum and/or urine glycoproteins may represent viable targets for development of innovative non-invasive or minimally invasive diagnostics in this debilitating disease. Trial registration number Not applicable
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Deriš, Helena, Ana Cindrić, Matthew Lauber, Tea Petrović, Alicia Bielik, Christopher H. Taron, Marleen van Wingerden, Gordan Lauc, and Irena Trbojević-Akmačić. "Robustness and repeatability of GlycoWorks RapiFluor-MS IgG N-glycan profiling in a long-term high-throughput glycomic study." Glycobiology, June 14, 2021. http://dx.doi.org/10.1093/glycob/cwab050.
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Abstract Protein glycosylation is the attachment of a carbohydrate moiety to a protein backbone affecting both structure and function of the protein. Abnormal glycosylation is associated with various diseases, and some of the changes in glycosylation are detectable even before symptom development. As such, glycans have emerged as compelling new biomarker candidates. A wide range of analytical methods exist for small-scale glycan analyses. However, there is a growing need for highly robust and reproducible high-throughput techniques that allow for large-scale glycoprofiling. Here, we describe the evaluation of robustness and repeatability of immunoglobulin G (IgG) N-glycan analysis using the GlycoWorks RapiFluor-MS N-Glycan Kit followed by hydrophilic interaction ultra-high-performance liquid chromatography (HILIC-UHPLC) from 335 technical replicates of human plasma randomly distributed across 67 96-well plates. The data was collected over a 5-month period using multiple UHPLC systems and chromatographic columns. Following relative IgG N-glycan quantification in acquired chromatograms, data analysis showed that the most abundant peaks that together made up for three-fourths of the detected IgG N-glycome all had coefficients of variation (CVs) lower than 2%. The highest CVs ranging from 16 to 29% accompanied low abundance glycan peaks with the individual relative peak area below 1% that together made up for <2% of the detected IgG N-glycome. These results show that the tested method is very robust and repeatable, making it suitable for the IgG N-glycan analysis of a large number of samples in a high-throughput manner over a longer period of time.
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Petrović, Tea, Amrita Vijay, Frano Vučković, Irena Trbojević-Akmačić, Benjamin J. Ollivere, Damir Marjanović, Tamer Bego, et al. "IgG N-glycome changes during the course of severe COVID-19: An observational study." eBioMedicine, June 2022, 104101. http://dx.doi.org/10.1016/j.ebiom.2022.104101.
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Trbojević-Akmačić, Irena, Frano Vučković, Tea Pribić, Marija Vilaj, Urh Černigoj, Jana Vidič, Jelena Šimunović, et al. "Comparative analysis of transferrin and IgG N-glycosylation in two human populations." Communications Biology 6, no. 1 (March 23, 2023). http://dx.doi.org/10.1038/s42003-023-04685-6.
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AbstractHuman plasma transferrin (Tf) N-glycosylation has been mostly studied as a marker for congenital disorders of glycosylation, alcohol abuse, and hepatocellular carcinoma. However, inter-individual variability of Tf N-glycosylation is not known, mainly due to technical limitations of Tf isolation in large-scale studies. Here, we present a highly specific robust high-throughput approach for Tf purification from human blood plasma and detailed characterization of Tf N-glycosylation on the level of released glycans by ultra-high-performance liquid chromatography based on hydrophilic interactions and fluorescence detection (HILIC-UHPLC-FLD), exoglycosidase sequencing, and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). We perform a large-scale comparative study of Tf and immunoglobulin G (IgG) N-glycosylation analysis in two human populations and demonstrate that Tf N-glycosylation is associated with age and sex, along with multiple biochemical and physiological traits. Observed association patterns differ compared to the IgG N-glycome corroborating tissue-specific N-glycosylation and specific N-glycans’ role in their distinct physiological functions.
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Zhang, Xiaoyu, Hui Yuan, Jihui Lyu, Xiaoni Meng, Qiuyue Tian, Yuejin Li, Jie Zhang, et al. "Association of dementia with immunoglobulin G N-glycans in a Chinese Han Population." npj Aging and Mechanisms of Disease 7, no. 1 (February 4, 2021). http://dx.doi.org/10.1038/s41514-021-00055-w.
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AbstractImmunoglobulin G (IgG) functionality can drastically change from anti- to proinflammatory by alterations in the IgG N-glycan patterns. Our previous studies have demonstrated that IgG N-glycans associated with the risk factors of dementia, such as aging, dyslipidemia, type 2 diabetes mellitus, hypertension, and ischemic stroke. Therefore, the aim is to investigate whether the effects of IgG N-glycan profiles on dementia exists in a Chinese Han population. A case–control study, including 81 patients with dementia, 81 age- and gender-matched controls with normal cognitive functioning (NC) and 108 non-matched controls with mild cognitive impairment (MCI) was performed. Plasma IgG N-glycans were separated by ultra-performance liquid chromatography. Fourteen glycan peaks reflecting decreased of sialylation and core fucosylation, and increased bisecting N-acetylglucosamine (GlcNAc) N-glycan structures were of statistically significant differences between dementia and NC groups after controlling for confounders (p < 0.05; q < 0.05). Similarly, the differences for these 14 initial glycans were statistically significant between AD and NC groups after adjusting for the effects of confounders (p < 0.05; q < 0.05). The area under the receiver operating curve (AUC) value of the model consisting of GP8, GP9, and GP14 was determined to distinguish dementia from NC group as 0.876 [95% confidence interval (CI): 0.815–0.923] and distinguish AD from NC group as 0.887 (95% CI: 0.819–0.936). Patients with dementia were of an elevated proinflammatory activity via the significant changes of IgG glycome. Therefore, IgG N-glycans might contribute to be potential novel biomarkers for the neurodegenerative process risk assessment of dementia.
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Stupin, Ana, Ana Cvetko, Gordana Kralik, Martina Mihalj, Petar Šušnjara, Nikolina Kolobarić, Željka Breškić Ćurić, et al. "The effect of n-3 polyunsaturated fatty acids-enriched hen eggs consumption on IgG and total plasma protein N-glycosylation in healthy individuals and cardiovascular patients." Glycobiology, June 14, 2021. http://dx.doi.org/10.1093/glycob/cwab051.
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Abstract This study determined the effect of n-3 polyunsaturated fatty acids (n-3 PUFAs)-enriched hen eggs consumption on immunoglobulin G (IgG) and total plasma protein N-glycan profiles and inflammatory biomarkers level in healthy individuals (N = 33) and cardiovascular (CV) patients (N = 21). Subjects were divided to Control-Healthy and Control-CV subgroups [consumed three regular hens’ eggs/daily (249 mg n-3 PUFAs/day)], and n-3 PUFAs-Healthy and n-3 PUFAs-CV subgroups [consumed three n-3 PUFAs-enriched hen eggs/daily (1053 mg n-3 PUFAs/day)] for 3 weeks. Serum-free fatty acids profile and high-sensitivity C-reactive protein, interleukin 6 and 10 (IL-6, IL-10) and tumor necrosis factor alpha were measured. Total plasma protein and IgG N-glycome have been profiled before and after dietary protocols. Serum n-3 PUFAs concentration significantly increased following n-3 PUFAs hen eggs consumption in both n-3 PUFAs-Healthy and n-3 PUFAs-CV. IL-10 significantly increased in both Healthy subgroups, whereas no change occurred in CV subgroups. Derived IgG N-glycan traits: bisecting N-acetylglucosamine (B) significantly decreased in n-3 PUFAs-Healthy, whereas agalactosylation (G0) and core fucosylation (CF) significantly increased in Control-Healthy. Derived total plasma protein N-glycan traits: high branching glycans, trigalactosylation, tetragalactosylation, trisialylation, tetrasialylation and antennary fucosylation significantly decreased, whereas G0, monogalactosylation (G1), neutral glycans (S0), B, CF and oligomannose structures significantly increased in n-3 PUFAs-CV. Digalactosylation significantly decreased, and G0, G1, S0, disialylation, B and CF significantly increased in Control-CV. n-3 PUFAs consumption alters IgG N-glycan traits and IL-10 in healthy individuals, and total plasma protein N-glycan traits in CV patients, by shifting them toward less inflammatory N-glycosylation profile.
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Mijakovac, Anika, Azra Frkatović, Maja Hanić, Jelena Ivok, Marina Martinić Kavur, Maja Pučić-Baković, Tim Spector, Vlatka Zoldoš, Massimo Mangino, and Gordan Lauc. "Heritability of the glycan clock of biological age." Frontiers in Cell and Developmental Biology 10 (December 22, 2022). http://dx.doi.org/10.3389/fcell.2022.982609.
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Immunoglobulin G is posttranslationally modified by the addition of complex N-glycans affecting its function and mediating inflammation at multiple levels. IgG glycome composition changes with age and health in a predictive pattern, presumably due to inflammaging. As a result, a novel biological aging biomarker, glycan clock of age, was developed. Glycan clock of age is the first of biological aging clocks for which multiple studies showed a possibility of clock reversal even with simple lifestyle interventions. However, none of the previous studies determined to which extent the glycan clock can be turned, and how much is fixed by genetic predisposition. To determine the contribution of genetic and environmental factors to phenotypic variation of the glycan clock, we performed heritability analysis on two TwinsUK female cohorts. IgG glycans from monozygotic and dizygotic twin pairs were analyzed by UHPLC and glycan age was calculated using the glycan clock. In order to determine additive genetic, shared, and unique environmental contributions, a classical twin design was applied. Heritability of the glycan clock was calculated for participants of one cross-sectional and one longitudinal cohort with three time points to assess the reliability of measurements. Heritability estimate for the glycan clock was 39% on average, suggesting a moderate contribution of additive genetic factors (A) to glycan clock variation. Remarkably, heritability estimates remained approximately the same in all time points of the longitudinal study, even though IgG glycome composition changed substantially. Most environmental contributions came from shared environmental factors (C), with unique environmental factors (E) having a minor role. Interestingly, heritability estimates nearly doubled, to an average of 71%, when we included age as a covariant. This intervention also inflated the estimates of unique environmental factors contributing to glycan clock variation. A complex interplay between genetic and environmental factors defines alternative IgG glycosylation during aging and, consequently, dictates the glycan clock’s ticking. Apparently, environmental factors (including lifestyle choices) have a strong impact on the biological age measured with the glycan clock, which additionally clarifies why this aging clock is one of the most potent biomarkers of biological aging.
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Park, Dong Ik, Jerko Štambuk, Genadij Razdorov, Maja Pučić-Baković, Daniel Martins-de-Souza, Gordan Lauc, and Christoph W. Turck. "Blood plasma/IgG N-glycome biosignatures associated with major depressive disorder symptom severity and the antidepressant response." Scientific Reports 8, no. 1 (January 9, 2018). http://dx.doi.org/10.1038/s41598-017-17500-0.
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Trzos, Sara, Paweł Link-Lenczowski, Grzegorz Sokołowski, and Ewa Pocheć. "Changes of IgG N-Glycosylation in Thyroid Autoimmunity: The Modulatory Effect of Methimazole in Graves’ Disease and the Association With the Severity of Inflammation in Hashimoto’s Thyroiditis." Frontiers in Immunology 13 (March 15, 2022). http://dx.doi.org/10.3389/fimmu.2022.841710.
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The N-glycome of immunoglobulin G (IgG), the most abundant glycoprotein in human blood serum, reflects pathological conditions of autoimmunity and is sensitive to medicines applied in disease therapy. Due to the high sensitivity of N-glycosylation, the IgG N-glycan profile may serve as an indicator of an ongoing inflammatory process. The IgG structure and its effector functions are strongly dependent on the composition of N-glycans attached to the Fc fragment, and the binding of antigens is regulated by Fab sugar moieties. Because of the crucial role of N-glycans in IgG function, remodeling of its N-oligosaccharides can induce pathological changes that ultimately contribute to the development of autoimmunity; restoration of their physiological structure is critical to the reduction of disease symptoms. Our recently published data have shown that the pathology of autoimmune thyroid diseases (AITDs), including Hashimoto’s thyroiditis (HT) and Graves’ disease (GD), is accompanied by alterations of the composition of IgG N-glycans. The present study is a more in-depth investigation of IgG glycosylation in both AITDs, designed to determine the relationship between the severity of thyroid inflammation and IgG N-glycan structures in HT, and to assess the impact of immunosuppressive therapy on the N-glycan profile in GD patients. The study material consisted of human serum samples collected from donors with elevated anti-thyroglobulin (Tg) and/or anti-thyroperoxidase (TPO) IgGs without symptoms of hypothyroidism (n=68), HT patients characterized by high autoantibody titers and advanced destruction of the thyroid gland (n=113), GD patients with up-regulated IgG against thyroid-stimulating hormone receptor (TSHR) before (n=62) and after (n=47) stabilization of TSH level as a result of methimazole therapy (study groups), and healthy donors (control group, n=90). IgG was isolated from blood serum using protein G affinity chromatography. N-glycans were released from IgG by PNGase F digestion and analyzed by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) after 2-aminobenzamide (2-AB) labeling. UPLC-MS chromatograms were integrated into 25 peaks (GP) in the Waters UNIFI Scientific Information System, and N-glycans were assigned based on the glucose unit values and mass-to-charge ratios (m/z) of the detected ions. The Kruskal-Wallis non-parametric test was used to determine the statistical significance of the results (p<0.05). The obtained results suggest that modifications of IgG sialylation, galactosylation and core-fucosylation are associated with the severity of HT symptoms. Methimazole therapy implemented in GD patients affected the IgG N-glycan profile; as a result, the content of the sialylated and galactosylated oligosaccharides with core fucose differed after treatment. Our results suggest that N-glycosylation of IgG undergoes dynamic changes during the intensification of thyroiditis in HT, and that in GD autoimmunity it is affected significantly by immunosuppressive therapy.
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Rudman, Najda, Simranjeet Kaur, Vesna Simunović, Domagoj Kifer, Dinko Šoić, Toma Keser, Tamara Štambuk, et al. "Integrated glycomics and genetics analyses reveal a potential role for N-glycosylation of plasma proteins and IgGs, as well as the complement system, in the development of type 1 diabetes." Diabetologia, March 13, 2023. http://dx.doi.org/10.1007/s00125-023-05881-z.
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Abstract Aims/hypothesis We previously demonstrated that N-glycosylation of plasma proteins and IgGs is different in children with recent-onset type 1 diabetes compared with their healthy siblings. To search for genetic variants contributing to these changes, we undertook a genetic association study of the plasma protein and IgG N-glycome in type 1 diabetes. Methods A total of 1105 recent-onset type 1 diabetes patients from the Danish Registry of Childhood and Adolescent Diabetes were genotyped at 183,546 genetic markers, testing these for genetic association with variable levels of 24 IgG and 39 plasma protein N-glycan traits. In the follow-up study, significant associations were validated in 455 samples. Results This study confirmed previously known plasma protein and/or IgG N-glycosylation loci (candidate genes MGAT3, MGAT5 and ST6GAL1, encoding beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase, alpha-1,6-mannosylglycoprotein 6-beta-N-acetylglucosaminyltransferase and ST6 beta-galactoside alpha-2,6-sialyltransferase 1 gene, respectively) and identified novel associations that were not previously reported for the general European population. First, novel genetic associations of IgG-bound glycans were found with SNPs on chromosome 22 residing in two genomic intervals close to candidate gene MGAT3; these include core fucosylated digalactosylated disialylated IgG N-glycan with bisecting N-acetylglucosamine (GlcNAc) (pdiscovery=7.65 × 10−12, preplication=8.33 × 10−6 for the top associated SNP rs5757680) and core fucosylated digalactosylated glycan with bisecting GlcNAc (pdiscovery=2.88 × 10−10, preplication=3.03 × 10−3 for the top associated SNP rs137702). The most significant genetic associations of IgG-bound glycans were those with MGAT3. Second, two SNPs in high linkage disequilibrium (missense rs1047286 and synonymous rs2230203) located on chromosome 19 within the protein coding region of the complement C3 gene (C3) showed association with the oligomannose plasma protein N-glycan (pdiscovery=2.43 × 10−11, preplication=8.66 × 10−4 for the top associated SNP rs1047286). Conclusions/interpretation This study identified novel genetic associations driving the distinct N-glycosylation of plasma proteins and IgGs identified previously at type 1 diabetes onset. Our results highlight the importance of further exploring the potential role of N-glycosylation and its influence on complement activation and type 1 diabetes susceptibility. Graphical abstract
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Wang, Chunqun, Lu Liu, Tianjiao Wang, Xin Liu, Wenjie Peng, Ratnesh Kumar Srivastav, Xing-Quan Zhu, Nishith Gupta, Robin B. Gasser, and Min Hu. "H11-induced immunoprotection is predominantly linked to N-glycan moieties during Haemonchus contortus infection." Frontiers in Immunology 13 (October 25, 2022). http://dx.doi.org/10.3389/fimmu.2022.1034820.
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Nematodes are one of the largest groups of animals on the planet. Many of them are major pathogens of humans, animals and plants, and cause destructive diseases and socioeconomic losses worldwide. Despite their adverse impacts on human health and agriculture, nematodes can be challenging to control, because anthelmintic treatments do not prevent re-infection, and excessive treatment has led to widespread drug resistance in nematode populations. Indeed, many nematode species of livestock animals have become resistant to almost all classes of anthelmintics used. Most efforts to develop commercial anti-nematode vaccines (native or recombinant) for use in animals and humans have not succeeded, although one effective (dead) vaccine (Barbervax) has been developed to protect animals against one of the most pathogenic parasites of livestock animals – Haemonchus contortus (the barber’s pole worm). This vaccine contains native molecules, called H11 and H-Gal-GP, derived from the intestine of this blood-feeding worm. In its native form, H11 alone consistently induces high levels (75-95%) of immunoprotection in animals against disease (haemonchosis), but recombinant forms thereof do not. Here, to test the hypothesis that post-translational modification (glycosylation) of H11 plays a crucial role in achieving such high immunoprotection, we explored the N-glycoproteome and N-glycome of H11 using the high-resolution mass spectrometry and assessed the roles of N-glycosylation in protective immunity against H. contortus. Our results showed conclusively that N-glycan moieties on H11 are the dominant immunogens, which induce high IgG serum antibody levels in immunised animals, and that anti-H11 IgG antibodies can confer specific, passive immunity in naïve animals. This work provides the first detailed account of the relevance and role of protein glycosylation in protective immunity against a parasitic nematode, with important implications for the design of vaccines against metazoan parasites.