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Singh, Sunny S., Annemieke Naber, Viktoria Dotz, Emma Schoep, Elham Memarian, Roderick C. Slieker, Petra J. M. Elders, et al. "Metformin and statin use associate with plasma protein N-glycosylation in people with type 2 diabetes." BMJ Open Diabetes Research & Care 8, no. 1 (July 2020): e001230. http://dx.doi.org/10.1136/bmjdrc-2020-001230.
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IntroductionRecent studies revealed N-glycosylation signatures of type 2 diabetes, inflammation and cardiovascular risk factors. Most people with diabetes use medication to reduce cardiovascular risk. The association of these medications with the plasma N-glycome is largely unknown. We investigated the associations of metformin, statin, ACE inhibitor/angiotensin II receptor blocker (ARB), sulfonylurea (SU) derivatives and insulin use with the total plasma N-glycome in type 2 diabetes.Research design and methodsAfter enzymatic release from glycoproteins, N-glycans were measured by matrix-assisted laser desorption/ionization mass spectrometry in the DiaGene (n=1815) and Hoorn Diabetes Care System (n=1518) cohorts. Multiple linear regression was used to investigate associations with medication, adjusted for clinical characteristics. Results were meta-analyzed and corrected for multiple comparisons.ResultsMetformin and statins were associated with decreased fucosylation and increased galactosylation and sialylation in glycans unrelated to immunoglobulin G. Bisection was increased within diantennary fucosylated non-sialylated glycans, but decreased within diantennary fucosylated sialylated glycans. Only few glycans were associated with ACE inhibitor/ARBs, while none associated with insulin and SU derivative use.ConclusionsWe conclude that metformin and statins associate with a total plasma N-glycome signature in type 2 diabetes. Further studies are needed to determine the causality of these relations, and future N-glycomic research should consider medication a potential confounder.
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Lin, Sihan, You Wang, Xinran Wang, Bin Yan, Weihua Lou, and Wen Di. "Serum immunoglobulin G N-glycome: a potential biomarker in endometrial cancer." Annals of Translational Medicine 8, no. 12 (June 2020): 748. http://dx.doi.org/10.21037/atm-20-3504.
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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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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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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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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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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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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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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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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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Li, Xingang, Hao Wang, Alyce Russell, Weijie Cao, Xueqing Wang, Siqi Ge, Yulu Zheng, et al. "Type 2 Diabetes Mellitus is Associated with the Immunoglobulin G N-Glycome through Putative Proinflammatory Mechanisms in an Australian Population." OMICS: A Journal of Integrative Biology 23, no. 12 (December 1, 2019): 631–39. http://dx.doi.org/10.1089/omi.2019.0075.
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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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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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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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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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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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Wang, Hao, Xingang Li, Xueqing Wang, Di Liu, Xiaoyu Zhang, Weijie Cao, Yulu Zheng, et al. "Next-Generation (Glycomic) Biomarkers for Cardiometabolic Health: A Community-Based Study of Immunoglobulin G N-Glycans in a Chinese Han Population." OMICS: A Journal of Integrative Biology 23, no. 12 (December 1, 2019): 649–59. http://dx.doi.org/10.1089/omi.2019.0099.
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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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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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Petrov, Vyacheslav A., Sodbo Zh Sharapov, Lev Shagam, Arina V. Nostaeva, Marija Pezer, Dalin Li, Maja Hanić, et al. "Association Between Human Gut Microbiome and N-Glycan Composition of Total Plasma Proteome." Frontiers in Microbiology 13 (April 29, 2022). http://dx.doi.org/10.3389/fmicb.2022.811922.
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Being one of the most dynamic entities in the human body, glycosylation of proteins fine-tunes the activity of the organismal machinery, including the immune system, and mediates the interaction with the human microbial consortium, typically represented by the gut microbiome. Using data from 194 healthy individuals, we conducted an associational study to uncover potential relations between the gut microbiome and the blood plasma N-glycome, including N-glycome of immunoglobulin G. While lacking strong linkages on the multivariate level, we were able to identify associations between alpha and beta microbiome diversity and the blood plasma N-glycome profile. Moreover, for two bacterial genera, namely, Bilophila and Clostridium innocuum, significant associations with specific glycans were also shown. The study’s results suggest a non-trivial, possibly weak link between the total plasma N-glycome and the gut microbiome, predominantly involving glycans related to the immune system proteins, including immunoglobulin G. Further studies of glycans linked to microbiome-related proteins in well-selected patient groups are required to conclusively establish specific associations.
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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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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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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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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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Radovani, Barbara, Gordan Lauc, and Ivan Gudelj. "Storage stability and HILIC-UHPLC-FLR analysis of immunoglobulin G N-glycome from saliva." Analytical and Bioanalytical Chemistry, April 14, 2023. http://dx.doi.org/10.1007/s00216-023-04682-y.
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Liu, Pengcheng, Xiaobing Wang, Aishe Dun, Yutong Li, Houqiang Li, Lu Wang, Yichun Zhang, et al. "High-Throughput Profiling of Serological Immunoglobulin G N-Glycome as a Noninvasive Biomarker of Gastrointestinal Cancers." Engineering, April 2023. http://dx.doi.org/10.1016/j.eng.2023.02.008.
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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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Gebrehiwot, Abrha G., Daniel Seifu Melka, Yimenashu Mamo Kassaye, Tufa Gemechu, Wajana Lako, Hiroshi Hinou, and Shin-Ichiro Nishimura. "Exploring serum and immunoglobulin G N-glycome as diagnostic biomarkers for early detection of breast cancer in Ethiopian women." BMC Cancer 19, no. 1 (June 17, 2019). http://dx.doi.org/10.1186/s12885-019-5817-8.
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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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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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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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Petralia, Laudine M. C., Esrath Santha, Anna-Janina Behrens, D. Linh Nguyen, Mehul B. Ganatra, Christopher H. Taron, Vishal Khatri, et al. "Alteration of rhesus macaque serum N-glycome during infection with the human parasitic filarial nematode Brugia malayi." Scientific Reports 12, no. 1 (September 21, 2022). http://dx.doi.org/10.1038/s41598-022-19964-1.
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AbstractSerum N-glycan profiling studies during the past decades have shown robust associations between N-glycan changes and various biological conditions, including infections, in humans. Similar studies are scarcer for other mammals, despite the tremendous potential of serum N-glycans as biomarkers for infectious diseases in animal models of human disease and in the veterinary context. To expand the knowledge of serum N-glycan profiles in important mammalian model systems, in this study, we combined MALDI-TOF-MS analysis and HILIC-UPLC profiling of released N-glycans together with glycosidase treatments to characterize the glycan structures present in rhesus macaque serum. We used this baseline to monitor changes in serum N-glycans during infection with Brugia malayi, a parasitic nematode of humans responsible for lymphatic filariasis, in a longitudinal cohort of infected rhesus macaques. Alterations of the HILIC-UPLC profile, notably of abundant structures, became evident as early as 5 weeks post-infection. Given its prominent role in the immune response, contribution of immunoglobulin G to serum N-glycans was investigated. Finally, comparison with similar N-glycan profiling performed during infection with the dog heartworm Dirofilaria immitis suggests that many changes observed in rhesus macaque serum N-glycans are specific for lymphatic filariasis.
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Farkas, Anna, Brigitta Mészáros, Máté Szarka, Márton Szigeti, János Kappelmayer, Miklós Szabó, Eszter Csánky, and András Guttman. "Modeling of the desialylated human serum N-glycome for molecular diagnostic applications in inflammatory and malignant lung diseases." Current Molecular Medicine 20 (April 22, 2020). http://dx.doi.org/10.2174/1566524020666200422085316.
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Background: Immunoglobulin G and A, transferrin, haptoglobin and alpha-1-antitrypsin are representing approximately 85% of the human serum glycoproteome and their N-glycosylation analysis may lead to discover important molecular disease markers. However, due to the labile nature of the sialic acid residues, the desialylated subset of the serum N-glycoproteome has been traditionally utilized for diagnostic applications. Objective: Creating a five-protein model to deconstruct the overall N-glycosylation fingerprints in inflammatory and malignant lung diseases. Methods: The N-glycan pool of human serum and the five high abundant serum glycoproteins were analyzed. Simultaneous endoglycosidase/sialidase digestion was followed by fluorophore labeling and separation by CE-LIF to establish the model. Pooled serum samples from patients with COPD, lung cancer (LC) and their comorbidity were all analyzed. Results: Nine significant (>1%) asialo-N-glycan structures were identified both in human serum and the standard protein mixture. The core-fucosylated-agalacto-biantennary glycan differentiated COPD and LC and both from the control and the comorbidity groups. Decrease in the core-fucosylated-agalacto-biantennary-bisecting, monogalacto and bigalacto structures differentiated all disease groups from the control. The significant increase of the fucosylated- galactosylated-triantennary structure was highly specific for LC, in medium extent for COPD and in lesser extent for comorbidity. Also, some increase of the afucosylated-galactosylatedbiantennary structure in all three disease types and afucosylated-galactosylated-triantennary structures in COPD and LC were observed in comparison to the control group. Conclusion: Our results suggested that changes in the desialylated human serum N-glycome holds glycoprotein specific molecular diagnostic potential for malignant and inflammatory lung diseases, which can be modeled with the five-protein mixture.
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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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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.
Full textAbstract:
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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Xu, Yaozheng, Jiawen Huo, Ruili Nie, Lili Ge, Chonghong Xie, Yuan Meng, Jianhua Liu, Lina Wu, and Xiaosong Qin. "Altered profile of glycosylated proteins in serum samples obtained from patients with Hashimoto′s thyroiditis following depletion of highly abundant proteins." Frontiers in Immunology 14 (June 30, 2023). http://dx.doi.org/10.3389/fimmu.2023.1182842.
Full textAbstract:
ObjectivesHashimoto’s thyroiditis (HT) is one of the most common autoimmune disorders; however, its underlying pathological mechanisms remain unclear. Although aberrant glycosylation has been implicated in the N-glycome of immunoglobulin G (IgG), changes in serum proteins have not been comprehensively characterized. This study aimed to investigate glycosylation profiles in serum samples depleted of highly abundant proteins from patients with HT and propose the potential functions of glycoproteins for further studies on the pathological mechanisms of HT.MethodsA lectin microarray containing 70 lectins was used to detect and analyze glycosylation of serum proteins using serum samples (N=27 HT; N=26 healthy control [HC]) depleted of abundant proteins. Significant differences in glycosylation status between HT patients and the HC group were verified using lectin blot analysis. A lectin-based pull-down assay combined with mass spectrometry was used to investigate potential glycoproteins combined with differentially present lectins, and an enzyme-linked immunosorbent assay (ELISA) was used to identify the expression of targeted glycoproteins in 131 patients with papillary thyroid carcinoma (PTC), 131 patients with benign thyroid nodules (BTN) patients, 130 patients with HT, and 128 HCs.ResultsCompared with the HC group, the majority of the lectin binding signals in HT group were weakened, while the Vicia villosa agglutinin (VVA) binding signal was increased. The difference in VVA binding signals verified by lectin blotting was consistent with the results of the lectin microarray. A total of 113 potential VVA-binding glycoproteins were identified by mass spectrometry and classified by gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) analyses. Using ELISA, we confirmed that lactoferrin (LTF) and mannan-binding lectin-associated serine protease 1 (MASP-1) levels were elevated in the serum of patients with HT and PTC.ConclusionFollowing depletion of abundant proteins, remaining serum proteins in HT patients exhibited lower glycosylation levels than those observed in HCs. An increased level of potential VVA-binding glycoproteins may play an important role in HT development. LTF and MASP-1 expression was significantly higher in the serum of HT and PTC patients, providing novel insight into HT and PTC.