Profiling and genetic control of the murine immunoglobulin G glycome

Krištić, Jasminka; Zaytseva, Olga O.; Ramesh, Ram; Nguyen, Quang Tri; Novokmet, Mislav; Vučković, Frano; Vilaj, Marija; Trbojević‐Akmačić, Irena; Pezer, Marija; Davern, Kathy M.; Morahan, Grant; Lauc, Gordan

doi:10.1038/s41589-018-0034-3

Cited by 63 publications

(72 citation statements)

References 48 publications

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“…A recent study of the IgG glycome in 95 mouse strains from the collaborative cross cohort revealed that differences in glycosylation make IgG structure quite diverse between different strains (26). Despite the absence of a direct genetic template for individual glycans, these differences are heritable, indicating that glycoprotein structure is being inherited as a complex trait.…”

Section: Discussionmentioning

confidence: 99%

Glycosylation of immunoglobulin G is regulated by a large network of genes pleiotropic with inflammatory diseases

et al. 2020

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Effector functions of immunoglobulin G (IgG) are regulated by the composition of a glycan moiety, thus affecting activity of the immune system. Aberrant glycosylation of IgG has been observed in many diseases, but little is understood about the underlying mechanisms. We performed a genome-wide association study of IgG N-glycosylation (N = 8090) and, using a data-driven network approach, suggested how associated loci form a functional network. We confirmed in vitro that knockdown of IKZF1 decreases the expression of fucosyltransferase FUT8, resulting in increased levels of fucosylated glycans, and suggest that RUNX1 and RUNX3, together with SMARCB1, regulate expression of glycosyltransferase MGAT3. We also show that variants affecting the expression of genes involved in the regulation of glycoenzymes colocalize with variants affecting risk for inflammatory diseases. This study provides new evidence that variation in key transcription factors coupled with regulatory variation in glycogenes modifies IgG glycosylation and has influence on inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

Glycosylation of immunoglobulin G is regulated by a large network of genes pleiotropic with inflammatory diseases

et al. 2020

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“…Since sex-specific IgG N-glycosylation was previously reported in humans (Pučić-Baković et al, 2013;Krištić et al, 2014) and mice (Krištić et al, 2018), we compared males and females separately in our analysis. In mice, females have lower levels of bisection and sialylation and higher levels of galactosylation than males (Krištić et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to IgG1, IgG2a/c, and IgG2b, IgG3 interact only very weakly with known FcγRs but is the most effective isotype to activate complement Bruhns, 2012;Sörman et al, 2014). Interestingly, there are known differences between mouse strains in the protein sequences of IgG1 and IgG2a/c heavy chains that occur in the proximity of the Fc N-glycosylation site (Zhang et al, 2012;Maresch and Altmann, 2016;de Haan et al, 2017;Zaytseva et al, 2018), and it has been hypothesized that the amino acid sequence of the heavy chain can impact the Fc glycosylation profile (Lund et al, 1996;Krištić et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Fc-Linked IgG N-Glycosylation in FcγR Knock-Out Mice

Zaytseva

Seeling

Krištić

et al. 2020

Front. Cell Dev. Biol.

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Immunoglobulin G (IgG) is the most abundant immunoglobulin isotype in the blood and is involved in the pathogenesis and progression of various diseases. Glycosylation of the IgG fragment crystallizable (Fc) region is shown to vary in different physiological and pathological states. Fc N-glycan composition can alter the effector functions of IgG by modulating its affinity for ligands, such as Fcγ receptors (FcγRs). However, it is not known whether IgG glycosylation is affected by the available repertoire of FcγRs, and if the Fc-linked N-glycome can compensate for modulation of the IgG-FcγR interaction. To explore this, we examined the subclass-specific Fc IgG glycoprofiles of healthy male and female FcγR knockout mice on C57BL/6 and BALB/c backgrounds. We observed slight changes in IgG Fc N-glycan profiles in different knockouts ; however, it seems that the strain background and sex have a stronger effect on N-glycosylation of IgG Fc regions than the FcγR repertoire.

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“…N-glycans also bind immunoglobulin (Ig)G, one of the large number of plasma glycoproteins, at asparagine 297 in the C H 2 domains of the fragment crystallization (Fc) region (Krištić et al, 2018;. These N-glycans are found to widely modulate anti-inflammatory and proinflammatory functions of IgG and influence the development of diseases (e.g., hypertension, systemic lupus erythematosus, rheumatoid arthritis, dyslipidemia, diabetes, inflammatory bowel disease, Alzheimer's disease, and Parkinson's disease) (Bermingham et al, 2018;Wang et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Hyperuricemia is Associated with Immunoglobulin G N-Glycosylation: A Community-Based Study of Glycan Biomarkers

Hou

Sun

et al. 2019

OMICS: A Journal of Integrative Biology

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The increasing prevalence of hyperuricemia has been recognized as an emerging public health concern in both developed and developing countries. Hyperuricemia is a metabolic condition characterized by an elevated serum uric acid, and associated with renal damage, diabetes, autoimmune disorders, and cardiovascular diseases. Although human genetic variation has been recognized as a factor, posttranslational cellular processes and glycan biomarkers have not been studied extensively for susceptibility to hyperuricemia. We evaluated whether immunoglobulin (Ig)G N-glycans play a role in hyperuricemia in the general population. This crosssectional study enrolled 635 participants (208 men and 427 women), ages ‡18 years, from a community-based population in Beijing, China. The IgG N-glycan composition of serum was analyzed by an ultraperformance liquid chromatography method. The prevalence of hyperuricemia observed in this sample was 5.98% (14.9% in men and 1.6% in women). Serum uric acid level was positively correlated with glycan peaks (GP)1, GP2, GP4, GP6, GP10, and GP11, whereas it was negatively correlated with GP12, GP13, GP14, GP15, GP18, and GP20. The combination of GP9, GP10, body mass index, and gender distinguished individuals with hyperuricemia from subjects without hyperuricemia, with an area under the curve value of 0.849 (95% confidence interval: 0.784-0.915). These findings collectively suggest a possible link between hyperuricemia and IgG N-glycans, which might be potentially mediated through inflammation-related mechanisms. Additional research on glycan biomarkers in independent and community-based population samples might allow the development of glycan diagnostics for hyperuricemia and gout in the future.

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Profiling and genetic control of the murine immunoglobulin G glycome

Cited by 63 publications

References 48 publications

Glycosylation of immunoglobulin G is regulated by a large network of genes pleiotropic with inflammatory diseases

Glycosylation of immunoglobulin G is regulated by a large network of genes pleiotropic with inflammatory diseases

Fc-Linked IgG N-Glycosylation in FcγR Knock-Out Mice

Hyperuricemia is Associated with Immunoglobulin G N-Glycosylation: A Community-Based Study of Glycan Biomarkers

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