Changes in IgG and total plasma protein glycomes in acute systemic inflammation

Novokmet, Mislav; Lukić, Edita; Vučković, Frano; Đurić, Željko; Keser, Toma; Rajšl, Katarina; Remondini, Daniel; Castellani, Gastone; Gašparović, Hrvoje; Gornik, Olga; Lauc, Gordan

doi:10.1038/srep04347

Cited by 129 publications

(115 citation statements)

References 49 publications

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“…There is growing evidence that the IgG1 Fc N-glycan composition changes in response to disease. [44][45][46][47][48] Our data indicate variations in Fc N-glycan composition profiles alter relative FcgR binding affinities. Considering the tissue-specific expression profile for the FcgRs, 3 changes to the IgG1 Fc N-glycan composition therefore have the potential to direct which leukocyte populations are affected and, as a result, direct the body's response to infection.…”

Section: Discussionmentioning

confidence: 96%

The immunoglobulin G1 N-glycan composition affects binding to each low affinity Fc γ receptor

Subedi

Barb

2016

mAbs

155

169

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Immunoglobulin G1 (IgG1) is the most abundant circulating human antibody and also the scaffold for many therapeutic monoclonal antibodies (mAbs). The destruction of IgG-coated targets by cell-mediated pathways begins with an interaction between the IgG Fc region and multiple varieties of membranebound Fc g receptors (FcgRs) on the surface of leukocytes. This interaction requires the presence of an asparagine-linked (N-)glycan on the Fc, and variations in the N-glycan composition can affect the affinity of CD16A binding (an FcgR). Contemporary efforts to glycoengineer mAbs focus on increasing CD16A affinity, and thus treatment efficacy, but it is unclear how these changes affect affinity for the other FcgRs. Here, we measure binding of the extracellular Fc-binding domains for human CD16A and B, CD32A, B and C, and CD64 to 6 well-defined IgG1 Fc glycoforms that cover »85% of the pool of human IgG1 Fc glycoforms. Core a1-6 fucosylation showed the greatest changes with CD16B (8.5-fold decrease), CD16A (3.9-fold decrease) and CD32B/C (1.8-fold decrease), but did not affect binding to CD32A. Adding galactose to the non-reducing termini of the complex-type, biantennary glycan increased affinity for all CD16s and 32s tested by 1.7-fold. Sialylation did not change the affinity of core-fucosylated Fc, but increased the affinity of afucosylated Fc slightly by an average of 1.16-fold for all CD16s and CD32s tested. The effects of fucose and galactose modification are additive, suggesting the contributions of these residues to Fc g receptor affinity are independent.

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Section: Discussionmentioning

confidence: 96%

The immunoglobulin G1 N-glycan composition affects binding to each low affinity Fc γ receptor

Subedi

Barb

2016

mAbs

155

169

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“…Hex 4 HexNAc 4 dHex 1 ) but differ in glycan structure (e.g. ␣1,3-branch galactosylation versus ␣1,6-branch galactosylation)-the complexity of the TPNG means that observed signals generally comprise a variety of distinct compositions (25)(26)(27)(28). Mass spectrometry provides orthogonal information from these methodologies, as it does not distinguish isomers but instead unambiguously evaluates glycans on a compositional level (29 -31).…”

mentioning

confidence: 99%

Human Plasma N-glycosylation as Analyzed by Matrix-Assisted Laser Desorption/Ionization-Fourier Transform Ion Cyclotron Resonance-MS Associates with Markers of Inflammation and Metabolic Health

Reiding

Ruhaak

et al. 2017

Molecular & Cellular Proteomics

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Glycosylation is an abundant co-and post-translational protein modification of importance to protein processing and activity. Although not template-defined, glycosylation does reflect the biological state of an organism and is a high-potential biomarker for disease and patient stratification. However, to interpret a complex but informative sample like the total plasma N-glycome, it is important to establish its baseline association with plasma protein levels and systemic processes. Thus far, large-scale studies (n >200) of the total plasma N-glycome have been performed with methods of chromatographic and electrophoretic separation, which, although being informative, are limited in resolving the structural complexity of plasma N-glycans. MS has the opportunity to contribute additional information on, among others, antennarity, sialylation, and the identity of high-mannose type species.Here, we have used matrix-assisted laser desorption/ ionization ( Glycosylation is a ubiquitous co-and post-translational protein modification of functional relevance to the processing and activity of the conjugate. Examples include quality control during protein folding, regulation of circulatory half-life, and modulation of receptor interactions by either providing the recognition motif or by affecting protein conformation (1-7). Consequentially, glycosylation has been associated with a multitude of diseases and states thereof, among which the progression and metastasis of cancer and the remission of rheumatoid arthritis (8 -11). Because the process of glycosylation is not template-defined, glycosylation integrates a large series of cellular conditions such as glycosidase/glycosyltransferase abundance and activity, endoplasmic reticulum From the ‡Center

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“…To reinforce our findings we searched for associations in an independent population with more severe renal phenotype To determine whether the findings were restricted to IgG or to a more general change in glycosylation of multiple proteins, we searched for association between total plasma glycome 25,26 and eGFR in a subset 426 individuals (eGFR, mL/min/1.73 m 2 : 78.95616.00). We found no difference in plasma glycosylation, suggesting that the effects we see here are likely direct effects of IgG glycosylation.…”

mentioning

confidence: 99%

Glycosylation Profile of IgG in Moderate Kidney Dysfunction

Barrios

Zierer

Gudelj

et al. 2016

Journal of the American Society of Nephrology

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Glycans constitute the most abundant and diverse form of the post-translational modifications, and animal studies have suggested the involvement of IgG glycosylation in mechanisms of renal damage. Here, we explored the associations between IgG glycans and renal function in 3274 individuals from the TwinsUK registry. We analyzed the correlation between renal function measured as eGFR and 76 N-glycan traits using linear regressions adjusted for covariates and multiple testing in the larger population. We replicated our results in 31 monozygotic twin pairs discordant for renal function. Results from both analyses were then meta-analyzed. Fourteen glycan traits were associated with renal function in the discovery sample (P,6.5310 24 ) and remained significant after validation. Those glycan traits belong to three main glycosylation features: galactosylation, sialylation, and level of bisecting N-acetylglucosamine of the IgG glycans. These results show the role of IgG glycosylation in kidney function and provide novel insight into the pathophysiology of CKD and potential diagnostic and therapeutic targets.

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Changes in IgG and total plasma protein glycomes in acute systemic inflammation

Cited by 129 publications

References 49 publications

The immunoglobulin G1 N-glycan composition affects binding to each low affinity Fc γ receptor

The immunoglobulin G1 N-glycan composition affects binding to each low affinity Fc γ receptor

Human Plasma N-glycosylation as Analyzed by Matrix-Assisted Laser Desorption/Ionization-Fourier Transform Ion Cyclotron Resonance-MS Associates with Markers of Inflammation and Metabolic Health

Glycosylation Profile of IgG in Moderate Kidney Dysfunction

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