Sialylated IgG-Fc: a novel biomarker of chronic inflammatory demyelinating polyneuropathy

Wong, Hiu Yi; Fukami, Yasuyuki; Sudo, Makoto; Kokubun, Norito; Hamada, Shinsuke; Yuki, Nobuhiro

doi:10.1136/jnnp-2014-309964

Cited by 36 publications

(25 citation statements)

References 26 publications

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“…11A). For example, we generated the di-glycan D221N/C309L/N297A/C575A mutant that displayed marked binding to Siglec-1 and Siglec-4 (MAG), both receptors being clinically implicated in the control of neuropathy (15, 25). This mutant showed no observable binding to either FcγRs or complement proteins (Tables II, III) yet was highly effective at blocking hemagglutination by influenza A virus (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…We recently published two complementary approaches that radically increase the sialic acid content of the Fc (24) first by insertion of the 18-aa tailpiece from IgM onto the C terminus of the IgG1–Fc into which a cysteine-to-alanine substitution is made at Cys 575 and second by the addition of an extra N -glycan to the N terminus at position Asn 221 . This approach resulted in both multimeric and monomeric molecules that are >75% sialylated (compared with 2% for the IgG–Fc control) that bind to sialic acid–dependent receptors, including Siglec-1 and myelin-associated glycoprotein (MAG) (24), which are clinically implicated in the control of neuropathology (15, 25). As many pathogens rely on glycans to infect host cells, these reagents may also be useful as inhibitors of infection (26).…”

Section: Introductionmentioning

confidence: 99%

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Insertion of N-Terminal Hinge Glycosylation Enhances Interactions of the Fc Region of Human IgG1 Monomers with Glycan-Dependent Receptors and Blocks Hemagglutination by the Influenza Virus

Blundell

Wilkinson

et al. 2019

The Journal of Immunology

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In therapeutic applications in which the Fc of IgG is critically important, the receptor binding and functional properties of the Fc are lost after deglycosylation or removal of the unique Asn 297 N-X-(T/S) sequon. A population of Fcs bearing sialylated glycans has been identified as contributing to this functionality, and high levels of sialylation also lead to longer serum retention times advantageous for therapy. The efficacy of sialylated Fc has generated an incentive to modify the unique N-linked glycosylation site at Asn 297 , either through chemical and enzymatic methods or by mutagenesis of the Fc, that disrupts the protein–Asn 297 carbohydrate interface. In this study, we took an alternative approach by inserting or deleting N-linked attachment sites into the body of the Fc to generate a portfolio of mutants with tailored effector functions. For example, we describe mutants with enhanced binding to low-affinity inhibitory human Fcγ and glycan receptors that may be usefully incorporated into existing Ab engineering approaches to treat or vaccinate against disease. The IgG1 Fc fragments containing complex sialylated glycans attached to the N-terminal Asn 221 sequon bound influenza virus hemagglutinin and disrupted influenza A–mediated agglutination of human erythrocytes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Insertion of N-Terminal Hinge Glycosylation Enhances Interactions of the Fc Region of Human IgG1 Monomers with Glycan-Dependent Receptors and Blocks Hemagglutination by the Influenza Virus

Blundell

Wilkinson

et al. 2019

The Journal of Immunology

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“…Changes in Fc glycosylation, i.e. a decrease in galactosylation and sialylation that contributes to a more inflammatory antibody profile, have been observed in various autoimmune disorders, most recently inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), multiple sclerosis (MS) and chronic inflammatory demyelinating polyneuropathy (CIDP) ( 31 – 34 ). In addition to autoimmune disorders, IgG glycosylation changes can also occur in infectious diseases, as was shown by recent studies on HIV infection, chronic hepatitis B and the parasitic disease visceral leishmaniasis ( 35 – 37 ).…”

Section: Igg-fc Glycosylation At Asn180/176/227/177 ('Asn297')mentioning

confidence: 99%

Recent Advances in Clinical Glycoproteomics of Immunoglobulins (Igs)

Plomp

Bondt

Haan

et al. 2016

Molecular & Cellular Proteomics

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Antibody glycosylation analysis has seen methodological progress resulting in new findings with regard to antibody glycan structure and function in recent years. For example, antigen-specific IgG glycosylation analysis is now applicable for clinical samples because of the increased sensitivity of measurements, and this has led to new insights in the relationship between IgG glycosylation and various diseases. Furthermore, many new methods have been developed for the purification and analysis of IgG Fc glycopeptides, notably multiple reaction monitoring for high-throughput quantitative glycosylation analysis. In addition, new protocols for IgG Fab glycosylation analysis were established revealing autoimmune disease-associated changes. Functional analysis has shown that glycosylation of IgA and IgE is involved in transport across the intestinal epithelium and receptor binding, respectively.

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“…[ 9 ] To date, oral glucocorticoids are considered the first line treatment, [ 11 ] together with plasmapheresis and intravenous human immune globulin (IVHIG). [ 1 , 12 ]…”

Section: Introductionmentioning

confidence: 99%

Chronic inflammatory demyelinating polyradiculoneuropathy relapse after mexiletine withdrawal in a patient with concomitant myotonia congenita

et al. 2020

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Introduction: we report on the first case of a woman affected by chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and recessive myotonia congenita (MC), treated with mexiletine. We aimed at describing the possible role of mexiletine in CIDP management. Patient Concerns: A 44-year-old female affected by CIDP and MC, gained beneficial effects for CIDP symptoms (muscle weakness, cramps, and fatigue) and relapses, after mexiletine intake (200 mg twice a day). The patient presented with detrimental effects after mexiletine drop out, with a worsening of CIDP symptoms. Interventions: The patient reported a nearly complete remission of muscle stiffness and weakness up to 3 years since mexiletine intake. Then, she developed an allergic reaction with glottis edema, maybe related to mexiletine intake, as per emergency room doctors’ evaluation, who suggested withdrawing the drug. Outcomes: The patient significantly worsened after the medication drop out concerning both CIDP and MC symptoms. Conclusion: This is the first report on the association of CIDP and MC in the same patient. Such diseases may share some clinical symptoms related to a persistent sodium currents increase, which maybe due either to the over-expression of sodium channels following axonal damage due to demyelination or to the chloride channel genes mutations. This is the possible reason why mexiletine maybe promising to treat CIDP symptoms.

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Sialylated IgG-Fc: a novel biomarker of chronic inflammatory demyelinating polyneuropathy

Abstract: Sialylation of IgG-Fc is reduced in CIDP. Its level correlated with clinical severity and increased after IVIG treatment. Sialylated as well as ratio of sialylated/agalactosylated IgG-Fc could be new measures to monitor the disease severity and treatment status in CIDP.

Cited by 36 publications

References 26 publications

Insertion of N-Terminal Hinge Glycosylation Enhances Interactions of the Fc Region of Human IgG1 Monomers with Glycan-Dependent Receptors and Blocks Hemagglutination by the Influenza Virus

Insertion of N-Terminal Hinge Glycosylation Enhances Interactions of the Fc Region of Human IgG1 Monomers with Glycan-Dependent Receptors and Blocks Hemagglutination by the Influenza Virus

Recent Advances in Clinical Glycoproteomics of Immunoglobulins (Igs)

Chronic inflammatory demyelinating polyradiculoneuropathy relapse after mexiletine withdrawal in a patient with concomitant myotonia congenita

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