Fully galactosyl-fucosyl-bisected IgG 1 reduces anti-HBV efficacy and liver histological improvement

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Abstract

N-glycosylation on the crystallizable fragment (Fc) governs antibody-mediated immune responses. This study addressed the relevance of N-acetylglucosamine (GlcNAc)-bisected IgG 1 on the disease progression and treatment efficacy in the immune active phase of chronic hepatitis B virus (HBV) infection. Serum IgG 1 N-glycan patterns from 166 HBV e antigen (HBeAg)-positive patients were analyzed using liquid chromatography-tandem mass spectrometry. The proportion of GlcNAc-bisected IgG 1 on the disease severity and efficacy of nucleos(t)ide analogue treatment were investigated. Cytokine-dependent regulations of IgG 1 GlcNAc bisection were also addressed using mouse IgG 1 -producing hybridoma cells. We found that IgG 1 bearing a fully galactosyl-fucosyl-N-acetylglucosamine-bisected (G2FN) glycoform in HBeAg-positive patients was associated with high levels of HBV DNA or HBV surface antigen, alanine aminotransferase <2 upper limits of normal, and a mild liver injury. Moreover, baseline IgG 1 -G2FN ≧ 1.5% was linked to lower probabilities of virological response (HBV DNA undetectable in serum), HBeAg seroconversion, HBV core antigen loss, and liver histological improvement after treatment. Cox and logistic regression analyses revealed that IgG 1 -G2FN was an unfavorable factor for the virological response (hazard ratio = 0.620, 95% confidence interval = 0.466–0.825, P = 0.001) or liver histological improvement (odds ratio = 0.513, 95% confidence interval = 0.279–0.943, P = 0.032), respectively. Results from in vitro studies showed that transforming growth factor (TGF)-β1 treatment downregulated mannosyl β-1,4-N-acetylglucosaminyltransferase 3 and β-1,4-galactosyltransferase 1 activities and thereby IgG 1 -G2FN production, and this phenomenon reflected an inverse correlation between IgG 1 -G2FN and TGF-β1 in sera of patients (r = −0.431, P < 0.001). In conclusion, IgG 1 -G2FN was related to an attenuated liver inflammation and unfavorable treatment responses in patients with HBeAg-positive chronic hepatitis B.

Original languageEnglish
Pages (from-to)1-10
Number of pages10
JournalAntiviral Research
Volume163
DOIs
Publication statusPublished - 2019 Mar 1

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Hepatitis B virus
Immunoglobulin G
Liver
Hepatitis B e Antigens
Acetylglucosamine
Chronic Hepatitis B
Transforming Growth Factors
Serum
Confidence Intervals
Galactosyltransferases
Hepatitis B Core Antigens
Immunoglobulin Fc Fragments
DNA
Hybridomas
Virus Diseases
Therapeutics
Hepatitis B Surface Antigens
Tandem Mass Spectrometry
Alanine Transaminase
Glycosylation

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Virology

Cite this

@article{4f96904ff8604537880f7f394f470b40,
title = "Fully galactosyl-fucosyl-bisected IgG 1 reduces anti-HBV efficacy and liver histological improvement",
abstract = "N-glycosylation on the crystallizable fragment (Fc) governs antibody-mediated immune responses. This study addressed the relevance of N-acetylglucosamine (GlcNAc)-bisected IgG 1 on the disease progression and treatment efficacy in the immune active phase of chronic hepatitis B virus (HBV) infection. Serum IgG 1 N-glycan patterns from 166 HBV e antigen (HBeAg)-positive patients were analyzed using liquid chromatography-tandem mass spectrometry. The proportion of GlcNAc-bisected IgG 1 on the disease severity and efficacy of nucleos(t)ide analogue treatment were investigated. Cytokine-dependent regulations of IgG 1 GlcNAc bisection were also addressed using mouse IgG 1 -producing hybridoma cells. We found that IgG 1 bearing a fully galactosyl-fucosyl-N-acetylglucosamine-bisected (G2FN) glycoform in HBeAg-positive patients was associated with high levels of HBV DNA or HBV surface antigen, alanine aminotransferase <2 upper limits of normal, and a mild liver injury. Moreover, baseline IgG 1 -G2FN ≧ 1.5{\%} was linked to lower probabilities of virological response (HBV DNA undetectable in serum), HBeAg seroconversion, HBV core antigen loss, and liver histological improvement after treatment. Cox and logistic regression analyses revealed that IgG 1 -G2FN was an unfavorable factor for the virological response (hazard ratio = 0.620, 95{\%} confidence interval = 0.466–0.825, P = 0.001) or liver histological improvement (odds ratio = 0.513, 95{\%} confidence interval = 0.279–0.943, P = 0.032), respectively. Results from in vitro studies showed that transforming growth factor (TGF)-β1 treatment downregulated mannosyl β-1,4-N-acetylglucosaminyltransferase 3 and β-1,4-galactosyltransferase 1 activities and thereby IgG 1 -G2FN production, and this phenomenon reflected an inverse correlation between IgG 1 -G2FN and TGF-β1 in sera of patients (r = −0.431, P < 0.001). In conclusion, IgG 1 -G2FN was related to an attenuated liver inflammation and unfavorable treatment responses in patients with HBeAg-positive chronic hepatitis B.",
author = "Ho, {Cheng Hsun} and Shu-Hui Chen and Hung-Wen Tsai and I-Chin Wu and Ting-Tsung Chang",
year = "2019",
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doi = "10.1016/j.antiviral.2018.12.021",
language = "English",
volume = "163",
pages = "1--10",
journal = "Antiviral Research",
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TY - JOUR

T1 - Fully galactosyl-fucosyl-bisected IgG 1 reduces anti-HBV efficacy and liver histological improvement

AU - Ho, Cheng Hsun

AU - Chen, Shu-Hui

AU - Tsai, Hung-Wen

AU - Wu, I-Chin

AU - Chang, Ting-Tsung

PY - 2019/3/1

Y1 - 2019/3/1

N2 - N-glycosylation on the crystallizable fragment (Fc) governs antibody-mediated immune responses. This study addressed the relevance of N-acetylglucosamine (GlcNAc)-bisected IgG 1 on the disease progression and treatment efficacy in the immune active phase of chronic hepatitis B virus (HBV) infection. Serum IgG 1 N-glycan patterns from 166 HBV e antigen (HBeAg)-positive patients were analyzed using liquid chromatography-tandem mass spectrometry. The proportion of GlcNAc-bisected IgG 1 on the disease severity and efficacy of nucleos(t)ide analogue treatment were investigated. Cytokine-dependent regulations of IgG 1 GlcNAc bisection were also addressed using mouse IgG 1 -producing hybridoma cells. We found that IgG 1 bearing a fully galactosyl-fucosyl-N-acetylglucosamine-bisected (G2FN) glycoform in HBeAg-positive patients was associated with high levels of HBV DNA or HBV surface antigen, alanine aminotransferase <2 upper limits of normal, and a mild liver injury. Moreover, baseline IgG 1 -G2FN ≧ 1.5% was linked to lower probabilities of virological response (HBV DNA undetectable in serum), HBeAg seroconversion, HBV core antigen loss, and liver histological improvement after treatment. Cox and logistic regression analyses revealed that IgG 1 -G2FN was an unfavorable factor for the virological response (hazard ratio = 0.620, 95% confidence interval = 0.466–0.825, P = 0.001) or liver histological improvement (odds ratio = 0.513, 95% confidence interval = 0.279–0.943, P = 0.032), respectively. Results from in vitro studies showed that transforming growth factor (TGF)-β1 treatment downregulated mannosyl β-1,4-N-acetylglucosaminyltransferase 3 and β-1,4-galactosyltransferase 1 activities and thereby IgG 1 -G2FN production, and this phenomenon reflected an inverse correlation between IgG 1 -G2FN and TGF-β1 in sera of patients (r = −0.431, P < 0.001). In conclusion, IgG 1 -G2FN was related to an attenuated liver inflammation and unfavorable treatment responses in patients with HBeAg-positive chronic hepatitis B.

AB - N-glycosylation on the crystallizable fragment (Fc) governs antibody-mediated immune responses. This study addressed the relevance of N-acetylglucosamine (GlcNAc)-bisected IgG 1 on the disease progression and treatment efficacy in the immune active phase of chronic hepatitis B virus (HBV) infection. Serum IgG 1 N-glycan patterns from 166 HBV e antigen (HBeAg)-positive patients were analyzed using liquid chromatography-tandem mass spectrometry. The proportion of GlcNAc-bisected IgG 1 on the disease severity and efficacy of nucleos(t)ide analogue treatment were investigated. Cytokine-dependent regulations of IgG 1 GlcNAc bisection were also addressed using mouse IgG 1 -producing hybridoma cells. We found that IgG 1 bearing a fully galactosyl-fucosyl-N-acetylglucosamine-bisected (G2FN) glycoform in HBeAg-positive patients was associated with high levels of HBV DNA or HBV surface antigen, alanine aminotransferase <2 upper limits of normal, and a mild liver injury. Moreover, baseline IgG 1 -G2FN ≧ 1.5% was linked to lower probabilities of virological response (HBV DNA undetectable in serum), HBeAg seroconversion, HBV core antigen loss, and liver histological improvement after treatment. Cox and logistic regression analyses revealed that IgG 1 -G2FN was an unfavorable factor for the virological response (hazard ratio = 0.620, 95% confidence interval = 0.466–0.825, P = 0.001) or liver histological improvement (odds ratio = 0.513, 95% confidence interval = 0.279–0.943, P = 0.032), respectively. Results from in vitro studies showed that transforming growth factor (TGF)-β1 treatment downregulated mannosyl β-1,4-N-acetylglucosaminyltransferase 3 and β-1,4-galactosyltransferase 1 activities and thereby IgG 1 -G2FN production, and this phenomenon reflected an inverse correlation between IgG 1 -G2FN and TGF-β1 in sera of patients (r = −0.431, P < 0.001). In conclusion, IgG 1 -G2FN was related to an attenuated liver inflammation and unfavorable treatment responses in patients with HBeAg-positive chronic hepatitis B.

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