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

N-glycosylation on the crystallizable fragment (Fc) governs antibody-mediated immune responses. This study addressed the relevance of N-acetylglucosamine (GlcNAc)-bisected IgG on the disease progression and treatment efficacy in the immune active phase of chronic hepatitis B virus (HBV) infection. Serum IgGN-glycan patterns from 166 HBV e antigen (HBeAg)-positive patients were analyzed using liquid chromatography-tandem mass spectrometry. The proportion of GlcNAc-bisected IgG on the disease severity and efficacy of nucleos(t)ide analogue treatment were investigated. Cytokine-dependent regulations of IgG GlcNAc bisection were also addressed using mouse IgG-producing hybridoma cells. We found that IgG 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-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-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-G2FN production, and this phenomenon reflected an inverse correlation between IgG-G2FN and TGF-β1 in sera of patients (r = -0.431, P < 0.001). In conclusion, IgG-G2FN was related to an attenuated liver inflammation and unfavorable treatment responses in patients with HBeAg-positive chronic hepatitis B.