Antibody sugar coatings shift as patients recover from Hantaan virus hemorrhagic fever
In hemorrhagic fever with renal syndrome, IgG fucosylation rose and bisecting GlcNAc fell as antibody titers climbed, tracking B cell glycosylation gene activity.
Summary
Hemorrhagic fever with renal syndrome (HFRS), caused by Hantaan virus, can be fatal, and rapid antibody responses are linked to recovery. Researchers profiled B cells by single-cell RNA sequencing and flow cytometry, and measured the sugar chains (N-glycans) on plasma IgG in 65 hospitalized patients, with paired acute and convalescent samples. Antibody-secreting memory B cells and plasmablasts expanded during acute illness and these cells highly expressed glycosylation genes such as RPN1 and RPN2. During recovery, and when antibody titers rose fourfold, IgG fucosylation increased and bisecting GlcNAc decreased. Galactosylation and sialylation were higher in acute illness and correlated with the size of the B cell subsets. The findings are associative and based on total rather than virus-specific IgG, but they suggest IgG glycan patterns could serve as recovery markers and inform glycoengineered antibody design.
Detailed Summary
Hantaan virus causes haemorrhagic fever with renal syndrome (HFRS), a rodent-borne disease concentrated in China, where fatality has ranged from 0.1% to 15%. Fast, effective antibody responses are linked to quicker recovery. The Fc region of IgG carries a conserved sugar chain at Asn297, and changes in its fucose, galactose, sialic acid or bisecting GlcNAc content can tune how strongly antibodies engage immune effector cells such as NK cells. Nobody had yet mapped these IgG glycan patterns in HFRS.
The team studied patients admitted to Baoji Central Hospital in China between 2019 and 2022; 65 of 166 suspected cases met the inclusion criteria. They analyzed peripheral blood mononuclear cells by single-cell RNA sequencing (15 patients, 8 healthy controls, supplemented with public datasets) and validated B cell subsets by flow cytometry in 27 acute and 25 convalescent samples. HTNV nucleocapsid-specific IgG was measured by ELISA, and plasma IgG glycans were quantified by ultra-performance liquid chromatography across 130 paired samples.
Antibody-secreting memory (ASM) B cells and plasmablasts expanded markedly in acute infection. By flow cytometry, plasmablasts made up about 24% of B cells in the acute phase versus 2.6% in convalescence, and ASM cells about 39% versus 25%. Naive and class-switched memory B cells recovered afterward. Acute-phase IgG showed more bisecting GlcNAc (15.7% vs 14.5%), galactosylation (74.3% vs 71.2%) and sialylation (22.4% vs 21.6%), and slightly less fucosylation (94.3% vs 94.9%) than convalescent IgG. In patients whose antibody titers rose at least fourfold, fucosylation increased and bisecting GlcNAc fell. Galactosylation correlated with ASM cell proportion, and sialylation correlated with both ASM and plasmablast proportions. ASM, plasmablast and resting memory B cells upregulated glycosylation genes, notably RPN1 and RPN2, which encode parts of the oligosaccharyltransferase complex, with enrichment of N-linked glycosylation pathways.
The authors propose that IgG glycosylation is dynamically regulated by B cell glycogene networks during HTNV infection and that rising fucosylation with falling bisecting GlcNAc accompanies effective humoral responses and recovery. This could support glycan-based biomarkers and glycoengineered therapeutic antibodies.
Important caveats apply. Glycan analysis used total plasma IgG, not HTNV-specific IgG, which may confound disease-specific signatures. The absolute glycan differences are small, and the design is observational, so causation and functional effects (such as ADCC) were not tested. Single-cell sample sizes were modest, and sex influenced galactosylation.
Key Findings
- Antibody-secreting memory B cells and plasmablasts expanded in acute HFRS; plasmablasts were ~24% of B cells acutely versus ~2.6% in convalescence.
- IgG fucosylation rose and bisecting GlcNAc fell during convalescence and after a fourfold rise in HTNV-specific antibody titers.
- Acute-phase IgG had higher galactosylation and sialylation, which correlated with ASM and plasmablast proportions (rs about 0.37–0.46).
- Glycosylation genes RPN1 and RPN2 were upregulated in ASM, plasmablast and resting memory B cells, with N-glycosylation pathway enrichment.
- Bisecting GlcNAc and sialylated IgG declined as HTNV nucleocapsid-specific antibody titers increased.
Methodology
Observational single-center cohort of 65 HFRS patients (from 166 suspected) in Baoji, China, with acute and convalescent samples. B cell subsets were assessed by scRNA-seq (15 patients, 8 controls, plus public GEO/GSA data) and flow cytometry (27 acute, 25 convalescent). Plasma IgG N-glycans were measured by UPLC and HTNV NP-specific IgG by ELISA, with Wilcoxon tests and multivariate regression.
Study Limitations
Glycans were measured on total plasma IgG rather than virus-specific IgG, and absolute differences were small, so confounding is possible. The design is observational and single-center, with modest scRNA-seq sample sizes and no functional assays (e.g., ADCC) to prove causal roles. Sex affected galactosylation, and cell-of-origin links rest on correlations.
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