EFB Dengue Literature Review

IgG

7 min read

IgG

Overview

IgG is the predominant antibody isotype in human serum and the primary product of class switch recombination from IgM in germinal centre and extrafollicular B cell responses. Surface IgG expression on B cells marks isotype-switched memory cells. IgG subclasses (IgG1–4) differ in effector functions (complement activation, Fc receptor binding).

Key Points from Literature

  • ~44% of DN (IgD⁻CD27⁻) B cells in healthy subjects express surface IgG, comparable to ~43% of CD27⁺ memory cells — demonstrating that isotype switching occurred in these cells despite their proposed extrafollicular origin (see Wei2007 - DN Memory B Cells in SLE, n=29 healthy cross-sectional).

  • IgG⁺ DN cells were the sorted population used for VH3 BCR sequencing in Wei et al., establishing the somatic hypermutation profile of the DN compartment (see Wei2007 - DN Memory B Cells in SLE).

  • IgG + IgA = majority of SLE ASC sequences: In circulating ASCs from both SLE patients and vaccinated healthy controls, IgG and IgA sequences are the predominant isotypes. IgM sequences contribute 5.42–19.53% in SLE ASCs. The predominance of switched isotypes in ASCs confirms that class switch recombination has occurred even in the EF-derived, low-SHM fraction of ASCs (see Tipton2015 - ASC Diversity and Origin in SLE).

  • DN2 cells have lower surface IgG and IgG3 enrichment: Surface IgG expression on DN2 cells is ~50% lower than on SWM or DN1 cells, consistent with the lower surface Ig levels expected in cells poised for PC differentiation (where Ig shifts from surface-bound to secreted). DN2 cells also show a higher frequency of IgG3⁺ cells compared with SWM or DN1 in both healthy donors and SLE patients. IgG3 enrichment may reflect the default isotype produced in TLR7-driven, T-bet-dependent class switching — IFN-γ promotes switching to IgG3 (and IgG1) in humans (see Jenks2018 - DN2 B Cells and EF Pathway in SLE, flow cytometry + in vitro differentiation).

  • IgG1 dominant switched isotype in COVID-19 ASC repertoire: Single-cell V(D)J sequencing of ASCs from a CoV-A patient showed IgG1 as the major switched isotype, with ongoing class switching from IgM to IgG1 (and IgA1). The majority of IgG1 clonotypes had germline (unmutated) VH genes, consistent with EF-derived, newly recruited ASCs rather than memory recall (see Woodruff2020 - EF B Cell Responses in COVID-19, 10x Chromium scV(D)J).

  • Anti-SARS-CoV-2 RBD IgG elevated in severe COVID-19: Anti-RBD IgG was significantly higher in ICU-C than OUT-C (P ≤ 0.001), with elevated titers by day 5 post-symptom onset. Despite being produced by a germline-dominant, EF-driven ASC response, these antibodies had confirmed neutralizing activity in vitro (see Woodruff2020 - EF B Cell Responses in COVID-19).

  • VH4-34/9G4 autoreactive IgG enriched in severe COVID-19: 85% of VH4-34-expressing ASC clonotypes retained the germline FR1 hydrophobic patch (defective clonal redemption). Serum 9G4 IgG concentrations were significantly elevated in ICU-C vs. HD (P ≤ 0.001) — paralleling the 9G4 enrichment seen in SLE (see Woodruff2020 - EF B Cell Responses in COVID-19).

  • First quantification of IgG dominance in dengue plasmablast response: Wrammert2012 demonstrated that the acute dengue plasmablast response is almost entirely IgG-secreting. ELISpot showed ≥70% (often ≥80%) of all IgG-secreting plasmablasts were DENV-specific, with several donors producing >10⁵ DENV-specific IgG spots per 10⁶ PBMC. IgA was ~100-fold lower; IgM was near-absent except in 4 primary responders. Serum DENV-specific IgG correlated with plasmablast frequency (r² = 0.3–0.4), but total serum IgG was not elevated — implying most plasmablasts are short-lived and do not contribute durably to the serum IgG pool (see Wrammert2012 - Plasmablast Responses in Acute Dengue, n=46 cohort, ELISpot + ELISA).

  • Anti-NS1 and anti-prM/M/E IgG elevated in severe dengue without increased neutralization: Binding IgG antibodies to DENV non-structural (NS1) and structural (prM/M/E) proteins are significantly higher in severe dengue, while FRNT₅₀ neutralizing titers do not differ between severity groups. This replicates the neutralizing Ab paradox from COVID-19 and suggests that EF-derived IgG may contribute to pathogenesis through non-neutralizing mechanisms (see Ansari2025 - Peripheral T Helper Subset Drives B Cell Response in Dengue, ELISA + FRNT, n=170 acute dengue).

  • DENV-specific IgG output is massive but not neutralizing in severe dengue: ELISpot showed ~40,000 DENV-reactive IgG-secreting cells per 10⁶ PBMC in secondary DFC (72% of all IgG ASCs). These IgG-producing plasmablasts cross-reacted with heterotypic serotypes (DENV-1, -2, -3) with 3-fold preference for the infecting serotype. Despite this massive DENV-specific IgG output, PRNT₅₀ neutralizing titers did not correlate with plasmablast frequency — the earliest demonstration of the plasmablast–neutralization disconnect in dengue (see GarciaBates2013 - Plasmablast Response and Dengue Severity, ELISpot + PRNT, n=84 cohort).

  • Plasmablast IgG mAbs are 85% E-specific and more potently neutralising than MBC-derived mAbs: In a dengue clonal analysis, PB-derived IgG mAbs were predominantly E protein-specific (85.3%) and neutralised DENV-1, -2, -3 at 0.1–10 µg/ml. MBC-derived IgG mAbs had broader specificity (55.6% complex epitope, 24.4% prM, 17.8% E) and required >10 µg/ml for neutralisation. No shared IgG CDR3 sequences were found between PBs and MBCs, reinforcing the clonal disconnect between these IgG-expressing populations (see Appanna2016 - Plasmablasts as Subset of Memory B Cell Pool, mAb cloning + neutralisation, n=12 dengue).

  • IgG-switched but poorly mutated — “natural” IgG antibodies in acute dengue: GodoyLozano2016 showed that the acute-phase IgG B cell repertoire is dominated by class-switched (IgG) clones with paradoxically low SHM. These IgG antibodies use biased IGHV segments (IGHV1-2, IGHV1-69) associated with innate-like “natural antibody” recognition. The authors propose these represent rapidly produced, germline-coded, cross-reactive IgG that are intrinsically poly-reactive — consistent with natural IgG antibodies described in other viral infections (VSV, Polyomavirus, Rotavirus). 78.9% of patients had cross-neutralizing serum antibodies to all 4 DENV serotypes, consistent with broad cross-reactivity of the hypomutated IgG response. These poorly mutated cross-reactive IgG antibodies are implicated as candidates for ADE-mediating antibodies in secondary dengue (see GodoyLozano2016 - Lower IgG SHM Rates in Acute Dengue, n=19 acute dengue, DENV RVP neutralisation + 454 pyrosequencing).

  • Cross-reactive E-specific IgG mAbs with near-universal ADE capacity: 53 mAbs cloned from single-cell sorted secondary DHF plasmablasts were predominantly IgG; 37/53 (70%) targeted E protein, all cross-reactive to ≥2 serotypes. 45/53 mAbs enhanced DENV infection of U937 cells (5–161-fold) regardless of neutralisation potency — even the most potently neutralising IgG mAbs caused ADE at sub-neutralising concentrations or against heterotypic serotypes. This establishes that the IgG produced during the secondary dengue plasmablast wave is intrinsically ADE-competent (see Priyamvada2016 - Cross-Reactive Memory Plasmablasts in Secondary Dengue, n=4 secondary DHF, mAb cloning + ADE assay).

  • OAS demonstrated at the IgG mAb level: In 2/4 secondary DENV2 patients, plasmablast-derived IgG mAbs preferentially neutralised DENV1 (median FRNT₅₀ 0.16 µg/ml) over the infecting DENV2 (median FRNT₅₀ 1.2 µg/ml), providing the strongest functional evidence for original antigenic sin in the dengue IgG response. These DENV1-biased IgG mAbs bound DENV2 weakly — the precise profile predicted to mediate ADE during secondary heterotypic infection (see Priyamvada2016 - Cross-Reactive Memory Plasmablasts in Secondary Dengue, n=4 secondary DHF, FRNT + capture virus ELISA).

Contradictions & Debates

None documented in current wiki sources.

Double-Negative B Cell, DN2 B Cell, Plasmablast, Memory B Cell, Class Switch Recombination, IgM, IgA, Somatic Hypermutation, Original Antigenic Sin, Antibody-Dependent Enhancement

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