EFB Dengue Literature Review

IgM

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IgM

Overview

IgM is the first immunoglobulin isotype produced by B cells and the default surface isotype on mature naive B cells (co-expressed with IgD). Secreted IgM is a pentamer and mediates efficient complement activation. IgM⁺ memory B cells (retaining surface IgM without isotype switching) represent a distinct memory subset; whether they originate from GC or GC-independent pathways is debated.

Key Points from Literature

  • ~15% of DN (IgD⁻CD27⁻) B cells in healthy subjects are IgM⁺ (surface IgM without IgD); similar proportion in SLE. Crucially, these IgM⁺DN cells lack IgD, distinguishing them from conventional unswitched CD27⁺ memory cells (IgM⁺IgD⁺) (see Wei2007 - DN Memory B Cells in SLE, n=29 healthy cross-sectional).

  • IgM⁺IgD⁺ CD27⁺ memory cells (conventional unswitched memory) are proposed to represent recirculating marginal zone B cells; IgM-only CD27⁺ memory cells may represent precursors to isotype-switched cells in the context of hyper-IgM syndrome. The IgM⁺ DN cells do not fit cleanly into either model (see Wei2007 - DN Memory B Cells in SLE).

  • IgM contribution to SLE ASC sequences: IgM accounts for 5.42–19.53% of all sequences in circulating ASCs from SLE patients (substantial inter-subject variability). The frequency of IgM sequences in the IgD⁻CD27⁺ memory compartment is significantly greater in SLE (20.9–68.1%) vs. vaccinated healthy controls (1.5–37.5%; p<0.05), consistent with active generation of IgM-only memory from recently activated naive cells — the first GC-independent memory layer (see Tipton2015 - ASC Diversity and Origin in SLE, NGS of sorted populations, n=5 SLE, n=8 vaccinated).

  • IgM⁻ memory cells as indicator of acN cell contribution: The high IgM fraction in SLE memory is attributed to naive cell recruitment — newly activated B cells produce IgM-only memory before undergoing class switch recombination, consistent with the acN → EF pathway (see Tipton2015 - ASC Diversity and Origin in SLE, citing Dogan et al. 2009).

  • IgM near-absent in secondary dengue plasmablast wave: In a predominantly secondary dengue cohort (42/46), IgM-secreting DENV-specific plasmablasts were detectable in only a minority of patients and were never IgM-only — all had concurrent IgG responses. The 4 primary responders all had detectable IgM by ELISpot, with one (Den01-066) showing an IgM response exceeding IgG. This confirms that the secondary dengue plasmablast response is overwhelmingly class-switched, with IgM production restricted to primary infection (see Wrammert2012 - Plasmablast Responses in Acute Dengue, ELISpot, n=46).

  • IgM⁺ DENV-binding MBCs dominate the virus-specific memory compartment and harbour the only PB-shared clones: In Appanna2016, a large fraction of DENV-binding convalescent MBCs expressed IgM (vs. IgG-dominant plasmablasts and IgG-dominant non-DENV-binding MBCs). The rare CDR3 sequences shared between PBs and DENV-binding MBCs were exclusively IgM, and shared clones that were expanded in the MBC compartment were also IgM. The authors interpret this as potential enrichment of low-affinity IgM binders during virus-based sorting (DENV binding was also observed in non-immune individuals). This connects to the Singh2026 finding that IgM⁺ DENV-specific MBCs are the only subset significantly elevated during acute secondary dengue (see Appanna2016 - Plasmablasts as Subset of Memory B Cell Pool, 454 + Sanger sequencing, n=12 dengue).

  • IgM⁺ memory B cells are predisposed to GC re-initiation, not PB differentiation: The isotype-fate segregation model (Seifert et al. 2015, cited in Bhattacharya2016 - Memory B Cell Subset Selection in Secondary Dengue, commentary) proposes that IgM⁺ memory B cells preferentially re-initiate germinal center reactions rather than differentiating into plasmablasts. This provides a mechanistic explanation for the IgM dominance of DENV-binding convalescent MBCs (Appanna2016) and the IgM⁺ MBC elevation during acute secondary dengue (Singh2026) — these IgM⁺ cells may be maintained or expanded via GC re-entry rather than contributing to the PB wave.

  • ★ IgM⁺ (and IgM⁺IgD⁺) memory is enriched for GC-INDEPENDENT origin — but the marker is not decisive. GC-specific fate mapping shows GC-independent early MBCs are enriched for unswitched IgM⁺IgD⁺ cells with low SHM, while GC-derived MBCs are more commonly class-switched. However, the distinction is not absolute: early MBCs include a significant fraction of class-switched cells, and GC-derived MBCs can retain an IgM⁺ or even IgM⁺IgD⁺ phenotype (see Glaros2025 - Multilayered Identity of B Cell Memory, review, no original data). Class-switch status is “insufficient to definitively discriminate” the two — see Class Switch Recombination.

  • IgM⁺ memory preferentially reenters secondary germinal centers — with a caveat. IgM⁺ MBCs (early-MBC-enriched) are more likely to reenter secondary GCs, whereas IgG1⁺ MBCs (GC-derived-enriched) are biased toward PC differentiation — consistent with the isotype-fate segregation model the wiki already carries from Bhattacharya2016 - Memory B Cell Subset Selection in Secondary Dengue. The caveat: GC-specific fate mapping found the secondary GC B cell pool was dominated by non-fate-mapped cells, and a follow-up study showed those derived primarily from naive B cells rather than from IgM⁺ memory (review).

  • Germline-encoded high-affinity precursors yield IgM⁺-dominated memory. Mice whose naive precursors bear germline-encoded, high-affinity BCRs develop memory compartments dominated by IgM⁺ MBCs, a subset likely enriched for early (GC-independent) MBCs (see Glaros2025 - Multilayered Identity of B Cell Memory, review, mouse).

  • Somatically hypermutated IgM⁺T-bet⁺ memory persists in tissue after a GC-absent infection. In murine Ehrlichia muris infection, where splenic GCs are absent, hypermutated IgM⁺T-bet⁺ MBC-like cells reside in liver and spleen and persist after clearance (see Glaros2025 - Multilayered Identity of B Cell Memory, review, mouse). See Tissue-Resident Memory B Cell.

  • Both IgM⁻ and IgM⁺ ABCs exist, with a range of surface IgD within the IgM⁺ fraction. Cancro’s speculative mapping: switched (IgM⁻IgD⁻) and unswitched (IgM⁺IgD⁻) memory arising from antigen-driven responses, versus homeostatically-expanded primary cells (IgM⁺IgD⁺) arising from a proposed non-antigen-driven route — consistent with ABCs including both somatically mutated and germline-configuration Ig genes (see Cancro2020 - Age-Associated B Cells, review — no original data; mouse).

  • IgM⁺CD11c⁺ extrafollicular splenic plasmablasts drive CD4-T-independent antibody responses in murine Ehrlichia infection (Racine et al. 2008, J Immunol), alongside protective T-bet⁺ memory B cells (see Cancro2020 - Age-Associated B Cells, review — no original data; mouse).

  • Acute-phase anti-dengue IgM is markedly higher in DHF than DF. Anti-DENV IgM was detectable in 63% of DHF versus 37% of DF sera; on tertile-split indices, high IgM was present in 58.5% of DHF versus 14% of DF, while 74% of DF sera were IgM-negative (see Posadas-Mondragon2020 - TLR Polymorphisms and Clinical Forms of Dengue, n=254 case-control, adult, WHO 1997, sampled days 1–8 post-onset). Two cautions attach. First, the 1–8 day window sits early relative to peak IgM, so an IgM-negative DF patient may simply have been sampled sooner. Second, the study assigns primary versus secondary infection from the IgM/IgG OD ratio on the same sera (>1.2 primary, <1.2 secondary), so the primary/secondary split is not independent of the IgM result — the two cannot be used to explain each other. Both groups came out ~70–73% secondary. Serology detail canonical to dengue-wiki/.

  • IgM’s status in the recommended core is internally inconsistent in this paper — worth knowing before quoting “the seven-marker core”. The body text lists the seven as (1) a CD3/CD14 dump, (2) CD19, (3) IgD, (4) CD27, (5) CD38, (6) CD24, (7) CD21 — no IgM. The footnote to Table 1 instead reads “Core Markers: CD19, IgM, IgD, CD27, CD38, CD24, CD21”, dropping the dump and adding IgM, while also listing IgM again among the additional markers. The review also cautions on anergy: IgD⁺IgMˡᵒ˾⁻ “BND” naive cells are <2% of blood B cells, and because IgM downregulation is also caused by BCR activation, IgM level alone should not be used to call anergy (see Sanz2019 - Consistent Classification of Human B Cell Populations, review — no original data).

  • IgM is the isotype the dengue-monocyte blockade experiments actually moved. DENV-infected monocytes drove IgG and IgM (but not IgA) secretion from resting allogeneic B cells above MDDC and B-cell-only controls, and both TACI-Fc (the BAFF/APRIL decoy) and anti-IL-10 significantly reduced IgM, whereas anti-IL-6 and anti-IP-10 did not, and no significant IgG reduction is reported for any arm (see Kwissa2014 - Monocytes Drive Plasmablast Differentiation in Dengue, in vitro, 4 independent experiments with 4 healthy blood donors). Separately, all five DENV-2-infected rhesus macaques developed DENV-2-specific plasma IgM (same source, NHP model, n=5), and dengue-specific IgM ELISA was one of the confirmatory diagnostics in the human cohort. ⚠ Do not read the in vitro IgM prominence against the in vivo secondary-dengue picture above (Wrammert2012 - Plasmablast Responses in Acute Dengue, IgM near-absent): this culture starts from resting bulk B cells including naive cells and is polyclonal and non-antigen-specific, so IgM output here is a property of the assay rather than a claim about secondary dengue.

  • The T-bet⁺CD11c⁺ recall response is IgG-dominated, and the IgM comparison is what demonstrates it. In sorted-transfer recall experiments into MD4 recipients, naive and memory B cell recipients produced more IgM than recipients of T-bet⁺CD11c⁺ cells, which instead gave a rapid anti-LCMV IgG response at days 5 and 10 (see Song2022 - Tfh Outside Germinal Centers Drive T-bet CD11c B Cells, mouse, LCMV-Armstrong, n=3–5 mice/group). This is consistent with the repertoire data showing the population is already class-switched — predominantly IgG2b/IgG2c, with isotype usage indistinguishable from GC B cells — so it enters a recall response with little unswitched reserve.

Contradictions & Debates

None documented in current wiki sources.

Double-Negative B Cell, Memory B Cell, Activated Naive B Cell, IgD, IgG, Class Switch Recombination, Early Memory B Cell, Tissue-Resident Memory B Cell

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