EFB Dengue Literature Review

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EFB Dengue Wiki — Master Index

Last updated: 2026-09-04 | Sources: 35 | Total pages: 148 (+3 meta)

Sources (35)

PageYearJournalDisease Context
Stone2019 - T-bet Promotes ASC Differentiation by Limiting IFN-gamma Inflammation2019ImmunityThe T-bet mechanism primary (Lund lab; mouse Be1/Be2 co-culture + ATAC-seq/RNA-seq + influenza and Hp infection; GEO GSE84948/GSE83697/GSE118984). ★ Resolves the wiki’s longest-standing flagged assertion in the opposite direction: Cancro2020’s unreferenced “T-bet represses Blimp-1” is contradicted in B cells — deleting Tbx21 leaves day-2 Prdm1 mRNA equivalent and Blimp-1-motif chromatin accessibility unchanged (ns, n=871 DARs) in the same panel where Th1 priming opens that identical motif set at p=3.8×10⁻⁹⁰ and T-bet’s own motifs move; probable provenance is the T cell literature (Oestreich 2012, Xin 2016). ★ T-bet is permissive, not instructive — it regulates no canonical ASC TF (Prdm1, Irf4, Xbp1, Pou2af1) and represses neither Pax5 nor Bcl6; instead it represses the IFN-γ-induced inflammatory programme (NF-κB/TLR/STAT-IRF). Causal add-back: NF-κB activator or TLR7/9 ligands given to wild-type Be1 cells reproduce the Tbx21⁻ᐟ⁻ ASC defect with proliferation unaffected. ★ The receptor, not the TF, opens the PC programme — Ifngr1⁻ᐟ⁻ Be1 cells lose Prdm1 and form almost no ASC (15.3%→0.6%). ★ Cytokine-context-dependent: B-intrinsic T-bet required after influenza, dispensable after Heligmosomoides polygyrus (IL-4-driven); IgG2c lost but IgG2b intact (TGF-β escape). ★ Memory maintenance and memory differentiation dissociate — inducible Tbx21 deletion from day-90 memory leaves the pool intact but cuts NP⁺ ASC recall ~10-fold and strips CXCR3. ★ T-bet⁺ ASC is an anatomical gradient: splenic ASC 32.5±19.4% reporter⁺ vs bone-marrow long-lived ASC 0.87±0.8%; GC B cells are reporter⁺ too, so T-bet positivity is not evidence of GC-independence. ⚠ Mouse throughout; the human DN2 link is asserted by citation, not tested — so the proposed Sutton2021↔Jenks2018 reconciliation is a mechanism proposed, not a contradiction closed. ⚠ Allogeneic MLR with strongly polarised effectors, not a physiological infection microenvironment. ⚠ No dengue/flavivirus data
Jenks2021 - B Cell Subset Composition in Cutaneous Lupus2021Ann Rheum DisSanz-lab primary across the lupus skin-disease spectrum — GOAL population cohort, n=207 patients (primary CCLE 69 / SLE+CCLE 53 / SLE-only 85) + 46 HCD, cross-sectional, 8-marker conventional flow on cryopreserved PBMC (LSRII). ★ Gates DN on CD21 × CD11c with NO CXCR5 and NO T-bet — DN1 CD21⁺CD11c⁻, DN2 CD21⁻CD11c⁺, DN3 CD21⁻CD11c⁻; aNAV = CD21⁻CD11c⁺ inside the naive gate; PB = IgD⁻CD27⁺⁺CD38⁺⁺; SM by subtraction; T1+T2 = CD24^hi^CD38^hi^. This makes the Emory side of the DN3 axis conflict first-party rather than relayed via Sanz2025 - Human Atypical B Cells Overview. ★ DN2:DN1 reported as an explicit log2 ratio panel (Fig 1E) — the Sanz lab’s third setting for the metric after Jenks2018 (SLE) and Woodruff2020 (acute COVID-19); precedent for Thesis Objectives and Grant Pitch. ★ DN expansion tracks organ involvement, not disease label: DN expanded in all three lupus groups but highest in SLE without skin disease, and within SLE the presence of CCLE tracked lower DN expansion — aligned with the DN2–nephritis association and the reduced nephritis rate in SLE+DLE. ★ Effector family (aNAV, DN2, DN3, PB) moves as a unit: unsupervised clustering on subset frequency alone yields 5 patient groups; HCD fall exclusively in the two memory/early clusters. ★ Primary CCLE is bimodal — 42% of patients have entirely healthy-like B cell profiles (vs 15–16% of SLE); the effector phenotype is a patient-stratum property, a direct warning against group-mean-first analysis in dengue. ★ USM contraction shared with Sjögren’s/RA/vasculitis/IBD. ⚠ Serology (Figs 3–5: 9G4/VH4.34, anti-dsDNA, anti-chromatin, anti-RNA, anti-Sm/RNP/Ro52/Ro60 by LIPS) is ~60% of the paper and is recorded as background only — out of scope under the standing [2026-05-02] 9G4 decision; no serology finding propagated (ELISA carries the method only). ⚠ Antibody panel not in the deposited PDF (online supplemental table 1); only 8 markers are recoverable from text/figures. ⚠ Significance reported as colour bands, not numeric p-values. ⚠ Cross-sectional — the SLE-progression hypothesis is proposed, not tested. ⚠ Two internal inconsistencies quarantined to the source page: the Fig 6 legend inverts its own cluster assignments, and Results say 42% HCD-like while the Discussion says 48%. ⚠ Not the JCI Jenks 2021 of External Citation Audit #36
Allard-Chamard2023 - DN3 B Cells Infiltrate Inflamed Tissues2023Cell ReportsThe DN3 primary — tissue infiltration in IgG4-RD and severe COVID-19; the paper three wiki reviews were relaying (Pillai/Ragon; n=38 IgG4-RD blood 13-colour FCM, n=4 sorted DN1–DN4 bulk RNA-seq [GEO GSE220582], n=10 SMG vs n=7 sialadenitis, n=6 vs n=6 COVID autopsy lung + thoracic LN): ★ Gates DN by CXCR5 × CD11c with NO CD21 and NO T-bet — DN1 CXCR5⁺CD11c⁻, DN2 CXCR5⁻CD11c⁺, DN3 CXCR5⁻CD11c⁻, DN4 CXCR5⁺CD11c⁺ (correcting the wiki’s Lamprinou-relayed DN4 = CXCR5⁺CD11c⁻, which would equal DN1). ★ DN3 tracks plasmablasts r = 0.6566, p < 0.0001 (DN2 r = 0.4496; DN1 ns) — the wiki’s best quantitative support for DN3-as-pre-plasmablast. ★ DN3 transcriptome is unique: proliferation + unfolded-protein-response + ASC features + the only B cells enriched for IGHG4; DN2/DN3 share a cytotoxic module (granzymes, GNLY, NKG7) and SLAMF7 (MFI DN2 2123 > DN3 1536 > DN4 956 > DN1 895). ★ DN2 is nearly absent from tissue — ~7 cells/mm² in COVID LN against DN3’s ~400, ~3% of the SMG DN pool: the subset carrying the wiki’s EF case is a blood finding. ★ Tissue T-B conjugates are DN-dominated and essentially CD4-restricted (StrataQuest cytoplasmic overlap, n=4) — the wiki’s first in-situ conjugate data for DN cells. ★ FcRL4⁺ = ~15–18% of blood DN in HIV vs ~1% in healthy/IgG4-RD (p<0.0001) — qualifies Wei2007’s “absent from all blood subsets.” ★ Staining pearl: CXCR5 clone J252D4 is 3D-conformation-dependent, stained first at 37 °C. ⚠ The title’s “extrafollicular” is a presumed origin, not an imaged location — no follicular-vs-EF quantification, anti-Bcl6 in the antibody list with no Bcl6 result reported; the GC-loss argument for those LNs belongs to Kaneko2020 - GC Loss and TFH Block in COVID-19. ⚠ Density rose, share did not — DN3’s share of the tissue DN pool is not increased in either arm (IgG4-RD SMG ~20% vs ~32% in non-fibrotic controls, distributions overlapping with no test reported; COVID vs inflamed control lung ~50% vs ~43%); no significance markers on any subset-level tissue panel, n=6–10, p-values uncorrected for multiplicity. ⚠ DN3 OR 113.5 with a 634-fold-wide CI (4.509–2857.1); ORs not comparable across predictors on different scales. ⚠ COVID blood panel (Fig 2C) is a re-analysis of Kaneko2020, not an independent cohort. ⚠ HLA class II direction contradicts itself between Results and Fig S3 legend
Eisenbarth2025 - A Roadmap for Defining Extrafollicular B Cell Responses2025ImmunityNomenclature consensus — bounds what a blood panel may claim; NO PRIMARY DATA (Perspective, 12 authors incl. Sanz, Shlomchik, Cyster, Kelsoe, Vinuesa, Baumgarth; refs to 137): ★ “EF” now names four distinguishable situations — (1) the original imaged foci in splenic bridging channels/red pulp and LN medullary cords, (2A) infection with architecture disruption, (2B) infection without it, (3) chronic low-mutation T-dependent activation, (4) blood phenotype with no location data — where every human study in this wiki sits. ★ The DN2 location claim is withdrawn, the origin claim is not: “the EF designation of this human DN2 cell refers to its presumed GC-independent origin rather than its location” — direct visualisation of DN2 in EF foci has never been done. ★ “No flow cytometry-based means alone can distinguish EF B cells nor their progeny”; absent CXCR5, low SHM, low affinity and IgM are each non-definitive. ★ CD21ˡᵒ/CXCR5⁻/CD11c⁺/CD71⁺ may report recent activation, not lineage. ★ CD11c⁺T-bet⁺ ≠ EF origin — mouse viral-infection ABCs are GC-derived memory; human post-flu-vaccine CD11c⁺T-bet⁺ cells are CD27⁺ high-SHM recent GC emigrants. ★ Retire “ABC” — four incompatible expansions (age-/autoimmunity-associated, atypical, activated-CD71⁺); mouse “DN” ≠ human “DN”. ★ Mutational load = rate × time → a probability of GC transit, not a measure (Fig 2); EF SHM rate can equal GC rate. ★ Phase 1–4 spatiotemporal framework; Box 2 GC-vs-EF commitment cues (IL-12/IFN-γ favour EF, IL-4 suppresses TLR7-driven EF, Tfh IL-2 → mTOR → IRF4 → BLIMP-1, TLR9+BCR drives EF selectively while TLR7 drives both). ★ GC-derived PCs mature at EF sites — an ASC’s location does not give its origin. ⚠ No new data; overwhelmingly mouse-derived while the problem it addresses is human; authors failed to reach consensus on whether the T-B border counts as EF; prescribes tissue imaging while conceding it is infeasible for human work, offering no alternative
Beckers2023 - Origins and Functions of DN B Cells2023Immunology LettersDN B cells across ~25 human conditions — the field’s landmark disease survey; NO DENGUE DATA (narrative review, 86 refs; Hasselt MS group, part own data): ★ Table 1 covers health, aging, 13 autoimmune diseases, 6 infections (meningitis/encephalitis, sepsis, malaria, rotavirus, HIV, COVID-19), vaccination, and 5 other conditions — dengue appears nowhere in the text, table or reference list. ★ Responsiveness is an open debate, not a settled property: four studies give four answers on DN proliferation to CpG (none / young-only / SM-level / none), donor age a likely hidden variable; DN1-3 nonetheless maintain BCR signalling, DN2 largest capacity. ★ Three unresolved origin hypotheses (premature GC exit → DN1 / SM-descent via CD27 downregulation / GC-independent → DN2-3), with scRNA velocity reported flowing both DN1→SM and SM→DN1; DN–SM clonal overlap only 0.2–2.2%. ★ DN1 also makes ASCs under the DN2 cocktail — softens the DN1-memory/DN2-effector split. ★ Exhausted-vs-activated splits by disease class: inhibitory receptors (FcRH3-5, CD22, CD85j) present in HIV/malaria/vaccinees/HD, absent in SLE and Hashimoto’s. New to the wiki: ABCB1⁻, short telomeres, Szelinski’s CD11c⁻ but plasmablast-like DN^low, granzyme B and LTα/TNF-α output. ⚠ Narrative review, no search strategy; Table 1 aggregates mutually incompatible DN gate definitions and reports no effect sizes
Wang2006 - Flavivirus Activation of pDCs and TLR7 Signaling2006J ImmunolDengue innate sensing, NO B CELL DATA (human pDCs + HEK/hTLR7-NF-κB reporter; dengue-2 vs influenza X31): ★ first ingested primary evidence that DENV itself engages human TLR7 — DENV-driven pDC IFN-α blocked by the TLR7 antagonist IRS 661 (p<0.02, n=4), EM places D2V in endocytic vacuoles at 5 min. ★ Genomic vRNA is 50–1000× more potent at TLR7 than short synthetic ssRNA (ssRNA40 inert across 0.02–2000 nM); potency set by higher-order shape, not length or 5′-phosphate (UV cross-link: dengue vRNA→23%, influenza→92%). TLR7 activation linked to fusion/uncoating, not mere endosomal arrival (chloroquine pH 5.2 blocks flu not dengue; bafilomycin pH 5.8 blocks both). Type I IFN arm has a higher threshold than the NF-κB/IL-8 arm — but the threshold is a property of the CELL: R-848 gave no type I IFN in the reporter line yet 13,694–18,381 pg/ml IFN-α in pDCs (IRF-7). ⚠ MOI confound between Figs 2 and 3; UV results n=2; TLR7 attribution via inhibitory ODN, not human knockout
Posadas-Mondragon2020 - TLR Polymorphisms and Clinical Forms of Dengue2020VirusesDengue host genetics, NO B CELL DATA (13 SNPs across TLR3/4/7/8; adult Veracruz cohort DF n=100 / DHF n=65 / GP n=89, WHO 1997, DENV-2-dominant, acute 1-8 d): TLR7 crude analysis NULL — no genotype/allele/model separated DF, DHF or dengue-vs-control; only TLR4 positive (rs2737190-G/G OR 0.34, rs11536865-G/C OR 0.19, TGCG haplotype OR 0.55) and it distinguishes dengue-vs-control, not severity. TLR7 X-linked → sex-split analysis (DHF women n=28). Exploratory TLR7 × IgG/IgG1/monocyte interactions are unadjusted, forest-plot-only and quarantined to the source page. Usable: DHF monocytes 14.44% vs DF 10.33%, p=0.0001 (independent replication of Kwissa2014)
Zumaquero2019 - IFN-gamma Programs T-bet-hi B Cells for ASC Differentiation2019eLifeSLE + healthy-donor in vitro reconstruction (RECEPTOR-LEVEL BACKBONE, with Jenks2018): naive B cells driven to a T-bet^hi^IRF4^int^ IgD⁻CD27⁻ pre-ASC state phenotypically, transcriptionally and functionally equivalent to SLE DN2; minimal signal set BCR + IFN-γ + IL-2 + IL-21 + BAFF + R848. ★ IFN-γ is a LICENSING signal acting in a discrete early priming window, not a mitogen — it opens chromatin at T-bet/NF-κB/STAT5/IRF4/BLIMP1 motifs, remodels PRDM1 and IL21R, and raises IL-21R protein 5.5–6× so the later IL-21 signal lands harder. T-bet^hi^ DN2 frequency correlates with anti-Sm titre (r=0.850, P<0.0001) and with TNFα/CXCL10/IL-6 — ★ but NOT with plasma IL-21 (r=0.087), despite IL-21 being functionally required in vitro. Authors state IFN-γ is NOT obligate for human ASC formation in general. No dengue data
Song2022 - Tfh Outside Germinal Centers Drive T-bet CD11c B Cells2022ImmunityMurine acute infection (LCMV-Armstrong, influenza PR8) — THE FATE-MAPPING PRIMARY behind GC-independent origin: ★ Tfh, not Th1, drive T-bet⁺CD11c⁺ B cell generation (Icos⁻/⁻, Sh2d1a⁻/⁻, CD4^Cre^Bcl6^fl/fl^, and sorted-Tfh-vs-Th1 adoptive transfer all concordant), with help delivered by spatial proximity at the follicular edge though the B cells never enter a GC; most cells GC-independent by four orthogonal methods including S1pr2 fate mapping. ★ First POSITIONAL mechanism in the wiki — CXCR3/S1PR3/CNR2 migration plus LFA-1/VLA-4 retention at the splenic marginal zone, reversible within hours. Entirely murine
Sanz2019 - Consistent Classification of Human B Cell Populations2019Front ImmunolHuman B cell NOMENCLATURE / panel-design paper (Sanz lab), no new cohort: ★ recommends a 7-marker core panel — lineage exclusion (CD3, CD14), CD19, IgD, CD27, CD38, CD24, CD21 — supporting IgD/CD27 and IgD/CD38 (Bm1–Bm5) simultaneously, with CD21 strongly recommended because it flags activated cells inside every parental population. Canonical Table 1: DN1 = CD38⁺CD24⁺CD21⁺CXCR5⁺FcRL4⁻FcRL5⁻ “memory precursors”; DN2 = CD38⁻CD24⁻CD21⁻T-bet⁺CD11c⁺FcRL5⁺SLAMF7⁺CXCR5⁻ “extrafollicular ASC precursors”. ★ SLE DN and HIV DN are NOT the same cell — FcRL5 and FcRL4 are reciprocally expressed between them. Bm1–Bm5 judged less categorical in blood; it does not separate CD27⁺ memory from DN
Kwissa2014 - Monocytes Drive Plasmablast Differentiation in Dengue2014Cell Host & MicrobeDengue (FIRST EXTRINSIC MECHANISM for the dengue PB response; whole-blood transcriptomics n=28 acute secondary + rhesus macaque + human coculture): DENV expands an intermediate CD14⁺CD16⁺ monocyte that drives plasmablast differentiation. ★ Shown by blockade — anti-BAFF, TACI-Fc and anti-IL-10 each reduce PB differentiation while anti-IL-6 and anti-IP-10 do not (in productive tension with GarciaBates2013’s null serum BAFF/APRIL correlation); R-848 (TLR7/8) reproduces the monocyte conversion, LPS does not. ★ The acute whole-blood transcriptome tracks viral load and duration of illness but does NOT discriminate DF from DHF at all; type I IFN is the top predicted upstream regulator of high-VL genes
Cancro2020 - Age-Associated B Cells2020Annu Rev ImmunolReview, NO ORIGINAL DATA, predominantly MURINE (the canonical ABC review, by the investigator who co-defined the subset): two founding definitions (Hao CD21⁻CD23⁻CD95⁻CD43⁻ vs Rubtsov CD11c⁺) that overlap but differ; ★ only ~2/3 of CD21⁻CD23⁻ cells are T-bet⁺ and ~half of those CD11c⁺ → ≥3 populations inside the ABC gate; ★ two-signal model — TLR7/9 POISING is necessary but NOT sufficient, must be followed by IFN-γ or IL-21, and BCR ligation ± CD40 does NOT enable ABC fate; IL-4 blocks the IL-21 route but not the IFN-γ route; ★ CD11c induction may be a DIRECT CYTOKINE EFFECT, not a T-bet target (converges with Glaros2025’s T-bet demotion five years earlier, from transcriptional rather than genetic evidence); ★ GC origin is INFERENCE, never demonstrated — ABC localisation in GCs never shown, SHM occurs GC-independently (Di Niro 2015), so ABCs may arise and hypermutate in EXTRAFOLLICULAR niches; ABCs arise from FO B cells (adoptive transfer) not from aged BM progenitors (irradiation); diverse germline V_H/V_κ congruent with FO pool, many mutated; BAFF-independent, displaces the FO pool; ABC-derived TNF-α suppresses B lymphopoiesis; ★ blood and splenic ABC pools NOT in equilibrium + blood ABCs fall on HIV ART → circulating frequency may be a MOBILISATION readout, not pool size; ★ ABCs proposed as the substrate of ORIGINAL ANTIGENIC SIN in sequential viral infection; ★ TLR9 is a tolerance checkpoint whose rescued cells become ABCs (TLR7 and TLR9 act in OPPOSITE directions on autoimmunity). ⚠ “T-bet represses Blimp-1 → ABC→PC requires T-bet loss” is asserted with NO reference. Zero dengue content
Glaros2025 - Multilayered Identity of B Cell Memory2026Cell Mol ImmunolReview, NO ORIGINAL DATA (memory-B-cell layered identity; heavy on the Atypical MBCs section): ABCs are antigen-experienced + T-help-dependent (CD40/CD40L-mutation and fixed-BCR evidence), expand in ACUTE infection then contract over weeks-months, share a transcriptional programme across malaria/HIV/autoimmunity; ★ T-bet NOT strictly required and ZEB2 is the cross-context driver (dual-edged: lupus-protective vs GC-costly in persistent Plasmodium); ★ GC-specific fate mapping assigns MAJORITY of acute-viral ABCs to a GC-INDEPENDENT pathway (mouse, one model); ★ the “ABCs can’t make PCs” result is largely a soluble-vs-membrane antigen artefact (FcγRIIB/FCRL5 synapse exclusion). Also: tripotent AP→ePC/eMBC/GCBC branch point; eMBCs reported to OUTNUMBER GC-derived MBCs (⚠ partly unpublished); CSR happens pre-GC so isotype/SHM fail as origin proxies; epigenetic Prdm1-accessibility recording of cumulative stimulation; liver-resident GC-independent IgM+T-bet+ MBCs. ⚠ “DN MBC” here = CD80⁻PD-L2⁻, NOT IgD⁻CD27⁻
Morra2018 - Defining Warning Signs and Severe Dengue2018Rev Med VirolClinical classification (LANDMARK): PRISMA systematic review of how 44 WHO-2009 studies operationally define warning signs / severe-dengue signs; only 2 of 16 signs (liver enlargement, liver involvement = AST/ALT >1000) had consensus definitions — both WHO-2009-predefined; “shock” defined via 23 distinct parameter-combinations; hematocrit/platelet/respiratory-rate cutoffs all divergent. Within-scheme definitional heterogeneity compounds Narvaez2011’s between-scheme heterogeneity; contains Narvaez2011 as its ref #40. No own diagnostic-accuracy data (73.0% vs 93.4% specificity borrowed from Macedo et al)
Narvaez2011 - Evaluating WHO Dengue Severity Classifications2011PLoS Negl Trop DisClinical classification (LANDMARK): evaluates WHO-1997 (DF/DHF/DSS) vs WHO-2009 (Dengue±Warning Signs / Severe Dengue) against clinical intervention level; n=544 pediatric Nicaragua; Severe Dengue sens/spec 92.1%/78.5% vs DHF/DSS 39.0%/75.5%; schemes agree only κ=0.25; DENV-2→DHF/DSS association lost under the revised scheme
Lamprinou2026 - ABCs and DN B Cells2026Front AgingOpinion (ABC↔DN identity): ABC is a heterogeneous superset (CD27⁺ + IgD⁺ + predominantly IgD⁻CD27⁻); only its IgD⁻CD27⁻ subset ≈ DN2; DN1–DN4 taxonomy (adds DN4); IL-21→CD11c, IFN-γ→T-bet; no dengue data; self-cited framework
Wrammert2012 - Plasmablast Responses in Acute Dengue2012J VirolDengue (FOUNDATIONAL: first systematic PB characterisation; 47% of B cells; >1,000-fold expansion; day 6–7 peak; ≥70% DENV-specific IgG; cross-serotype reactive; no severity correlation [confounded])
Parameswaran2013 - Convergent Antibody Signatures in Dengue2013Cell Host MicrobeDengue (FIRST BCR REPERTOIRE: convergent CDR3s across patients; 4.4–6.9% V mutation = memory-derived; higher clonality in secondary; convergent evolution from multiple V genes; n=60)
GarciaBates2013 - Plasmablast Response and Dengue Severity2013J ImmunolDengue (LANDMARK: severity-stratified plasmablast data; 46% mean/87% peak in 2° DFC; >70% DENV-specific; serotype cross-reactive; plasmablast-PRNT₅₀ disconnect; B cell apoptosis)
Ansari2025 - Peripheral T Helper Subset Drives B Cell Response in Dengue2025Cell ReportsDengue (LANDMARK: first EF B cell evidence; Tph→IL-21→memory B cell→plasmablast; CD21⁻CD11c⁺ DN expansion; severity association; neutralizing Ab paradox)
Appanna2016 - Plasmablasts as Subset of Memory B Cell Pool2016EBioMedicineDengue (CLONAL DISCONNECT: PBs and DENV-binding MBCs clonally unrelated; PBs 85% E-specific, MBCs 56% complex epitope; VH4-34 enrichment in PBs; IgM-dominant DENV-binding MBCs; n=12)
Priyamvada2016 - Cross-Reactive Memory Plasmablasts in Secondary Dengue2016J VirolDengue (OAS + ADE: 53 mAbs from sorted 2° DHF PBs; 70% E-specific, all cross-reactive; 45/53 ADE-competent; OAS in 2/4 patients — DENV1 neutralised over infecting DENV2; mean 18.1 VH mutations = memory origin; n=4 2° DHF)
GodoyLozano2016 - Lower IgG SHM Rates in Acute Dengue2016Genome MedicineDengue (LANDMARK: first direct SHM measurement in dengue IgG plasmablasts; paradoxically low SHM in acute phase; lower in secondary than primary; lower in DWS+ than DWS−; IGHV1-2/1-69 bias; convergent CDRH3s at 52% prevalence; GC-independent pathway proposed; n=19)
Singh2026 - DENV-Specific Memory B Cell Subsets2026bioRxivDengue (DENV-specific MBC subsets; primary vs secondary; longitudinal to 18M)
Scharer2019 - Epigenetic Programming in SLE B Cells2019Nat ImmunolSLE (multi-omic epigenetics; RRBS + ATAC-seq + RNA-seq; T-BET/AP-1/EGR/ATF3 programmes)
Sanz2025 - Human Atypical B Cells Overview2025Immunol RevReview (AtB nomenclature, DN classification, cross-disease context)
Woodruff2020 - EF B Cell Responses in COVID-192020Nat ImmunolCOVID-19 (EF pathway in acute viral infection; DN2/aN/ASC expansion; neutralizing Ab paradox)
Jenks2018 - DN2 B Cells and EF Pathway in SLE2018ImmunitySLE (DN2 B cells, complete EF pathway, TLR7)
Tipton2015 - ASC Diversity and Origin in SLE2015Nat ImmunolSLE (ASC diversity, EF origin, acN cells)
Wei2007 - DN Memory B Cells in SLE2007J ImmunolSLE (comparative immunology baseline)
William2002 - Extrafollicular Somatic Hypermutation in Autoimmune Mice2002ScienceSLE/Autoimmunity (LANDMARK: first direct demonstration of SHM outside GCs; ~0.3 mut/gene/gen at T zone–red pulp border; genealogical trees; FDC-absent, DC-rich EF niche; TLR9 co-stimulation; tolerance escape; 585 citations)
Bhattacharya2016 - Memory B Cell Subset Selection in Secondary Dengue2016EBioMedicineCommentary on Appanna2016: isotype-fate segregation (IgM→GC, IgG→PB); PB analysis insufficient as DENV immunity correlate; MBC subset recruitment
Sutton2021 - Alternative Lineage B Cells in Vaccination and Infection2021Cell ReportsMalaria/Vaccination (LANDMARK: scRNA-seq + CITE-seq defines “alternative lineage” (atBC1-3 + MBC1) vs “classical lineage”; T-bet/CD11c/FCRL5 defining markers; CD21⁻CD27⁻ gating captures only 44.7% of transcriptomic atBCs; ~20% of B cells in healthy donors; no PC genes in atBCs — challenges EF pre-PB model; MBC1 = quiescent alternative memory; IgG3 enrichment; n=4 10x Chromium + n=11 Smart-seq2)
Kaneko2020 - GC Loss and TFH Block in COVID-192020CellCOVID-19 (LANDMARK TISSUE: GC loss + TFH block in post-mortem LN/spleen; Bcl-6⁺ GC B cell depletion; AID⁺ preservation; TNF-α-mediated TFH block; DN/aN/PB expansion with RBD specificity; tissue-level foundation for EF dominance model)
Anolik2004 - Rituximab and B Cell Abnormalities in SLE2004Arthritis RheumSLE (B cell homeostasis; rituximab trial)

Entities (64)

B Cell Subsets

  • Atypical B Cell — umbrella / hub for the atypical / age-associated B cell cluster (the wiki’s cellular spine); synonymy map AtB/ABC/T-bet⁺/CD11c⁺/DN/alternative-lineage → precise sub-populations; foregrounds the Sanz2025 nomenclature debate; routes to the DN sub-pages without restating them (sources: 16)
  • Age-Associated B Cell — murine-origin CD19⁺CD21⁻CD23⁻T-bet⁺CD11c⁺ population; heterogeneous superset (CD27⁺ + IgD⁺ + predominantly IgD⁻CD27⁻); only its IgD⁻CD27⁻ subset ≈ DN2; TLR7/9+IFN-γ/IL-21 driven; GC-experienced origin debated; therapeutics portfolio (sources: 9)
  • Double-Negative B Cell — IgD⁻CD27⁻ memory B cells; DN1/DN2/DN3 (+DN4) subdivision; CD21⁻CD11c⁺ EF phenotype now confirmed in dengue; tissue-level DN in COVID-19 follicular + EF sites; alternative lineage framework recontextualises DN (sources: 22)
  • DN2 B Cell — IgD⁻CD27⁻CXCR5⁻CD21⁻CD11c⁺CD19^hi; EF pre-plasmablast; human counterpart of murine ABC; first dengue evidence from Ansari2025; RBD-specific in COVID-19; alternative lineage framework (Sutton2021) (sources: 18)
  • DN3 B Cell — IgD⁻CD27⁻CXCR5⁻CD21⁻CD11c⁻T-bet⁻; pre-plasmablast; proliferation+UPR signature; COVID-19/IgG4-RD/SLE-activity (sources: 10)
  • Plasmablast — CD20⁻CD38⁺⁺CD27⁺Ki67⁺CD71⁺CXCR3⁺; tissue-level IgG⁺ PBs in follicular + EF sites (Kaneko2020); 47% of B cells (Wrammert2012); 46% mean/87% peak in severe 2° dengue; plasmablast–neutralization disconnect; high SHM + OAS + near-universal ADE; atBCs do NOT upregulate PC genes (Sutton2021) (sources: 27)
  • Activated Naive B Cell — CD19^hi, MTG⁺/CD11c⁺, CD24⁻, CD21⁻; EF ASC precursor; RBD-specific in COVID-19; epigenetically closer to DN2 in SLE (sources: 11)
  • Switched Memory B Cell — IgD⁻CD27⁺ GC-derived memory; the germinal-center comparator to DN/DN2 (side-by-side in the IgD/CD27 quadrant, differ only by CD27); resting (CD21⁺) vs activated (CD21⁻) split; sM↔DN boundary blurred by CD27 shedding; recall reservoir for the IgG⁺ PB burst in 2° dengue (sources: 18)
  • Early Memory B Cell — eMBC / GC-independent “pre-GC” memory; one of three fates of a tripotent activated precursor (ePC / eMBC / GCBC); formed passively by antigen withdrawal (“differentiation by default”); OUTNUMBERS GC-derived memory by fate mapping; IgM⁺IgD⁺-enriched, low-SHM, CD80⁻PD-L2⁻ — but no marker separates it cleanly from GC-derived memory (sources: 2)
  • Tissue-Resident Memory B Cell — BRM; non-recirculating memory in lung/skin/gut/liver + LN-SCS, splenic marginal zone, bone marrow; CD69↑/S1PR1↓; ★ liver holds GC-independent somatically-hypermutated IgM⁺T-bet⁺ MBCs (GC-absent Ehrlichia model) + atypical MBCs in chronic-HBV liver; IgA-dominant lung pool needs mucosal priming; ⚠ Aicda fate mapping cannot prove GC origin (sources: 5)
  • Memory B Cell — see Concepts (foundational concept page)

T Cell Subsets

  • Peripheral Helper T Cell — CXCR5⁻PD-1⁺ CD4⁺; ~75% of activated CD4⁺ T cells in dengue; IL-21⁺ helper vs GZMB⁺ cytotoxic subclusters; drives memory B cell→PB differentiation (sources: 3)

Other Cell Types

  • Inflammatory Monocyte — CD14⁺→CD14⁺CD16⁺ conversion by DENV; drives plasmablast differentiation via BAFF/APRIL and IL-10; R-848 (TLR7/8) reproduces the conversion, LPS does not; monocyte % rises with dengue severity in two independent cohorts (Kwissa2014 Thai; Posadas-Mondragon2020 Mexican adult, 14.44% DHF vs 10.33% DF, p=0.0001) (sources: 5)
  • Plasmacytoid Dendritic Cell — highest-TLR7 human cell and the type I IFN factory; the cell in which dengue was shown to engage human TLR7 (IRS 661 blockade); EM-confirmed D2V in endocytic vacuoles; runs the TLR7→type I IFN arm that reporter lines cannot (IRF-7); dengue needs ~50× influenza’s MOI, and UV inactivation collapses it to 2.6% of live. Not a B cell — filing under Other Cell Types is easily overruled (sources: 1)

Surface Markers & Receptors

  • CD19 — pan-B cell marker; CD19^hi marks DN2 and acN cells; CD19^lo marks plasmablasts (sources: 19)
  • CD20 — B cell marker lost on plasmablasts; rituximab target reduces ABC/DN in SLE; PB gating in dengue (sources: 10)
  • CD21 — complement receptor; CD21⁻ defines EF populations; CD21⁻CD11c⁺ B cells expanded in dengue; progressive CD21 loss along alternative lineage pseudotime (sources: 14)
  • CD23 — low-affinity IgE receptor; CD23⁻ marks acN cells; disease-activity proxy (sources: 3)
  • CD24 — CD24⁻ shared by acN and DN2 cells; discriminates from transitional B cells (sources: 6)
  • CD27 — canonical memory marker; obsolete as sole memory marker; CD27 can be modulated; some ABCs are CD27⁺ (only IgD⁻CD27⁻ ABCs map to DN); CD27⁻ does not cleanly separate alternative from classical lineage (sources: 25)
  • CD38 — activation/differentiation marker; CD38^hi on plasmablasts; CD38⁺HLA-DR⁺ on activated T cells (sources: 19)
  • CD10 — transitional/GC marker; CD10⁻ on DN cells and acN cells; mature B cell gate in dengue (sources: 5)
  • CD11c — ITGAX integrin; defining marker of DN2/aNAV/ABC; IL-21-induced; CD11c⁺ EF B cells confirmed in dengue; CD11c⁺ DCs at EF sites (William2002); best single surface marker for alternative lineage by CITE-seq (sources: 17)
  • CD138 — plasmablast maturation marker; CD138⁺ enriched in severe COVID-19 ASCs; first dengue panel inclusion (sources: 6)
  • CD40L — CD154; T-B costimulation; inhibits EF pathway from naive cells; expressed on Tph in dengue (sources: 4)
  • CD71 — transferrin receptor; proliferation marker on dengue plasmablasts (sources: 3)
  • ICOS — co-stimulatory receptor; CD4⁺ICOS⁺ TFH diminished in COVID-19 tissue (sources: 2)
  • CXCR5 — follicle-homing receptor; top axis of DN1–DN4 classification (DN1/DN4 CXCR5⁺ vs DN2/DN3 CXCR5⁻); absent on DN2 B cells and Tph T cells; Bcl-6⁺CXCR5⁺ GC-TFH absent in COVID-19; CXCL13 elevated in dengue (sources: 11)
  • CXCR3 — IFN-γ-driven tissue homing; CXCR3⁺ on dengue plasmablasts and COVID-19 EF populations; measured by CITE-seq on alternative lineage (sources: 6)
  • FCRL5 — Fc receptor-like 5; expressed on DN2/aNAV; therapeutic target candidate; defining marker of alternative lineage (sources: 7)
  • FcRH4 — inhibitory Fc receptor homolog; absent on circulating DN cells and DN2 (sources: 7)
  • SLAMF7 — CD319; expressed on DN2/aNAV/PC; therapeutic target (approved for myeloma) (sources: 4)
  • IgD — surface immunoglobulin; retained on acN cells; lost at DN2 transition; used for DN gating; IgD⁺ ABCs are antigen-experienced (SHM⁺), not naive (sources: 19)
  • IgG — predominant switched isotype; DENV-specific IgG massive but non-neutralizing; anti-NS1/anti-prM elevated in severe dengue; PB IgG 85% E-specific and more neutralizing; near-universal ADE; OAS bias; IgG⁺ MBCs predisposed to PB fate; predominant ABC isotype; IgG3 enriched in alternative lineage; anti-DENV IgG/IgG1/IgG4 skewed high in DHF while IgG3 runs the opposite way (Posadas-Mondragon2020) (sources: 24)
  • IgM — unswitched isotype; balanced with IgG1/IgA1 in COVID-19 ASC; ongoing CSR to switched isotypes; IgM-dominant in DENV-binding MBCs; IgM⁺ MBCs predisposed to GC re-initiation; acute anti-DENV IgM higher in DHF than DF, but the primary/secondary split is derived from the same IgM/IgG ratio (Posadas-Mondragon2020) (sources: 14)
  • IgA — mucosal isotype; IgA1 in COVID-19 ASC repertoire; anti-RBD IgA elevated in severe COVID; one of two dominant ABC switched isotypes (sources: 11)
  • B220 — CD45R isoform; heterogeneous in memory B cells (sources: 3)
  • IL-21R — the node where IFN-gamma priming is cashed out as responsiveness to T cell help: surface protein up 5.5–6× after IFN-γ, IL21R locus remodelled; the only receptor in this wiki that has been blocked in a human dengue B cell response (sources: 5)
  • TACI — TNFRSF13B; binds both BAFF and APRIL; appears in two roles — blocking reagent (TACI-Fc) and surface receptor on atypical B cells, which sits oddly against those cells’ reported BAFF-independence (sources: 3)
  • LFA-1 — αLβ2 (CD11a/CD18), ligand ICAM-1; with VLA-4 the wiki’s only adhesion mechanism — physically retains T-bet⁺CD11c⁺ B cells at the splenic marginal zone, reversibly within hours ⇒ ★ circulating frequency may partly read retention failure rather than pool size. ⚠ CD11a ≠ CD11c (sources: 2)
  • VLA-4 — α4β1 (CD49d/CD29), ligand VCAM-1; blocked together with LFA-1 in the single experiment demonstrating marginal-zone retention, so the two contributions are not separated (sources: 2)
  • S1PR3 — sphingosine-1-phosphate receptor implicated in migration of T-bet⁺CD11c⁺ B cells toward the splenic marginal zone; a cautionary case — essential for S1P-directed chemotaxis in vitro and completely dispensable in vivo, in the same paper (sources: 1)

Transcription Factors & Signalling

  • Bcl-6 — GC master TF; Bcl-6⁺ GC B cells and GC-TFH strikingly absent in COVID-19; DN1 Bcl-6-pathway associated; link to GC failure→EF dominance (sources: 5)
  • T-bet — TBX21; defining TF of ABC; IFN-γ-induced; highest in DN2/aNAV; only DN subset (DN2) highly T-bet⁺; T-BET motifs top enriched in DN2 chromatin; TH1 CD4⁺ T-bet⁺ expansion in COVID-19 tissue; not stained in dengue; defines alternative lineage transcriptomically (sources: 15)
  • ZEB2 — primary driver of ABC formation; represses Mef2b (GC TF); cooperates with T-bet (sources: 5)
  • ATF3 — stress-response TF; key SLE DN2-specific regulator; 98 target genes (sources: 1)
  • EGR — EGR1-4 family; EGR4 highest PageRank in SLE network (sources: 1)
  • PD-1 — PDCD1; ~60% PD-1⁺ on DN2 B cells; defining marker of Tph T cells in dengue (sources: 2)
  • IRF4 — PC differentiation TF; high IRF4/low IRF8 ratio in DN2; NOT upregulated in atBC clusters (Sutton2021) (sources: 8)
  • BLIMP-1 — PRDM1-encoded; elevated in DN2/aNAV; progressive demethylation; NOT upregulated in atBC clusters (Sutton2021) (sources: 11)
  • BACH2 — terminal differentiation repressor; absent in DN2/aNAV (sources: 3)
  • TRAF5 — negative TLR regulator; uniquely low in DN2/aNAV (sources: 2)
  • TLR7 — ssRNA sensor; TLR7 GoF causes SLE; X-linked (female bias); ABCs hyper-responsive to TLR7+TLR9; monogenic + indirect mutations drive ABC/DN2; TLR9 EF precedent (William2002); R848 early-survival/late-proliferation split + IFN-γ synergy at 100×-subthreshold dose (Zumaquero2019); germline TLR7 variation does NOT stratify dengue clinical form — null, and why that is not a refutation (Posadas-Mondragon2020); ★ DENV itself engages human TLR7 (IRS 661 blockade in pDCs, Wang2006) + genomic vRNA 50–1000× more potent than synthetic ssRNA, potency set by higher-order shape; ⚠ reporter-line negatives ≠ ligand negatives (sources: 15)
  • TLR9 — CpG/DNA sensor; sufficient mitogen for DN B cell proliferation without BCR crosslinking and upregulates CD27 (Wei2007); ★ tolerance checkpoint acting OPPOSITE to TLR7 — TLR9 knockouts exacerbate autoimmunity (Cancro2020); TLR9⁻/⁻ pDCs used as the off-target control validating a TLR7 inhibitor, and TLR9 multimerization is the cited precedent for the TLR7 multimerization model (Wang2006) (sources: 7)
  • HOPX — marks cytotoxic GZMB⁺ Tph subcluster in dengue scRNA-seq (sources: 1)
  • TOX2 — marks IL-21⁺ helper Tph subcluster; Tfh-associated TF on CXCR5⁻ cells (sources: 1)
  • STAT3 — downstream of IL-21R and the wiki’s only measured JAK-STAT readout; phospho-STAT3 is the assay that turns “IFN-γ reprograms the cell” from a chromatin inference into a measured signalling difference. ⚠ stub, single source; no STAT1/STAT5/JAK content in the corpus (sources: 1)
  • XBP1 — UPR transcription factor required for the plasma-cell secretory apparatus; earns a page because the sources disagree informatively — high in murine T-bet⁺CD11c⁺ B cells, a negative result in human atypical B cells, DN3-associated — making it a proxy for how far along the PC differentiation path these cells actually are (sources: 6)

Enzymes

  • AID — activation-induced cytidine deaminase; initiates SHM and CSR; AID⁺ B cells preserved in COVID-19 despite GC loss; EF SHM at GC-comparable rates (William2002) (sources: 4)

Cytokines

  • TNF-alpha — pleiotropic pro-inflammatory cytokine; aberrant accumulation in COVID-19 LNs blocks GC-TFH differentiation; dose-dependent GC role; murine TNF-α blockade rescues GCs (sources: 3)
  • IL-21 — key EF differentiation cytokine; produced by Tph and Tfh; robustly induces CD11c in ABC differentiation; blocking reduces PB output ~60% in dengue (sources: 8)
  • Type I Interferon — IFNα/IFNβ; top predicted upstream regulator of high-viral-load genes in acute dengue (Kwissa2014); in the atypical B cell literature a correlate, never a tested driver; ★ no source has tested whether type I IFN can substitute for IFN-γ in the pre-ASC priming window — the key barrier to transferring the DN2 model into type-I-dominated dengue; DENV-driven pDC IFN-α is TLR7-dependent and the type I IFN arm has a higher threshold than NF-κB/IL-8, but the threshold is a property of the cell (Wang2006) (sources: 7)
  • IFN-gamma — type II interferon; the licensing signal of the DN2 triad (with TLR7 ligand and IL-21): it does not make B cells divide, it reprograms them so the other two signals land harder. ★ Dengue’s early response is type-I- not type-II-dominated — the central untested transfer in the SLE→dengue model (sources: 10)
  • BAFF — BLyS/TNFSF13B, plus the BAFF-R/TACI/BCMA receptor family; ★ the wiki’s sharpest unresolved conflict: a murine review calls ABCs BAFF-independent, one dengue primary finds no serum correlation with plasmablast output, and a second finds that blocking BAFF functionally reduces plasmablast differentiation (sources: 8)
  • APRIL — TNFSF13; shares TACI and BCMA with BAFF and is almost always measured and blocked together with it, so its independent contribution is rarely separable; BAFF is the main page for the axis (sources: 5)

Concepts (14)

  • GC-Independent Response — NEW 2026-08-27: the origin claim, held separately from the location claim; evidence-to-claim table for what a blood panel may and may not conclude; GC-independence is inferable from SHM load, GC-ablation genetics, tissue architecture and clonal connectivity — extrafollicular location is not; asymmetry (EF ⇒ GC-independent, not conversely); the wiki’s replacement vocabulary for “EF” wherever the evidence is peripheral blood (sources: 11)
  • Extrafollicular Response — FIRST DENGUE EVIDENCE: Tph→IL-21→memory B cell→PB axis; CD21⁻CD11c⁺ EF B cells; tissue-level GC suppression + EF dominance (Kaneko2020): antigen-driven expansion, FDC-preserved lymphocyte block, naive/transitional consumption; 47%/87% PB severity association; plasmablast–neutralization disconnect; isotype-fate segregation (IgG→PB, IgM→GC); LANDMARK murine proof of EF SHM (William2002); alternative lineage challenges EF pre-PB model — context-dependent; ABC differentiation programme (TLR7/9+IFN-γ/IL-21) as comparative backbone (sources: 30)
  • Germinal Center — canonical differentiation; SM vs DN2 epigenetic bifurcation; tissue-level GC loss in fatal COVID-19 (Kaneko2020): Bcl-6⁺ GC B cells and GC-TFH absent, TNF-α implicated; concurrent GC activity in dengue (CXCL13↑); GCs not required for SHM (William2002); alternative lineage SHM consistent with post-GC origin; ABCs partly GC-experienced + T-bet⁺ B cells promote GC formation (sources: 27)
  • Memory B Cell — Tph preferentially drive memory (not naive) B cell→PB in dengue; DENV-specific qualitative reprogramming in 2°; convergent CDR3s from affinity-matured memory B cells; PBs non-representative subset of MBC pool; OAS = strongest functional evidence of memory origin; isotype-fate segregation (IgM→GC, IgG→PB); MBC1 = quiescent alternative lineage memory (Sutton2021) (sources: 23)
  • Somatic Hypermutation — LANDMARK: EF SHM at GC-comparable rates (William2002); AID⁺ B cells preserved despite GC loss (Kaneko2020); >50% germline VH in COVID-19 ASCs; FIRST DENGUE BCR DATA: 4.4–6.9% V mutation in convergent CDR3-bearing cells; paradoxically low in acute dengue; HIGH SHM (18.1 VH) in sorted 2° PBs = memory origin; significant SHM in alternative lineage clusters; ABCs (incl. IgD⁺ fraction) carry SHM (sources: 23)
  • Class Switch Recombination — EF CSR-competence confirmed; AID preserved outside GCs (Kaneko2020); class-switched memory B cells are Tph responders in dengue; IgG-dominant PBs vs IgM-enriched DENV-binding MBCs; ABCs predominantly switched (IgG/IgA) with unswitched IgD⁺ fraction (sources: 24)
  • Original Antigenic Sin — memory recall bias toward prior serotype; 2/4 patients preferentially neutralise DENV1 over infecting DENV2; OAS at mAb level; lower SHM in secondary (GodoyLozano2016); convergent CDR3s more prevalent in secondary (Parameswaran2013); selective E-specific IgG memory recruitment (Appanna2016); Tph→MBC→PB recall engine (Ansari2025); contested — Brazilian cohort shows infecting-serotype dominance (GarciaBates2013) (sources: 9)
  • Toll-like Receptor Signaling in B Cells — the wiring page for endosomal TLR input: DN2 hyper-responsiveness via TRAF5/A20 brake failure; TLR7 rewires CD72/CD32b/HLA-DR; R848 early-survival / late-proliferation split; IFN-γ sensitises to 100×-subthreshold R848; TLR9 as tolerance checkpoint; in dengue, TLR signalling is documented in non-B cells only — monocytes (Kwissa2014) and now pDCs, where DENV itself is blocked at TLR7 (Wang2006); germline TLR variation does not stratify clinical form (Posadas-Mondragon2020) (sources: 12)
  • Antibody-Dependent Enhancement — 45/53 dengue PB mAbs enhance infection regardless of neutralisation potency; ADE-competent IgG from memory recall; future-exposure risk; plasmablast–PRNT₅₀ disconnect (GarciaBates2013); neutralizing Ab paradox across dengue and COVID-19 (Ansari2025, Woodruff2020); unmeasured BMPC compartment (Bhattacharya2016); secondary infection NOT enriched in the severe arm of one adult cohort — 73% DF vs 70.8% DHF (Posadas-Mondragon2020) (sources: 7)
  • Dengue Severity Classification — clinical-context anchor for the severity axis; WHO-1997 (DF/DHF/DSS = plasma-leakage syndrome) vs WHO-2009 (Dengue±Warning Signs / Severe Dengue); revised scheme more sensitive for triage (92.1% vs 39.0%) but dissolves the pathogenic entity; schemes agree only κ=0.25 → severity findings are scheme-dependent (Narvaez2011, between-scheme); and “WHO-2009” is not one operational definition — only 2 of 16 signs have a consensus definition (Morra2018, within-scheme) → the two heterogeneities stack; and WHO-1997 is still in active use with a two-variable operationalisation (platelets + any bleeding, no leakage measurement) (Posadas-Mondragon2020) (sources: 4)
  • Atypical B Cell Effector Output — what these cells do to other cells and tissues, as distinct from the signals that create them: ASC differentiation, cytokine secretion, antigen presentation, tissue localisation. ★ Evidence-quality warning — only the ASC/antibody arm rests on primary human data; the cytokine arm rests almost entirely on one murine review, and no source in this wiki has measured cytokine secretion by sorted human DN2 cells (sources: 16)
  • B Cell Receptor Signaling — the third input building DN2 cells, alongside TLR and cytokine signals; dissolves the “atypical B cells are BCR-hyporesponsive” vs “DN2 proximal signalling is intact” contradiction without invoking exhaustion: the BCR signal must be early and transient, and continuous engagement actively suppresses ASC output. ⚠ no Syk/Lyn/SHP-1/CD79 data in the corpus (sources: 6)
  • Extrafollicular T Cell Help — extrafollicular responses are not T-independent; two different helper cells that should not be merged — Tfh acting outside GCs at the follicular edge (murine, Song2022) and Tph in blood and inflamed tissue (human, Ansari2025) — reaching a similar outcome by different routes (sources: 8)
  • Follicular Exclusion — where DN2/atypical cells are excluded from, where they go instead, and what holds them there: the negative/transcriptional half (CXCR5 and CD21 loss, GC TF repression) plus the positive/positional half added by Song2022 (CXCR3/S1PR3/CNR2 homing; LFA-1/VLA-4 retention at the splenic marginal zone) (sources: 10)

Methods (26)

  • SNP Genotyping — TaqMan real-time PCR allelic discrimination; 5 inheritance models by AIC; HWE per group; EM haplotypes + linkage disequilibrium; X-linked genes must be sex-split, which halves every stratum; germline variation is a weak proxy for pathway use (sources: 1)
  • TLR Reporter Cell Assay — single human TLR + NF-κB-luciferase in HEK293 vs parent line; paired luciferase + supernatant ELISA reads two signalling arms from one assay; RNA ligands lipofected, dosed as moles of RNA segments; ★ a negative in a reporter line is not a negative for the ligand — the line reports only the branches it is equipped to run (sources: 1)
  • ELISA — cytokine quantification from culture supernatants (IFN-α/IFN-β/IL-8); duplicates, dilutions within the standard curve; ⚠ IFN-α in pg/ml vs IFN-β in IU/ml are not interchangeable; % -of-control plots hide absolute magnitude. Undercounts actual ELISA use across the wiki — serology-using sources not yet retro-fitted (sources: 2)
  • Transmission Electron Microscopy — 4 °C synchronised binding → 37 °C chase → glutaraldehyde/osmium, 70-nm sections, Philips CM10 at 80 kV; placed D2V in pDC endocytic vacuoles at 5 min; ★ morphology is not identity — no immunogold, no endosomal marker, and no quantification (sources: 1)
  • Spectral Flow Cytometry — 24-marker Cytek Aurora panels; UMAP; Woodruff2020 Table 1 standardised B cell definitions (sources: 2)
  • CITE-seq — multi-modal scRNA-seq + surface protein (ADT); CD21⁻CD27⁻ captures only 44.7% of transcriptomic atBCs; CD11c best single marker (sources: 1)
  • Multi-color Immunofluorescence — tissue-based imaging; TissueFAXS/TissueQuest/StrataQuest; 5–7-color multispectral; cell-to-cell contact quantification; FFPE tissue analysis (sources: 3)
  • Conventional Flow Cytometry — multi-color panels; Wrammert2012 (5-color) + GarciaBates2013 + Appanna2016 + Ansari2025 + Priyamvada2016 + Kaneko2020 (13-color) panels; CITE-seq gating validation; non-B-cell purity checks (pDC lineage⁻CD123⁺HLA-DR⁺, >85%) (sources: 26)
  • Bm Classification — IgD/CD38 Bm1–Bm5 developmental staging framework (sources: 3)
  • FACS Sorting — multi-population sort for multi-omic profiling; antigen-specific live virus sorting; RBD dual-fluorophore probes (Kaneko2020); activated CD4⁺ T cell sorting for scRNA-seq; tetramer-based sorting for Smart-seq2; >98% purity standard where sorted cells are the genetic control (Wang2006 TLR7⁻/⁻/TLR9⁻/⁻ pDCs) (sources: 15)
  • BCR Sequencing — Sanger, NGS, 10x Chromium scV(D)J, 454 pyrosequencing, microdissection+Vκ PCR, Smart-seq2 full-length BCR; germline-dominant repertoire in COVID-19 EF ASCs; first dengue BCR data (Parameswaran2013); PB/MBC clonal overlap analysis; ImmunediveRsity pipeline + Monte Carlo deconvolution; EF genealogical trees (William2002) (sources: 15)
  • RNA Sequencing — 5,090 DEGs; PageRank TF network; EGR4 apex; ATF3 DN2-specific (sources: 8)
  • ATAC-seq — comprehensive multi-subset comparison; T-BET/AP-1/EGR motifs in DN2 (sources: 5)
  • RRBS — reduced-representation bisulfite sequencing; progressive hypomethylation hierarchy (sources: 1)
  • ELISpot — antigen-specific ASC quantification; DENV-specific IgG quantification; FluoroSpot for IL-21/IFN-γ in dengue (sources: 11)
  • In Vitro B Cell Stimulation — TLR7/IFN-γ/IL-21 EF differentiation; T-B coculture (sources: 11)
  • Phospho-Flow Cytometry — pERK/pMAPKp38 TLR7 readout; DN2/aNAV hyper-responsiveness (sources: 3)
  • Serum Proteomics — LC-MS/MS identification of serum antibodies from NGS databases (sources: 1)
  • Activation-Induced Marker Assay — CD25⁺OX40⁺ AIM assay for DENV-specific T cell responses (sources: 1)
  • Single-Cell RNA Sequencing — 10x Genomics scRNA-seq + scTCR-seq; Tph subcluster identification in dengue; Smart-seq2 + 10x Chromium + CITE-seq for B cell lineage definition (sources: 6)
  • T-B Coculture Assay — Tph-driven memory B cell→PB differentiation; IL-21 blocking (sources: 4)
  • FRNT — focus reduction neutralization test; neutralizing titers not different by dengue severity; OAS demonstrated at mAb FRNT₅₀ level (sources: 2)
  • PRNT — plaque reduction neutralization test; PRNT₅₀ not correlated with plasmablast frequency in dengue (sources: 2)
  • Immunohistochemistry — tissue-based protein localisation; EF B cell localisation at T zone–red pulp border (sources: 3)
  • Compensation and FMO Controls — spillover matrix vs. FMO controls distinction; curator’s 11-color DN2 panel worked example: FMO-anchored IgD/CD27 cutoffs reveal old DN gate undercounted by ~4.5x (1.99%→8.90% of B cells) (sources: 4)
  • DN2 Panel - Staining, Compensation, and Gating Protocol — end-to-end operational SOP for the curator’s 11-color DN2 panel: whole-blood prep → unstained/single-stain-bead/FMO controls → FlowJo compensation → FMO-anchored gating, with worked examples, analogies, and an honest limitations section (sources: 2)

Analyses (10)

The Dengue Severity Binarization Spec (WHO-1997 + WHO-2009 data-dictionary) was moved off the public wiki on 2026-06-30 — it now embeds the clinical-DB column schema and is held privately (_private/, not web-published).

  • Why DN B Cells Matter - Disease Relevance and Infectious Disease Case — the justification layer: eight arguments the corpus supports for DN/atypical importance, each tiered A (ingested primary with original DN data) vs B (review-carried); ★ only 3 non-dengue infection primaries exist (Woodruff2020, Kaneko2020, Sutton2021 core n=4) and dengue DN rests on 2 papers using different gates; ★ the protective/pro-immunity counter-case (LCMV, γHV68, Ehrlichia, ZEB2 dual-edge) stated in the open; ★ names the autoimmunity→infection transfer the wiki’s case actually runs on; gaps route Moir2008/Weiss2009/Portugal2015/Holla2021 to the ingest Queue
  • Mechanistic Case for DN and DN2 Cells in Dengue — Discussion source material for the ABC stat analysis manuscript (HC n=13 / DF n=12 / DHF n=15, WHO-1997): DN2-like cells rise 0.91% → 1.58% → 1.87% of non-plasmablast B cells (Kruskal–Wallis p=0.0115) but not on a total-B denominator, because ASC expand from 0.75% to ~40–50% of B cells and roughly halve it; ★ the honest claim is proportional enrichment among non-secreting B cells that the current data cannot separate from redistribution — weaker than “severe dengue has more DN2 cells”, and more mechanistically interesting
  • B Cell Panel Variant 1 — intracellular-capable B-cell panels for the 3-laser/14-channel instrument; recommended single-tube 13-color workhorse (Panel 4) confirming DN2/ABC (adds T-bet) + DN2:DN1 ratio (adds CXCR5) + plasmablast/EF-effector output; 3-tube suite (Panels 1–3) for higher cell yield; supersedes the surface-only DN2 Gating Strategy panel
  • DN2 Gating Strategy — council-reviewed 11-color gating strategy for DN/DN2-phenotype isolation in dengue PBMCs; Ansari2025-comparable; Sanz2025 IgD-audit compliant
  • Research Plan - DN B Cell Expansion in Dengue — wet-lab protocol (Rev 4): flow cytometry panel, cohort design (DF/DHF/HC), DN1-like/DN2-phenotype/DN3-like surrogate subdivision, sample size estimates
  • Thesis Objectives and Grant Pitch — strategic layer for the pilot: central thesis (one low-fidelity antibody, two faces), falsifiable objectives (cells→ANA bridge as primary), statistical-honesty framing, confounder pre-emption (age/sex first-order for ABCs), antibody layer (ANA + FRNT×4 + IgG/IgM), severity-scheme decision, pilot→grant trajectory; complements the Research Plan
  • Open Research Questions — the research agenda the corpus leaves open, aggregated from every source page’s ## Questions Raised and grouped into six themes: is the dengue “DN” compartment actually DN2 · EF vs GC origin · drivers (TLR7/IL-21/IFN-γ/T help) · antibody output (OAS, ADE, autoreactivity) · kinetics, compartments and what blood cannot see · transfer from the SLE/malaria/COVID-19 benchmarks; ★ the aggregation itself is the finding — the same origin question is asked independently by papers spanning 2002–2026 that largely do not cite each other (sources: 28)
  • Notable Findings — running log of striking cross-cutting observations (29 entries)
  • Curator Highlights — aggregated ==highlights== and “ from wiki pages (2 highlights)
  • External Citation Audit — catalog of ~89 external papers cited inline across the wiki; DOIs, backlinks, verification status (entries 67–77 added 2026-08-16 from Cancro2020; only 1 paper independently verified corpus-wide)

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