EFB Dengue Literature Review

CD21

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CD21

Overview

CD21 (Complement Receptor 2, CR2) is a complement receptor expressed on mature naive and memory B cells that binds C3d-opsonised antigen. It forms a co-receptor complex with CD19 and CD81 that lowers the activation threshold of the BCR. CD21 expression is downregulated upon B cell activation; loss of CD21 (CD21^lo or CD21⁻ phenotype) marks activated or anergic B cells and is used in flow cytometry panels to distinguish resting from recently activated B cell populations.

Key Points from Literature

  • CD21⁻ phenotype marks acN cells: In SLE flares, activated naive (acN) B cells (CD19^hi, IgD⁺, CD27⁻, MTG⁺, CD24⁻) are CD21⁻, consistent with downregulation of the complement co-receptor upon sustained B cell activation. In healthy subjects, the CD19⁺IgD⁺CD27⁻ compartment is dominated by CD21⁺ resting naive B cells (see Tipton2015 - ASC Diversity and Origin in SLE, multi-color flow cytometry).

  • Mechanistic basis of CD21 downregulation: B cell activation leads to shedding of complement receptor type II (CR2/CD21) from the cell surface. This is consistent with the CD21⁻ phenotype of acN cells reflecting sustained BCR engagement rather than a developmental stage (see Tipton2015 - ASC Diversity and Origin in SLE, citing Masilamani et al. 2003).

  • CD21^lo B cells previously characterised in SLE: A CD21^lo activated B cell population was previously described in peripheral blood of SLE patients (Wehr et al. 2004, cited in Tipton2015 - ASC Diversity and Origin in SLE). That prior work ascribed this population to CD27⁺ B cells; Tipton2015 clarifies that the relevant activated population is within the CD27⁻ compartment, detectable by MTG and CD24 staining.

  • CD21lo alone is an unreliable marker of AtB/ABC: Sanz (2025) argues that CD21lo cells include several distinct populations — activated naive, DN2, DN3 (pre-plasmablasts), activated memory, and anergic cells — with different functions. Low CD21 in isolation should not be used to identify B cells with pre-defined function (see Sanz2025 - Human Atypical B Cells Overview, review).

  • CD21 and CD11c are not reciprocal: CD21lo cells can be CD11c⁻ (as in DN3 B Cell), and CD11c⁺ cells can be CD21⁺ (as in resting ABC memory). CD21 vs. CD11c is therefore an informative two-dimensional gating strategy, not a single-axis readout (see Sanz2025 - Human Atypical B Cells Overview, review, Figure 2B).

  • Generalised CD21 downregulation in SLE: SLE B cells show a generalised lower level of CD21 expression across all subsets compared with healthy donors, with increased populations of CD21-negative cells. This means CD21lo gating thresholds validated in healthy donors may be inappropriate for SLE samples (see Sanz2025 - Human Atypical B Cells Overview, review, Figure 2C).

  • CD21lo cells have increased TLR7 sensitivity: This could contribute to their recruitment into the ABC compartment and SLE expansion (see Sanz2025 - Human Atypical B Cells Overview, review citing Zhu et al. 2024).

  • CD21lo transitional B cells expanded in mild COVID-19: OUT-C patients showed expansion of CD21lo transitional B cells (>10% of CD19⁺ B cells, with CD21lo cells making up >50% of the gain). CD21lo Tr cells expressed higher IgM, CD24, CD10 and lower CD21, CXCR5 than CD21hi Tr cells, but also showed unexpectedly higher CD138 expression — a marker usually restricted to ASCs (see Woodruff2020 - EF B Cell Responses in COVID-19, spectral FCM).

  • CD21 vs. CD11c gating for DN subdivision in COVID-19 panel: The Woodruff2020 24-marker panel uses CD21 vs. CD11c within the DN gate (IgD⁻CD27⁻CD38⁻CD24⁻) to resolve DN1 (CD21⁺CD11c⁻), DN2 (CD21⁻CD11c⁺), and DN3 (CD21⁻CD11c⁻). Three CD21⁻ populations (aN, DN2, DN3) were all expanded in ICU patients and correlated with ASC expansion — CD21 loss as a shared feature of EF pathway activation (see Woodruff2020 - EF B Cell Responses in COVID-19, Table 1).

  • CD21⁻ marks EF B cells in acute dengue: CD21⁻CD11c⁺ B cells within the IgD⁻CD27⁻ (DN) gate are significantly expanded during acute dengue — the first demonstration of CD21 loss on EF-phenotype B cells in dengue, consistent with the DN2 phenotype defined in SLE and COVID-19 (see Ansari2025 - Peripheral T Helper Subset Drives B Cell Response in Dengue, multi-color FCM, n=170 acute dengue).

  • CD21⁺ defines naive B cells in dengue gating: In the GarciaBates2013 panel, naive B cells are defined as CD27⁻CD21⁺ within CD19⁺CD10⁻ mature B cells. Naive B cells contracted to ~30% of B cells in secondary DFC (from ~50% in health), reflecting displacement by the CD21⁻ plasmablast wave. The atypical memory gate (CD27⁻CD21⁻) was also identified, corresponding to DN B cells (see GarciaBates2013 - Plasmablast Response and Dengue Severity, LSRII FCM, n=84 dengue).

Contradictions & Debates

None documented in current wiki sources.

Activated Naive B Cell, CD19, CD24, CD11c, CXCR5, DN2 B Cell, DN3 B Cell, Memory B Cell, Extrafollicular Response, Conventional Flow Cytometry, Peripheral Helper T Cell

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