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Germinal-centre and extrafollicular B cell pathways in systemic lupus erythematosus

Nature Reviews Rheumatology (2026)Cite this article

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Abstract

Autoantibody flares are important drivers of pathology in systemic lupus erythematosus (SLE), highlighting the pivotal role of B cells in initiating and propagating chronic autoimmunity. Although autoreactive specificities are a normal feature of the naive B cell repertoire, these cells are normally suppressed by layered tolerance checkpoints that limit inappropriate activation. Autoimmune-prone environments can lower these tolerance thresholds, rendering naive autoreactive B cells more sensitive to aberrant cues. Cytokines and other microenvironmental signals shape tissue niches that direct autoreactive B cells towards either germinal-centre or extrafollicular differentiation pathways. Germinal centres support the entry, selection and diversification of autoreactive B cells, with T cell help sustaining these repertoires. By contrast, naive autoreactive B cells entering the extrafollicular pathway exhibit an attenuated requirement for cognate T cell help and strong dependence on complement and TLR signalling. Emerging evidence continues to refine our understanding of germinal-centre and extrafollicular responses as complementary sources of autoreactive effector cells. With this progress, investigations into the origin, development, longevity and tissue dynamics of autoreactive memory B cells as chronic sources of autoantibodies are warranted. Although broad B cell depletion therapies have yielded benefit, a key challenge now is developing precision strategies that selectively target pathogenic B cell subsets.

Key points

  • Intrinsic autoreactivity is embedded in naive T cell and B cell repertoires and autoimmune environments drive autoreactive B cells towards germinal-centre or extrafollicular fates.

  • Autoreactive B cell fate commitment is shaped by contextual, genetic and metabolic cues.

  • Autoreactive germinal centres indicate peripheral B cell tolerance breakdown in systemic lupus erythematosus (SLE) and serve as T cell-dependent sites of pathogenic autoantibody diversification.

  • Extrafollicular B cell responses provide rapid production of autoantibodies in SLE, supported by heterogeneous CD4+ T cell help.

  • Mechanistic characterization of autoreactive B cell fate decisions informs memory B cell dynamics and supports the development of precision therapies in SLE.

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Fig. 1: Drivers of autoreactive B cell activation and differentiation.
Fig. 2: Contextual determinants of extrafollicular and germinal-centre B cell pathways.
Fig. 3: Components of an autoreactive germinal centre.
Fig. 4: Germinal-centre-independent T cell help in extrafollicular B cell responses.

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Acknowledgements

The work of the authors is supported by National Institutes of Health (NIH) grants R01AR074105 and R01AR072965 (M.C.C.), Lupus Research Alliance Lupus Mechanisms and Targets Award (M.C.C.), DoD grant HT94252410598 (M.C.C.), Lupus Research Alliance Empowering Lupus Research Career Development Award (C.C.), Canadian Institutes of Health Research Doctoral Foreign Study Award 202110DFD-475148-94277 (D.Y.-D.Z.).

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Authors and Affiliations

  1. Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Danni Yi-Dan Zhu & Michael C. Carroll

  2. Harvard Graduate Program in Virology, Boston, MA, USA

    Danni Yi-Dan Zhu

  3. Department of Microbiology, Harvard Medical School, Boston, MA, USA

    Danni Yi-Dan Zhu

  4. Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA

    Carlos Castrillon

  5. Massachusets General Hospital, Boston, MA, USA

    Elliot Akama-Garren

  6. Department of Pediatrics, Harvard Medical School, Boston, MA, USA

    Michael C. Carroll

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All authors researched data for the article and contributed substantially to discussion of the content. D.Y.-D.Z., C.C. and E.A.-G. wrote the article. M.C.C., D.Y.-D.Z. and C.C. reviewed and edited the manuscript before submission.

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Glossary

Affinity maturation

The process by which B cells progressively acquire increased antigen-binding specificity and affinity through somatic hypermutation and selection in the germinal centre197.

Age-associated B cells

(ABCs). A non-germinal-centre non-antibody-secreting murine B cell subset that expands with age and accumulates more rapidly in autoimmune strains, initially defined as CD19+B220+CD11c+CD21−CD23−52,53,198.

Atypical B cells

(atBCs). A pathogenic B cell subset observed in infectious settings and phenotypically analogous to age-associated B cells199.

B1a cells

A self-renewing, innate-like B cell lineage that resides mostly in the peritoneal and pleural cavities; these cells carry repertoires biased towards bacterial and self-antigens and produce naturally occurring polyreactive IgM antibodies200.

Class-switch recombination

A B cell-specific DNA rearrangement mechanism that replaces IgM expression with IgG, IgE or IgA201.

Clonal anergy

A peripheral tolerance mechanism in which a self-reactive B cell is reprogrammed to become functionally unresponsive, exhibiting reduced responsiveness to B cell receptor stimulation and diminished expression of IgM120,202.

Clonal redemption

The process by which anergic self-reactive B cell clones regain functionality through the selection of mutated progeny with reduced inherent autoreactivity compared with before entry into the germinal centre119,120,203.

Epitope spreading

The diversification and shifting of antigenic targets recognized by the autoantibody repertoire7.

Extrafollicular bridging channel

An anatomical region in the spleen that bridges the T cell zone and the red pulp45.

Follicular B cells

Recirculating mature B cells derived from bone-marrow B2 lineage precursors; these cells localize to the B cell follicles and typically display an IgDhiIgMlowCD21mid (follicular type 1) or IgDhiIgMhiCD21mid (follicular type 2) phenotype204.

Marginal-zone B cells

A B2-derived B cell enriched in the splenic marginal zone between marginal sinus and red pulp; in rodents, these cells are non-recirculating and characterized by IgMhiIgDlowCD21hiCD1dhiCD23− and mount rapid responses to blood-borne pathogens and lipid antigens204,205. In humans, marginal-zone B cells are found in the lymphoid organs and circulation, and exhibit a IgMhiIgDloCD23−CD21+CD1c+ surface phenotype206.

Secondary lymphoid organs

Lymph nodes, spleen, Peyer’s patches, tonsils, adenoids and (in rodents) nasal-associated lymphoid tissue; these anatomically organized lymphoid structures serve as major sites of immune responses and tolerance induction207.

Somatic hypermutation

A diversification process in which antigen-experienced B cells acquire rapid point mutations in immunoglobulin V-region genes, mediated by the enzyme activation-induced cytidine deaminase (AID); occurs at high frequency in germinal-centre B cells and at a low frequency in extrafollicular responses64,197.

T cell ignorance

A form of immunological tolerance in which antigen-specific T cells remain clonally ignorant despite the presence of their target antigen, maintaining a naive phenotype208.

T follicular helper cells

(TFH cells). Specialized CD4+CCR7lowPSGL1low helper T cells that are essential for germinal-centre formation and antibody production; the majority of germinal-centre T follicular helper cells are PD1hiBCL6hiSAPhiCXCR5hi. B cells receive cognate and indirect help from T follicular helper cells via CD40L, IL-4 and IL-21 for activation and differentiation17,121,209.

T follicular regulatory cells

(TFR cells). A population of CD4+ T cells that differentiate from CD25hiFOXP3+ regulatory T cells and that migrate to B cell follicles and germinal centres upon antigen stimulation and regulate development and differentiation of T follicular helper cells210.

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Zhu, D.YD., Castrillon, C., Akama-Garren, E. et al. Germinal-centre and extrafollicular B cell pathways in systemic lupus erythematosus. Nat Rev Rheumatol (2026). https://doi.org/10.1038/s41584-026-01365-7

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