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The essential roles of memory B cells in the pathogenesis of systemic lupus erythematosus

Nature Reviews Rheumatology volume 20, pages 770–782 (2024)Cite this article

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Abstract

Emerging evidence indicates that memory B cells are dysfunctional in systemic lupus erythematosus (SLE). They are hyporesponsive to signalling through the B cell receptor (BCR) but retain responsiveness to Toll-like receptor (TLR) and type I interferon signalling, as well as to T cell-mediated activation via CD40–CD154. Chronic exposure to immune complexes of ribonucleoprotein (RNP)-specific autoantibodies and TLR-engaging or BCR-engaging cargo is likely to contribute to this partially anergic phenotype. TLR7 or TLR8 signalling and the resulting production of type I interferon, as well as the sustained activation by bystander T cells, fuel a positive feedforward loop in memory B cells that can evade negative selection and permit preferential expansion of anti-RNP autoantibodies. Clinical trials of autologous stem cell transplantation or of B cell-targeted monoclonal antibodies and chimeric antigen receptor (CAR) T cells have correlated replenishment of the memory B cell population with relapse of SLE. Moreover, the BCR hyporesponsiveness of memory B cells might explain the failure of non-depleting B cell-targeting approaches in SLE, including BTK inhibitors and anti-CD22 monoclonal antibodies. Thus, targeting of dysfunctional memory B cells might prove effective in SLE, while also avoiding the adverse events of broad-spectrum targeting of B cell and plasma cell subsets that are not directly involved in disease pathogenesis.

Key points

  • In systemic lupus erythematosus (SLE), memory B cells are hyporesponsive to B cell receptor (BCR) stimulation but can be activated upon engagement of Toll-like receptors (TLRs) and interaction with T cells (mainly via the CD40–CD40L axis). Both innate and adaptive immune signalling by B cells (‘bridging’) contribute to SLE pathology, possibly via a pathogenic positive feedforward loop.

  • This feedforward loop is accentuated by anti-ribonucleoprotein (anti-RNP) autoantibodies sequestering RNP antigens, which, when internalized via the BCR, stimulate TLR7 and TLR8 signalling and type I interferon production.

  • Incomplete X chromosomal inactivation of TLR7, TLR8 and CD40L might further contribute to such a positive feedforward loop, thereby potentially explaining the female sex bias in SLE.

  • Clinical outcomes of B cell depletion in SLE, via anti-CD20 or anti-CD19 or autologous stem cell transplantation, have clearly associated relapse with memory B cell repletion, independently of the recurrence of naive B cells or autoantibodies.

  • The safety and efficacy of CD19-targeted and BCMA-targeted chimeric antigen receptor (CAR) T cells, or bispecific T cell engagers in SLE, and their impact on tissue-resident memory B cells remain to be elucidated.

  • BCR signalling inhibition approaches did not result in sufficient efficacy potentially owing to an incomplete impact on memory B cells.

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Fig. 1: Signalling abnormalities in B cells, especially memory B cells, in systemic lupus erythematosus.
Fig. 2: A positive feedforward loop links abnormal memory B cell signalling, autoantibody production and the type I interferon signature of SLE.
Fig. 3: Selective targets of B cell depletion.

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Acknowledgements

The DRFZ is funded by the Leibniz Society and the Senate of Berlin. The authors thank J. C. Ritter for his graphical support in the preparation of Fig. 1.

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Authors and Affiliations

  1. Department Medicine/Rheumatology and Clinical Immunology, Charite Universitätsmedizin Berlin & Deutsches Rheumaforschungszentrum (DRFZ), Berlin, Germany

    Thomas Dörner

  2. AMPEL BioSolutions, Charlottesville, VA, USA

    Peter E. Lipsky

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  1. Thomas Dörner
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The authors contributed equally to all aspects of the article, including data research, discussion of content and writing the article. All authors reviewed and edited the manuscript before approval and submission.

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Correspondence to Thomas Dörner.

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Competing interests

T.D. declares honoraria for scientific advice from Abelzeta, BMS, Janssen, Novartis, Roche/GNE and UCB, and fees for clinical studies (paid to the university) by BMS, Novartis, Eli Lilly & Company, Janssen and Roche. P.E.L. is co-founder of AMPEL Biosolutions and an adviser to Abelzeta.

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Glossary

Age-associated B cells

(ABCs). B cells that increase in number as a result of ageing, viral infections, immunodeficiency and autoimmune diseases (rheumatoid arthritis and systemic lupus erythematosus). ABCs are identified by CD11c expression.

Atypical memory B cells

A term largely applied to CD27−IgD− B cells that lack expression of CD27, a marker of memory B cells, but otherwise have features of B cell memory.

Follicular dendritic cells

(FDCs). Cells of mesenchymal origin that are found in the germinal centre light zone of primary and secondary lymphoid tissue. FDCs capture and present antigens to support B cell activation and, along with CD40–CD40L-based B cell–T cell interactions, ensure negative selection of autoimmune B cells.

Germinal centres

Transiently formed structures within the B cell zone (follicles) in secondary lymphoid organs that harbour a dark zone where immunoglobulin class switching and somatic hypermutation are taking place and a light zone where BCR/immunoglobulin selection occurs based on T cell and follicular dendritic cell interactions.

Heavy and light chains of the B cell receptor

Antibody molecules are composed of two immunoglobulin heavy chains and two immunoglobulin light chain proteins, the variable regions of which define their binding specificity.

T follicular helper cells

(TFH cells). TFH cells are antigen-experienced CD4+ T cells expressing PD1 and typically producing IL-21, able to initiate and maintain germinal centre formation within secondary lymphoid organs.

T peripheral helper cells

(TPH cells). Unlike T follicular helper cells (TFH cells), which interact with B cells within lymphoid organs, TPH cells provide help to B cells, and especially to memory B cells, within inflamed tissues, supporting plasma cell differentiation. Distinct features of TPH cells, as compared with TFH cells, are the expression of CXCR5, which is associated with TPH cell localization within inflamed tissues, and a low BCL6 to BLIMP1 ratio. TPH cells depend on various cytokines for their survival within tissues, such as IL-6, type I interferon and IL-12 or IL-23.

Tissue-resident memory T cells

(TRM cells). CD4+ memory T cells that express BCL6 and are crucially involved in the development of autoimmune B cell and CD8+ T cell memory responses. TRM cells can permit the activation of B cells at extrafollicular or tissue sites and thus escape censoring by germinal centres.

TLR7 and TLR8

Members of the Toll-like receptor family and innate receptors DAMPs (damage-associated molecular pattern molecules) able to recognize GU-rich single-stranded RNA (ssRNA) (TLR7) or U-rich ssRNA (TLR8) in endosomes and to initiate B cell activation in the contexts of viral and autoimmune responses.

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Dörner, T., Lipsky, P.E. The essential roles of memory B cells in the pathogenesis of systemic lupus erythematosus. Nat Rev Rheumatol 20, 770–782 (2024). https://doi.org/10.1038/s41584-024-01179-5

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