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  • Review Article
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Beyond pan-B-cell-directed therapy — new avenues and insights into the pathogenesis of SLE

Nature Reviews Rheumatology volume 12, pages 645–657 (2016)Cite this article

Subjects

Key Points

  • Pan-B-cell-directed agents show only modest evidence of clinical benefit in systemic lupus erythematosus (SLE), despite the crucial role of B-lineage cells in its pathogenesis

  • Trials of pan-B-cell-directed agents have provided evidence of antibody-independent contributions of CD20+ B cells as well as antibody–dependent contributions of CD20− plasma cells to rheumatic disease

  • The contributions of antibody-independent B-cell functions (antigen presentation, cytokine production and co-stimulation) to the pathogenesis of SLE suggest a role for B-cell-targeted approaches beyond pan-B-cell depletion

  • In SLE, diminished B-cell receptor signalling and reduced cytokine production indicate impaired function of B regulatory cells, which implies that the regulatory capacity of these cells could be a therapeutic target

  • Strategies specifically targeting B cells, plasma cells or pathogenic B-lineage cells could influence key interactions of innate and adaptive immunity in SLE and hold promise to improve patients' outcomes

  • A current challenge is to determine whether inhibition of specific B-cell pathways or improving the regulatory functions of B cells will also improve the clinical efficacy and safety of B-cell-directed therapies

Abstract

New insights into the mechanisms of autoimmune diseases have been obtained not only from preclinical studies, but also from clinical trials of pan-B-cell-directed therapy. Overall, the results of these clinical trials suggest that more-specific approaches focusing on pathogenic B-cell functions, and perhaps sparing or even enhancing regulatory B-cell activity, might be attractive alternatives. Importantly, pathogenic B-cell subpopulations function within a network of cellular interactions, many of which might require additional interventions to restore immunologic balance and suppress autoimmune disease. Thus, approaches that simultaneously target innate immune cells as well as multiple nodes of T-cell and B-cell interactions might hold the promise of improved therapeutic efficacy. Interfering with B-cell intracellular signalling pathways, altering their intracellular metabolic pathways and perturbing transcription factors are additional options. This Review critically analyses these approaches, examines the role of cytokines and other functions of B-lineage cells separate from antibody secretion, and provides insights into the potential next generation of therapies targeting B-lineage cells.

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Figure 1: Induction, maintenance and resolution of chronic autoimmunity in SLE.
Figure 2: Heat map of targeted therapies in autoimmune diseases.
Figure 3: B-cell involvement in the immunopathogenesis of SLE and relevant therapeutic targets.

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Authors and Affiliations

  1. Departments of Medicine, Rheumatology and Clinical Immunology, Charité–University Medicine Berlin and the German Rheumatism Research Centre (DRFZ), Chariteplatz 01, Berlin, 10117, Germany

    Thomas Dörner

  2. RILITE Foundation, 1001 Research Park Boulevard, Suite 301, Charlottesville, 22911, Virginia, USA

    Peter E. Lipsky

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Dörner, T., Lipsky, P. Beyond pan-B-cell-directed therapy — new avenues and insights into the pathogenesis of SLE. Nat Rev Rheumatol 12, 645–657 (2016). https://doi.org/10.1038/nrrheum.2016.158

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