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Plasma cells as an innovative target in autoimmune disease with renal manifestations

Nature Reviews Nephrology volume 12, pages 232–240 (2016)Cite this article

Subjects

Key Points

  • Two independent plasma-cell compartments can secrete pathogenic autoantibodies: short-lived proliferating plasmablasts that reflect B-cell hyperactivity and non-dividing long-lived memory plasma cells

  • Long-lived memory plasma cells reside in survival niches in the bone marrow and inflamed tissues where they secrete autoantibodies independently of antigen-contact, B cells and T-cell help

  • Expansions of short-lived plasmablasts are associated with increasing autoantibody levels and disease flares, whereas long-lived memory plasma cells are responsible for maintenance of humoral autoimmunity and refractory disease activity

  • Long-lived plasma cells are refractory to conventional immunosuppression and to therapies that target B cells or T cells; an urgent need to identify therapeutic targets on these plasma cells exists

  • A challenging strategy is to selectively deplete pathogenic long-lived plasma cells in an autoantigen-specific manner without removing long-lived plasma cells that provide protective humoral memory

  • Antithymocyte globulin and proteasome inhibitors can deplete short-lived plasmablasts and long-lived plasma cells; replenishment of autoreactive long-lived plasma cells can be avoided by targeting their precursor cells

Abstract

Autoantibodies are secreted by plasma cells and have an essential role in driving the renal manifestations of autoimmune diseases such as systemic lupus erythematosus and antineutrophil cytoplasmic autoantibody-associated vasculitis. Effective depletion of autoreactive plasma cells might be the key to curative treatment of these diseases. Two major plasma-cell compartments exist: short-lived plasmablasts or plasma cells, which result from differentiation of activated B cells, and long-lived plasma cells, which result from secondary immune responses. Long-lived plasma cells reside in survival niches in bone marrow and inflamed tissue and provide the basis of humoral memory and refractory autoimmune disease activity. Unlike short-lived plasmablasts, long-lived plasma cells do not respond to conventional immunosuppression or to therapies that target B cells. Existing therapies that target long-lived plasma cells, such as proteasome inhibitors and antithymocyte globulin, as well as promising approaches that target survival factors, cell homing or surface molecules, deplete the whole memory plasma cell pool, including cells that secrete protective antibodies. By contrast, we have developed a novel strategy that uses an affinity matrix to deplete pathogenic long-lived plasma cells in an autoantigen-specific manner without removing protective plasma cells. Targeting B-cell precursors to prevent replenishment of autoreactive long-lived plasma cells should also be considered.

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Figure 1: Two independent plasma cell compartments contribute to autoantibody secretion.
Figure 2: Potential therapeutic targets against plasma cells in the bone marrow niche.
Figure 3: Autoantigen-specific plasma cell depletion using an affinity matrix.

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Acknowledgements

The authors' research is supported by the Deutsche Forschungsgemeinschaft (TRR130 project 15, SFB 650 projects 12 and 17).

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  1. Charité - Universitätsmedizin Berlin and Deutsches Rheumaforschungszentrum Berlin, ein Institut der Leibniz-Gemeinschaft, Charitéplatz 1, 10117, Berlin, Germany

    Falk Hiepe & Andreas Radbruch

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F.H. researched the data and wrote the article. Both authors made substantial contributions to discussions of the content and reviewed and/or edited the manuscript before submission.

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Correspondence to Falk Hiepe.

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F.H. and A.R. are inventors of the international patent application PCT/EP2013/068503 dealing with the autoantigen-specific depletion of plasma cells in vivo. The applicant is the Deutsches RheumaForschungszentrum Berlin.

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Hiepe, F., Radbruch, A. Plasma cells as an innovative target in autoimmune disease with renal manifestations. Nat Rev Nephrol 12, 232–240 (2016). https://doi.org/10.1038/nrneph.2016.20

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