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Long-lived autoreactive plasma cells drive persistent autoimmune inflammation

Abstract

Aberrant production of autoantibodies by inappropriately self-reactive plasma cells is an inherent characteristic of autoimmune diseases. Several therapeutic strategies aim to deplete the plasma cell pool, or to prevent maturation of B cells into plasma cells. However, accepted views of B-cell biology are changing; recent findings show that long-lived plasma cells refractory to immunosuppressants and B-cell depletion therapies contribute to the maintenance of humoral memory and, in autoimmunity, to autoreactive memory. As a consequence of their longevity and persistence, long-lived plasma cells can support chronic inflammatory processes in autoimmune diseases by continuously secreting pathogenic antibodies, and they can contribute to flares of symptoms. As long-lived plasma cells are not sufficiently eliminated by current therapies, these findings are extremely relevant to the development of novel concepts for the treatment of autoimmune diseases. Thus, long-lived plasma cells appear to be a promising new therapeutic target.

Key Points

  • Long-lived plasma cells arise as the result of B-cell differentiation in a secondary immune response

  • They reside immobilized in specific survival niches in the bone marrow and inflamed tissues, where they secrete antibodies for months, years or a lifetime, independent of antigenic stimulation

  • Long-lived plasma cells are resistant to glucocorticoids, conventional immunosuppressive and cytotoxic drugs, irradiation and B-cell depletion therapies

  • During disease flares, waves of newly generated autoreactive plasma cells might contribute to the occupation of plasma cell niches by autoreactive long-lived plasma cells, replacing old, protective plasma cells

  • Autoreactive long-lived plasma cells maintain autoimmunity and inflammatory processes, which can be resolved by depletion of these cells

  • The depletion of pathogenic long-lived plasma cells seems to be key to the development of curative therapies in patients with antibody-mediated disease

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Figure 1: Autoreactive long-lived plasma cells maintain autoimmunity and might contribute to reactivation of autoimmune disease.
Figure 2: Development of autoreactive long-lived plasma cells.
Figure 3: Strategies for regulating and targeting long-lived plasma cells.

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Acknowledgements

This work was supported by a grant from the German Research Foundation (SFB 650).

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F. Hiepe, T. Dörner, A. E. Hauser, B. F. Hoyer, H. Mei and A. Radbruch researched the data for the article and provided substantial contributions to discussions of the content. F. Hiepe wrote the article. F. Hiepe and A. Radbruch contributed equally to review and/or editing of the manuscript before submission.

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Correspondence to Falk Hiepe.

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Hiepe, F., Dörner, T., Hauser, A. et al. Long-lived autoreactive plasma cells drive persistent autoimmune inflammation. Nat Rev Rheumatol 7, 170–178 (2011). https://doi.org/10.1038/nrrheum.2011.1

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