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
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
References
Zinkernagel, R. M. et al. On immunological memory. Annu. Rev. Immunol. 14, 333–367 (1996).
Manz, R. A., Thiel, A. & Radbruch, A. Lifetime of plasma cells in the bone marrow. Nature 388, 133–134 (1997).
Manz, R. A., Löhning, M., Cassese, G., Thiel, A. & Radbruch, A. Survival of long-lived plasma cells is independent of antigen. Int. Immunol. 10, 1703–1711 (1998).
Slifka, M. K., Antia, R., Whitmire, J. K. & Ahmed, R. Humoral immunity due to long-lived plasma cells. Immunity 8, 363–372 (1998).
Martin, F. & Chan, A. C. B cell immunobiology in disease: evolving concepts from the clinic. Annu. Rev. Immunol. 24, 467–496 (2006).
Gould, H. J. & Sutton, B. J. IgE in allergy and asthma today. Nat. Rev. Immunol. 8, 205–217 (2008).
Hoyer, B. F. et al. Short-lived plasmablasts and long-lived plasma cells contribute to chronic humoral autoimmunity in NZB/W mice. J. Exp. Med. 199, 1577–1584 (2004).
Luger, E. O. et al. Induction of long-lived allergen-specific plasma cells by mucosal allergen challenge. J. Allergy Clin. Immunol. 124, 819–826 (2009).
Tarlinton, D., Radbruch, A., Hiepe, F. & Dörner, T. Plasma cell differentiation and survival. Curr. Opin. Immunol. 20, 162–169 (2008).
Radbruch, A. et al. Competence and competition: the challenge of becoming a long-lived plasma cell. Nat. Rev. Immunol. 6, 741–750 (2006).
Hargreaves, D. C. et al. A coordinated change in chemokine responsiveness guides plasma cell movements. J. Exp. Med. 194, 45–56 (2001).
Hauser, A. E. et al. Chemotactic responsiveness toward ligands for CXCR3 and CXCR4 is regulated on plasma blasts during the time course of a memory immune response. J. Immunol. 169, 1277–1282 (2002).
Muehlinghaus, G. et al. Regulation of CXCR3 and CXCR4 expression during terminal differentiation of memory B cells into plasma cells. Blood 105, 3965–3971 (2005).
Manz, R. A., Hauser, A. E., Hiepe, F. & Radbruch, A. Maintenance of serum antibody levels. Annu. Rev. Immunol. 23, 367–386 (2005).
MacLennan, I. C. & Gray, D. Antigen-driven selection of virgin and memory B cells. Immunol. Rev. 91, 61–85 (1986).
Cappione, A., 3rd. et al. Germinal center exclusion of autoreactive B cells is defective in human systemic lupus erythematosus. J. Clin. Invest. 115, 3205–3216 (2005).
Smith, K. G., Light, A., Nossal, G. J. & Tarlinton, D. M. The extent of affinity maturation differs between the memory and antibody-forming cell compartments in the primary immune response. EMBO J. 16, 2996–3006 (1997).
Blink, E. J. et al. Early appearance of germinal center-derived memory B cells and plasma cells in blood after primary immunization. J. Exp. Med. 201, 545–554 (2005).
William, J., Euler, C., Christensen, S. & Shlomchik, M. J. Evolution of autoantibody responses via somatic hypermutation outside of germinal centers. Science 297, 2066–2070 (2002).
Amanna, I. J., Carlson, N. E. & Slifka, M. K. Duration of humoral immunity to common viral and vaccine antigens. N. Engl. J. Med. 357, 1903–1915 (2007).
Achatz-Straussberger, G. et al. Migration of antibody secreting cells towards CXCL12 depends on the isotype that forms the BCR. Eur. J. Immunol. 38, 3167–3177 (2008).
Holt, P. G., Sedgwick, J. D., O'Leary, C., Krska, K. & Leivers, S. Long-lived IgE- and IgG-secreting cells in rodents manifesting persistent antibody responses. Cell. Immunol. 89, 281–289 (1984).
Voigt, C. Characterization of short- and long-lived plasma cell populations in a murine model of systemic lupus erythematosus [German]. Thesis, Charité Univeritätsmedizin Berlin (2008).
Turner, C. A. Jr., Mack, D. H. & Davis, M. M. Blimp-1, a novel zinc finger-containing protein that can drive the maturation of B lymphocytes into immunoglobulin-secreting cells. Cell 77, 297–306 (1994).
Shapiro-Shelef, M., Lin, K. I., Savitsky, D., Liao, J. & Calame, K. Blimp-1 is required for maintenance of long-lived plasma cells in the bone marrow. J. Exp. Med. 202, 1471–1476 (2005).
Shapiro-Shelef, M. & Calame, K. Regulation of plasma-cell development. Nat. Rev. Immunol. 5, 230–242 (2005).
Kallies, A. et al. Initiation of plasma-cell differentiation is independent of the transcription factor Blimp-1. Immunity 26, 555–566 (2007).
Manz, R. A. et al. Humoral immunity and long-lived plasma cells. Curr. Opin. Immunol. 14, 517–521 (2002).
Benner, R., Hijmans, W. & Haaijman, J. J. The bone marrow: the major source of serum immunoglobulins, but still a neglected site of antibody formation. Clin. Exp. Immunol. 46, 1–8 (1981).
Haaijman, J. J., Schuit, H. R. & Hijmans, W. Immunoglobulin-containing cells in different lymphoid organs of the CBA mouse during its life-span. Immunology 32, 427–434 (1977).
Brieva, J. A., Roldán, E., De la Sen, M. L. & Rodriguez, C. Human in vivo-induced spontaneous IgG-secreting cells from tonsil, blood and bone marrow exhibit different phenotype and functional level of maturation. Immunology 72, 580–583 (1991).
Cassese, G. et al. Inflamed kidneys of NZB/W mice are a major site for the homeostasis of plasma cells. Eur. J. Immunol. 31, 2726–2732 (2001).
van Laar, J. M. et al. Sustained secretion of immunoglobulin by long-lived human tonsil plasma cells. Am. J. Pathol. 171, 917–927 (2007).
Hiepe, F. & Radbruch, A. Is long-term humoral immunity in the mucosa provided by long-lived plasma cells? A question still open. Eur. J. Immunol. 36, 1068–1069 (2006).
Cassese, G. et al. Plasma cell survival is mediated by synergistic effects of cytokines and adhesion-dependent signals. J. Immunol. 171, 1684–1690 (2003).
Tokoyoda, K., Egawa, T., Sugiyama, T., Choi, B. I. & Nagasawa, T. Cellular niches controlling B lymphocyte behavior within bone marrow during development. Immunity 20, 707–718 (2004).
Tokoyoda, K., Hauser, A. E., Nakayama, T. & Radbruch, A. Organization of immunological memory by bone marrow stroma. Nat. Rev. Immunol. 10, 193–200 (2010).
Chu, V. T., Fröhich, A., Steinhauser, G., Scheel. T., Roch, T., Fillatreau, S., Lee, J. J., Löhning, M. & Berek, C. Eosinophils are required for the maintenance of plasma cells in the bone marrow. Nat. Immunol. (in press).
Winter, O. et al. Megakaryocytes constitute a functional component of a plasma cell niche in the bone marrow. Blood 116, 1867–1875 (2010).
Geffroy-Luseau, A., Jégo, G., Bataille, R., Campion, L. & Pellat-Deceunynck, C. Osteoclasts support the survival of human plasma cells in vitro. Int. Immunol. 20, 775–782 (2008).
O'Connor, B. P. et al. BCMA is essential for the survival of long-lived bone marrow plasma cells. J. Exp. Med. 199, 91–98 (2004).
Avery, D. T. et al. BAFF selectively enhances the survival of plasmablasts generated from human memory B cells. J. Clin. Invest. 112, 286–297 (2003).
Benson, M. J. et al. Cutting edge: the dependence of plasma cells and independence of memory B cells on BAFF and APRIL. J. Immunol. 180, 3655–3659 (2008).
Gross, J. A. et al. TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature 404, 995–999 (2000).
Belnoue, E. et al. APRIL is critical for plasmablast survival in the bone marrow and poorly expressed by early-life bone marrow stromal cells. Blood 111, 2755–2764 (2008).
Underhill, G. H., Minges Wols, H. A., Fornek, J. L., Witte, P. L. & Kansas, G. S. IgG plasma cells display a unique spectrum of leukocyte adhesion and homing molecules. Blood 99, 2905–2912 (2002).
Chevrier, S. et al. CD93 is required for maintenance of antibody secretion and persistence of plasma cells in the bone marrow niche. Proc. Natl Acad. Sci. USA 106, 3895–3900 (2009).
Xiang, Z. et al. FcγRIIb controls bone marrow plasma cell persistence and apoptosis. Nat. Immunol. 8, 419–429 (2007).
Neubert, K. et al. The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis. Nat. Med. 14, 748–755 (2008).
Mumtaz, I. M. Effects of immunosuppressive drugs and CD4+ T cell depletion on plasma cell survival in lupus prone (NZB/W) mice. Thesis, Charité Universitätsmedizin Berlin (2009).
Jacobi, A. M. et al. HLA-DRhigh/CD27high plasmablasts indicate active disease in patients with systemic lupus erythematosus. Ann. Rheum. Dis. 69, 305–308 (2010).
Ahuja, A., Anderson, S. M., Khalil, A. & Shlomchik, M. J. Maintenance of the plasma cell pool is independent of memory B cells. Proc. Natl Acad. Sci. USA 105, 4802–1807 (2008).
DiLillo, D. J. et al. Maintenance of long-lived plasma cells and serological memory despite mature and memory B cell depletion during CD20 immunotherapy in mice. J. Immunol. 180, 361–371 (2008).
Cambridge, G. et al. Serologic changes following B lymphocyte depletion therapy for rheumatoid arthritis. Arthritis Rheum. 48, 2146–2154 (2003).
Ferraro, A. J., Drayson, M. T., Savage, C. O. & MacLennan, I. C. Levels of autoantibodies, unlike antibodies to all extrinsic antigen groups, fall following B cell depletion with Rituximab. Eur. J. Immunol. 38, 292–298 (2008).
Ahmed, A. R., Spigelman, Z., Cavacini, L. A. & Posner, M. R. Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin. N. Engl. J. Med. 355, 1772–1779 (2006).
Cambridge, G. et al. B cell depletion therapy in systemic lupus erythematosus: relationships among serum B lymphocyte stimulator levels, autoantibody profile and clinical response. Ann. Rheum. Dis. 67, 1011–1016 (2008).
Cohen, S. B. et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum. 54, 2793–2806 (2006).
Edwards, J. C. et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N. Engl. J. Med. 350, 2572–2581 (2004).
Ioannou, Y. et al. B cell depletion therapy for patients with systemic lupus erythematosus results in a significant drop in anticardiolipin antibody titres. Ann. Rheum. Dis. 67, 425–426 (2008).
Lu, T. Y. et al. A retrospective seven-year analysis of the use of B cell depletion therapy in systemic lupus erythematosus at University College London Hospital: the first fifty patients. Arthritis Rheum. 61, 482–487 (2009).
Smith, K. G., Jones, R. B., Burns, S. M. & Jayne, D. R. Long-term comparison of rituximab treatment for refractory systemic lupus erythematosus and vasculitis: Remission, relapse, and re-treatment. Arthritis Rheum. 54, 2970–2982 (2006).
Tew, G. W. et al. Baseline autoantibody profiles predict normalization of complement and anti-dsDNA autoantibody levels following Rituximab treatment in systemic lupus erythematosus. Lupus 19, 146–157 (2010).
Ng, K. P. et al. B cell depletion therapy in systemic lupus erythematosus: long-term follow-up and predictors of response. Ann. Rheum. Dis. 66, 1259–1262 (2007).
Vallin, H., Perers, A., Alm, G. V. & Rönnblom, L. Anti-double-stranded DNA antibodies and immunostimulatory plasmid DNA in combination mimic the endogenous IFN-α inducer in systemic lupus erythematosus. J. Immunol. 163, 6306–6313 (1999).
Eloranta, M. L. et al. A possible mechanism for endogenous activation of the type I interferon system in myositis patients with anti-Jo-1 or anti-Ro 52/anti-Ro 60 autoantibodies. Arthritis Rheum. 56, 3112–3124 (2007).
Baccala, R., Hoebe, K., Kono, D. H., Beutler, B. & Theofilopoulos, A. N. TLR-dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity. Nat. Med. 13, 543–551 (2007).
Hall, J. C. & Rosen, A. Type I interferons: crucial participants in disease amplification in autoimmunity. Nat. Rev. Rheumatol. 6, 40–49 (2010).
Banchereau, J., Pascual, V. & Palucka, A. K. Autoimmunity through cytokine-induced dendritic cell activation. Immunity 20, 539–550 (2004).
Clavel, C. et al. Induction of macrophage secretion of tumor necrosis factor α through Fcgγ receptor IIa engagement by rheumatoid arthritis-specific autoantibodies to citrullinated proteins complexed with fibrinogen. Arthritis Rheum. 58, 678–688 (2008).
Shlomchik, M. J. Activating systemic autoimmunity: B's, T's, and tolls. Curr. Opin. Immunol. 21, 626–633 (2009).
Arbuckle, M. R. et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N. Engl. J. Med. 349, 1526–1533 (2003).
Nielen, M. M. et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 50, 380–386 (2004).
Rantapää-Dahlqvist, S. et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 48, 2741–2749 (2003).
Teng, Y. K., Levarht, E. W., Toes, R. E., Huizinga, T. W. & van Laar, J. M. Residual inflammation after rituximab treatment is associated with sustained synovial plasma cell infiltration and enhanced B cell repopulation. Ann. Rheum. Dis. 68, 1011–1016 (2009).
Sekine, H., Watanabe, H. & Gilkeson, G. S. Enrichment of anti-glomerular antigen antibody-producing cells in the kidneys of MRL/MpJ-Fas(lpr) mice. J. Immunol. 172, 3913–3921 (2004).
Salomonsson, S. et al. Cellular basis of ectopic germinal center formation and autoantibody production in the target organ of patients with Sjögren's syndrome. Arthritis Rheum. 48, 3187–3201 (2003).
Tengner, P., Halse, A. K., Haga, H. J., Jonsson, R. & Wahren-Herlenius, M. Detection of anti-Ro/SSA and anti-La/SSB autoantibody-producing cells in salivary glands from patients with Sjögren's syndrome. Arthritis Rheum. 41, 2238–2248 (1998).
Odendahl, M. et al. Generation of migratory antigen-specific plasma blasts and mobilization of resident plasma cells in a secondary immune response. Blood 105, 1614–1621 (2005).
Höfer, T. et al. Adaptation of humoral memory. Immunol. Rev. 211, 295–302 (2006).
Bernasconi, N. L., Traggiai, E. & Lanzavecchia, A. Maintenance of serological memory by polyclonal activation of human memory B cells. Science 298, 2199–2202 (2002).
Odendahl, M. et al. Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus. J. Immunol. 165, 5970–5979 (2000).
Sykes, M. & Nikolic, B. Treatment of severe autoimmune disease by stem-cell transplantation. Nature 435, 620–627 (2005).
Tyndall, A. & Gratwohl, A. Adult stem cell transplantation in autoimmune disease. Curr. Opin. Hematol. 16, 285–291 (2009).
Nikolov, N. P. & Pavletic, S. Z. Technology Insight: hematopoietic stem cell transplantation for systemic rheumatic disease. Nat. Clin. Pract. Rheumatol. 4, 184–191 (2008).
Zand, M. S. et al. Polyclonal rabbit antithymocyte globulin triggers B-cell and plasma cell apoptosis by multiple pathways. Transplantation 79, 1507–1515 (2005).
Zand, M. S. et al. Apoptosis and complement-mediated lysis of myeloma cells by polyclonal rabbit antithymocyte globulin. Blood 107, 2895–2903 (2006).
Alexander, T. et al. Depletion of autoreactive immunologic memory followed by autologous hematopoietic stem cell transplantation in patients with refractory SLE induces long-term remission through de novo generation of a juvenile and tolerant immune system. Blood 113, 214–223 (2009).
Meister, S. et al. Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition. Cancer Res. 67, 1783–1792 (2007).
Everly, M. J. et al. Reducing de novo donor-specific antibody levels during acute rejection diminishes renal allograft loss. Am. J. Transplant. 9, 1063–1071 (2009).
Everly, M. J. et al. Proteasome inhibition reduces donor-specific antibody levels. Transplant. Proc. 41, 105–107 (2009).
Trivedi, H. L. et al. Abrogation of anti-HLA antibodies via proteasome inhibition. Transplantation 87, 1555–1561 (2009).
Ngo, H. T. et al. SDF-1/CXCR4 and VLA-4 interaction regulates homing in Waldenstrom macroglobulinemia. Blood 112, 150–158 (2008).
Azab, A. K. et al. CXCR4 inhibitor AMD3100 disrupts the interaction of multiple myeloma cells with the bone marrow microenvironment and enhances their sensitivity to therapy. Blood 113, 4341–4351 (2009).
Ramanujam, M. et al. Similarities and differences between selective and nonselective BAFF blockade in murine SLE. J. Clin. Invest. 116, 724–734 (2006).
Dall'Era, M. et al. Reduced B lymphocyte and immunoglobulin levels after atacicept treatment in patients with systemic lupus erythematosus: results of a multicenter, phase Ib, double-blind, placebo-controlled, dose-escalating trial. Arthritis Rheum. 56, 4142–4150 (2007).
Jacobi, A. M. et al. Effect of long-term belimumab treatment on b cells in systemic lupus erythematosus: extension of a phase II, double-blind, placebo-controlled, dose-ranging study. Arthritis Rheum. 62, 201–210 (2009).
Moser, K., Tokoyoda, K., Radbruch, A., MacLennan, I. & Manz, R. A. Stromal niches, plasma cell differentiation and survival. Curr. Opin. Immunol. 18, 265–270 (2006).
Yao, K. et al. Reactivation of human herpesvirus-6 in natalizumab treated multiple sclerosis patients. PLoS ONE 3, e2028 (2008).
Yoshida, T. et al. Memory B and memory plasma cells. Immunol. Rev. 237, 117–139 (2010).
Ikeda, H. et al. The monoclonal antibody nBT062 conjugated to cytotoxic Maytansinoids has selective cytotoxicity against CD138-positive multiple myeloma cells in vitro and in vivo. Clin. Cancer Res. 15, 4028–4037 (2009).
Polson, A. G. & Sliwkowski, M. X. Toward an effective targeted chemotherapy for multiple myeloma. Clin. Cancer Res. 15, 3906–3907 (2009).
Post, J., Vooijs, W. C., Bast, B. J. & De Gast, G. C. Efficacy of an anti-CD138 immunotoxin and doxorubicin on drug-resistant and drug-sensitive myeloma cells. Int. J. Cancer 83, 571–576 (1999).
Martins, G. & Calame, K. Regulation and functions of Blimp-1 in T and B lymphocytes. Annu. Rev. Immunol. 26, 133–169 (2008).
Acknowledgements
This work was supported by a grant from the German Research Foundation (SFB 650).
Author information
Authors and Affiliations
Contributions
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.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
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
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrrheum.2011.1
This article is cited by
-
Bortezomib is efficacious in the treatment of severe childhood-onset neuropsychiatric systemic lupus erythematosus with psychosis: a case series and mini-review of B-cell immunomodulation in antibody-mediated diseases
Clinical Rheumatology (2023)
-
Hematopoietic stem cell transplantation and cellular therapies for autoimmune diseases: overview and future considerations from the Autoimmune Diseases Working Party (ADWP) of the European Society for Blood and Marrow Transplantation (EBMT)
Bone Marrow Transplantation (2022)
-
Supplying the trip to antibody production—nutrients, signaling, and the programming of cellular metabolism in the mature B lineage
Cellular & Molecular Immunology (2022)
-
B-Lymphozyten und Plasmazellen als Treiber rheumatischer Erkrankungen
Zeitschrift für Rheumatologie (2022)
-
Immunological memory in rheumatic inflammation — a roadblock to tolerance induction
Nature Reviews Rheumatology (2021)