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  • Review Article
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Competence and competition: the challenge of becoming a long-lived plasma cell

Nature Reviews Immunology volume 6, pages 741–750 (2006)Cite this article

Key Points

  • Humoral memory is provided by long-lived plasma cells.

  • Plasmablasts that are competent to become long-lived plasma cells are generated from memory B cells, but it has not been excluded that they might be generated from other B-cell subtypes.

  • The survival of plasma cells requires cell-intrinsic competence, as well as signals from an extrinsic survival niche.

  • Plasma-cell survival niches are located in the bone marrow, secondary lymphoid organs and inflamed tissue.

  • Competent plasmablasts can migrate to survival niches, whereas plasma cells cannot.

  • The resolution of inflammation destroys plasma-cell survival niches in inflamed tissue and therefore eliminates these plasma cells, which are immobile and tissue resident, after an immune response.

  • Humoral memory adapts to new antigens by successful competition between newly generated plasmablasts (which have a migratory capacity) and previously generated ('old') resident bone-marrow plasma cells (which are immobile) for survival niches in the bone marrow.

  • Long-lived plasma cells can drive chronic autoimmunity and allergy and are a candidate target for curative therapies of these diseases.

Abstract

Plasma cells provide humoral immunity. They have traditionally been viewed mainly as short-lived end-stage products of B-cell differentiation that deserve little interest. This view is changing, however, because we now know that plasma cells can survive for long periods in the appropriate survival niches and that they are an independent cellular component of immunological memory. Studies of the biology of plasma cells reveal a mechanism of intriguing simplicity and elegance that focuses memory provided by plasma cells on recently encountered pathogens while minimizing the 'fading' of memory for pathogens encountered in the distant past. This mechanism is based on competition for survival niches between newly generated plasmablasts and older plasma cells.

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Figure 1: Three concepts for the maintenance of serum concentrations of specific antibody.
Figure 2: Competition between plasmablasts and plasma cells for survival niches, which is driven by CXC-chemokine ligand 12, both as an attractant of plasmablasts and as a survival factor for long-lived plasma cells.
Figure 3: Ontogeny of plasma cells.
Figure 4: The kinetics of the humoral immune response in BALB/c mice following secondary immunization with ovalbumin.

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References

  1. Behring, E. V. & Kitasato, S. Ueber das Zustandekommen der Diphtherie-Immunitaet und der Tetanus-Immunitaet bei Thieren. Dtsch. Med. Wochenschr. 16, 1113–1114 (1890) (in German).

    Google Scholar 

  2. Fagraeus, A. Antibody production in relation to the development of plasma cells. In vivo and in vitro experiments. Acta Med. Scand. 130, 7–122 (1948).

    Google Scholar 

  3. Ahmed, R. & Gray, D. Immunological memory and protective immunity: understanding their relation. Science 272, 54–60 (1996).

    CAS  PubMed  Google Scholar 

  4. Bernasconi, N. L., Traggiai, E. & Lanzavecchia, A. Maintenance of serological memory by polyclonal activation of human memory B cells. Science 298, 2199–2202 (2002). Introduces the concept that polyclonal bystander activation of memory B cells maintains serum antibody concentrations (that is, humoral memory).

    CAS  PubMed  Google Scholar 

  5. Manz, R. A., Thiel, A. & Radbruch, A. Lifetime of plasma cells in the bone marrow. Nature 388, 133–134 (1997). Directly shows longevity of bone-marrow plasma cells.

    CAS  PubMed  Google Scholar 

  6. Szakal, A. K., Kosco, M. H. & Tew, J. G. Microanatomy of lymphoid tissue during humoral immune responses: structure function relationships. Annu. Rev. Immunol. 7, 91–109 (1989).

    CAS  PubMed  Google Scholar 

  7. Zinkernagel, R. M. et al. On immunological memory. Annu. Rev. Immunol. 14, 333–367 (1996).

    CAS  PubMed  Google Scholar 

  8. Traggiai, E., Puzone, R. & Lanzavecchia, A. Antigen dependent and independent mechanisms that sustain serum antibody levels. Vaccine 21, S35–S37 (2003).

    PubMed  Google Scholar 

  9. Cooper, E. H. Production of lymphocytes and plasma cells in the rat following immunization with human serum albumin. Immunology 4, 219–231 (1961).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Nossal, G. J. Genetic control of lymphopoiesis, plasma cell formation, and antibody production. Int. Rev. Exp. Pathol. 1, 1–72 (1962).

    CAS  PubMed  Google Scholar 

  11. Schooley, J. C. Autoradiographic observations of plasma cell formation. J. Immunol. 86, 331–337 (1961).

    CAS  PubMed  Google Scholar 

  12. 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).

    CAS  PubMed  Google Scholar 

  13. Slifka, M. K., Antia, R., Whitmire, J. K. & Ahmed, R. Humoral immunity due to long-lived plasma cells. Immunity 8, 363–372 (1998).

    CAS  PubMed  Google Scholar 

  14. Iwakoshi, N. N. et al. Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1. Nature Immunol. 4, 321–329 (2003).

    CAS  Google Scholar 

  15. Shapiro-Shelef, M. & Calame, K. Regulation of plasma-cell development. Nature Rev. Immunol. 5, 230–242 (2005).

    CAS  Google Scholar 

  16. Rajewsky, K. Clonal selection and learning in the antibody system. Nature 381, 751–758 (1996).

    CAS  PubMed  Google Scholar 

  17. Carsetti, R., Rosado, M. M. & Wardmann, H. Peripheral development of B cells in mouse and man. Immunol. Rev. 197, 179–191 (2004).

    PubMed  Google Scholar 

  18. MacLennan, I. C. Germinal centers. Annu. Rev. Immunol. 12, 117–139 (1994).

    CAS  PubMed  Google Scholar 

  19. Liu, Y. J. & Arpin, C. Germinal center development. Immunol. Rev. 156, 111–126 (1997).

    CAS  PubMed  Google Scholar 

  20. Schittek, B. & Rajewsky, K. Maintenance of B-cell memory by long-lived cells generated from proliferating precursors. Nature 346, 749–751 (1990).

    CAS  PubMed  Google Scholar 

  21. Tarlinton, D. M. & Smith, K. G. Apoptosis and the B cell response to antigen. Int. Rev. Immunol. 15, 53–71 (1997).

    CAS  PubMed  Google Scholar 

  22. 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).

    CAS  PubMed  Google Scholar 

  23. Smith, K. G. et al. bcl-2 transgene expression inhibits apoptosis in the germinal center and reveals differences in the selection of memory B cells and bone marrow antibody-forming cells. J. Exp. Med. 191, 475–484 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Ochsenbein, A. F. et al. Protective long-term antibody memory by antigen-driven and T help-dependent differentiation of long-lived memory B cells to short-lived plasma cells independent of secondary lymphoid organs. Proc. Natl Acad. Sci. USA 97, 13263–13268 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Driver, D. J., McHeyzer-Williams, L. J., Cool, M., Stetson, D. B. & McHeyzer-Williams, M. G. Development and maintenance of a B220− memory B cell compartment. J. Immunol. 167, 1393–1405 (2001).

    CAS  PubMed  Google Scholar 

  27. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Dorner, T. & Radbruch, A. Selecting B cells and plasma cells to memory. J. Exp. Med. 201, 497–499 (2005).

    PubMed  PubMed Central  Google Scholar 

  29. Ozaki, K. et al. Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6. J. Immunol. 173, 5361–5371 (2004).

    CAS  PubMed  Google Scholar 

  30. 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).

    CAS  PubMed  Google Scholar 

  31. Lin, K. I., Tunyaplin, C. & Calame, K. Transcriptional regulatory cascades controlling plasma cell differentiation. Immunol. Rev. 194, 19–28 (2003).

    CAS  PubMed  Google Scholar 

  32. Ho, F., Lortan, J. E., MacLennan, I. C. & Khan, M. Distinct short-lived and long-lived antibody-producing cell populations. Eur. J. Immunol. 16, 1297–1301 (1986).

    CAS  PubMed  Google Scholar 

  33. 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). Shows that both long-lived and short-lived plasma cells produce autoantibodies.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Koch, G. & Benner, R. Differential requirement for B-memory and T-memory cells in adoptive antibody formation in mouse bone marrow. Immunology 45, 697–704 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Ellyard, J. I. et al. Antigen-selected, immunoglobulin-secreting cells persist in human spleen and bone marrow. Blood 103, 3805–3812 (2004).

    CAS  PubMed  Google Scholar 

  36. Smith, K. G., Hewitson, T. D., Nossal, G. J. & Tarlinton, D. M. The phenotype and fate of the antibody-forming cells of the splenic foci. Eur. J. Immunol. 26, 444–448 (1996).

    CAS  PubMed  Google Scholar 

  37. McMillan, R. et al. Immunoglobulin synthesis by human lymphoid tissues: normal bone marrow as a major site of IgG production. J. Immunol. 109, 1386–1394 (1972).

    CAS  PubMed  Google Scholar 

  38. Medina, F., Segundo, C., Campos-Caro, A., Gonzalez-Garcia, I. & Brieva, J. A. The heterogeneity shown by human plasma cells from tonsil, blood, and bone marrow reveals graded stages of increasing maturity, but local profiles of adhesion molecule expression. Blood 99, 2154–2161 (2002).

    CAS  PubMed  Google Scholar 

  39. 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).

    CAS  PubMed  Google Scholar 

  40. Hutloff, A. et al. Involvement of inducible costimulator in the exaggerated memory B cell and plasma cell generation in systemic lupus erythematosus. Arthritis Rheum. 50, 3211–3220 (2004).

    PubMed  Google Scholar 

  41. Tsubaki, T. et al. Accumulation of plasma cells expressing CXCR3 in the synovial sublining regions of early rheumatoid arthritis in association with production of Mig/CXCL9 by synovial fibroblasts. Clin. Exp. Immunol. 141, 363–371 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Schroder, A. E., Greiner, A., Seyfert, C. & Berek, C. Differentiation of B cells in the nonlymphoid tissue of the synovial membrane of patients with rheumatoid arthritis. Proc. Natl Acad. Sci. USA 93, 221–225 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Bullard, D. C. et al. Infectious susceptibility and severe deficiency of leukocyte rolling and recruitment in E-selectin and P-selectin double mutant mice. J. Exp. Med. 183, 2329–2336 (1996).

    CAS  PubMed  Google Scholar 

  44. 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).

    CAS  PubMed  Google Scholar 

  45. Ellyard, J. I., Avery, D. T., Mackay, C. R. & Tangye, S. G. Contribution of stromal cells to the migration, function and retention of plasma cells in human spleen: potential roles of CXCL12, IL-6 and CD54. Eur. J. Immunol. 35, 699–708 (2005).

    CAS  PubMed  Google Scholar 

  46. Pabst, O. et al. Egress of newly generated plasma cells from peripheral lymph nodes depends on β2 integrin. J. Immunol. 174, 7492–7495 (2005). Provides evidence that β 2 -integrins are required for the exit of plasma cells from peripheral lymph nodes.

    CAS  PubMed  Google Scholar 

  47. Cassese, G. et al. Plasma cell survival is mediated by synergistic effects of cytokines and adhesion-dependent signals. J. Immunol. 171, 1684–1690 (2003).

    CAS  PubMed  Google Scholar 

  48. Barker, H. F., Hamilton, M. S., Ball, J., Drew, M. & Franklin, I. M. Expression of adhesion molecules LFA-3 and N-CAM on normal and malignant human plasma cells. Br. J. Haematol. 81, 331–335 (1992).

    CAS  PubMed  Google Scholar 

  49. Allen, C. D. et al. Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5. Nature Immunol. 5, 943–952 (2004).

    CAS  Google Scholar 

  50. Wehrli, N. et al. Changing responsiveness to chemokines allows medullary plasmablasts to leave lymph nodes. Eur. J. Immunol. 31, 609–616 (2001). Describes the role of CXCR4 in plasmablast migration.

    CAS  PubMed  Google Scholar 

  51. Hargreaves, D. C. et al. A coordinated change in chemokine responsiveness guides plasma cell movements. J. Exp. Med. 194, 45–56 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 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).

    CAS  PubMed  Google Scholar 

  53. Nie, Y. et al. The role of CXCR4 in maintaining peripheral B cell compartments and humoral immunity. J. Exp. Med. 200, 1145–1156 (2004). Shows that plasma-cell accumulation in the bone marrow is impaired in CXCR4-deficient mice. However, following immunization, normal numbers of bone-marrow plasma cells are generated, indicating that CXCR4 is important, but not essential, for this process.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 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). Shows that plasma cells and CXCL12-expressing stromal cells colocalize in the bone marrow.

    CAS  PubMed  Google Scholar 

  55. 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).

    CAS  PubMed  Google Scholar 

  56. Baggiolini, M. Chemokines and leukocyte traffic. Nature 392, 565–568 (1998).

    CAS  PubMed  Google Scholar 

  57. Bowman, E. P. et al. The intestinal chemokine thymus-expressed chemokine (CCL25) attracts IgA antibody-secreting cells. J. Exp. Med. 195, 269–275 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Kunkel, E. J. & Butcher, E. C. Plasma-cell homing. Nature Rev. Immunol. 3, 822–829 (2003).

    CAS  Google Scholar 

  59. Kunkel, E. J. et al. CCR10 expression is a common feature of circulating and mucosal epithelial tissue IgA Ab-secreting cells. J. Clin. Invest. 111, 1001–1010 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Lazarus, N. H. et al. A common mucosal chemokine (mucosae-associated epithelial chemokine/CCL28) selectively attracts IgA plasmablasts. J. Immunol. 170, 3799–3805 (2003).

    CAS  PubMed  Google Scholar 

  61. Etchart, N. et al. Intranasal immunisation with inactivated RSV and bacterial adjuvants induces mucosal protection and abrogates eosinophilia upon challenge. Eur. J. Immunol. 36, 1136–1144 (2006).

    CAS  PubMed  Google Scholar 

  62. 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).

    CAS  PubMed  Google Scholar 

  63. Cyster, J. G. Homing of antibody secreting cells. Immunol. Rev. 194, 48–60 (2003).

    CAS  PubMed  Google Scholar 

  64. 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). Reports that the mobilization of plasmablasts into the blood occurs together with the mobilization of resident bone-marrow plasma cells. Provides evidence for the concept of competition between plasmablasts and plasma cells.

    CAS  PubMed  Google Scholar 

  65. Nossal, G. J., Szenberg, A., Ada, G. L. & Austin, C. M. Single cell studies on 19S antibody production. J. Exp. Med. 119, 485–502 (1964).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Nossal, G. J. & Makela, O. Kinetic studies on the incidence of cells appearing to form two antibodies. J. Immunol. 88, 604–612 (1962).

    CAS  PubMed  Google Scholar 

  67. Höfer, T. et al. Adaptation of humoral memory. Immunol. Rev. 211, 295–302 (2006).

    PubMed  Google Scholar 

  68. Miller, J. J. 3rd . An autoradiographic study of plasma cell and lymphocyte survival in rat popliteal lymph nodes. J. Immunol. 92, 673–681 (1964).

    PubMed  Google Scholar 

  69. Manz, R. A., Lohning, M., Cassese, G., Thiel, A. & Radbruch, A. Survival of long-lived plasma cells is independent of antigen. Int. Immunol. 10, 1703–1711 (1998).

    CAS  PubMed  Google Scholar 

  70. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Shapiro-Shelef, M. et al. Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells. Immunity 19, 607–620 (2003).

    CAS  PubMed  Google Scholar 

  72. Iwakoshi, N. N., Lee, A. H. & Glimcher, L. H. The X-box binding protein-1 transcription factor is required for plasma cell differentiation and the unfolded protein response. Immunol. Rev. 194, 29–38 (2003).

    CAS  PubMed  Google Scholar 

  73. Shaffer, A. L. et al. XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity 21, 81–93 (2004).

    CAS  PubMed  Google Scholar 

  74. Lee, A. H., Iwakoshi, N. N., Anderson, K. C. & Glimcher, L. H. Proteasome inhibitors disrupt the unfolded protein response in myeloma cells. Proc. Natl Acad. Sci. USA 100, 9946–9951 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Cortes, M. & Georgopoulos, K. Aiolos is required for the generation of high affinity bone marrow plasma cells responsible for long-term immunity. J. Exp. Med. 199, 209–219 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Ren, B., Chee, K. J., Kim, T. H. & Maniatis, T. PRDI-BF1/Blimp-1 repression is mediated by corepressors of the Groucho family of proteins. Genes Dev. 13, 125–137 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Yu, J., Angelin-Duclos, C., Greenwood, J., Liao, J. & Calame, K. Transcriptional repression by Blimp-1 (PRDI-BF1) involves recruitment of histone deacetylase. Mol. Cell. Biol. 20, 2592–2603 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Gyory, I., Wu, J., Fejer, G., Seto, E. & Wright, K. L. PRDI-BF1 recruits the histone H3 methyltransferase G9a in transcriptional silencing. Nature Immunol. 5, 299–308 (2004).

    CAS  Google Scholar 

  79. Minges Wols, H. A., Underhill, G. H., Kansas, G. S. & Witte, P. L. The role of bone marrow-derived stromal cells in the maintenance of plasma cell longevity. J. Immunol. 169, 4213–4221 (2002).

    CAS  PubMed  Google Scholar 

  80. Uchiyama, H., Barut, B. A., Mohrbacher, A. F., Chauhan, D. & Anderson, K. C. Adhesion of human myeloma-derived cell lines to bone marrow stromal cells stimulates interleukin-6 secretion. Blood 82, 3712–3720 (1993).

    CAS  PubMed  Google Scholar 

  81. 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). Defines a role for BCMA in the establishment or maintenance of humoral memory.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Ingold, K. et al. Identification of proteoglycans as the APRIL-specific binding partners. J. Exp. Med. 201, 1375–1383 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Hirano, T. & Kishimoto, T. Interleukin 6 and plasma cell neoplasias. Prog. Growth Factor Res. 1, 133–142 (1989).

    CAS  PubMed  Google Scholar 

  85. MacLennan, I. & Vinuesa, C. Dendritic cells, BAFF, and APRIL: innate players in adaptive antibody responses. Immunity 17, 235–238 (2002).

    CAS  PubMed  Google Scholar 

  86. Schneider, P. The role of APRIL and BAFF in lymphocyte activation. Curr. Opin. Immunol. 17, 282–289 (2005).

    CAS  PubMed  Google Scholar 

  87. Terstappen, L. W., Johnsen, S., Segers-Nolten, I. M. & Loken, M. R. Identification and characterization of plasma cells in normal human bone marrow by high-resolution flow cytometry. Blood 76, 1739–1747 (1990).

    CAS  PubMed  Google Scholar 

  88. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Trepel, F. Number and distribution of lymphocytes in man. A critical analysis. Klin. Wochenschr. 52, 511–515 (1974).

    CAS  PubMed  Google Scholar 

  90. Pihlgren, M. et al. Delayed and deficient establishment of the long-term bone marrow plasma cell pool during early life. Eur. J. Immunol. 31, 939–946 (2001).

    CAS  PubMed  Google Scholar 

  91. Schauer, U. et al. Levels of antibodies specific to tetanus toxoid, Haemophilus influenzae type b, and pneumococcal capsular polysaccharide in healthy children and adults. Clin. Diagn. Lab. Immunol. 10, 202–207 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Vieira, P. & Rajewsky, K. The half-lives of serum immunoglobulins in adult mice. Eur. J. Immunol. 18, 313–316 (1988).

    CAS  PubMed  Google Scholar 

  93. Simonsen, O. et al. Revaccination of adults against diphtheria. II: combined diphtheria and tetanus revaccination with different doses of diphtheria toxoid 20 years after primary vaccination. Acta Pathol. Microbiol. Immunol. Scand. C 94, 219–225 (1986).

    CAS  PubMed  Google Scholar 

  94. Lichtenstein, L. M., Ishizaka, K., Norman, P. S., Sobotka, A. K. & Hill, B. M. IgE antibody measurements in ragweed hay fever. Relationship to clinical severity and the results of immunotherapy. J. Clin. Invest. 52, 472–482 (1973).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Hallstrand, T. S. et al. Long-term acquisition of allergen-specific IgE and asthma following allogeneic bone marrow transplantation from allergic donors. Blood 104, 3086–3090 (2004).

    CAS  PubMed  Google Scholar 

  96. Bergstedt-Lindqvist, S. et al. Interleukin 4 instructs uncommitted B lymphocytes to switch to IgG1 and IgE. Eur. J. Immunol. 18, 1073–1077 (1988).

    CAS  PubMed  Google Scholar 

  97. Cheong, H. S. et al. CXCR3 polymorphisms associated with risk of asthma. Biochem. Biophys. Res. Commun. 334, 1219–1225 (2005).

    CAS  PubMed  Google Scholar 

  98. Chvatchko, Y., Kosco-Vilbois, M. H., Herren, S., Lefort, J. & Bonnefoy, J. Y. Germinal center formation and local immunoglobulin E (IgE) production in the lung after an airway antigenic challenge. J. Exp. Med. 184, 2353–2360 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Astrom, K. et al. Analysis of ɛ germline transcripts and IL-4 mRNA expression in the adenoids suggests local IgE switching. Allergy 55, 1049–1055 (2000).

    CAS  PubMed  Google Scholar 

  100. Coker, H. A., Durham, S. R. & Gould, H. J. Local somatic hypermutation and class switch recombination in the nasal mucosa of allergic rhinitis patients. J. Immunol. 171, 5602–5610 (2003).

    CAS  PubMed  Google Scholar 

  101. Wyczolkowska, J., Brzezinska-Blaszczyk, E. & Maslinski, C. Kinetics of specific IgE antibody and total IgE responses in mice: the effect of immunosuppressive treatment. Int. Arch. Allergy Appl. Immunol. 72, 16–21 (1983).

    CAS  PubMed  Google Scholar 

  102. Brunette, M. G., Bonny, Y., Spigelblatt, L. & Barrette, G. Long-term immunosuppressive treatment of a child with Takayasu's arteritis and high IgE immunoglobulins. Pediatr. Nephrol. 10, 67–69 (1996).

    CAS  PubMed  Google Scholar 

  103. Martin, F. & Chan, A. C. Pathogenic roles of B cells in human autoimmunity: insights from the clinic. Immunity 20, 517–527 (2004).

    CAS  PubMed  Google Scholar 

  104. Lipsky, P. E. Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity. Nature Immunol. 2, 764–766 (2001).

    CAS  Google Scholar 

  105. von Muhlen, C. A. & Tan, E. M. Autoantibodies in the diagnosis of systemic rheumatic diseases. Semin. Arthritis Rheum. 24, 323–358 (1995).

    CAS  PubMed  Google Scholar 

  106. Chiovato, L. et al. Disappearance of humoral thyroid autoimmunity after complete removal of thyroid antigens. Ann. Intern. Med. 139, 346–351 (2003).

    CAS  PubMed  Google Scholar 

  107. de Groot, P. G. & Derksen, R. H. Pathophysiology of the antiphospholipid syndrome. J. Thromb. Haemost. 3, 1854–1860 (2005).

    CAS  PubMed  Google Scholar 

  108. Hughes, B. W., Moro De Casillas, M. L. & Kaminski, H. J. Pathophysiology of myasthenia gravis. Semin. Neurol. 24, 21–30 (2004).

    PubMed  Google Scholar 

  109. Amagai, M. Autoimmunity against desmosomal cadherins in pemphigus. J. Dermatol. Sci. 20, 92–102 (1999).

    CAS  PubMed  Google Scholar 

  110. Gross, W. L. Churg–Strauss syndrome: update on recent developments. Curr. Opin. Rheumatol. 14, 11–14 (2002).

    CAS  PubMed  Google Scholar 

  111. Carroll, M. C. A protective role for innate immunity in systemic lupus erythematosus. Nature Rev. Immunol. 4, 825–831 (2004).

    CAS  Google Scholar 

  112. Brard, F., Shannon, M., Prak, E. L., Litwin, S. & Weigert, M. Somatic mutation and light chain rearrangement generate autoimmunity in anti-single-stranded DNA transgenic MRL/lpr mice. J. Exp. Med. 190, 691–704 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Shlomchik, M. et al. Anti-DNA antibodies from autoimmune mice arise by clonal expansion and somatic mutation. J. Exp. Med. 171, 265–292 (1990).

    CAS  PubMed  Google Scholar 

  114. Ishii, Y., Nagasawa, K., Mightumi, T. & Niho, Y. Clinical importance of persistence of anticardiolipin antibodies in systemic lupus erythematosus. Ann. Rheum. Dis. 49, 387–390 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Jacobi, A. M. et al. Correlation between circulating CD27high plasma cells and disease activity in patients with systemic lupus erythematosus. Arthritis Rheum. 48, 1332–1342 (2003).

    PubMed  Google Scholar 

  116. Odendahl, M. et al. Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus. J. Immunol. 165, 5970–5979 (2000).

    CAS  PubMed  Google Scholar 

  117. Hiepe, F. et al. Long-lived CD20neg plasma cells contribute significantly to autoantibody production in SLE and represent a novel and essential target for cellular therapies. Arthritis Rheum. 50, S260 (2004).

    Google Scholar 

  118. 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).

    PubMed  Google Scholar 

  119. Scofield, R. H. Autoantibodies as predictors of disease. Lancet 363, 1544–1546 (2004).

    CAS  PubMed  Google Scholar 

  120. Arbuckle, M. R. et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N. Engl. J. Med. 349, 1526–1533 (2003).

    CAS  PubMed  Google Scholar 

  121. McClain, M. T. et al. The prevalence, onset, and clinical significance of antiphospholipid antibodies prior to diagnosis of systemic lupus erythematosus. Arthritis Rheum. 50, 1226–1232 (2004).

    PubMed  Google Scholar 

  122. Zand, M. S. et al. Polyclonal rabbit antithymocyte globulin triggers B-cell and plasma cell apoptosis by multiple pathways. Transplantation 79, 1507–1515 (2005).

    CAS  PubMed  Google Scholar 

  123. Jayne, D. & Tyndall, A. Autologous stem cell transplantation for systemic lupus erythematosus. Lupus 13, 359–365 (2004).

    CAS  PubMed  Google Scholar 

  124. Statkute, L. et al. Antiphospholipid syndrome in patients with systemic lupus erythematosus treated by autologous hematopoietic stem cell transplantation. Blood 106, 2700–2709 (2005).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank C. Raulfs for critical reading of the manuscript and the members of the Berlin B Cell Club for helpful discussions. We are especially grateful to R. A. Manz for helpful comments. This work was supported by the Deutsche Forschungs-gemeinschaft (Germany).

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Authors and Affiliations

  1. Deutsches Rheuma-Forschungszentrum Berlin, Charitéplatz 1, Berlin, D-10117, Germany

    Andreas Radbruch, Gwendolin Muehlinghaus, Ayako Inamine, Thomas Dörner & Falk Hiepe

  2. Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, Berlin, D-10117, Germany

    Andreas Radbruch & Falk Hiepe

  3. Department of Dermatology and Allergy, Allergy-Center-Charité, Charité - Universitätsmedizin Berlin, Charitéplatz 1, Berlin, D-10117, Germany

    Elke O. Luger

  4. Cambridge Institute for Medical Research and the Department of Medicine, University of Cambridge School of Clinical Medicine, Box 139, Addenbrooke's Hospital, Cambridge, CB2 2XY, UK

    Kenneth G. C. Smith

  5. Clinical Hemostaseology and Transfusion Medicine, Charité - Universitätsmedizin Berlin, Charitéplatz 1, Berlin, D-10117, Germany

    Thomas Dörner

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  1. Andreas Radbruch
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  2. Gwendolin Muehlinghaus
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  4. Ayako Inamine
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Correspondence to Andreas Radbruch.

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FURTHER INFORMATION

Deutsches Rheuma-Forschungszentrum Berlin

Glossary

Plasma cell

A non-dividing, terminally differentiated, immobile antibody-secreting cell of the B-cell lineage.

Unfolded-protein response

A response that increases the ability of the endoplasmic reticulum to fold and translocate proteins, decreases the synthesis of proteins, and causes the arrest of the cell cycle and apoptosis.

Plasmablast

A dividing antibody-secreting cell of the B-cell lineage that has migratory potential. These cells can further mature into plasma cells, which do not divide.

Marginal-zone B cell

A mature B cell that is enriched mainly in the marginal zone of the spleen, which is located at the border of the white pulp.

Germinal centre

A highly specialized and dynamic microenvironment that gives rise to secondary B-cell follicles during an immune response. It is the main site of B-cell maturation, leading to the generation of memory B cells and plasma cells that produce high-affinity antibody.

Class-switch recombination

A molecular alteration of the constant-region gene of the antibody heavy chain (CH) that leads to a switch in expression from the Cμ (or Cδ) region to one of the other CH genes. This leads to a switch in the class of the antibody that is displayed on the cell surface of the B cell (and that plasma cells subsequently produce) — from IgM (or IgD) to IgG, IgA or IgE — without altering the specificity of the antibody. This imparts flexibility to the humoral immune response and allows it to exploit the different capacities of the antibody classes to activate the appropriate downstream effector mechanisms.

Somatic hypermutation

A unique mutation mechanism that is targeted to the variable regions of rearranged immunoglobulin gene segments. Combined with selection for B cells that produce high-affinity antibody, somatic hypermutation leads to affinity maturation of B cells in germinal centres.

(NZB × NZW)F1 mice

The F1 generation of the cross between NZB mice and NZW mice. (NZB × NZW)F1 mice have a disease that closely resembles the human disease systemic lupus erythematosus.

Systemic lupus erythematosus

(SLE). An autoimmune disease in which autoantibodies specific for DNA, RNA or proteins associated with nucleic acids form immune complexes that damage small blood vessels, especially in the kidneys. Patients with SLE generally have abnormal B- and T-cell function.

Rheumatoid arthritis

An immune disorder that is characterized by symmetrical polyarthritis, often progressing to crippling deformation after years of synovitis. It is associated with systemic immune activation, with acute-phase reactants — as well as rheumatoid factor (antibodies specific for IgG), which forms immune complexes that are deposited in many tissues — being present in the peripheral blood.

Antibody-secreting cells

A term that encompasses both plasmablasts, which proliferate, and plasma cells, which do not proliferate. It is used when both cell types might be present.

Aiolos

A lymphoid-regulatory protein that is a member of the Ikaros family. It is a haematopoietic-cell-specific transcription factor that is involved in B-cell development and function.

Ikaros family

A family of zinc-finger-containing transcription factors. These factors are pleiotropic regulators of haematopoiesis and are required for the generation of lymphocyte and dendritic-cell lineages, as well as lymph nodes and Peyer's patches.

Stromal cells

Cells of non-lymphoid origin that form the framework of each organ. By expressing various molecules, these cells can support adhesion, proliferation and survival of distinct cell subsets.

Flow-cytometric analysis

A method that allows simultaneous detection of cell-surface and intracellular molecules on single cells, through the use of fluorescently labelled antibodies.

Type 1 allergy

An allergy or hypersensitivity of type 1 is an abnormal immune response that involves IgE specific for otherwise harmless proteins.

Autoreactive antibody

An antibody that is specific for a self-antigen.

Citrullinated peptide

A peptide that incorporates the amino acid citrulline. These peptides are generated post-translationally by peptidylarginine deiminases. The citrulline moiety is the essential part of the antigenic determinant towards which characteristic autoantibodies in patients with rheumatoid arthritis are generated.

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Radbruch, A., Muehlinghaus, G., Luger, E. et al. Competence and competition: the challenge of becoming a long-lived plasma cell. Nat Rev Immunol 6, 741–750 (2006). https://doi.org/10.1038/nri1886

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