Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

B-cell anergy: from transgenic models to naturally occurring anergic B cells?

Nature Reviews Immunology volume 7, pages 633–643 (2007)Cite this article

Key Points

  • Normal B-cell development results in the generation of self-reactive B cells. The regulation of these potentially pathogenic B cells is essential in the prevention of autoimmune disease.

  • Three mechanisms regulate these cells: deletion by apoptosis, the generation of antigen receptors with new specificity by receptor editing, and anergy. Anergy refers to a state in which self-reactive B cells exist in the periphery but are quiescent and unresponsive to antigen stimulation.

  • Numerous transgenic mouse models have been used to study B-cell anergy, each with advantages and disadvantages. Anergic B cells have also been identified in non-transgenic mice (An1 B cells) and share features with anergic B cells from mouse models of anergy.

  • Anergic B cells do not respond to in vivo antigen stimulation by secreting antibody. Many anergic B cells also exhibit attenuated B-cell-receptor signalling in response to either antigen or Toll-like-receptor stimulation in vitro .

  • Many anergic B cells also have a shortened lifespan and altered anatomical localization compared with naive, non-self-reactive B cells.

Abstract

Anergy, a condition in which cells persist in the periphery but are unresponsive to antigen, is responsible for silencing many self-reactive B cells. Loss of anergy is known to contribute to the development of autoimmune diseases, including systemic lupus erythematosus and type 1 diabetes. Multiple transgenic mouse models have enabled the dissection of mechanisms that underlie anergy, and recently, anergic B cells have been identified in the periphery of wild-type mice. Heterogeneity of mechanistic concepts developed using model systems has complicated our understanding of anergy and its biological features. In this Review, we compare and contrast the salient features of anergic B cells with a view to developing unifying mechanistic hypotheses that explain their lifestyles.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Stages of B-cell development.
Figure 2: B-cell signalling in response to acute or chronic antigen stimulation.

Similar content being viewed by others

References

  1. Wardemann, H. et al. Predominant autoantibody production by early human B cell precursors. Science 301, 1374–1377 (2003). This paper shows that a high frequency of early immature B cells generated during human B-cell development are self-reactive.

    Article  CAS  PubMed  Google Scholar 

  2. Gay, D., Saunders, T., Camper, S. & Weigert, M. Receptor editing: an approach by autoreactive B cells to escape tolerance. J. Exp. Med. 177, 999–1008 (1993).

    Article  CAS  PubMed  Google Scholar 

  3. Tiegs, S. L., Russell, D. M. & Nemazee, D. Receptor editing in self-reactive bone marrow B cells. J. Exp. Med. 177, 1009–1020 (1993).

    Article  CAS  PubMed  Google Scholar 

  4. Nemazee, D. A. & Burki, K. Clonal deletion of B lymphocytes in a transgenic mouse bearing anti-MHC class I antibody genes. Nature 337, 562–566 (1989).

    Article  CAS  PubMed  Google Scholar 

  5. Goodnow, C. C., Brink, R. & Adams, E. Breakdown of self-tolerance in anergic B lymphocytes. Nature 352, 532–536 (1991).

    Article  CAS  PubMed  Google Scholar 

  6. Goodnow, C. C. et al. Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature 334, 676–682 (1988). This work identifies key phenotypic features of anergic cells in the classic HEL-specific B-cell model.

    Article  CAS  PubMed  Google Scholar 

  7. Goodnow, C. C., Crosbie, J., Jorgensen, H., Brink, R. A. & Basten, A. Induction of self-tolerance in mature peripheral B lymphocytes. Nature 342, 385–391 (1989).

    Article  CAS  PubMed  Google Scholar 

  8. Goodnow, C. C. et al. Clonal silencing of self-reactive B lymphocytes in a transgenic mouse model. Cold Spring Harb. Symp. Quant. Biol. 54, 907–920 (1989).

    Article  CAS  PubMed  Google Scholar 

  9. Rui, L., Vinuesa, C. G., Blasioli, J. & Goodnow, C. C. Resistance to CpG DNA-induced autoimmunity through tolerogenic B cell antigen receptor ERK signaling. Nature Immunol. 4, 594–600 (2003).

    Article  CAS  Google Scholar 

  10. Rui, L., Healy, J. I., Blasioli, J. & Goodnow, C. C. ERK signaling is a molecular switch integrating opposing inputs from B cell receptor and T cell cytokines to control TLR4-driven plasma cell differentiation. J. Immunol. 177, 5337–5346 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Shlomchik, M. J., Aucoin, A. H., Pisetsky, D. S. & Weigert, M. G. Structure and function of anti-DNA autoantibodies derived from a single autoimmune mouse. Proc. Natl Acad. Sci. USA 84, 9150–9154 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Erikson, J. et al. Expression of anti-DNA immunoglobulin transgenes in non-autoimmune mice. Nature 349, 331–334 (1991).

    Article  CAS  PubMed  Google Scholar 

  13. Roark, J. H., Bui, A., Nguyen, K. A., Mandik, L. & Erikson, J. Persistence of functionally compromised anti-double-stranded DNA B cells in the periphery of non-autoimmune mice. Int. Immunol. 9, 1615–1626 (1997).

    Article  CAS  PubMed  Google Scholar 

  14. Nguyen, K. A. et al. Characterization of anti-single-stranded DNA B cells in a non-autoimmune background. J. Immunol. 159, 2633–2644 (1997).

    CAS  PubMed  Google Scholar 

  15. Mandik-Nayak, L. et al. MRL-lpr/lpr mice exhibit a defect in maintaining developmental arrest and follicular exclusion of anti-double-stranded DNA B cells. J. Exp. Med. 189, 1799–1814 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Tan, E. M. Antinuclear antibodies: diagnostic markers for autoimmune diseases and probes for cell biology. Adv. Immunol. 44, 93–151 (1989).

    Article  CAS  PubMed  Google Scholar 

  17. Lau, C. M. et al. RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J. Exp. Med. 202, 1171–1177 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bloom, D. D., Davignon, J. L., Cohen, P. L., Eisenberg, R. A. & Clarke, S. H. Overlap of the anti-Sm and anti-DNA responses of MRL/Mp-lpr/lpr mice. J. Immunol. 150, 1579–1590 (1993).

    CAS  PubMed  Google Scholar 

  19. Qian, Y. et al. Autoreactive MZ and B-1 B-cell activation by Faslpr is coincident with an increased frequency of apoptotic lymphocytes and a defect in macrophage clearance. Blood 108, 974–982 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Qian, Y., Wang, H. & Clarke, S. H. Impaired clearance of apoptotic cells induces the activation of autoreactive anti-Sm marginal zone and B-1 B cells. J. Immunol. 172, 625–635 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Culton, D. A. et al. Early preplasma cells define a tolerance checkpoint for autoreactive B cells. J. Immunol. 176, 790–802 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Santulli-Marotto, S., Retter, M. W., Gee, R., Mamula, M. J. & Clarke, S. H. Autoreactive B cell regulation: peripheral induction of developmental arrest by lupus-associated autoantigens. Immunity 8, 209–219 (1998).

    Article  CAS  PubMed  Google Scholar 

  23. Retter, M. W., Eisenberg, R. A., Cohen, P. L. & Clarke, S. H. Sm and DNA binding by dual reactive B cells requires distinct VH, Vκ, and VH CDR3 structures. J. Immunol. 155, 2248–2257 (1995).

    CAS  PubMed  Google Scholar 

  24. Borrero, M. & Clarke, S. H. Low-affinity anti-Smith antigen B cells are regulated by anergy as opposed to developmental arrest or differentiation to B-1. J. Immunol. 168, 13–21 (2002).

    Article  CAS  PubMed  Google Scholar 

  25. Ewulonu, U. K., Nell, L. J. & Thomas, J. W. VH and VL gene usage by murine IgG antibodies that bind autologous insulin. J. Immunol. 144, 3091–3098 (1990).

    CAS  PubMed  Google Scholar 

  26. Rojas, M., Hulbert, C. & Thomas, J. W. Anergy and not clonal ignorance determines the fate of B cells that recognize a physiological autoantigen. J. Immunol. 166, 3194–3200 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Acevedo-Suarez, C. A., Hulbert, C., Woodward, E. J. & Thomas, J. W. Uncoupling of anergy from developmental arrest in anti-insulin B cells supports the development of autoimmune diabetes. J. Immunol. 174, 827–833 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Benschop, R. J. et al. Activation and anergy in bone marrow B cells of a novel immunoglobulin transgenic mouse that is both hapten specific and autoreactive. Immunity 14, 33–43 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Merrell, K. T. et al. Identification of anergic B cells within a wild-type repertoire. Immunity 25, 953–962 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Gauld, S. B., Benschop, R. J., Merrell, K. T. & Cambier, J. C. Maintenance of B cell anergy requires constant antigen receptor occupancy and signaling. Nature Immunol. 6, 1160–1167 (2005). This paper suggests that anergy is a rapidly reversible phenotype that is dependent on constant self-antigen binding to the antigen receptor.

    Article  CAS  Google Scholar 

  31. Teague, B. N. et al. Cutting Edge: Transitional t3 B cells do not give rise to mature B cells, have undergone selection, and are reduced in murine lupus. J. Immunol. 178, 7511–7515 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Mandik-Nayak, L., Bui, A., Noorchashm, H., Eaton, A. & Erikson, J. Regulation of anti-double-stranded DNA B cells in nonautoimmune mice: localization to the T–B interface of the splenic follicle. J. Exp. Med. 186, 1257–1267 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Noorchashm, H. et al. Characterization of anergic anti-DNA B cells: B cell anergy is a T cell-independent and potentially reversible process. Int. Immunol. 11, 765–776 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. Fulcher, D. A. & Basten, A. Reduced life span of anergic self-reactive B cells in a double-transgenic model. J. Exp. Med. 179, 125–134 (1994). This paper is one of several key studies that identify the short half-life of self-reactive B cells.

    Article  CAS  PubMed  Google Scholar 

  35. Tough, D. F. & Sprent, J. Lifespan of lymphocytes. Immunol. Res. 14, 1–12 (1995).

    Article  CAS  PubMed  Google Scholar 

  36. Cyster, J. G., Hartley, S. B. & Goodnow, C. C. Competition for follicular niches excludes self-reactive cells from the recirculating B-cell repertoire. Nature 371, 389–395 (1994). This work shows that competition of anergic B cells within a normal B-cell repertoire contributes to their short lifespan.

    Article  CAS  PubMed  Google Scholar 

  37. Cyster, J. G. & Goodnow, C. C. Antigen-induced exclusion from follicles and anergy are separate and complementary processes that influence peripheral B cell fate. Immunity 3, 691–701 (1995). This paper highlights the exclusion of self-reactive B cells from follicular areas and shows their localization to the T-cell–B-cell interface.

    Article  CAS  PubMed  Google Scholar 

  38. Mackay, F., Schneider, P., Rennert, P. & Browning, J. BAFF AND APRIL: a tutorial on B cell survival. Annu. Rev. Immunol. 21, 231–264 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Lesley, R. et al. Reduced competitiveness of autoantigen-engaged B cells due to increased dependence on BAFF. Immunity 20, 441–453 (2004). This paper shows the reduced capacity of self-reactive B cells to compete for the B-cell survival signal BAFF, thereby contributing to their short lifespan.

    Article  CAS  PubMed  Google Scholar 

  40. Oliver, P. M., Vass, T., Kappler, J. & Marrack, P. Loss of the proapoptotic protein, Bim, breaks B cell anergy. J. Exp. Med. 203, 731–741 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Mandik-Nayak, L. et al. Functional consequences of the developmental arrest and follicular exclusion of anti-double-stranded DNA B cells. J. Immunol. 164, 1161–1168 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Weintraub, J. P. et al. Immunological and pathological consequences of mutations in both Fas and Fas ligand. Cell. Immunol. 186, 8–17 (1998).

    Article  CAS  PubMed  Google Scholar 

  43. Rathmell, J. C. et al. CD95 (Fas)-dependent elimination of self-reactive B cells upon interaction with CD4+ T cells. Nature 376, 181–184 (1995).

    Article  CAS  PubMed  Google Scholar 

  44. Rathmell, J. C., Fournier, S., Weintraub, B. C., Allison, J. P. & Goodnow, C. C. Repression of B7.2 on self-reactive B cells is essential to prevent proliferation and allow Fas-mediated deletion by CD4+ T cells. J. Exp. Med. 188, 651–659 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Feuerstein, N., Chen, F., Madaio, M., Maldonado, M. & Eisenberg, R. A. Induction of autoimmunity in a transgenic model of B cell receptor peripheral tolerance: changes in coreceptors and B cell receptor-induced tyrosine-phosphoproteins. J. Immunol. 163, 5287–5297 (1999)

    CAS  PubMed  Google Scholar 

  46. Sekiguchi, D. R. et al. Chronic graft-versus-host in Ig knockin transgenic mice abrogates B cell tolerance in anti-double-stranded DNA B cells. J. Immunol. 168, 4142–4153 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Seo, S. J. et al. The impact of T helper and T regulatory cells on the regulation of anti-double-stranded DNA B cells. Immunity 16, 535–546 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Cooke, M. P. et al. Immunoglobulin signal transduction guides the specificity of B cell–T cell interactions and is blocked in tolerant self-reactive B cells. J. Exp. Med. 179, 425–438 (1994).

    Article  CAS  PubMed  Google Scholar 

  49. Foote, L. C., Marshak-Rothstein, A. & Rothstein, T. L. Tolerant B lymphocytes acquire resistance to Fas-mediated apoptosis after treatment with interleukin 4 but not after treatment with specific antigen unless a surface immunoglobulin threshold is exceeded. J. Exp. Med. 187, 847–853 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Cook, M. C., Basten, A. & Fazekas de St Groth, B. Rescue of self-reactive B cells by provision of T cell help in vivo. Eur. J. Immunol. 28, 2549–2558 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Reif, K. et al. Balanced responsiveness to chemoattractants from adjacent zones determines B-cell position. Nature 416, 94–99 (2002).

    Article  PubMed  Google Scholar 

  52. Pisitkun, P. et al. Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication. Science 312, 1669–1672 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Kilmon, M. A., Rutan, J. A., Clarke, S. H. & Vilen, B. J. Low-affinity, Smith antigen-specific B cells are tolerized by dendritic cells and macrophages. J. Immunol. 175, 37–41 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Gilbert, M. R. et al. Dendritic cells from lupus-prone mice are defective in repressing immunoglobulin secretion. J. Immunol. 178, 4803–4810 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Kilmon, M. A. et al. Macrophages prevent the differentiation of autoreactive B cells by secreting CD40 ligand and IL-6. Blood (in the press).

  56. Lenschow, D. J. et al. Differential up-regulation of the B7-1 and B7-2 costimulatory molecules after Ig receptor engagement by antigen. J. Immunol. 153, 1990–1997 (1994).

    CAS  PubMed  Google Scholar 

  57. Vilen, B. J., Famiglietti, S. J., Carbone, A. M., Kay, B. K. & Cambier, J. C. B cell antigen receptor desensitization: disruption of receptor coupling to tyrosine kinase activation. J. Immunol. 159, 231–243 (1997).

    CAS  PubMed  Google Scholar 

  58. Vilen, B. J., Burke, K. M., Sleater, M. & Cambier, J. C. Transmodulation of BCR signaling by transduction-incompetent antigen receptors: implications for impaired signaling in anergic B cells. J. Immunol. 168, 4344–4351 (2002).

    Article  CAS  PubMed  Google Scholar 

  59. Weintraub, B. C. et al. Entry of B cell receptor into signaling domains is inhibited in tolerant B cells. J. Exp. Med. 191, 1443–1448 (2000). This paper highlights defective B-cell signalling by anergic B cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Healy, J. I. et al. Different nuclear signals are activated by the B cell receptor during positive versus negative signaling. Immunity 6, 419–428 (1997). This work highlights key signalling phenotypes of self-reactive B cells.

    Article  CAS  PubMed  Google Scholar 

  61. Acevedo-Suarez, C. A., Kilkenny, D. M., Reich, M. B. & Thomas, J. W. Impaired intracellular calcium mobilization and NFATc1 availability in tolerant anti-insulin B cells. J. Immunol. 177, 2234–2241 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Radic, M., Marion, T. & Monestier, M. Nucleosomes are exposed at the cell surface in apoptosis. J. Immunol. 172, 6692–6700 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Leadbetter, E. A. et al. Chromatin–IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416, 603–607 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Ho, W. Y., Cooke, M. P., Goodnow, C. C. & Davis, M. M. Resting and anergic B cells are defective in CD28-dependent costimulation of naive CD4+ T cells. J. Exp. Med. 179, 1539–1549 (1994).

    Article  CAS  PubMed  Google Scholar 

  65. Eris, J. M. et al. Anergic self-reactive B cells present self antigen and respond normally to CD40-dependent T-cell signals but are defective in antigen-receptor-mediated functions. Proc. Natl Acad. Sci. USA 91, 4392–4396 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Rathmell, J. C., Townsend, S. E., Xu, J. C., Flavell, R. A. & Goodnow, C. C. Expansion or elimination of B cells in vivo: dual roles for CD40- and Fas (CD95)-ligands modulated by the B cell antigen receptor. Cell 87, 319–329 (1996).

    Article  CAS  PubMed  Google Scholar 

  67. Smith, K. G., Tarlinton, D. M., Doody, G. M., Hibbs, M. L. & Fearon, D. T. Inhibition of the B cell by CD22: a requirement for Lyn. J. Exp. Med. 187, 807–811 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. O'Keefe, T. L., Williams, G. T., Batista, F. D. & Neuberger, M. S. Deficiency in CD22, a B cell-specific inhibitory receptor, is sufficient to predispose to development of high affinity autoantibodies. J. Exp. Med. 189, 1307–1313 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Hibbs, M. L. et al. Sustained activation of Lyn tyrosine kinase in vivo leads to autoimmunity. J. Exp. Med. 196, 1593–1604 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Pao, L. I., Famiglietti, S. J. & Cambier, J. C. Asymmetrical phosphorylation and function of immunoreceptor tyrosine-based activation motif tyrosines in B cell antigen receptor signal transduction. J. Immunol. 160, 3305–3314 (1998).

    CAS  PubMed  Google Scholar 

  71. Miyamoto, A. et al. Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Cδ. Nature 416, 865–859 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Mecklenbrauker, I., Saijo, K., Zheng, N. Y., Leitges, M. & Tarakhovsky, A. Protein kinase Cδ controls self-antigen-induced B-cell tolerance. Nature 416, 860–865 (2002).

    Article  PubMed  CAS  Google Scholar 

  73. Mecklenbrauker, I., Kalled, S. L., Leitges, M., Mackay, F. & Tarakhovsky, A. Regulation of B-cell survival by BAFF-dependent PKCδ-mediated nuclear signalling. Nature 431, 456–461 (2004).

    Article  PubMed  CAS  Google Scholar 

  74. Mackay, F. et al. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J. Exp. Med. 190, 1697–1710 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Brauweiler, A., Merrell, K., Gauld, S. B. & Cambier, J. C. Cutting Edge: Acute and chronic exposure of immature B cells to antigen leads to impaired homing and SHIP1-dependent reduction in stromal cell-derived factor-1 responsiveness. J. Immunol. 178, 3353–3357 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Thien, M. et al. Excess BAFF rescues self-reactive B cells from peripheral deletion and allows them to enter forbidden follicular and marginal zone niches. Immunity 20, 785–798 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Shlomchik, M. J., Euler, C. W., Christensen, S. C. & William, J. Activation of rheumatoid factor (RF) B cells and somatic hypermutation outside of germinal centers in autoimmune-prone MRL/lpr mice. Ann. N. Y. Acad. Sci. 987, 38–50 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. Wang, H. & Shlomchik, M. J. Autoantigen-specific B cell activation in Fas-deficient rheumatoid factor immunoglobulin transgenic mice. J. Exp. Med. 190, 639–649 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Pugh-Bernard, A. E. et al. Regulation of inherently autoreactive VH4-34 B cells in the maintenance of human B cell tolerance. J. Clin. Invest. 108, 1061–1070 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Stevenson, F. K., Smith, G. J., North, J., Hamblin, T. J. & Glennie, M. J. Identification of normal B-cell counterparts of neoplastic cells which secrete cold agglutinins of anti-I and anti-i specificity. Br. J. Haematol. 72, 9–15 (1989).

    Article  CAS  PubMed  Google Scholar 

  81. Isenberg, D. A. et al. Correlation of 9G4 idiotope with disease activity in patients with systemic lupus erythematosus. Ann. Rheum. Dis. 57, 566–570 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. van Vollenhoven, R. F. et al. VH4-34 encoded antibodies in systemic lupus erythematosus: a specific diagnostic marker that correlates with clinical disease characteristics. J. Rheumatol. 26, 1727–1733 (1999).

    CAS  PubMed  Google Scholar 

  83. Allman, D. et al. . Resolution of three nonproliferative immature splenic B cell subsets reveals multiple selection points during peripheral B cell maturation. J. Immunol. 167, 6834–6840 (2001).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank S. H. Clarke, J. M. Thomas and L. J. Wysocki for their help and input.

Author information

Authors and Affiliations

  1. Department of Immunology, University of Colorado Health Science Center and National Jewish Medical Research Center, 1400 Jackson Street, Denver, 80206, Colorado, USA

    John C. Cambier, Stephen B. Gauld & Kevin T. Merrell

  2. Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, 27599, North Carolina, USA

    Barbara J. Vilen

Authors
  1. John C. Cambier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stephen B. Gauld
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kevin T. Merrell
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Barbara J. Vilen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John C. Cambier.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

John C. Cambier's homepage

Glossary

Receptor editing

A molecular process that involves secondary rearrangements (mostly of the light chains) that replace existing immunoglobulin molecules and generate a new antigen receptor with altered specificity.

Central tolerance

Self-tolerance that is created at the level of the central lymphoid organs. Developing T cells in the thymus, and B cells in the bone marrow, that strongly recognize self antigen face deletion or marked suppression.

Anergy

A state of non-responsiveness to antigen. Anergic T or B cells cannot respond to their cognate antigens under optimal conditions of stimulation.

Systemic lupus erythematosus

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

MRL.Faslpr/lpr mice

A mouse strain that spontaneously develops glomerulonephritis and other symptoms of systemic lupus erythematosus. The lpr mutation causes a defect in FAS (also known as CD95), preventing the apoptosis of activated lymphocytes; the MRL strain contributes disease-associated mutations that have yet to be identified.

Small nuclear ribonucleoprotein

(snRNP). A nuclear particle that consists of a short RNA (<300 nucleotides) and one or more tightly bound proteins. They are involved in pre-mRNA processing and tRNA biogenesis.

Non-obese diabetic mice

(NOD mice). A strain of mice that normally develop idiopathic autoimmune diabetes that closely resembles type 1 diabetes in humans. The main component of susceptibility is the unique MHC haplotype H2g7.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cambier, J., Gauld, S., Merrell, K. et al. B-cell anergy: from transgenic models to naturally occurring anergic B cells?. Nat Rev Immunol 7, 633–643 (2007). https://doi.org/10.1038/nri2133

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2133

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing