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 cells move to centre stage: novel opportunities for autoimmune disease treatment

Nature Reviews Drug Discovery volume 5, pages 564–576 (2006)Cite this article

Key Points

  • In recent years, a popular view of the pathogenesis of autoimmune disorders has been that B-cell derived events are ancillary to a basic breakdown in T-cell tolerance, and that although autoantibodies are present, the effector function of T cells is the fundamental pathological component.

  • However, the B-cell-depleting antibody rituximab — originally developed as a lymphoma therapy — has recently been shown to be effective in the treatment of rheumatoid arthritis, and has received regulatory approval for this indication.

  • This success, as well as indicating that removal of the B-cell component is beneficial in rheumatoid arthritis, has ushered in a new era of exploration of the contribution of B cells to a range of immune disorders in general.

  • This review discusses the role of B cells in autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus and Sjogrens syndrome, and considers various therapeutic strategies involving modulation of B-cell function, including B-cell depletion, manipulation of B-cell survival, and targeting T-cell help, Toll-like receptors and Fc receptors.

Abstract

The B-cell arm of the immune system has long been appreciated for its crucial role in pathogen resistance, but in the study of many autoimmune diseases, T cells have dominated the limelight for decades. However, the development of the B-cell-depleting antibody rituximab as a lymphoma therapy has provided a tool to probe the contribution made by B cells in several immune disorders. Recently, the success of B-cell depletion with rituximab in the treatment of rheumatoid arthritis has stimulated investigation of its effects in several other immune disorders, and considerable interest in the potential of drugs that can modulate B-cell function for the treatment of such diseases in general. This article discusses the role of B cells in a range of autoimmune disorders, including rheumatoid arthritis and systemic lupus erythematosus, and analyses approaches to therapeutic B-cell manipulation.

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: B-cell lineages.
Figure 2: How B cells can be bad.
Figure 3: Mechanism of action of anti-CD20 antibodies.
Figure 4: Manipulation of B-cell survival.

Similar content being viewed by others

References

  1. 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).

    Article  CAS  PubMed  Google Scholar 

  2. Edwards, J. C. & Cambridge, G. B-cell targeting in rheumatoid arthritis and other autoimmune diseases. Nature Rev. Immunol. 6, 394–403 (2006).

    Article  CAS  Google Scholar 

  3. St Clair, E. W. & Tedder, T. F. New prospects for autoimmune disease therapy: B cells on deathwatch. Arthritis Rheum. 54, 1–9 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Martin, F. & Chan, A. C. B cell immunobiology in disease: evolving concepts from the clinic. Annu. Rev. Immunol. 24, 467–496 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Baumgarth, N., Tung, J. W. & Herzenberg, L. A. Inherent specificities in natural antibodies: a key to immune defense against pathogen invasion. Springer Semin. Immunopathol. 26, 347–362 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Haas, K. M., Poe, J. C., Steeber, D. A. & Tedder, T. F. B-1a and B-1b cells exhibit distinct developmental requirements and have unique functional roles in innate and adaptive immunity to S. pneumoniae. Immunity 23, 7–18 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Milner, E. C., Anolik, J., Cappione, A. & Sanz, I. Human innate B cells: a link between host defense and autoimmunity? Springer Semin. Immunopathol. 26, 433–452 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Goodnow, C. C., Sprent, J., Fazekas de St Groth, B. & Vinuesa, C. G. Cellular and genetic mechanisms of self tolerance and autoimmunity. Nature 435, 590–597 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Lopes-Carvalho, T. & Kearney, J. F. Marginal zone B cell physiology and disease. Curr. Dir. Autoimmun. 8, 91–123 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Bendelac, A., Bonneville, M. & Kearney, J. F. Autoreactivity by design: innate B and T lymphocytes. Nature Rev. Immunol. 1, 177–186 (2001).

    Article  CAS  Google Scholar 

  11. McHeyzer-Williams, L. J. & McHeyzer-Williams, M. G. Antigen-specific memory B cell development. Annu. Rev. Immunol. 23, 487–513 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  13. MacLennan, I. C. et al. Extrafollicular antibody responses. Immunol. Rev. 194, 8–18 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Manser, T. Textbook germinal centers? J. Immunol. 172, 3369–3375 (2004).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  17. Lund, F. E., Garvy, B. A., Randall, T. D. & Harris, D. P. Regulatory roles for cytokine-producing B cells in infection and autoimmune disease. Curr. Dir. Autoimmun. 8, 25–54 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Harris, D. P., Goodrich, S., Gerth, A. J., Peng, S. L. & Lund, F. E. Regulation of IFN-γ production by B effector 1 cells: essential roles for T-bet and the IFN-γ receptor. J. Immunol. 174, 6781–6790 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Harris, D. P., Goodrich, S., Mohrs, K., Mohrs, M. & Lund, F. E. Cutting edge: the development of IL-4-producing B Cells (B effector 2 cells) is controlled by IL-4, IL-4 receptor-α, and Th2 cells. J. Immunol. 175, 7103–7137 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Gommerman, J. L. & Browning, J. L. Lymphotoxin/light, lymphoid microenvironments and autoimmune disease. Nature Rev. Immunol. 3, 642–655 (2003).

    Article  CAS  Google Scholar 

  21. Braun, A., Takemura, S., Vallejo, A. N., Goronzy, J. J. & Weyand, C. M. Lymphotoxin β-mediated stimulation of synoviocytes in rheumatoid arthritis. Arthritis Rheum. 50, 2140–2150 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Drayton, D. L., Liao, S., Mounzer, R. H. & Ruddle, N. H. Lymphoid organ development: from ontogeny to neogenesis. Nature Immunol. 7, 344–353 (2006).

    Article  CAS  Google Scholar 

  23. Aloisi, F. & Pujol-Borrell, R. Lymphoid neogenesis in chronic inflammatory diseases. Nature Rev. Immunol. 6, 205–217 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  26. 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).

    Article  PubMed  Google Scholar 

  27. Gianani, R. & Eisenbarth, G. S. The stages of type 1A diabetes: 2005. Immunol. Rev. 204, 232–249 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Samuels, J., Ng, Y. S., Coupillaud, C., Paget, D. & Meffre, E. Impaired early B cell tolerance in patients with rheumatoid arthritis. J. Exp. Med. 201, 1659–1667 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Burkhardt, H. et al. Humoral immune response to citrullinated collagen type II determinants in early rheumatoid arthritis. Eur. J. Immunol. 35, 1643–1652 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Rantapaa-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).

    Article  PubMed  CAS  Google Scholar 

  31. 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).

    Article  PubMed  Google Scholar 

  32. Berger, T. et al. Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event. N. Engl. J. Med. 349, 139–145 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Melanitou, E., Devendra, D., Liu, E., Miao, D. & Eisenbarth, G. S. Early and quantal (by litter) expression of insulin autoantibodies in the nonobese diabetic mice predict early diabetes onset. J. Immunol. 173, 6603–6610 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Lee, L. A. Transient autoimmunity related to maternal autoantibodies: neonatal lupus. Autoimmun. Rev. 4, 207–213 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Vincent, A. et al. Antibodies in myasthenia gravis and related disorders. Ann. NY Acad. Sci. 998, 324–335 (2003).

    Article  CAS  PubMed  Google Scholar 

  36. Svensson, J. et al. Thyroid autoantibodies in cord blood sera from children and adolescents with autoimmune thyroiditis. Thyroid 16, 79–83 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Greeley, S. A. et al. Elimination of maternally transmitted autoantibodies prevents diabetes in nonobese diabetic mice. Nature Med. 8, 399–402 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Eisenberg, R. Do autoantigens define autoimmunity or vice versa? Eur. J. Immunol. 35, 367–370 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Lim, E. T. et al. Anti-myelin antibodies do not allow earlier diagnosis of multiple sclerosis. Mult. Scler. 11, 492–494 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Wipke, B. T., Wang, Z., Nagengast, W., Reichert, D. E. & Allen, P. M. Staging the initiation of autoantibody-induced arthritis: a critical role for immune complexes. J. Immunol. 172, 7694–7702 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Wong, F. S. et al. Investigation of the role of B-cells in type 1 diabetes in the NOD mouse. Diabetes 53, 2581–2587 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Wardemann, H. et al. Predominant autoantibody production by early human B cell precursors. Science 301, 1374–1377 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. Yurasov, S. et al. Defective B cell tolerance checkpoints in systemic lupus erythematosus. J. Exp. Med. 201, 703–711 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Oldstone, M. B. Molecular mimicry, microbial infection, and autoimmune disease: evolution of the concept. Curr. Top. Microbiol. Immunol. 296, 1–17 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. McClain, M. T. et al. Early events in lupus humoral autoimmunity suggest initiation through molecular mimicry. Nature Med. 11, 85–89 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Omdal, R. et al. Neuropsychiatric disturbances in SLE are associated with antibodies against NMDA receptors. Eur. J. Neurol. 12, 392–398 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Chan, O. T., Madaio, M. P. & Shlomchik, M. J. The central and multiple roles of B cells in lupus pathogenesis. Immunol. Rev. 169, 107–121 (1999).

    Article  CAS  PubMed  Google Scholar 

  48. Shlomchik, M. J., Craft, J. E. & Mamula, M. J. From T to B and back again: positive feedback in systemic autoimmune disease. Nature Rev. Immunol. 1, 147–153 (2001).

    Article  CAS  Google Scholar 

  49. Novobrantseva, T. I. et al. Attenuated liver fibrosis in the absence of B cells. J. Clin. Invest. 115, 3072–3082 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. O'Neill, S. K. et al. Antigen-specific B cells are required as APCs and autoantibody-producing cells for induction of severe autoimmune arthritis. J. Immunol. 174, 3781–3788 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. Chan, O. T., Hannum, L. G., Haberman, A. M., Madaio, M. P. & Shlomchik, M. J. A novel mouse with B cells but lacking serum antibody reveals an antibody-independent role for B cells in murine lupus. J. Exp. Med. 189, 1639–1648 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Liu, C. C., Manzi, S. & Ahearn, J. M. Biomarkers for systemic lupus erythematosus: a review and perspective. Curr. Opin. Rheumatol. 17, 543–549 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. Croker, J. A. & Kimberly, R. P. SLE: challenges and candidates in human disease. Trends Immunol. 26, 580–586 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Sfikakis, P. P., Boletis, J. N. & Tsokos, G. C. Rituximab anti-B-cell therapy in systemic lupus erythematosus: pointing to the future. Curr. Opin. Rheumatol. 17, 550–557 (2005).

    Article  CAS  PubMed  Google Scholar 

  55. Weyand, C. M., Seyler, T. M. & Goronzy, J. J. B cells in rheumatoid synovitis. Arthritis Res. Ther. 7 (Suppl. 3), S9–S12 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  56. van Dinther-Janssen, A. C., Pals, S. T., Scheper, R., Breedveld, F. & Meijer, C. J. Dendritic cells and high endothelial venules in the rheumatoid synovial membrane. J. Rheumatol. 17, 11–17 (1990).

    CAS  PubMed  Google Scholar 

  57. Manzo, A. et al. Systematic microanatomical analysis of CXCL13 and CCL21 in situ production and progressive lymphoid organization in rheumatoid synovitis. Eur. J. Immunol. 35, 1347–1359 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Barone, F. et al. Association of CXCL13 and CCL21 expression with the progressive organization of lymphoid-like structures in Sjogren's syndrome. Arthritis Rheum. 52, 1773–1784 (2005).

    Article  CAS  PubMed  Google Scholar 

  59. Salomonsson, S. et al. Cellular basis of ectopic germinal center formation and autoantibody production in the target organ of patients with Sjogren's syndrome. Arthritis Rheum. 48, 3187–3201 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. Colvin, R. B. & Smith, R. N. Antibody-mediated organ-allograft rejection. Nature Rev. Immunol. 5, 807–817 (2005).

    Article  CAS  Google Scholar 

  61. Krukemeyer, M. G. et al. Description of B lymphocytes and plasma cells, complement, and chemokines/receptors in acute liver allograft rejection. Transplantation 78, 65–70 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Moeller, J. et al. Molecular case report: IgVH analysis in acute humoral and cellular liver allograft rejection suggests a selected accumulation of effector B cells and plasma cells. Virchows Arch. 446, 325–332 (2005).

    Article  PubMed  Google Scholar 

  63. Vongwiwatana, A., Tasanarong, A., Hidalgo, L. G. & Halloran, P. F. The role of B cells and alloantibody in the host response to human organ allografts. Immunol. Rev. 196, 197–218 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Sospedra, M. & Martin, R. Immunology of multiple sclerosis. Annu. Rev. Immunol. 23, 683–747 (2005).

    Article  CAS  PubMed  Google Scholar 

  65. Uccelli, A., Aloisi, F. & Pistoia, V. Unveiling the enigma of the CNS as a B-cell fostering environment. Trends Immunol. 26, 254–259 (2005).

    Article  CAS  PubMed  Google Scholar 

  66. Pender, M. P. The pathogenesis of primary progressive multiple sclerosis: antibody-mediated attack and no repair? J. Clin. Neurosci. 11, 689–692 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. Corcione, A. et al. Recapitulation of B cell differentiation in the central nervous system of patients with multiple sclerosis. Proc. Natl Acad. Sci. USA 101, 11064–11069 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Krumbholz, M. et al. BAFF is produced by astrocytes and up-regulated in multiple sclerosis lesions and primary central nervous system lymphoma. J. Exp. Med. 201, 195–200 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Liu, J. et al. Genomic view of systemic autoimmunity in MRLlpr mice. Genes Immun 7, 156–168 (2006).

    Article  CAS  PubMed  Google Scholar 

  70. Hasegawa, M., Fujimoto, M., Takehara, K. & Sato, S. Pathogenesis of systemic sclerosis: altered B cell function is the key linking systemic autoimmunity and tissue fibrosis. J. Dermatol. Sci. 39, 1–7 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. Takehara, K. & Sato, S. Localized scleroderma is an autoimmune disorder. Rheumatology (Oxford) 44, 274–279 (2005).

    Article  CAS  Google Scholar 

  72. Matsushita, T. et al. Elevated serum BAFF levels in patients with systemic sclerosis: Enhanced BAFF signaling in systemic sclerosis B lymphocytes. Arthritis Rheum. 54, 192–201 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. Jindal, S. K. & Agarwal, R. Autoimmunity and interstitial lung disease. Curr. Opin. Pulm. Med. 11, 438–446 (2005).

    Article  PubMed  Google Scholar 

  74. Carroll, M. C. & Holers, V. M. Innate autoimmunity. Adv. Immunol. 86, 137–157 (2005).

    Article  CAS  PubMed  Google Scholar 

  75. Burne-Taney, M. J., Yokota-Ikeda, N. & Rabb, H. Effects of combined T- and B-cell deficiency on murine ischemia reperfusion injury. Am. J. Transplant. 5, 1186–1193 (2005).

    Article  PubMed  Google Scholar 

  76. Kotlan, B. et al. Novel ganglioside antigen identified by B cells in human medullary breast carcinomas: the proof of principle concerning the tumor-infiltrating B lymphocytes. J. Immunol. 175, 2278–2285 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. de Visser, K. E., Korets, L. V. & Coussens, L. M. De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell 7, 411–423 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Guillem, E. B. & Sampsel, J. W. Immune-promoted tumor cell invasion and metastasis. New considerations in cancer therapy. Adv. Exp. Med. Biol. 532, 153–173 (2003).

    Article  CAS  PubMed  Google Scholar 

  79. Looney, R. J., Anolik, J. & Sanz, I. Treatment of SLE with anti-CD20 monoclonal antibody. Curr. Dir. Autoimmun. 8, 193–205 (2005).

    Article  CAS  PubMed  Google Scholar 

  80. Keystone, E. C. B cells in rheumatoid arthritis: from hypothesis to the clinic. Rheumatology (Oxford) 44, (Suppl. 2), ii8–ii12 (2005).

    Article  CAS  Google Scholar 

  81. Cohen, S. B. B-cell depletion for rheumatic diseases: where are we? MedGenMed 7, 72 (2005).

    PubMed  Google Scholar 

  82. Panayi, G. S. B cell-directed therapy in rheumatoid arthritis — clinical experience. J. Rheumatol. Suppl 73, 19–24; discussion 29–30 (2005).

    CAS  PubMed  Google Scholar 

  83. Edwards, J. C. & Cambridge, G. Prospects for B-cell-targeted therapy in autoimmune disease. Rheumatology (Oxford) 44, 151–156 (2005).

    Article  CAS  Google Scholar 

  84. Pijpe, J. et al. Rituximab treatment in patients with primary Sjogren's syndrome: an open-label phase II study. Arthritis Rheum. 52, 2740–2750 (2005).

    Article  CAS  PubMed  Google Scholar 

  85. Keogh, K. A. et al. Rituximab for refractory Wegener's granulomatosis: report of a prospective, open-label pilot trial. Am. J. Respir. Crit. Care Med. 173, 180–187 (2006).

    Article  CAS  PubMed  Google Scholar 

  86. Leandro, M. J., Cambridge, G., Edwards, J. C., Ehrenstein, M. R. & Isenberg, D. A. B-cell depletion in the treatment of patients with systemic lupus erythematosus: a longitudinal analysis of 24 patients. Rheumatology (Oxford) 44, 1542–1545 (2005).

    Article  CAS  Google Scholar 

  87. Silverman, G. J. Anti-CD20 therapy in systemic lupus erythematosus: a step closer to the clinic. Arthritis Rheum. 52, 371–377 (2005).

    Article  PubMed  Google Scholar 

  88. Chambers, S. A. & Isenberg, D. Anti-B cell therapy (rituximab) in the treatment of autoimmune diseases. Lupus 14, 210–214 (2005).

    Article  CAS  PubMed  Google Scholar 

  89. Vugmeyster, Y. et al. Depletion of B cells by a humanized anti-CD20 antibody PRO70769 in Macaca fascicularis. J. Immunother. 28, 212–219 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Hamaguchi, Y., Xiu, Y., Komura, K., Nimmerjahn, F. & Tedder, T. F. Antibody isotype-specific engagement of Fcγ receptors regulates B lymphocyte depletion during CD20 immunotherapy. J. Exp. Med. 203, 743–753 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Uchida, J. et al. The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptor-dependent mechanisms during anti-CD20 antibody immunotherapy. J. Exp. Med. 199, 1659–1669 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Cartron, G., Watier, H., Golay, J. & Solal-Celigny, P. From the bench to the bedside: ways to improve rituximab efficacy. Blood 104, 2635–2642 (2004).

    Article  CAS  PubMed  Google Scholar 

  93. Gong, Q. et al. Importance of cellular microenvironment and circulatory dynamics in B cell immunotherapy. J. Immunol. 174, 817–826 (2005).

    Article  CAS  PubMed  Google Scholar 

  94. Janas, E., Priest, R., Wilde, J. I., White, J. H. & Malhotra, R. Rituxan (anti-CD20 antibody)-induced translocation of CD20 into lipid rafts is crucial for calcium influx and apoptosis. Clin. Exp. Immunol. 139, 439–446 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Anolik, J. H. et al. Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus. Arthritis Rheum. 50, 3580–3590 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. Hamaguchi, Y. et al. The peritoneal cavity provides a protective niche for B1 and conventional B lymphocytes during anti-CD20 immunotherapy in mice. J. Immunol. 174, 4389–99 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Schroder, C. et al. Anti-CD20 treatment depletes B-cells in blood and lymphatic tissue of cynomolgus monkeys. Transpl. Immunol. 12, 19–28 (2003).

    Article  CAS  PubMed  Google Scholar 

  98. Leandro, M. J., Cambridge, G., Ehrenstein, M. R. & Edwards, J. C. Reconstitution of peripheral blood B cells after depletion with rituximab in patients with rheumatoid arthritis. Arthritis Rheum. 54, 613–620 (2006).

    Article  CAS  PubMed  Google Scholar 

  99. Cambridge, G. et al. Serologic changes following B lymphocyte depletion therapy for rheumatoid arthritis. Arthritis Rheum. 48, 2146–2154 (2003).

    Article  PubMed  Google Scholar 

  100. Cambridge, G. et al. Circulating levels of B lymphocyte stimulator in patients with rheumatoid arthritis following rituximab treatment: relationships with B cell depletion, circulating antibodies, and clinical relapse. Arthritis Rheum. 54, 723–732 (2006).

    Article  CAS  PubMed  Google Scholar 

  101. Rouziere, A. S., Kneitz, C., Palanichamy, A., Dorner, T. & Tony, H. P. Regeneration of the immunoglobulin heavy-chain repertoire after transient B-cell depletion with an anti-CD20 antibody. Arthritis Res. Ther. 7, R714–R724 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Sato, T. et al. Aberrant B1 cell migration into the thymus results in activation of CD4 T cells through its potent antigen-presenting activity in the development of murine lupus. Eur. J. Immunol. 34, 3346–3358 (2004).

    Article  CAS  PubMed  Google Scholar 

  103. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Hoyer, B. F., Manz, R. A., Radbruch, A. & Hiepe, F. Long-lived plasma cells and their contribution to autoimmunity. Ann. NY Acad. Sci. 1050, 124–133 (2005).

    Article  CAS  PubMed  Google Scholar 

  105. Openshaw, H. et al. Peripheral blood stem cell transplantation in multiple sclerosis with busulfan and cyclophosphamide conditioning: report of toxicity and immunological monitoring. Biol. Blood. Marrow. Transplant. 6, 563–575 (2000).

    Article  CAS  PubMed  Google Scholar 

  106. Qin, Y. et al. Intrathecal B-cell clonal expansion, an early sign of humoral immunity, in the cerebrospinal fluid of patients with clinically isolated syndrome suggestive of multiple sclerosis. Lab. Invest. 83, 1081–1088 (2003).

    Article  PubMed  Google Scholar 

  107. Saiz, A. et al. MRI and CSF oligoclonal bands after autologous hematopoietic stem cell transplantation in MS. Neurology 56, 1084–1089 (2001).

    Article  CAS  PubMed  Google Scholar 

  108. Treon, S. P. et al. Polymorphisms in FcγRIIIA (CD16) receptor expression are associated with clinical response to rituximab in Waldenstrom's macroglobulinemia. J. Clin. Oncol. 23, 474–481 (2005).

    Article  CAS  PubMed  Google Scholar 

  109. Anolik, J. H. et al. The relationship of FcγRIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus. Arthritis Rheum. 48, 455–459 (2003).

    Article  CAS  PubMed  Google Scholar 

  110. Cartron, G. et al. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcγRIIIa gene. Blood 99, 754–758 (2002).

    Article  CAS  PubMed  Google Scholar 

  111. Weng, W. K. & Levy, R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J. Clin. Oncol. 21, 3940–3947 (2003).

    Article  CAS  PubMed  Google Scholar 

  112. Tedder, T. F., Poe, J. C. & Haas, K. M. CD22: a multifunctional receptor that regulates B lymphocyte survival and signal transduction. Adv. Immunol. 88, 1–50 (2005).

    Article  CAS  PubMed  Google Scholar 

  113. Yazawa, N., Hamaguchi, Y., Poe, J. C. & Tedder, T. F. Immunotherapy using unconjugated CD19 monoclonal antibodies in animal models for B lymphocyte malignancies and autoimmune disease. Proc. Natl Acad. Sci. USA 102, 15178–15183 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Dillon, S. R., Gross, J. A., Ansell, S. M. & Novak, A. J. An APRIL to remember: novel TNF ligands as therapeutic targets. Nature Rev. Drug Discov. 5, 235–246 (2006).

    Article  CAS  Google Scholar 

  115. Crowley, J. E., Treml, L. S., Stadanlick, J. E., Carpenter, E. & Cancro, M. P. Homeostatic niche specification among naive and activated B cells: a growing role for the BLyS family of receptors and ligands. Semin. Immunol. 17, 193–199 (2005).

    Article  CAS  PubMed  Google Scholar 

  116. Kalled, S. L. The role of BAFF in immune function and implications for autoimmunity. Immunol. Rev. 204, 43–54 (2005).

    Article  CAS  PubMed  Google Scholar 

  117. Mackay, F., Sierro, F., Grey, S. T. & Gordon, T. P. The BAFF/APRIL system: an important player in systemic rheumatic diseases. Curr. Dir. Autoimmun. 8, 243–265 (2005).

    Article  CAS  PubMed  Google Scholar 

  118. Ng, L. G., Mackay, C. R. & Mackay, F. The BAFF/APRIL system: life beyond B lymphocytes. Mol. Immunol. 42, 763–772 (2005).

    Article  CAS  PubMed  Google Scholar 

  119. Vugmeyster, Y. et al. A soluble BAFF antagonist, BR3-Fc, decreases peripheral blood B cells and lymphoid tissue marginal zone and follicular B cells in cynomolgus monkeys. Am. J. Pathol. 168, 476–489 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Halpern, W. G. et al. Chronic administration of belimumab, a blys antagonist, decreases tissue and peripheral blood b-lymphocyte populations in cynomolgus monkeys: pharmacokinetic, pharmacodynamic and toxicologic effects. Toxicol Sci 91, 586–599 (2006).

    Article  CAS  PubMed  Google Scholar 

  121. 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).

    Article  CAS  PubMed  Google Scholar 

  122. Castigli, E. et al. TACI and BAFF-R mediate isotype switching in B cells. J. Exp. Med. 201, 35–39 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Castigli, E. et al. TACI is mutant in common variable immunodeficiency and IgA deficiency. Nature Genet. 37, 829–834 (2005).

    Article  CAS  PubMed  Google Scholar 

  124. Salzer, U. et al. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nature Genet. 37, 820–828 (2005).

    Article  CAS  PubMed  Google Scholar 

  125. Salzer, U. & Grimbacher, B. TACItly changing tunes: farewell to a yin and yang of BAFF receptor and TACI in humoral immunity? New genetic defects in common variable immunodeficiency. Curr. Opin. Allergy Clin. Immunol. 5, 496–503 (2005).

    Article  CAS  PubMed  Google Scholar 

  126. De Vos, J. et al. Microarray-based understanding of normal and malignant plasma cells. Immunol. Rev. 210, 86–104 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Haberman, A. M. & Shlomchik, M. J. Reassessing the function of immune-complex retention by follicular dendritic cells. Nature Rev. Immunol. 3, 757–764 (2003).

    Article  CAS  Google Scholar 

  128. Mao, C. et al. T cell-independent somatic hypermutation in murine B cells with an immature phenotype. Immunity 20, 133–144 (2004).

    Article  CAS  PubMed  Google Scholar 

  129. Quezada, S. A., Jarvinen, L. Z., Lind, E. F. & Noelle, R. J. CD40/CD154 interactions at the interface of tolerance and immunity. Annu. Rev. Immunol. 22, 307–328 (2004).

    Article  CAS  PubMed  Google Scholar 

  130. Yazdany, J. & Davis, J. The role of CD40 ligand in systemic lupus erythematosus. Lupus 13, 377–380 (2004).

    Article  CAS  PubMed  Google Scholar 

  131. Boumpas, D. T. et al. A short course of BG9588 (anti-CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis. Arthritis Rheum. 48, 719–727 (2003).

    Article  CAS  PubMed  Google Scholar 

  132. Huang, W. et al. The effect of anti-CD40 ligand antibody on B cells in human systemic lupus erythematosus. Arthritis Rheum. 46, 1554–1562 (2002).

    Article  CAS  PubMed  Google Scholar 

  133. Danese, S. & Fiocchi, C. Platelet activation and the CD40/CD40 ligand pathway: mechanisms and implications for human disease. Crit. Rev. Immunol. 25, 103–121 (2005).

    Article  CAS  PubMed  Google Scholar 

  134. Wang, Y. & Carter, R. H. CD19 regulates B cell maturation, proliferation, and positive selection in the FDC zone of murine splenic germinal centers. Immunity 22, 749–761 (2005).

    Article  CAS  PubMed  Google Scholar 

  135. Davidson, A., Diamond, B., Wofsy, D. & Daikh, D. Block and tackle: CTLA4Ig takes on lupus. Lupus 14, 197–203 (2005).

    Article  CAS  PubMed  Google Scholar 

  136. Watts, T. H. TNF/TNFR family members in costimulation of T cell responses. Annu. Rev. Immunol. 23, 23–68 (2005).

    Article  CAS  PubMed  Google Scholar 

  137. 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).

    Article  PubMed  Google Scholar 

  138. Warnatz, K. et al. Human ICOS deficiency abrogates the germinal center reaction and provides a monogenic model for common variable immunodeficiency. Blood 107, 3045–3052 (2006).

    Article  CAS  PubMed  Google Scholar 

  139. Tackey, E., Lipsky, P. E. & Illei, G. G. Rationale for interleukin-6 blockade in systemic lupus erythematosus. Lupus 13, 339–343 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Veldhoen, M., Hocking, R. J., Atkins, C. J., Locksley, R. M. & Stockinger, B. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006).

    Article  CAS  PubMed  Google Scholar 

  141. Mihara, M., Nishimoto, N. & Ohsugi, Y. The therapy of autoimmune diseases by anti-interleukin-6 receptor antibody. Expert Opin. Biol. Ther. 5, 683–690 (2005).

    Article  CAS  PubMed  Google Scholar 

  142. Yokota, S. et al. Therapeutic efficacy of humanized recombinant anti-interleukin-6 receptor antibody in children with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 52, 818–825 (2005).

    Article  CAS  PubMed  Google Scholar 

  143. Kishimoto, T. Interleukin-6: from basic science to medicine — 40 years in immunology. Annu. Rev. Immunol. 23, 1–21 (2005).

    Article  CAS  PubMed  Google Scholar 

  144. Nishimoto, N. et al. Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease. Blood 106, 2627–2632 (2005).

    Article  CAS  PubMed  Google Scholar 

  145. 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).

    Article  CAS  PubMed  Google Scholar 

  146. Baechler, E. C. et al. Gene expression profiling in human autoimmunity. Immunol. Rev. 210, 120–137 (2006).

    Article  CAS  PubMed  Google Scholar 

  147. Banchereau, J., Pascual, V. & Palucka, A. K. Autoimmunity through cytokine-induced dendritic cell activation. Immunity 20, 539–550 (2004).

    Article  CAS  PubMed  Google Scholar 

  148. Pasare, C. & Medzhitov, R. Control of B-cell responses by Toll-like receptors. Nature 438, 364–648 (2005).

    Article  CAS  PubMed  Google Scholar 

  149. Barrat, F. J. et al. Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus. J. Exp. Med. 202, 1131–1139 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. 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 

  151. Vollmer, J. et al. Immune stimulation mediated by autoantigen binding sites within small nuclear RNAs involves Toll-like receptors 7 and 8. J. Exp. Med. 202, 1575–1585 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Rifkin, I. R., Leadbetter, E. A., Busconi, L., Viglianti, G. & Marshak-Rothstein, A. Toll-like receptors, endogenous ligands, and systemic autoimmune disease. Immunol. Rev. 204, 27–42 (2005).

    Article  CAS  PubMed  Google Scholar 

  153. Christensen, S. R. et al. Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus. J. Exp. Med. 202, 321–331 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Means, T. K. & Luster, A. D. Toll-like receptor activation in the pathogenesis of systemic lupus erythematosus. Ann. NY Acad. Sci. 1062, 242–251 (2005).

    Article  PubMed  Google Scholar 

  155. Theofilopoulos, A. N., Baccala, R., Beutler, B. & Kono, D. H. Type I interferons (α/β) in immunity and autoimmunity. Annu. Rev. Immunol. 23, 307–336 (2005).

    Article  CAS  PubMed  Google Scholar 

  156. Nimmerjahn, F. & Ravetch, J. V. Fcγ receptors: old friends and new family members. Immunity 24, 19–28 (2006).

    Article  CAS  PubMed  Google Scholar 

  157. Nakamura, A., Akiyama, K. & Takai, T. Fc receptor targeting in the treatment of allergy, autoimmune diseases and cancer. Expert Opin. Ther. Targets 9, 169–190 (2005).

    Article  CAS  PubMed  Google Scholar 

  158. Fukuyama, H., Nimmerjahn, F. & Ravetch, J. V. The inhibitory Fcγ receptor modulates autoimmunity by limiting the accumulation of immunoglobulin G+ anti-DNA plasma cells. Nature Immunol. 6, 99–106 (2005).

    Article  CAS  Google Scholar 

  159. McGaha, T. L., Sorrentino, B. & Ravetch, J. V. Restoration of tolerance in lupus by targeted inhibitory receptor expression. Science 307, 590–593 (2005).

    Article  CAS  PubMed  Google Scholar 

  160. Floto, R. A. et al. Loss of function of a lupus-associated FcγRIIb polymorphism through exclusion from lipid rafts. Nature Med. 11, 1056–1058 (2005).

    Article  CAS  PubMed  Google Scholar 

  161. Kono, H. et al. FcγRIIB Ile232Thr transmembrane polymorphism associated with human systemic lupus erythematosus decreases affinity to lipid rafts and attenuates inhibitory effects on B cell receptor signaling. Hum. Mol. Genet. 14, 2881–2892 (2005).

    Article  CAS  PubMed  Google Scholar 

  162. Blank, M. C. et al. Decreased transcription of the human FCGR2B gene mediated by the-343 G/C promoter polymorphism and association with systemic lupus erythematosus. Hum. Genet. 117, 220–227 (2005).

    Article  CAS  PubMed  Google Scholar 

  163. Sturfelt, G. & Truedsson, L. Complement and its breakdown products in SLE. Rheumatology (Oxford) 44, 1227–1232 (2005).

    Article  CAS  Google Scholar 

  164. Lemieux, R., Bazin, R. & Neron, S. Therapeutic intravenous immunoglobulins. Mol. Immunol. 42, 839–848 (2005).

    Article  CAS  PubMed  Google Scholar 

  165. Vaccaro, C., Zhou, J., Ober, R. J. & Ward, E. S. Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels. Nature Biotechnol. 23, 1283–1288 (2005).

    Article  CAS  Google Scholar 

  166. Iglesias, J., D'Agati, V. D. & Levine, J. S. Acute glomerulonephritis occurring during immunoadsorption with staphylococcal protein A column (Prosorba). Nephrol. Dial. Transplant. 19, 3155–3159 (2004).

    Article  PubMed  Google Scholar 

  167. Zandman-Goddard, G. & Shoenfeld, Y. Novel approaches to therapy for SLE. Clin. Rev. Allergy Immunol. 25, 105–112 (2003).

    Article  CAS  PubMed  Google Scholar 

  168. Jonkers, R. E. & van der Zee, J. S. Anti-IgE and other new immunomodulation-based therapies for allergic asthma. Neth. J. Med. 63, 121–128 (2005).

    CAS  PubMed  Google Scholar 

  169. Holgate, S. T., Djukanovic, R., Casale, T. & Bousquet, J. Anti-immunoglobulin E treatment with omalizumab in allergic diseases: an update on anti-inflammatory activity and clinical efficacy. Clin. Exp. Allergy 35, 408–416 (2005).

    Article  CAS  PubMed  Google Scholar 

  170. Zhang, K. et al. Inhibition of allergen-specific IgE reactivity by a human Ig Fcγ–Fcɛ bifunctional fusion protein. J. Allergy Clin. Immunol. 114, 321–327 (2004).

    Article  CAS  PubMed  Google Scholar 

  171. Kimby, E. Tolerability and safety of rituximab (MabThera). Cancer Treat. Rev. 31, 456–473 (2005).

    Article  CAS  PubMed  Google Scholar 

  172. Manz, R. A., Hauser, A. E., Hiepe, F. & Radbruch, A. Maintenance of serum antibody levels. Annu. Rev. Immunol. 23, 367–386 (2005).

    Article  CAS  PubMed  Google Scholar 

  173. Merrill, J. T., Erkan, D. & Buyon, J. P. Challenges in bringing the bench to bedside in drug development for SLE. Nature Rev. Drug Discov. 3, 1036–1046 (2004).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The author would like to thank M. Kehry, E. Notidis, A. Ranger, E. Beckman, S. Kalled and L. Burkly for helpful discussions and critical reading.

Author information

Authors and Affiliations

  1. Department of Immunobiology, Biogen Idec, 12 Cambridge Center, Cambridge, 02445, Massachusetts, USA

    Jeffrey L. Browning

Authors
  1. Jeffrey L. Browning
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

J.B. is employed at Biogen Idec, which, along with Genentech and Roche are developing and selling Rituximab for the treatment of autoimmune disease. Likewise, Biogen Idec and Genentech are jointly developing BAFF receptor blockers for similar indications. A favourable article could be seen as advertising.

Related links

Related links

DATABASES

OMIM

Crohn's disease

Grave's disease

Multiple sclerosis

Myasthenia gravis

Pemphigus vulgaris

Rheumatoid arthritis

Sjögren's syndrome

Systemic lupus erythematosus

Waldenstrom's macroglobulinaemia

Glossary

Rheumatoid factors (Rf)

Antibodies capable of recognizing soluble immunoglobulins. These antibodies represent a form of autoreactivity and are prevalent in rheumatoid arthritis and SLE.

Natural antibodies

Typically IgM antibodies formed early in development. These antibodies are produced by B1 cells (in mice) and do not display extensive hypermutation. They often have a low affinity for structures on the surfaces of bacteria and often can recognize multiple antigens — that is, they are polyreactive.

Plasma cells

Terminally differentiated B cells essentially dedicated to massive secretion of immunoglobulins. Short (2–3 days) and long-lived (∼0.5–1 year) versions exist; long-lived cells reside in the bone marrow and the short-lived cells remain in the splenic red pulp and the medullary cords of the lymph nodes. The gut compartment also has large numbers of plasma cells.

Extrafollicular response

For 2–6 days following B-cell activation in the presence of T-cell help, B cells undergo rapid proliferation and differentiation, leading to a burst of plasmablasts. Foci containing these cells remain in the T-cell region of the secondary lymphoid tissues. The resultant plasmablasts reside in the red pulp or medullary cords of the lymph nodes and survive for about 2–3 days.

Germinal-centre reaction

A collection of rapidly dividing B cells assembled on a scaffold of reticular cells. Within this nucleus, affinity maturation and class-switching events are optimized, and memory B cells and plasmablasts are generated.

Fc receptors

A family of generally low-affinity receptors that bind the immunoglobulin Fc domain. Oligomerized immunoglobulin is required for effective binding, and so these receptors serve a pivotal role as one of the primary sensors of immune complex formation. The receptors come in activating and inhibitory versions, and the balance between these two functions determines whether there is a response to immune complexes.

Complement

An enzyme cascade triggered by IgG immune complexes, bound IgM, some mannose-containing substances or certain bacterial surfaces. Activation deposits covalently the protein C3b on the antigen or pathogen, thereby marking it for binding by the various complement receptors. In the case of a cell surface, complement activation triggers the assembly of the membrane attack complex that kills the cell by forming pores in membrane.

Co-stimulatory molecules

A central dogma of immunology states that activation of T- or B-cell receptors alone is insufficient to initiate an immune response. Only when activation is accompanied by a second or third signal does cell activation ensue. The membrane receptors and ligands that provide the second and third signals are collectively referred to as co-stimulatory molecules.

Lymphotoxin system

Within the TNF family, the lymphotoxin-α/βligand binds to the lymphotoxin-β receptor on a subset of specialized stromal or endothelial cells to maintain their differentiation status. Constitutive lymphotoxin-β receptor signalling is required to maintain various micro-environments such as the polarized B-cell follicles, follicular dendritic cells and high endothelial venules.

Non-obese diabetic mice

(NOD mouse). A strain of autoimmune-prone mice that spontaneously develops diabetes due to an autoimmune attack on the pancreatic islet cells. This mouse serves as a common model for autoimmune disease and specifically human type I diabetes.

Lymphoid neogenesis

Within chronically inflamed tissues, leukocytic infiltrates can organize into an ectopic structure that resembles a lymph node. Aggregates of T and B cells, macrophages and dendritic cells assemble and specialized 'high endothelial venules' develop, allowing for additional trafficking opportunities. In the most organized cases, T cells segregate spatially from B cells, and germinal-centre reactions form within the B-cell follicle.

Antibody-dependent cellular cytotoxicity

(ADCC). Antibody-coated cells can be recognized by Fc receptors on natural killer cells and macrophages. Receptor engagement leads to direct killing of the coated cell by release of various agents.

Complement-dependent cytotoxicity

(CDC). Complement components assemble on complexes between antibodies and antigen (immune complexes). The assembly culminates with formation of the membrane attack complex, which directly creates pores in the membrane surface and kills the cell.

Affinity maturation

Somatic hypermutation results in altered antibodies and occurs efficiently in the germinal centre. Antibodies with higher affinity for the antigen are selected for as the response progresses.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Browning, J. B cells move to centre stage: novel opportunities for autoimmune disease treatment. Nat Rev Drug Discov 5, 564–576 (2006). https://doi.org/10.1038/nrd2085

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd2085

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