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Regulatory B cells in autoimmune diseases

Abstract

B cells are generally considered to be positive regulators of the immune response because of their capability to produce antibodies, including autoantibodies. The production of antibodies facilitates optimal CD4+ T-cell activation because B cells serve as antigen-presenting cells and exert other modulatory functions in immune responses. However, certain B cells can also negatively regulate the immune response by producing regulatory cytokines and directly interacting with pathogenic T cells via cell-to-cell contact. These types of B cells are defined as regulatory B (Breg) cells. The regulatory function of Breg cells has been demonstrated in mouse models of inflammation, cancer, transplantation, and particularly in autoimmunity. In this review, we focus on the recent advances that lead to the understanding of the development and function of Breg cells and the implications of B cells in human autoimmune diseases.

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References

  1. Osmond DG . B cell development in the bone marrow. Semin Immunol 1990; 2: 173–180.

    CAS  PubMed  Google Scholar 

  2. Cooper MD . Exploring lymphocyte differentiation pathways. Immunol Rev 2002; 185: 175–185.

    CAS  PubMed  Google Scholar 

  3. Welner RS, Pelayo R, Kincade PW . Evolving views on the genealogy of B cells. Nat Rev Immunol 2008; 8: 95–106.

    CAS  PubMed  Google Scholar 

  4. Katz SI, Parker D, Turk JL . B-cell suppression of delayed hypersensitivity reactions. Nature 1974; 251: 550–551.

    CAS  PubMed  Google Scholar 

  5. Neta R, Salvin SB . Specific suppression of delayed hypersensitivity: the possible presence of a suppressor B cell in the regulation of delayed hypersensitivity. J Immunol 1974; 113: 1716–1725.

    CAS  PubMed  Google Scholar 

  6. Mizoguchi A, Bhan AK . A case for regulatory B cells. J Immunol 2006; 176: 705–710.

    CAS  PubMed  Google Scholar 

  7. Lundy SK . Killer B lymphocytes: the evidence and the potential. Inflamm Res 2009; 58: 345–357.

    CAS  PubMed  Google Scholar 

  8. Gray D, Gray M . What are regulatory B cells? Eur J Immunol 2010; 40: 2677–2679.

    CAS  PubMed  Google Scholar 

  9. DiLillo DJ, Matsushita T, Tedder TF . B10 cells and regulatory B cells balance immune responses during inflammation, autoimmunity, and cancer. Ann NY Acad Sci 2010; 1183: 38–57.

    CAS  PubMed  Google Scholar 

  10. Blair PA, Norena LY, Flores-Borja F, Rawlings DJ, Isenberg DA, Ehrenstein MR et al. CD19+CD24hiCD38hi B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic Lupus Erythematosus patients. Immunity 2010; 32: 129–140.

    CAS  PubMed  Google Scholar 

  11. Iwata Y, Matsushita T, Horikawa M, Dilillo DJ, Yanaba K, Venturi GM et al. Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. Blood 2011; 117: 530–541.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Wolf SD, Dittel BN, Hardardottir F, Janeway CA Jr . Experimental autoimmune encephalomyelitis induction in genetically B cell-deficient mice. J Exp Med 1996; 184: 2271–2278.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Fillatreau S, Sweenie CH, McGeachy MJ, Gray D, Anderton SM . B cells regulate autoimmunity by provision of IL-10. Nat Immunol 2002; 3: 944–950.

    CAS  PubMed  Google Scholar 

  14. Mizoguchi A, Mizoguchi E, Smith RN, Preffer FI, Bhan AK . Suppressive role of B cells in chronic colitis of T cell receptor alpha mutant mice. J Exp Med 1997; 186: 1749–1756.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Mizoguchi A, Mizoguchi E, Takedatsu H, Blumberg RS, Bhan AK . Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation. Immunity 2002; 16: 219–230.

    CAS  PubMed  Google Scholar 

  16. O'Garra A, Chang R, Go N, Hastings R, Haughton G, Howard M . Ly-1 B (B-1) cells are the main source of B cell-derived interleukin 10. Eur J Immunol 1992; 22: 711–717.

    CAS  PubMed  Google Scholar 

  17. Spencer NF, Daynes RA . IL-12 directly stimulates expression of IL-10 by CD5+ B cells and IL-6 by both CD5+ and CD5− B cells: possible involvement in age-associated cytokine dysregulation. Int Immunol 1997; 9: 745–754.

    CAS  PubMed  Google Scholar 

  18. Lenert P, Brummel R, Field EH, Ashman RF . TLR-9 activation of marginal zone B cells in lupus mice regulates immunity through increased IL-10 production. J Clin Immunol 2005; 25: 29–40.

    CAS  PubMed  Google Scholar 

  19. Evans JG, Chavez-Rueda KA, Eddaoudi A, Meyer-Bahlburg A, Rawlings DJ, Ehrenstein MR et al. Novel suppressive function of transitional 2 B cells in experimental arthritis. J Immunol 2007; 178: 7868–7878.

    CAS  PubMed  Google Scholar 

  20. Yanaba K, Bouaziz JD, Haas KM, Poe JC, Fujimoto M, Tedder TF . A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses. Immunity 2008; 28: 639–650.

    CAS  PubMed  Google Scholar 

  21. Rafei M, Hsieh J, Zehntner S, Li M, Forner K, Birman E et al. A granulocyte-macrophage colony-stimulating factor and interleukin-15 fusokine induces a regulatory B cell population with immune suppressive properties. Nat Med 2009; 15: 1038–1045.

    CAS  PubMed  Google Scholar 

  22. Ding Q, Yeung M, Camirand G, Zeng Q, Akiba H, Yagita H et al. Regulatory B cells are identified by expression of TIM-1 and can be induced through TIM-1 ligation to promote tolerance in mice. J Clin Invest 2011; 121: 3645–3656.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Qian L, Qian C, Chen Y, Bai Y, Bao Y, Lu L et al. Regulatory dendritic cells program B cells to differentiate into CD19hiFcgammaIIbhi regulatory B cells through IFN-beta and CD40L. Blood 2012; 120: 581–591.

    CAS  PubMed  Google Scholar 

  24. Duddy M, Niino M, Adatia F, Hebert S, Freedman M, Atkins H et al. Distinct effector cytokine profiles of memory and naive human B cell subsets and implication in multiple sclerosis. J Immunol 2007; 178: 6092–6099.

    CAS  PubMed  Google Scholar 

  25. Duddy ME, Alter A, Bar-Or A . Distinct profiles of human B cell effector cytokines: a role in immune regulation? J Immunol 2004; 172: 3422–3427.

    CAS  PubMed  Google Scholar 

  26. Edwards JC, Cambridge G, Abrahams VM . Do self-perpetuating B lymphocytes drive human autoimmune disease? Immunology 1999; 97: 188–196.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Shimomura Y, Mizoguchi E, Sugimoto K, Kibe R, Benno Y, Mizoguchi A et al. Regulatory role of B-1 B cells in chronic colitis. Int Immunol 2008; 20: 729–737.

    CAS  PubMed  Google Scholar 

  28. Shlomchik MJ, Craft JE, Mamula MJ . From T to B and back again: positive feedback in systemic autoimmune disease. Nat Rev Immunol 2001; 1: 147–153.

    CAS  PubMed  Google Scholar 

  29. Rodriguez-Pinto D, Moreno J . B cells can prime naive CD4+ T cells in vivo in the absence of other professional antigen-presenting cells in a CD154−CD40-dependent manner. Eur J Immunol 2005; 35: 1097–1105.

    CAS  PubMed  Google Scholar 

  30. Yan J, Harvey BP, Gee RJ, Shlomchik MJ, Mamula MJ . B cells drive early T cell autoimmunity in vivo prior to dendritic cell-mediated autoantigen presentation. J Immunol 2006; 177: 4481–4487.

    CAS  PubMed  Google Scholar 

  31. Fuchs EJ, Matzinger P . B cells turn off virgin but not memory T cells. Science 1992; 258: 1156–1159.

    CAS  PubMed  Google Scholar 

  32. Eynon EE, Parker DC . Small B cells as antigen-presenting cells in the induction of tolerance to soluble protein antigens. J Exp Med 1992; 175: 131–138.

    CAS  PubMed  Google Scholar 

  33. Harris DP, Haynes L, Sayles PC, Duso DK, Eaton SM, Lepak NM et al. Reciprocal regulation of polarized cytokine production by effector B and T cells. Nat Immunol 2000; 1: 475–482.

    CAS  PubMed  Google Scholar 

  34. Feldmann M, Brennan FM, Maini RN . Rheumatoid arthritis. Cell 1996; 85: 307–310.

    CAS  PubMed  Google Scholar 

  35. Scott DL, Wolfe F, Huizinga TW . Rheumatoid arthritis. Lancet 2010; 376: 1094–1108.

    PubMed  Google Scholar 

  36. Trentham DE, Townes AS, Kang AH . Autoimmunity to type II collagen an experimental model of arthritis. J Exp Med 1977; 146: 857–868.

    CAS  PubMed  Google Scholar 

  37. Lu L, Osmond DG . Apoptosis and its modulation during B lymphopoiesis in mouse bone marrow. Immunol Rev 2000; 175: 158–174.

    CAS  PubMed  Google Scholar 

  38. Zhang M, Srivastava G, Lu L . The pre-B cell receptor and its function during B cell development. Cell Mol Immunol 2004; 1: 89–94.

    CAS  PubMed  Google Scholar 

  39. Zhang M, Ko KH, Lam QL, Lo CK, Srivastava G, Zheng B et al. Expression and function of TNF family member B cell-activating factor in the development of autoimmune arthritis. Int Immunol 2005; 17: 1081–1092.

    CAS  PubMed  Google Scholar 

  40. Yanaba K, Bouaziz JD, Matsushita T, Magro CM, St Clair EW, Tedder TF . B-lymphocyte contributions to human autoimmune disease. Immunol Rev 2008; 223: 284–299.

    CAS  PubMed  Google Scholar 

  41. Lo CK, Lam QL, Sun L, Wang S, Ko KH, Xu H et al. Natural killer cell degeneration exacerbates experimental arthritis in mice via enhanced interleukin-17 production. Arthritis Rheum 2008; 58: 2700–2711.

    PubMed  Google Scholar 

  42. Yanaba K, Hamaguchi Y, Venturi GM, Steeber DA, St Clair EW, Tedder TF . B cell depletion delays collagen-induced arthritis in mice: arthritis induction requires synergy between humoral and cell-mediated immunity. J Immunol 2007; 179: 1369–1380.

    CAS  PubMed  Google Scholar 

  43. Mauri C, Gray D, Mushtaq N, Londei M . Prevention of arthritis by interleukin 10-producing B cells. J Exp Med 2003; 197: 489–501.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Gray M, Miles K, Salter D, Gray D, Savill J . Apoptotic cells protect mice from autoimmune inflammation by the induction of regulatory B cells. Proc Natl Acad Sci USA 2007; 104: 14080–14085.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Yang M, Deng J, Liu Y, Ko KH, Wang X, Jiao Z et al. IL-10-producing regulatory B10 cells ameliorate collagen-induced arthritis via suppressing Th17 cell generation. Am J Pathol 2012; 180: 2375–2385.

    CAS  PubMed  Google Scholar 

  46. Yang M, Sun L, Wang S, Ko KH, Xu H, Zheng BJ et al. Novel function of B cell-activating factor in the induction of IL-10-producing regulatory B cells. J Immunol 2010; 184: 3321–3325.

    CAS  PubMed  Google Scholar 

  47. Anderson MS, Bluestone JA . The NOD mouse: a model of immune dysregulation. Annu Rev Immunol 2005; 23: 447–485.

    CAS  PubMed  Google Scholar 

  48. Silveira PA, Grey ST . B cells in the spotlight: innocent bystanders or major players in the pathogenesis of type 1 diabetes. Trends Endocrinol Metab 2006; 17: 128–135.

    CAS  PubMed  Google Scholar 

  49. Fox CJ, Danska JS . Independent genetic regulation of T-cell and antigen-presenting cell participation in autoimmune islet inflammation. Diabetes 1998; 47: 331–338.

    CAS  PubMed  Google Scholar 

  50. Kendall PL, Yu G, Woodward EJ, Thomas JW . Tertiary lymphoid structures in the pancreas promote selection of B lymphocytes in autoimmune diabetes. J Immunol 2007; 178: 5643–5651.

    CAS  PubMed  Google Scholar 

  51. Henry RA, Kendall PL . CXCL13 blockade disrupts B lymphocyte organization in tertiary lymphoid structures without altering B cell receptor bias or preventing diabetes in nonobese diabetic mice. J Immunol 2010; 185: 1460–1465.

    CAS  PubMed  Google Scholar 

  52. Yanaba K, Bouaziz JD, Matsushita T, Magro CM, St Clair EW, Tedder TF . B-lymphocyte contributions to human autoimmune disease. Immunol Rev 2008; 223: 284–299.

    CAS  PubMed  Google Scholar 

  53. Xiu Y, Wong CP, Bouaziz JD, Hamaguchi Y, Wang Y, Pop SM et al. B lymphocyte depletion by CD20 monoclonal antibody prevents diabetes in nonobese diabetic mice despite isotype-specific differences in Fc gamma R effector functions. J Immunol 2008; 180: 2863–2875.

    CAS  PubMed  Google Scholar 

  54. Marino E, Villanueva J, Walters S, Liuwantara D, Mackay F, Grey ST . CD4+CD25+ T-cells control autoimmunity in the absence of B-cells. Diabetes 2009; 58: 1568–1577.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Smith SH, Tedder TF . Targeting B-cells mitigates autoimmune diabetes in NOD mice: what is plan B? Diabetes 2009; 58: 1479–1481.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Hussain S, Delovitch TL . Intravenous transfusion of BCR-activated B cells protects NOD mice from type 1 diabetes in an IL-10-dependent manner. J Immunol 2007; 179: 7225–7232.

    CAS  PubMed  Google Scholar 

  57. Tian J, Zekzer D, Hanssen L, Lu Y, Olcott A, Kaufman DL . Lipopolysaccharide-activated B cells down-regulate Th1 immunity and prevent autoimmune diabetes in nonobese diabetic mice. J Immunol 2001; 167: 1081–1089.

    CAS  PubMed  Google Scholar 

  58. Hussain S, Delovitch TL . Intravenous transfusion of BCR-activated B cells protects NOD mice from type 1 diabetes in an IL-10-dependent manner. J Immunol 2007; 179: 7225–7232.

    CAS  PubMed  Google Scholar 

  59. Williams KC, Ulvestad E, Hickey WF . Immunology of multiple sclerosis. Clin Neurosci 1994; 2: 229–245.

    CAS  PubMed  Google Scholar 

  60. Fillatreau S, Sweenie CH, McGeachy MJ, Gray D, Anderton SM . B cells regulate autoimmunity by provision of IL-10. Nat Immunol 2002; 3: 944–950.

    CAS  PubMed  Google Scholar 

  61. Cross AH, Trotter JL, Lyons J . B cells and antibodies in CNS demyelinating disease. J Neuroimmunol 2001; 112: 1–14.

    CAS  PubMed  Google Scholar 

  62. Bouaziz JD, Yanaba K, Tedder TF . Regulatory B cells as inhibitors of immune responses and inflammation. Immunol Rev 2008; 224: 201–214.

    CAS  PubMed  Google Scholar 

  63. Matsushita T, Yanaba K, Bouaziz JD, Fujimoto M, Tedder TF . Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression. J Clin Invest 2008; 118: 3420–3430.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Ray A, Mann MK, Basu S, Dittel BN . A case for regulatory B cells in controlling the severity of autoimmune-mediated inflammation in experimental autoimmune encephalomyelitis and multiple sclerosis. J Neuroimmunol 2011; 230: 1–9.

    CAS  PubMed  Google Scholar 

  65. Matsushita T, Horikawa M, Iwata Y, Tedder TF . Regulatory B cells (B10 cells) and regulatory T cells have independent roles in controlling experimental autoimmune encephalomyelitis initiation and late-phase immunopathogenesis. J Immunol 2010; 185: 2240–2252.

    CAS  PubMed  Google Scholar 

  66. Lipsky PE . Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity. Nat Immunol 2001; 2: 764–766.

    CAS  PubMed  Google Scholar 

  67. Grammer AC, Slota R, Fischer R, Gur H, Girschick H, Yarboro C et al. Abnormal germinal center reactions in systemic lupus erythematosus demonstrated by blockade of CD154–CD40 interactions. J Clin Invest 2003; 112: 1506–1520.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Mountz J . Animal models of systemic lupus erythematosus and Sjogren's syndrome. Curr Opin Rheumatol 1990; 2: 740–748.

    CAS  PubMed  Google Scholar 

  69. Wither JE, Roy V, Brennan LA . Activated B cells express increased levels of costimulatory molecules in young autoimmune NZB and (NZB×NZW)F1 mice. Clin Immunol 2000; 94: 51–63.

    CAS  PubMed  Google Scholar 

  70. Schuster H, Martin T, Marcellin L, Garaud JC, Pasquali JL, Korganow AS . Expansion of marginal zone B cells is not sufficient for the development of renal disease in NZB×NZW F1 mice. Lupus 2002; 11: 277–286.

    CAS  PubMed  Google Scholar 

  71. Atencio S, Amano H, Izui S, Kotzin BL . Separation of the New Zealand Black genetic contribution to lupus from New Zealand Black determined expansions of marginal zone B and B1a cells. J Immunol 2004; 172: 4159–4166.

    CAS  PubMed  Google Scholar 

  72. Vyse TJ, Halterman RK, Rozzo SJ, Izui S, Kotzin BL . Control of separate pathogenic autoantibody responses marks MHC gene contributions to murine lupus. Proc Natl Acad Sci USA 1999; 96: 8098–8103.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Chan OT, Madaio MP, Shlomchik MJ . The central and multiple roles of B cells in lupus pathogenesis. Immunol Rev 1999; 169: 107–121.

    CAS  PubMed  Google Scholar 

  74. Haas KM, Watanabe R, Matsushita T, Nakashima H, Ishiura N, Okochi H et al. Protective and pathogenic roles for B cells during systemic autoimmunity in NZB/W F1 mice. J Immunol 2010; 184: 4789–4800.

    CAS  PubMed  Google Scholar 

  75. Watanabe R, Ishiura N, Nakashima H, Kuwano Y, Okochi H, Tamaki K et al. Regulatory B cells (B10 cells) have a suppressive role in murine lupus: CD19 and B10 cell deficiency exacerbates systemic autoimmunity. J Immunol 2010; 184: 4801–4809.

    CAS  PubMed  Google Scholar 

  76. Blair PA, Chavez-Rueda KA, Evans JG, Shlomchik MJ, Eddaoudi A, Isenberg DA et al. Selective targeting of B cells with agonistic anti-CD40 is an efficacious strategy for the generation of induced regulatory T2-like B cells and for the suppression of lupus in MRL/lpr mice. J Immunol 2009; 182: 3492–3502.

    CAS  PubMed  Google Scholar 

  77. Palanichamy A, Barnard J, Zheng B, Owen T, Quach T, Wei C et al. Novel human transitional B cell populations revealed by B cell depletion therapy. J Immunol 2009; 182: 5982–5993.

    CAS  PubMed  Google Scholar 

  78. Plebani A, Lougaris V, Soresina A, Meini A, Zunino F, Losi CG et al. A novel immunodeficiency characterized by the exclusive presence of transitional B cells unresponsive to CpG. Immunology 2007; 121: 183–188.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Anolik JH, Barnard J, Owen T, Zheng B, Kemshetti S, Looney RJ et al. Delayed memory B cell recovery in peripheral blood and lymphoid tissue in systemic lupus erythematosus after B cell depletion therapy. Arthritis Rheum 2007; 56: 3044–3056.

    CAS  PubMed  Google Scholar 

  80. Sanz I, Wei C, Lee FE, Anolik J . Phenotypic and functional heterogeneity of human memory B cells. Semin Immunol 2008; 20: 67–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Agematsu K, Hokibara S, Nagumo H, Komiyama A . CD27: a memory B-cell marker. Immunol Today 2000; 21: 204–206.

    CAS  PubMed  Google Scholar 

  82. Bouaziz JD, Calbo S, Maho-Vaillant M, Saussine A, Bagot M, Bensussan A et al. IL-10 produced by activated human B cells regulates CD4+ T-cell activation in vitro. Eur J Immunol 2010; 40: 2686–2691.

    CAS  PubMed  Google Scholar 

  83. Edwards JC, Cambridge G . Sustained improvement in rheumatoid arthritis following a protocol designed to deplete B lymphocytes. Rheumatology (Oxford) 2001; 40: 205–211.

    CAS  Google Scholar 

  84. Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004; 350: 2572–2581.

    CAS  PubMed  Google Scholar 

  85. Leandro MJ, Cambridge G, Ehrenstein MR, Edwards JC . Reconstitution of peripheral blood B cells after depletion with rituximab in patients with rheumatoid arthritis. Arthritis Rheum 2006; 54: 613–620.

    CAS  PubMed  Google Scholar 

  86. Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 2008; 358: 676–688.

    CAS  PubMed  Google Scholar 

  87. Looney RJ, Anolik JH, Campbell D, Felgar RE, Young F, Arend LJ et al. B cell depletion as a novel treatment for systemic lupus erythematosus: a phase I/II dose-escalation trial of rituximab. Arthritis Rheum 2004; 50: 2580–2589.

    CAS  PubMed  Google Scholar 

  88. Goetz M, Atreya R, Ghalibafian M, Galle PR, Neurath MF . Exacerbation of ulcerative colitis after rituximab salvage therapy. Inflamm Bowel Dis 2007; 13: 1365–1368.

    PubMed  Google Scholar 

  89. Dass S, Vital EM, Emery P . Development of psoriasis after B cell depletion with rituximab. Arthritis Rheum 2007; 56: 2715–2718.

    CAS  PubMed  Google Scholar 

  90. Lampropoulou V, Hoehlig K, Roch T, Neves P, Calderon Gomez E, Sweenie CH et al. TLR-activated B cells suppress T cell-mediated autoimmunity. J Immunol 2008; 180: 4763–4773.

    CAS  PubMed  Google Scholar 

  91. Yanaba K, Bouaziz JD, Matsushita T, Tsubata T, Tedder TF . The development and function of regulatory B cells expressing IL-10 (B10 cells) requires antigen receptor diversity and TLR signals. J Immunol 2009; 182: 7459–7472.

    CAS  PubMed  Google Scholar 

  92. Gary-Gouy H, Harriague J, Bismuth G, Platzer C, Schmitt C, Dalloul AH . Human CD5 promotes B-cell survival through stimulation of autocrine IL-10 production. Blood 2002; 100: 4537–4543.

    CAS  PubMed  Google Scholar 

  93. Tu W, Lau YL, Zheng J, Liu Y, Chan PL, Mao H et al. Efficient generation of human alloantigen-specific CD4+ regulatory T cells from naive precursors by CD40-activated B cells. Blood 2008; 112: 2554–2562.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Schiemann B, Gommerman JL, Vora K, Cachero TG, Shulga-Morskaya S, Dobles M et al. An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science 2001; 293: 2111–2114.

    CAS  PubMed  Google Scholar 

  95. Schneider P, Takatsuka H, Wilson A, Mackay F, Tardivel A, Lens S et al. Maturation of marginal zone and follicular B cells requires B cell activating factor of the tumor necrosis factor family and is independent of B cell maturation antigen. J Exp Med 2001; 194: 1691–1697.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Walters S, Webster KE, Sutherland A, Gardam S, Groom J, Liuwantara D et al. Increased CD4+Foxp3+ T cells in BAFF-transgenic mice suppress T cell effector responses. J Immunol 2009; 182: 793–801.

    CAS  PubMed  Google Scholar 

  97. Gray M, Miles K, Salter D, Gray D, Savill J . Apoptotic cells protect mice from autoimmune inflammation by the induction of regulatory B cells. Proc Natl Acad Sci USA 2007; 104: 14080–14085.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Lopes-Carvalho T, Kearney JF . Development and selection of marginal zone B cells. Immunol Rev 2004; 197: 192–205.

    PubMed  Google Scholar 

  99. Evans JG, Chavez-Rueda KA, Eddaoudi A, Meyer-Bahlburg A, Rawlings DJ, Ehrenstein MR et al. Novel suppressive function of transitional 2 B cells in experimental arthritis. J Immunol 2007; 178: 7868–7878.

    CAS  PubMed  Google Scholar 

  100. Mauri C . Regulation of immunity and autoimmunity by B cells. Curr Opin Immunol 2010; 22: 761–767.

    CAS  PubMed  Google Scholar 

  101. Carter NA, Vasconcellos R, Rosser EC, Tulone C, Munoz-Suano A, Kamanaka M et al. Mice lacking endogenous IL-10-producing regulatory B cells develop exacerbated disease and present with an increased frequency of Th1/Th17 but a decrease in regulatory T cells. J Immunol 2011; 186: 5569–5579.

    CAS  PubMed  Google Scholar 

  102. Moulin V, Andris F, Thielemans K, Maliszewski C, Urbain J, Moser M . B lymphocytes regulate dendritic cell (DC) function in vivo: increased interleukin 12 production by DCs from B cell-deficient mice results in T helper cell type 1 deviation. J Exp Med 2000; 192: 475–482.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Tian J, Zekzer D, Hanssen L, Lu Y, Olcott A, Kaufman DL . Lipopolysaccharide-activated B cells down-regulate Th1 immunity and prevent autoimmune diabetes in nonobese diabetic mice. J Immunol 2001; 167: 1081–1089.

    CAS  PubMed  Google Scholar 

  104. Parekh VV, Prasad DV, Banerjee PP, Joshi BN, Kumar A, Mishra GC . B cells activated by lipopolysaccharide, but not by anti-Ig and anti-CD40 antibody, induce anergy in CD8+ T cells: role of TGF-beta 1. J Immunol 2003; 170: 5897–5911.

    CAS  PubMed  Google Scholar 

  105. Tedder TF, Matsushit, T. Regulatory B cells that produce IL-10: a breath of fresh air in allergic airway disease. J Allergy Clin Immunol 2010; 125: 1125–1127.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Amu S, Saunders SP, Kronenberg M, Mangan NE, Atzberger A, Fallon PG . Regulatory B cells prevent and reverse allergic airway inflammation via FoxP3-positive T regulatory cells in a murine model. J Allergy Clin Immunol 2010; 125: 1114–1124.e8.

    CAS  PubMed  Google Scholar 

  107. Carter NA, Rosser EC, Mauri C . IL-10 produced by B cells is crucial for the suppression of Th17/Th1 responses, induction of Tr1 cells and reduction of collagen-induced arthritis. Arthritis Res Ther 2012; 14: R32.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Bialecki E, Paget C, Fontaine J, Capron M, Trottein F, Faveeuw C . Role of marginal zone B lymphocytes in invariant NKT cell activation. J Immunol 2009; 182: 6105–6113.

    CAS  PubMed  Google Scholar 

  109. Sonoda KH, Stein-Streilein J . CD1d on antigen-transporting APC and splenic marginal zone B cells promotes NKT cell-dependent tolerance. Eur J Immunol 2002; 32: 848–857.

    CAS  PubMed  Google Scholar 

  110. Croxford JL, Miyake S, Huang YY, Shimamura M, Yamamura T . Invariant Valpha19i T cells regulate autoimmune inflammation. Nat Immunol 2006; 7: 987–994.

    CAS  PubMed  Google Scholar 

  111. Bosma A, Abdel-Gadir A, Isenberg DA, Jury EC, Mauri C . Lipid-antigen presentation by CD1d+ B cells is essential for the maintenance of invariant natural killer T cells. Immunity 2012; 36: 477–490.

    CAS  PubMed  Google Scholar 

  112. Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ . The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol 2007; 8: 239–245.

    CAS  PubMed  Google Scholar 

  113. Alderson MR, Lynch DH . Receptors and ligands that mediate activation-induced death of T cells. Springer Semin Immunopathol 1998; 19: 289–300.

    CAS  PubMed  Google Scholar 

  114. Anel A, Bosque A, Naval J, Pineiro A, Larrad L, Alava MA et al. Apo2L/TRAIL and immune regulation. Front Biosci 2007; 12: 2074–2084.

    CAS  PubMed  Google Scholar 

  115. Ray A, Basu S, Williams CB, Salzman NH, Dittel BN . A novel IL-10-independent regulatory role for B cells in suppressing autoimmunity by maintenance of regulatory T cells via GITR ligand. J Immunol 2012; 188: 3188–3198.

    CAS  PubMed  Google Scholar 

  116. Mann MK, Maresz K, Shriver LP, Tan Y, Dittel BN . B cell regulation of CD4+CD25+ T regulatory cells and IL-10 via B7 is essential for recovery from experimental autoimmune encephalomyelitis. J Immunol 2007; 178: 3447–3456.

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors dedicate this review manuscript to Dr Dennis G Osmond at McGill University for his mentorship. Dr Lu is a Croucher Senior Research Fellow supported by Hong Kong Croucher Foundation. This work was supported by grants from the National Basic Research Program of China (Grant No. 2010 CB 529100) and Research Grants Council of Hong Kong. The authors apologize to those researchers whose work could not be cited due to space limitations.

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Correspondence to Liwei Lu.

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Yang, M., Rui, K., Wang, S. et al. Regulatory B cells in autoimmune diseases. Cell Mol Immunol 10, 122–132 (2013). https://doi.org/10.1038/cmi.2012.60

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  • DOI: https://doi.org/10.1038/cmi.2012.60

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