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B-lymphocyte effector functions in health and disease

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Abstract

B-lymphocytes have traditionally been thought to contribute to immunity and autoimmune disease through terminal differentiation into plasma cells that secrete antibody. However, studies in mice and recent clinical studies have demonstrated that genetically altered B-cell function and B-cell-targeted therapies can significantly affect autoimmune diseases that were predominantly thought to be T-cell-mediated. B-cell depletion in mouse models of disease has also led to the identification of alternative B-cell effector functions that regulate normal immune responses and autoimmune disease. This review highlights multiple B-cell effector mechanisms, including the promotion of cellular immunity, the negative regulation of immune responses, and the production of pathogenic antibodies.

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References

  1. Levesque MC, St Clair EW. B cell-directed therapies for autoimmune disease and correlates of disease response and relapse. J Allergy Clin Immunol. 2008;121:13–21.

    Article  PubMed  CAS  Google Scholar 

  2. Yanaba K, Bouaziz JD, Matsushita T, Magro CM, St Clair EW, Tedder TF. B-lymphocyte contributions to human autoimmune disease. Immunol Rev. 2008;223:284–99.

    Article  PubMed  CAS  Google Scholar 

  3. Kennedy AD, Beum PV, Solga MD, DiLillo DJ, Lindorfer MA, Hess CE, Densmore JJ, Williams ME, Taylor RP. Rituximab infusion promotes rapid complement depletion and acute CD20 loss in chronic lymphocytic leukemia. J Immunol. 2004;172:3280–8.

    PubMed  CAS  Google Scholar 

  4. Smith MR. Rituximab (monoclonal anti-CD20 antibody): mechanisms of action and resistance. Oncogene. 2003;22:7359–68.

    Article  PubMed  CAS  Google Scholar 

  5. Taylor RP, Lindorfer MA. Immunotherapeutic mechanisms of anti-CD20 monoclonal antibodies. Curr Opin Immunol. 2008;20:444–9.

    Article  PubMed  CAS  Google Scholar 

  6. Joao C, Ogle BM, Gay-Rabinstein C, Platt JL, Cascalho M. B cell-dependent TCR diversification. J Immunol. 2004;172:4709–16.

    PubMed  CAS  Google Scholar 

  7. Asano MS, Ahmed R. CD8 T cell memory in B cell-deficient mice. J Exp Med. 1996;183:2165–74.

    Article  PubMed  CAS  Google Scholar 

  8. Crowley MT, Reilly CR, Lo D. Influence of lymphocytes on the presence and organization of dendritic cell subsets in the spleen. J Immunol. 1999;163:4894–900.

    PubMed  CAS  Google Scholar 

  9. 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;192:475–82.

    Article  PubMed  CAS  Google Scholar 

  10. Uchida J, Lee Y, Hasegawa M, Liang Y, Bradney A, Oliver JA, Bowen K, Steeber DA, Haas KM, Poe JC, Tedder TF. Mouse CD20 expression and function. Int Immunol. 2004;16:119–29.

    Article  PubMed  CAS  Google Scholar 

  11. Uchida J, Hamaguchi Y, Oliver JA, Ravetch JV, Poe JC, Haas KM, Tedder TF. The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptor-dependent mechanisms during anti-CD20 antibody immunotherapy. J Exp Med. 2004;199:1659–69.

    Article  PubMed  CAS  Google Scholar 

  12. Hamaguchi Y, Xiu Y, Komura K, Nimmerjahn F, Tedder TF. Antibody isotype-specific engagement of Fcγ receptors regulates B lymphocyte depletion during CD20 immunotherapy. J Exp Med. 2006;203:743–53.

    Article  PubMed  CAS  Google Scholar 

  13. Hamaguchi Y, Uchida J, Cain DW, Venturi GM, Poe JC, Haas KM, Tedder TF. The peritoneal cavity provides a protective niche for B1 and conventional B lymphocytes during anti-CD20 immunotherapy in mice. J Immunol. 2005;174:4389–99.

    PubMed  CAS  Google Scholar 

  14. Yazawa N, Hamaguchi Y, Poe JC, Tedder TF. Immunotherapy using unconjugated CD19 monoclonal antibodies in animal models for B lymphocyte malignancies and autoimmune disease. Proc Natl Acad Sci USA. 2005;102:15178–83.

    Article  PubMed  CAS  Google Scholar 

  15. Minard-Colin V, Xiu Y, Poe JC, Horikawa M, Hamaguchi Y, Haas KM, Tedder TF. Lymphoma depletion during CD20 immunotherapy in mice is mediated by macrophage FcγRI, FcγRIII, and FcγRIV. Blood. 2008;112:1205–13.

    Article  PubMed  CAS  Google Scholar 

  16. Bouaziz JD, Yanaba K, Venturi GM, Wang Y, Tisch RM, Poe JC, Tedder TF. Therapeutic B cell depletion impairs adaptive and autoreactive CD4+ T cell activation in mice. Proc Natl Acad Sci USA. 2007;104:20882–7.

    Article  Google Scholar 

  17. DiLillo DJ, Yanaba K, Tedder TF. B cells are required for optimal CD4+ and CD8+ T cell tumor immunity: therapeutic B cell depletion enhances B16 melanoma growth in mice. J Immunol. 2010;184:4006–16.

    Article  PubMed  CAS  Google Scholar 

  18. 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;179:1369–80.

    PubMed  CAS  Google Scholar 

  19. Xiu Y, Wong CP, Hamaguchi Y, Wang Y, Pop S, Tisch RM, Tedder TF. B lymphocytes depletion by CD20 monoclonal antibody prevents diabetes in NOD mice despite isotype-specific differences in FcγR effector functions. J Immunol. 2008;180:2863–75.

    PubMed  CAS  Google Scholar 

  20. Hasegawa M, Hamaguchi Y, Yanaba K, Bouaziz J-D, Uchida J, Fujimoto M, Matsushita T, Matsushita Y, Horikawa M, Komura K, Takehara K, Sato S, Tedder TF. B-lymphocyte depletion reduces skin fibrosis and autoimmunity in the tight-skin mouse model for systemic sclerosis. Am J Pathol. 2006;169:954–66.

    Article  PubMed  CAS  Google Scholar 

  21. Hayakawa I, Tedder TF, Zhuang Y. B-lymphocyte depletion ameliorates Sjogren’s syndrome in Id3 knockout mice. Immunology. 2007;122:73–9.

    Article  PubMed  CAS  Google Scholar 

  22. Haas KM, Watanabe R, Matsushita T, Nakashima H, Ishiura N, Okochi H, Fujimoto M, Tedder TF. Protective and pathogenic roles for B cells during systemic autoimmunity in NZB/W F1 mice. J Immunol. 2010;184:4789–800.

    Article  PubMed  CAS  Google Scholar 

  23. Matsushita T, Yanaba K, Bouaziz J-D, Fujimoto M, Tedder TF. Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression. J Clin Invest. 2008;118:3420–30.

    PubMed  CAS  Google Scholar 

  24. Rivera A, Chen CC, Ron N, Dougherty JP, Ron Y. Role of B cells as antigen-presenting cells in vivo revisited: antigen-specific B cells are essential for T cell expansion in lymph nodes and for systemic T cell responses to low antigen concentrations. Int Immunol. 2001;13:1583–93.

    Article  PubMed  CAS  Google Scholar 

  25. Crawford A, Macleod M, Schumacher T, Corlett L, Gray D. Primary T cell expansion and differentiation in vivo requires antigen presentation by B cells. J Immunol. 2006;176:3498–506.

    PubMed  CAS  Google Scholar 

  26. Linton PJ, Harbertson J, Bradley LM. A critical role for B cells in the development of memory CD4 cells. J Immunol. 2000;165:5558–65.

    PubMed  CAS  Google Scholar 

  27. Linton PJ, Bautista B, Biederman E, Bradley ES, Harbertson J, Kondrack RM, Padrick RC, Bradley LM. Costimulation via OX40L expressed by B cells is sufficient to determine the extent of primary CD4 cell expansion and Th2 cytokine secretion in vivo. J Exp Med. 2003;197:875–83.

    Article  PubMed  CAS  Google Scholar 

  28. O’Neill SK, Cao Y, Hamel KM, Doodes PD, Hutas G, Finnegan A. Expression of CD80/86 on B cells is essential for autoreactive T cell activation and the development of arthritis. J Immunol. 2007;179:5109–16.

    PubMed  Google Scholar 

  29. LeBien TW, Tedder TF. B-lymphocytes: how they develop and function. Blood. 2008;112:1570–9.

    Article  PubMed  CAS  Google Scholar 

  30. DiLillo DJ, Hamaguchi Y, Ueda Y, Yang K, Uchida J, Haas KM, Kelsoe G, Tedder TF. Maintenance of long-lived plasma cells and serological memory despite mature and memory B cell depletion during CD20 immunotherapy in mice. J Immunol. 2008;180:361–71.

    PubMed  CAS  Google Scholar 

  31. Katz SI, Parker D, Turk JL. B-cell suppression of delayed hypersensitivity reactions. Nature. 1974;251:550–1.

    Article  PubMed  CAS  Google Scholar 

  32. 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;113:1716–25.

    PubMed  CAS  Google Scholar 

  33. DiLillo DJ, Griffiths R, Seshan SV, Magro CM, Ruiz P, Coffman TM, Tedder TF. B lymphocytes differentially influence acute and chronic allograft rejection in mice. J Immunol. 2011 (in press).

  34. Wolf SD, Dittel BN, Hardardottir F, Janeway CA Jr. Experimental autoimmune encephalomyelitis induction in genetically B cell-deficient mice. J Exp Med. 1996;184:2271–8.

    Article  PubMed  CAS  Google Scholar 

  35. Fillatreau S, Sweenie CH, McGeachy MJ, Gray D, Anderton SM. B cells regulate autoimmunity by provision of IL-10. Nat Immunol. 2002;3:944–50.

    Article  PubMed  CAS  Google Scholar 

  36. Fillatreau S, Gray D, Anderton SM. Not always the bad guys B cells as regulators of autoimmune pathology. Nature Rev Immunol. 2008;8:391–7.

    Article  CAS  Google Scholar 

  37. 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;16:219–30.

    Article  PubMed  CAS  Google Scholar 

  38. Mizoguchi A, Bhan AK. A case for regulatory B cells. J Immunol. 2006;176:705–10.

    PubMed  CAS  Google Scholar 

  39. Serra P, Santamaria P. To ‘B’ regulated: B cells as members of the regulatory workforce. Trends Immunol. 2006;27:7–10.

    Article  PubMed  CAS  Google Scholar 

  40. Mauri C, Ehrenstein MR. The ‘short’ history of regulatory B cells. Trends Immunol. 2008;29:34–40.

    Article  PubMed  CAS  Google Scholar 

  41. Lund FE. Cytokine-producing B lymphocytes-key regulators of immunity. Curr Opin Immunol. 2008;20:332–8.

    Article  PubMed  CAS  Google Scholar 

  42. Bouaziz J-D, Yanaba K, Tedder TF. Regulatory B cells as inhibitors of immune responses and inflammation. Immunol Rev. 2008;224:201–14.

    Article  PubMed  CAS  Google Scholar 

  43. 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;28:639–50.

    Article  PubMed  CAS  Google Scholar 

  44. Matsushita T, Horikawa M, Iwata Y, Tedder TF. Regulatory B cells (B10 cells) and regulatory T cells have independent roles in controlling EAE initiation and late-phase immunopathogenesis. J Immunol. 2010;185:2240–52.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  46. Matsushita T, Tedder TF. Identifying regulatory B cells (B10 cells) that produce IL-10. Methods Mol Biol. 2010;677:99–111.

    Article  Google Scholar 

  47. Yanaba K, Bouaziz J-D, 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;182:7459–72.

    Article  PubMed  CAS  Google Scholar 

  48. Duddy ME, Alter A, Bar-Or A. Distinct profiles of human B cell effector cytokines: a role in immune regulation. J Immunol. 2004;172:3422–7.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  50. Mizoguchi A, Mizoguchi E, Smith RN, Preffer FI, Bhan AK. Suppressive role of B cells in chronic colitis of T cell receptor α mutant mice. J Exp Med. 1997;186:1749–56.

    Article  PubMed  CAS  Google Scholar 

  51. Iwata Y, Matsushita T, Horikawa M, DiLillo DJ, Yanaba K, Venturi GM, Szabolcs PM, Bernstein SH, Magro CM, Williams AD, Hall RP, St Clair EW, Tedder TF. Characterization of a rare IL-10-competent B cell subset in man that parallels mouse regulatory B10 cells. Blood. 2010 (in press).

  52. Radbruch A, Muehlinghaus G, Luger EO, Inamine A, Smith KG, Dorner T, Hiepe F. Competence and competition: the challenge of becoming a long-lived plasma cell. Nature Rev Immunol. 2006;6:741–50.

    Article  CAS  Google Scholar 

  53. Zinkernagel RM, Bachmann MF, Kundig TM, Oehen S, Pirchet H, Hengartner H. On immunological memory. Annu Rev Immunol. 1996;14:333–67.

    Article  PubMed  CAS  Google Scholar 

  54. Bernasconi NL, Traggiai E, Lanzavecchia A. Maintenance of serological memory by polyclonal activation of human memory B cells. Science. 2002;298:2199–202.

    Article  PubMed  CAS  Google Scholar 

  55. Slifka MK, Antia R, Whitmire JK, Ahmed R. Humoral immunity due to long-lived plasma cells. Immunity. 1998;8:363–72.

    Article  PubMed  CAS  Google Scholar 

  56. Manz RA, Thiel A, Radbruch A. Lifetime of plasma cells in the bone marrow. Nature. 1997;388:133–4.

    Article  PubMed  CAS  Google Scholar 

  57. Ahuja A, Anderson SM, Khalil A, Shlomchik MJ. Maintenance of the plasma cell pool is independent of memory B cells. Proc Natl Acad Sci USA. 2008;105:4802–7.

    Article  PubMed  CAS  Google Scholar 

  58. Chan OT, Hannum LG, Haberman AM, Madaio MP, Shlomchik MJ. A novel mouse with B cells but lacking serum antibody reveals an antibody-independent role for B cells in murine lupus. J Exp Med. 1999;189:1639–48.

    Article  PubMed  CAS  Google Scholar 

  59. Attanavanich K, Kearney JF. Marginal zone, but not follicular B cells, are potent activators of naive CD4 T cells. J Immunol. 2004;172:803–11.

    PubMed  CAS  Google Scholar 

  60. Pillai S, Cariappa A, Moran ST. Marginal zone B cells. Annu Rev Immunol. 2005;23:161–96.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Immunology, Duke University Medical Center, Room 353 Jones Building, Research Drive, Box 3010, Durham, NC, 27710, USA

    David J. DiLillo, Mayuka Horikawa & Thomas F. Tedder

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  1. David J. DiLillo
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  2. Mayuka Horikawa
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  3. Thomas F. Tedder
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Correspondence to Thomas F. Tedder.

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DiLillo, D.J., Horikawa, M. & Tedder, T.F. B-lymphocyte effector functions in health and disease. Immunol Res 49, 281–292 (2011). https://doi.org/10.1007/s12026-010-8189-3

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