Cell Biochemistry and Biophysics

, Volume 53, Issue 1, pp 1–16 | Cite as

The BLyS Family: Toward a Molecular Understanding of B Cell Homeostasis

  • John F. Treml
  • Yi Hao
  • Jason E. Stadanlick
  • Michael P. Cancro
Review Paper

Abstract

The B Lymphocyte Stimulator (BLyS) family of ligands and receptors regulates humoral immunity by controlling B lymphocyte survival and differentiation. Herein, we review the ligands and receptors of this family, their biological functions, and the biochemical processes through which they operate. Pre-immune B lymphocytes rely on BLyS signaling for their survival, whereas antigen experienced B lymphocytes generally interact more avidly with a homologous cytokine, A Proliferation Inducing Ligand (APRIL). The molecular basis for signaling via the three BLyS family receptors reveals complex interplay with other B lymphocyte signaling systems, affording the integration of selective and homeostatic processes. As our understanding of this system advances, molecular targets for manipulating humoral immunity in both health and disease should be revealed.

Keywords

BLyS family B cell homeostasis Plasma cell NF-κB 

References

  1. 1.
    Schiemann, B., Gommerman, J. L., Vora, K., Cachero, T. G., Shulga-Morskaya, S., Dobles, M., et al. (2001). An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science, 293, 2111–2114.PubMedGoogle Scholar
  2. 2.
    Schneider, P., Takatsuka, H., Wilson, A., Mackay, F., Tardivel, A., Lens, S., et al. (2001). 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. Journal of Experimental Medicine, 194, 1691–1697.PubMedGoogle Scholar
  3. 3.
    Thompson, J. S., Schneider, P., Kalled, S. L., Wang, L., Lefevre, E. A., Cachero, T. G., et al. (2000). BAFF binds to the tumor necrosis factor receptor-like molecule B cell maturation antigen and is important for maintaining the peripheral B cell population. Journal of Experimental Medicine, 192, 129–135.PubMedGoogle Scholar
  4. 4.
    Casola, S., Otipoby, K. L., Alimzhanov, M., Humme, S., Uyttersprot, N., Kutok, J. L., et al. (2004). B cell receptor signal strength determines B cell fate. Nature Immunology, 5, 317–327.PubMedGoogle Scholar
  5. 5.
    Do, R. K., & Chen-Kiang, S. (2002). Mechanism of BLyS action in B cell immunity. Cytokine and Growth Factor Reviews, 13, 19–25.PubMedGoogle Scholar
  6. 6.
    Ambrose, C. M. (2002). Baff-R. Journal of Biological Regulators and Homeostatic Agents, 16, 211–213.PubMedGoogle Scholar
  7. 7.
    Defrance, T., Casamayor-Palleja, M., & Krammer, P. H. (2002). The life and death of a B cell. Advances in Cancer Research, 86, 195–225.PubMedGoogle Scholar
  8. 8.
    Laabi, Y., Egle, A., & Strasser, A. (2001). TNF cytokine family: More BAFF-ling complexities. Current Biology, 11, R1013–R1016.PubMedGoogle Scholar
  9. 9.
    Mackay, F., & Ambrose, C. (2003). The TNF family members BAFF and APRIL: The growing complexity. Cytokine and Growth Factor Reviews, 14, 311–324.PubMedGoogle Scholar
  10. 10.
    Mackay, F., & Browning, J. L. (2002). BAFF: A fundamental survival factor for B cells. Nature Reviews Immunology, 2, 465–475.PubMedGoogle Scholar
  11. 11.
    Kalled, S. L. (2002). BAFF: A novel therapeutic target for autoimmunity. Current Opinion in Investigational Drugs, 3, 1005–1010.PubMedGoogle Scholar
  12. 12.
    Mak, T. W., & Yeh, W. C. (2002). Signaling for survival and apoptosis in the immune system. Arthritis Research, 3(4 Suppl), S243–S252.Google Scholar
  13. 13.
    Nardelli, B., Moore, P. A., Li, Y., & Hilbert, D. M. (2002). B lymphocyte stimulator (BLyS): A therapeutic trichotomy for the treatment of B lymphocyte diseases. Leukaemia & Lymphoma, 43, 1367–1373.Google Scholar
  14. 14.
    Stohl, W. (2002). B lymphocyte stimulator protein levels in systemic lupus erythematosus and other diseases. Current Rheumatology Reports, 4, 345–350.PubMedGoogle Scholar
  15. 15.
    Carter, R. H. (2003). A role for BLyS in tissue inflammation? Arthritis and Rheumatism, 48, 882–885.PubMedGoogle Scholar
  16. 16.
    Harless Smith, S., & Cancro, M. P. (2003). Integrating B cell homeostasis and selection with BLyS. Archivum Immunologiae et Therapiae Experimentalis (Warsz), 51, 209–218.Google Scholar
  17. 17.
    Harless Smith, S., & Cancro, M. P. (2003). BLyS: The pivotal determinant of peripheral B cell selection and lifespan. Current Pharmaceutical Design, 9, 1833–1847.PubMedGoogle Scholar
  18. 18.
    Mackay, F., Schneider, P., Rennert, P., & Browning, J. (2003). BAFF AND APRIL: A tutorial on B cell survival. Annual Review of Immunology, 21, 231–264.PubMedGoogle Scholar
  19. 19.
    Melchers, F. (2003). Actions of BAFF in B cell maturation and its effects on the development of autoimmune disease. Annals of the Rheumatic Diseases, 62(Suppl 2), ii25–ii27.PubMedGoogle Scholar
  20. 20.
    Schneider, P., & Tschopp, J. (2003). BAFF and the regulation of B cell survival. Immunology Letters, 88, 57–62.PubMedGoogle Scholar
  21. 21.
    Cancro, M. P. (2004). The BLyS family of ligands and receptors: An archetype for niche-specific homeostatic regulation. Immunological Reviews, 202, 237–249.PubMedGoogle Scholar
  22. 22.
    Gavin, A., Ait-Azzouzene, D., Martensson, A., Duong, B., Verkoczy, L., Skog, J. L., et al. (2004). Peripheral B lymphocyte tolerance. Keio Journal of Medicine, 53, 151–158.PubMedGoogle Scholar
  23. 23.
    Mackay, F., & Tangye, S. G. (2004). The role of the BAFF/APRIL system in B cell homeostasis and lymphoid cancers. Current Opinion in Pharmacology, 4, 347–354.PubMedGoogle Scholar
  24. 24.
    Anolik, J. H., & Aringer, M. (2005). New treatments for SLE: Cell-depleting and anti-cytokine therapies. Best Practice & Research. Clinical Rheumatology, 19, 859–878.Google Scholar
  25. 25.
    Crowley, J. E., Treml, L. S., Stadanlick, J. E., Carpenter, E., & Cancro, M. P. (2005). Homeostatic niche specification among naive and activated B cells: A growing role for the BLyS family of receptors and ligands. Seminars in Immunology, 17, 193–199.PubMedGoogle Scholar
  26. 26.
    Jelinek, D. F., & Darce, J. R. (2005). Human B lymphocyte malignancies: Exploitation of BLyS and APRIL and their receptors. Current Directions in Autoimmunity, 8, 266–288.PubMedGoogle Scholar
  27. 27.
    Kalled, S. L., Ambrose, C., & Hsu, Y. M. (2005). The biochemistry and biology of BAFF, APRIL and their receptors. Current Directions in Autoimmunity, 8, 206–242.PubMedGoogle Scholar
  28. 28.
    Mackay, F., Sierro, F., Grey, S. T., & Gordon, T. P. (2005). The BAFF/APRIL system: An important player in systemic rheumatic diseases. Current Directions in Autoimmunity, 8, 243–265.PubMedGoogle Scholar
  29. 29.
    Noelle, R. J., & Erickson, L. D. (2005). Determinations of B cell fate in immunity and autoimmunity. Current Directions in Autoimmunity, 8, 1–24.PubMedGoogle Scholar
  30. 30.
    Schneider, P. (2005). The role of APRIL and BAFF in lymphocyte activation. Current Opinion in Immunology, 17, 282–289.PubMedGoogle Scholar
  31. 31.
    Brink, R. (2006). Regulation of B cell self-tolerance by BAFF. Seminars in Immunology, 18, 276–283.PubMedGoogle Scholar
  32. 32.
    Mackay, F., & Leung, H. (2006). The role of the BAFF/APRIL system on T cell function. Seminars in Immunology, 18, 284–289.PubMedGoogle Scholar
  33. 33.
    Kalled, S. L. (2006). Impact of the BAFF/BR3 axis on B cell survival, germinal center maintenance and antibody production. Seminars in Immunology, 18, 290–296.PubMedGoogle Scholar
  34. 34.
    Treml, L. S., Crowley, J. E., & Cancro, M. P. (2006). BLyS receptor signatures resolve homeostatically independent compartments among naive and antigen-experienced B cells. Seminars in Immunology, 18, 297–304.PubMedGoogle Scholar
  35. 35.
    Mackay, F., Silveira, P. A., & Brink, R. (2007). B cells and the BAFF/APRIL axis: Fast-forward on autoimmunity and signaling. Current Opinion in Immunology, 19, 327–336.PubMedGoogle Scholar
  36. 36.
    Tangye, S. G., Bryant, V. L., Cuss, A. K., & Good, K. L. (2006). BAFF, APRIL and human B cell disorders. Seminars in Immunology, 18, 305–317.PubMedGoogle Scholar
  37. 37.
    Gardam, S., Sierro, F., Basten, A., Mackay, F., & Brink, R. (2008). TRAF2 and TRAF3 signal adapters act cooperatively to control the maturation and survival signals delivered to B cells by the BAFF receptor. Immunity, 28, 391–401.PubMedGoogle Scholar
  38. 38.
    Grech, A. P., Amesbury, M., Chan, T., Gardam, S., Basten, A., & Brink, R. (2004). TRAF2 differentially regulates the canonical and noncanonical pathways of NF-kappaB activation in mature B cells. Immunity, 21, 629–642.PubMedGoogle Scholar
  39. 39.
    Do, R. K., Hatada, E., Lee, H., Tourigny, M. R., Hilbert, D., & Chen-Kiang, S. (2000). Attenuation of apoptosis underlies B lymphocyte stimulator enhancement of humoral immune response. Journal of Experimental Medicine, 192, 953–964.PubMedGoogle Scholar
  40. 40.
    Locksley, R. M., Killeen, N., & Lenardo, M. J. (2001). The TNF and TNF receptor superfamilies: Integrating mammalian biology. Cell, 104, 487–501.PubMedGoogle Scholar
  41. 41.
    Mackay, F., Woodcock, S. A., Lawton, P., Ambrose, C., Baetscher, M., Schneider, P., et al. (1999). Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. Journal of Experimental Medicine, 190, 1697–1710.PubMedGoogle Scholar
  42. 42.
    Moore, P. A., Belvedere, O., Orr, A., Pieri, K., LaFleur, D. W., Feng, P., et al. (1999). BLyS: Member of the tumor necrosis factor family and B lymphocyte stimulator. Science, 285, 260–263.PubMedGoogle Scholar
  43. 43.
    Schneider, P., MacKay, F., Steiner, V., Hofmann, K., Bodmer, J. L., Holler, N., et al. (1999). BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. Journal of Experimental Medicine, 189, 1747–1756.PubMedGoogle Scholar
  44. 44.
    Bodmer, J. L., Schneider, P., & Tschopp, J. (2002). The molecular architecture of the TNF superfamily. Trends in Biochemical Sciences, 27, 19–26.PubMedGoogle Scholar
  45. 45.
    Hahne, M., Kataoka, T., Schroter, M., Hofmann, K., Irmler, M., Bodmer, J. L., et al. (1998). APRIL, a new ligand of the tumor necrosis factor family, stimulates tumor cell growth. Journal of Experimental Medicine, 188, 1185–1190.PubMedGoogle Scholar
  46. 46.
    Kelly, K., Manos, E., Jensen, G., Nadauld, L., & Jones, D. A. (2000). APRIL/TRDL-1, a tumor necrosis factor-like ligand, stimulates cell death. Cancer Research, 60, 1021–1027.PubMedGoogle Scholar
  47. 47.
    Pradet-Balade, B., Medema, J. P., Lopez-Fraga, M., Lozano, J. C., Kolfschoten, G. M., Picard, A., et al. (2002). An endogenous hybrid mRNA encodes TWE-PRIL, a functional cell surface TWEAK-APRIL fusion protein. EMBO Journal, 21, 5711–5720.PubMedGoogle Scholar
  48. 48.
    Kolfschoten, G. M., Pradet-Balade, B., Hahne, M., & Medema, J. P. (2003). TWE-PRIL; a fusion protein of TWEAK and APRIL. Biochemical Pharmacology, 66, 1427–1432.PubMedGoogle Scholar
  49. 49.
    Wallweber, H. J., Compaan, D. M., Starovasnik, M. A., & Hymowitz, S. G. (2004). The crystal structure of a proliferation-inducing ligand, APRIL. Journal of Molecular Biology, 343, 283–290.PubMedGoogle Scholar
  50. 50.
    Hymowitz, S. G., Patel, D. R., Wallweber, H. J., Runyon, S., Yan, M., Yin, J., et al. (2005). Structures of APRIL-receptor complexes: Like BCMA, TACI employs only a single cysteine-rich domain for high affinity ligand binding. Journal of Biological Chemistry, 280, 7218–7227.PubMedGoogle Scholar
  51. 51.
    Bossen, C., & Schneider, P. (2006). BAFF, APRIL and their receptors: Structure, function and signaling. Seminars in Immunology, 18, 263–275.PubMedGoogle Scholar
  52. 52.
    Bossen, C., Cachero, T. G., Tardivel, A., Ingold, K., Willen, L., Dobles, M., et al. (2008). TACI, unlike BAFF-R, is solely activated by oligomeric BAFF and APRIL to support survival of activated B cells and plasmablasts. Blood, 111, 1004–1012.Google Scholar
  53. 53.
    Hendriks, J., Planelles, L., de Jong-Odding, J., Hardenberg, G., Pals, S. T., Hahne, M., et al. (2005). Heparan sulfate proteoglycan binding promotes APRIL-induced tumor cell proliferation. Cell Death and Differentiation, 12, 637–648.PubMedGoogle Scholar
  54. 54.
    Ingold, K., Zumsteg, A., Tardivel, A., Huard, B., Steiner, Q. G., Cachero, T. G., et al. (2005). Identification of proteoglycans as the APRIL-specific binding partners. Journal of Experimental Medicine, 201, 1375–1383.PubMedGoogle Scholar
  55. 55.
    Khare, S. D., & Hsu, H. (2001). The role of TALL-1 and APRIL in immune regulation. Trends in Immunology, 22, 61–63.PubMedGoogle Scholar
  56. 56.
    Stein, J. V., Lopez-Fraga, M., Elustondo, F. A., Carvalho-Pinto, C. E., Rodriguez, D., Gomez-Caro, R., et al. (2002). APRIL modulates B and T cell immunity. Journal of Clinical Investigation, 109, 1587–1598.PubMedGoogle Scholar
  57. 57.
    Medema, J. P., Planelles-Carazo, L., Hardenberg, G., & Hahne, M. (2003). The uncertain glory of APRIL. Cell Death and Differentiation, 10, 1121–1125.PubMedGoogle Scholar
  58. 58.
    Sakurai, D., Hase, H., Kanno, Y., Kojima, H., Okumura, K., & Kobata, T. (2007). TACI regulates IgA production by APRIL in collaboration with HSPG. Blood, 109, 2961–2967.Google Scholar
  59. 59.
    Belnoue, E., Pihlgren, M., McGaha, T. L., Tougne, C., Rochat, A. F., Bossen, C., et al. (2008). APRIL is critical for plasmablast survival in the bone marrow and poorly expressed by early-life bone marrow stromal cells. Blood, 111, 2755–2764.PubMedGoogle Scholar
  60. 60.
    Benson, M. J., Dillon, S. R., Castigli, E., Geha, R. S., Xu, S., Lam, K. P., et al. (2008). Cutting edge: The dependence of plasma cells and independence of memory B cells on BAFF and APRIL. Journal of Immunology, 180, 3655–3659.Google Scholar
  61. 61.
    Moreaux, J., Cremer, F. W., Reme, T., Raab, M., Mahtouk, K., Kaukel, P., et al. (2005). The level of TACI gene expression in myeloma cells is associated with a signature of microenvironment dependence versus a plasmablastic signature. Blood, 106, 1021–1030.PubMedGoogle Scholar
  62. 62.
    O’Connor, B. P., Raman, V. S., Erickson, L. D., Cook, W. J., Weaver, L. K., Ahonen, C., et al. (2004). BCMA is essential for the survival of long-lived bone marrow plasma cells. Journal of Experimental Medicine, 199, 91–98.PubMedGoogle Scholar
  63. 63.
    Hardenberg, G., Planelles, L., Schwarte, C. M., van Bostelen, L., Le Huong, T., Hahne, M., et al. (2007). Specific TLR ligands regulate APRIL secretion by dendritic cells in a PKR-dependent manner. European Journal of Immunology, 37, 2900–2911.PubMedGoogle Scholar
  64. 64.
    Ware, C. F. (2000). APRIL and BAFF connect autoimmunity and cancer. Journal of Experimental Medicine, 192, F35–F38.PubMedGoogle Scholar
  65. 65.
    Chiu, A., Xu, W., He, B., Dillon, S. R., Gross, J. A., Sievers, E., et al. (2007). Hodgkin lymphoma cells express TACI and BCMA receptors and generate survival and proliferation signals in response to BAFF and APRIL. Blood, 109, 729–739.PubMedGoogle Scholar
  66. 66.
    Batten, M., Groom, J., Cachero, T. G., Qian, F., Schneider, P., Tschopp, J., et al. (2000). BAFF mediates survival of peripheral immature B lymphocytes. Journal of Experimental Medicine, 192, 1453–1466.PubMedGoogle Scholar
  67. 67.
    Gavin, A. L., Ait-Azzouzene, D., Ware, C. F., & Nemazee, D. (2003). DeltaBAFF, an alternate splice isoform that regulates receptor binding and biopresentation of the B cell survival cytokine, BAFF. Journal of Biological Chemistry, 278, 38220–38228.PubMedGoogle Scholar
  68. 68.
    Gavin, A. L., Duong, B., Skog, P., Ait-Azzouzene, D., Greaves, D. R., Scott, M. L., et al. (2005). deltaBAFF, a splice isoform of BAFF, opposes full-length BAFF activity in vivo in transgenic mouse models. Journal of Immunology, 175, 319–328.Google Scholar
  69. 69.
    Vogt, G., Chapgier, A., Yang, K., Chuzhanova, N., Feinberg, J., Fieschi, C., et al. (2005). Gains of glycosylation comprise an unexpectedly large group of pathogenic mutations. Nature Genetics, 37, 692–700.PubMedGoogle Scholar
  70. 70.
    Koskela, K., Nieminen, P., Kohonen, P., Salminen, H., & Lassila, O. (2004). Chicken B-cell-activating factor: Regulator of B-cell survival in the bursa of fabricius. Scandinavian Journal of Immunology, 59, 449–457.PubMedGoogle Scholar
  71. 71.
    Guan, Z. B., Ye, J. L., Dan, W. B., Yao, W. J., & Zhang, S. Q. (2007). Cloning, expression and bioactivity of duck BAFF. Molecular Immunology, 44, 1471–1476.PubMedGoogle Scholar
  72. 72.
    Schneider, K., Kothlow, S., Schneider, P., Tardivel, A., Gobel, T., Kaspers, B., et al. (2004). Chicken BAFF—a highly conserved cytokine that mediates B cell survival. International Immunology, 16, 139–148.PubMedGoogle Scholar
  73. 73.
    Kothlow, S., Morgenroth, I., Graef, Y., Schneider, K., Riehl, I., Staeheli, P., et al. (2007). Unique and conserved functions of B cell-activating factor of the TNF family (BAFF) in the chicken. International Immunology, 19, 203–215.PubMedGoogle Scholar
  74. 74.
    Scapini, P., Bazzoni, F., & Cassatella, M. A. (2008). Regulation of B-cell-activating factor (BAFF)/B lymphocyte stimulator (BLyS) expression in human neutrophils. Immunology Letters, 116, 1–6.PubMedGoogle Scholar
  75. 75.
    Nardelli, B., Belvedere, O., Roschke, V., Moore, P. A., Olsen, H. S., Migone, T. S., et al. (2001). Synthesis and release of B-lymphocyte stimulator from myeloid cells. Blood, 97, 198–204.PubMedGoogle Scholar
  76. 76.
    Roschke, V., Sosnovtseva, S., Ward, C. D., Hong, J. S., Smith, R., Albert, V., et al. (2002). BLyS and APRIL form biologically active heterotrimers that are expressed in patients with systemic immune-based rheumatic diseases. Journal of Immunology, 169, 4314–4321.Google Scholar
  77. 77.
    Madry, C., Laabi, Y., Callebaut, I., Roussel, J., Hatzoglou, A., Le Coniat, M., et al. (1998). The characterization of murine BCMA gene defines it as a new member of the tumor necrosis factor receptor superfamily. International Immunology, 10, 1693–1702.PubMedGoogle Scholar
  78. 78.
    von Bulow, G. U., & Bram, R. J. (1997). NF-AT activation induced by a CAML-interacting member of the tumor necrosis factor receptor superfamily. Science, 278, 138–141.Google Scholar
  79. 79.
    Miller, D. J., & Hayes, C. E. (1991). Phenotypic and genetic characterization of a unique B lymphocyte deficiency in strain A/WySnJ mice. European Journal of Immunology, 21, 1123–1130.PubMedGoogle Scholar
  80. 80.
    Miller, D. J., Hanson, K. D., Carman, J. A., & Hayes, C. E. (1992). A single autosomal gene defect severely limits IgG but not IgM responses in B lymphocyte-deficient A/WySnJ mice. European Journal of Immunology, 22, 373–379.PubMedGoogle Scholar
  81. 81.
    Lentz, V. M., Cancro, M. P., Nashold, F. E., & Hayes, C. E. (1996). Bcmd governs recruitment of new B cells into the stable peripheral B cell pool in the A/WySnJ mouse. Journal of Immunology, 157, 598–606.Google Scholar
  82. 82.
    Harless, S. M., Lentz, V. M., Sah, A. P., Hsu, B. L., Clise-Dwyer, K., Hilbert, D. M., et al. (2001). Competition for BLyS-mediated signaling through Bcmd/BR3 regulates peripheral B lymphocyte numbers. Current Biology, 11, 1986–1989.PubMedGoogle Scholar
  83. 83.
    Yan, M., Brady, J. R., Chan, B., Lee, W. P., Hsu, B., Harless, S., et al. (2001). Identification of a novel receptor for B lymphocyte stimulator that is mutated in a mouse strain with severe B cell deficiency. Current Biology, 11, 1547–1552.PubMedGoogle Scholar
  84. 84.
    Laabi, Y., Gras, M. P., Brouet, J. C., Berger, R., Larsen, C. J., & Tsapis, A. (1994). The BCMA gene, preferentially expressed during B lymphoid maturation, is bidirectionally transcribed. Nucleic Acids Research, 22, 1147–1154.PubMedGoogle Scholar
  85. 85.
    Stockfleth, E., Trefzer, U., Garcia-Bartels, C., Wegner, T., Schmook, T., & Sterry, W. (2003). The use of Toll-like receptor-7 agonist in the treatment of basal cell carcinoma: An overview. The British Journal of Dermatology, 149(Suppl 66), 53–56.PubMedGoogle Scholar
  86. 86.
    Day, E. S., Cachero, T. G., Qian, F., Sun, Y., Wen, D., Pelletier, M., et al. (2005). Selectivity of BAFF/BLyS and APRIL for binding to the TNF family receptors BAFFR/BR3 and BCMA. Biochemistry, 44, 1919–1931.PubMedGoogle Scholar
  87. 87.
    Roth, W., Wagenknecht, B., Klumpp, A., Naumann, U., Hahne, M., Tschopp, J., et al. (2001). APRIL, a new member of the tumor necrosis factor family, modulates death ligand-induced apoptosis. Cell Death and Differentiation, 8, 403–410.PubMedGoogle Scholar
  88. 88.
    Seshasayee, D., Valdez, P., Yan, M., Dixit, V. M., Tumas, D., & Grewal, I. S. (2003). Loss of TACI causes fatal lymphoproliferation and autoimmunity, establishing TACI as an inhibitory BLyS receptor. Immunity, 18, 279–288.PubMedGoogle Scholar
  89. 89.
    Treml, L. S., Carlesso, G., Hoek, K. L., Stadanlick, J. E., Kambayashi, T., Bram, R. J., et al. (2007). TLR stimulation modifies BLyS receptor expression in follicular and marginal zone B cells. Journal of Immunology, 178, 7531–7539.Google Scholar
  90. 90.
    Castigli, E., Scott, S., Dedeoglu, F., Bryce, P., Jabara, H., Bhan, A. K., et al. (2004). Impaired IgA class switching in APRIL-deficient mice. Proceedings of the National Academy of Sciences of the United States of America, 101, 3903–3908.PubMedGoogle Scholar
  91. 91.
    Castigli, E., Wilson, S. A., Scott, S., Dedeoglu, F., Xu, S., Lam, K. P., et al. (2005). TACI and BAFF-R mediate isotype switching in B cells. Journal of Experimental Medicine, 201, 35–39.PubMedGoogle Scholar
  92. 92.
    Shulga-Morskaya, S., Dobles, M., Walsh, M. E., Ng, L. G., MacKay, F., Rao, S. P., et al. (2004). B cell-activating factor belonging to the TNF family acts through separate receptors to support B cell survival and T cell-independent antibody formation. Journal of Immunology, 173, 2331–2341.Google Scholar
  93. 93.
    Hardy, R. R., Kincade, P. W., & Dorshkind, K. (2007). The protean nature of cells in the B lymphocyte lineage. Immunity, 26, 703–714.PubMedGoogle Scholar
  94. 94.
    Osmond, D. G., Rolink, A., & Melchers, F. (1998). Murine B lymphopoiesis: Towards a unified model. Immunology Today, 19, 65–68.PubMedGoogle Scholar
  95. 95.
    Burrows, P. D., Kearney, J. F., Schroeder, H. W., Jr., & Cooper, M. D. (1993). Normal B lymphocyte differentiation. Baillieres Clinical Haematology, 6, 785–806.Google Scholar
  96. 96.
    Singh, H. (1996). Gene targeting reveals a hierarchy of transcription factors regulating specification of lymphoid cell fates. Current Opinion in Immunology, 8, 160–165.PubMedGoogle Scholar
  97. 97.
    Georgopoulos, K. (2002). Haematopoietic cell-fate decisions, chromatin regulation and ikaros. Nature Reviews Immunology, 2, 162–174.PubMedGoogle Scholar
  98. 98.
    Cancro, M. P. (2004). Peripheral B-cell maturation: The intersection of selection and homeostasis. Immunological Reviews, 197, 89–101.PubMedGoogle Scholar
  99. 99.
    Srivastava, B., Lindsley, R. C., Nikbakht, N., & Allman, D. (2005). Models for peripheral B cell development and homeostasis. Seminars in Immunology, 17, 175–182.PubMedGoogle Scholar
  100. 100.
    Allman, D. M., Ferguson, S. E., Lentz, V. M., & Cancro, M. P. (1993). Peripheral B cell maturation. II. Heat-stable antigen(hi) splenic B cells are an immature developmental intermediate in the production of long-lived marrow-derived B cells. Journal of Immunology, 151, 4431–4444.Google Scholar
  101. 101.
    Osmond, D. G. (1986). Population dynamics of bone marrow B lymphocytes. Immunological Reviews, 93, 103–124.PubMedGoogle Scholar
  102. 102.
    Goodnow, C. C., Sprent, J., Fazekas de St Groth, B., & Vinuesa, C. G. (2005). Cellular and genetic mechanisms of self tolerance and autoimmunity. Nature, 435, 590–597.PubMedGoogle Scholar
  103. 103.
    Nemazee, D., & Buerki, K. (1989). Clonal deletion of autoreactive B lymphocytes in bone marrow chimeras. Proceedings of the National Academy of Sciences of the United States of America, 86, 8039–8043.PubMedGoogle Scholar
  104. 104.
    Basten, A., Brink, R., Peake, P., Adams, E., Crosbie, J., Hartley, S., et al. (1991). Self tolerance in the B-cell repertoire. Immunological Reviews, 122, 5–19.PubMedGoogle Scholar
  105. 105.
    Hartley, S. B., Crosbie, J., Brink, R., Kantor, A. B., Basten, A., & Goodnow, C. C. (1991). Elimination from peripheral lymphoid tissues of self-reactive B lymphocytes recognizing membrane-bound antigens. Nature, 353, 765–769.PubMedGoogle Scholar
  106. 106.
    Yurasov, S., Wardemann, H., Hammersen, J., Tsuiji, M., Meffre, E., Pascual, V., et al. (2005). Defective B cell tolerance checkpoints in systemic lupus erythematosus. Journal of Experimental Medicine, 201, 703–711.PubMedGoogle Scholar
  107. 107.
    Yurasov, S., Hammersen, J., Tiller, T., Tsuiji, M., & Wardemann, H. (2005). B-cell tolerance checkpoints in healthy humans and patients with systemic lupus erythematosus. Annals of the New York Academy of Sciences, 1062, 165–174.PubMedGoogle Scholar
  108. 108.
    Wang, H., Ye, J., Arnold, L. W., McCray, S. K., & Clarke, S. H. (2001). A VH12 transgenic mouse exhibits defects in pre-B cell development and is unable to make IgM + B cells. Journal of Immunology, 167, 1254–1262.Google Scholar
  109. 109.
    Levine, M. H., Haberman, A. M., Sant’Angelo, D. B., Hannum, L. G., Cancro, M. P., Janeway, C. A., Jr., et al. (2000). A B-cell receptor-specific selection step governs immature to mature B cell differentiation. Proceedings of the National Academy of Sciences of the United States of America, 97, 2743–2748.PubMedGoogle Scholar
  110. 110.
    Clarke, S. H., & McCray, S. K. (1993). VH CDR3-dependent positive selection of murine VH12-expressing B cells in the neonate. European Journal of Immunology, 23, 3327–3334.PubMedGoogle Scholar
  111. 111.
    Gu, H., Tarlinton, D., Muller, W., Rajewsky, K., & Forster, I. (1991). Most peripheral B cells in mice are ligand selected. Journal of Experimental Medicine, 173, 1357–1371.PubMedGoogle Scholar
  112. 112.
    Lam, K. P., Kuhn, R., & Rajewsky, K. (1997). In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell, 90, 1073–1083.PubMedGoogle Scholar
  113. 113.
    Smith, S. H., & Cancro, M. P. (2003). Cutting edge: B cell receptor signals regulate BLyS receptor levels in mature B cells and their immediate progenitors. Journal of Immunology, 170, 5820–5823.Google Scholar
  114. 114.
    Rosado, M. M., & Freitas, A. A. (1998). The role of the B cell receptor V region in peripheral B cell survival. European Journal of Immunology, 28, 2685–2693.PubMedGoogle Scholar
  115. 115.
    McLean, A. R., Rosado, M. M., Agenes, F., Vasconcellos, R., & Freitas, A. A. (1997). Resource competition as a mechanism for B cell homeostasis. Proceedings of the National Academy of Sciences of the United States of America, 94, 5792–5797.PubMedGoogle Scholar
  116. 116.
    Freitas, A. A., Rosado, M. M., Viale, A. C., & Grandien, A. (1995). The role of cellular competition in B cell survival and selection of B cell repertoires. European Journal of Immunology, 25, 1729–1738.PubMedGoogle Scholar
  117. 117.
    Sprent, J., & Basten, A. (1973). Circulating T and B lymphocytes of the mouse. II. Lifespan. Cellular Immunology, 7, 40–59.PubMedGoogle Scholar
  118. 118.
    Hsu, B. L., Harless, S. M., Lindsley, R. C., Hilbert, D. M., & Cancro, M. P. (2002). Cutting edge: BLyS enables survival of transitional and mature B cells through distinct mediators. Journal of Immunology, 168, 5993–5996.Google Scholar
  119. 119.
    von Bulow, G. U., van Deursen, J. M., & Bram, R. J. (2001). Regulation of the T-independent humoral response by TACI. Immunity, 14, 573–582.Google Scholar
  120. 120.
    Lentz, V. M., Hayes, C. E., & Cancro, M. P. (1998). Bcmd decreases the life span of B-2 but not B-1 cells in A/WySnJ mice. Journal of Immunology, 160, 3743–3747.Google Scholar
  121. 121.
    Hoag, K. A., Clise-Dwyer, K., Lim, Y. H., Nashold, F. E., Gestwicki, J., Cancro, M. P., et al. (2000). A quantitative-trait locus controlling peripheral B-cell deficiency maps to mouse Chromosome 15. Immunogenetics, 51, 924–929.PubMedGoogle Scholar
  122. 122.
    Miller, J. P., Stadanlick, J. E., & Cancro, M. P. (2006). Space, selection, and surveillance: Setting boundaries with BLyS. Journal of Immunology, 176, 6405–6410.Google Scholar
  123. 123.
    Stohl, W. (2005). BlySfulness does not equal blissfulness in systemic lupus erythematosus: A therapeutic role for BLyS antagonists. Current Directions in Autoimmunity, 8, 289–304.PubMedGoogle Scholar
  124. 124.
    Cancro, M. P., & Smith, S. H. (2003). Peripheral B cell selection and homeostasis. Immunologic Research, 27, 141–148.PubMedGoogle Scholar
  125. 125.
    Lesley, R., Xu, Y., Kalled, S. L., Hess, D. M., Schwab, S. R., Shu, H. B., et al. (2004). Reduced competitiveness of autoantigen-engaged B cells due to increased dependence on BAFF. Immunity, 20, 441–453.PubMedGoogle Scholar
  126. 126.
    Thien, M., Phan, T. G., Gardam, S., Amesbury, M., Basten, A., Mackay, F., et al. (2004). 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.PubMedGoogle Scholar
  127. 127.
    Hondowicz, B. D., Alexander, S. T., Quinn, W. J., 3rd, Pagan, A. J., Metzgar, M. H., & Cancro, M. P. (2007). The role of BLyS/BLyS receptors in anti-chromatin B cell regulation. International Immunology, 19(4), 465–475.PubMedGoogle Scholar
  128. 128.
    Stadanlick, J. E., & Cancro, M. P. (2008). BAFF and the plasticity of peripheral B cell tolerance. Current Opinion in Immunology, 20, 158–161.PubMedGoogle Scholar
  129. 129.
    Sasaki, Y., Derudder, E., Hobeika, E., Pelanda, R., Reth, M., Rajewsky, K., et al. (2006). Canonical NF-kappaB activity, dispensable for B cell development, replaces BAFF-receptor signals and promotes B cell proliferation upon activation. Immunity, 24, 729–739.PubMedGoogle Scholar
  130. 130.
    Shinners, N. P., Carlesso, G., Castro, I., Hoek, K. L., Corn, R. A., Woodland, R. T., et al. (2007). Bruton’s tyrosine kinase mediates NF-kappa B activation and B cell survival by B cell-activating factor receptor of the TNF-R family. Journal of Immunology, 179, 3872–3880.Google Scholar
  131. 131.
    Siebenlist, U., Brown, K., & Claudio, E. (2005). Control of lymphocyte development by nuclear factor-kappaB. Nature Reviews Immunology, 5, 435–445.PubMedGoogle Scholar
  132. 132.
    Stadanlick, J. E., Kaileh, M., Karnell, F. G., Scholz, J. L., Miller, J. P., & Quinn, W. J., 3rd. (2008). Tonic B cell antigen receptor signals supply an NF-kB substrate for prosurvival signaling. Nature Immunology, 9, 1379–1387.Google Scholar
  133. 133.
    Shinohara, H., Yasuda, T., Aiba, Y., Sanjo, H., Hamadate, M., Watarai, H., et al. (2005). PKC{beta} regulates BCR-mediated IKK activation by facilitating the interaction between TAK1 and CARMA1. Journal of Experimental Medicine, 202, 1423–1431.PubMedGoogle Scholar
  134. 134.
    Weih, F., Durham, S. K., Barton, D. S., Sha, W. C., Baltimore, D., & Bravo, R. (1997). p50-NF-kappaB complexes partially compensate for the absence of RelB: Severely increased pathology in p50(-/-)relB(-/-) double-knockout mice. Journal of Experimental Medicine, 185, 1359–1370.PubMedGoogle Scholar
  135. 135.
    Hayden, M. S., & Ghosh, S. (2004). Signaling to NF-kappaB. Genes and Development, 18, 2195–2224.PubMedGoogle Scholar
  136. 136.
    Bonizzi, G., & Karin, M. (2004). The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends in Immunology, 25, 280–288.PubMedGoogle Scholar
  137. 137.
    Sen, R. (2006). Control of B lymphocyte apoptosis by the transcription factor NF-kappaB. Immunity, 25, 871–883.PubMedGoogle Scholar
  138. 138.
    Enzler, T., Bonizzi, G., Silverman, G. J., Otero, D. C., Widhopf, G. F., Anzelon-Mills, A., et al. (2006). Alternative and classical NF-kappa B signaling retain autoreactive B cells in the splenic marginal zone and result in lupus-like disease. Immunity, 25, 403–415.PubMedGoogle Scholar
  139. 139.
    Yang, M., Hase, H., Legarda-Addison, D., Varughese, L., Seed, B., & Ting, A. T. (2005). B cell maturation antigen, the receptor for a proliferation-inducing ligand and B cell-activating factor of the TNF family, induces antigen presentation in B cells. Journal of Immunology, 175, 2814–2824.Google Scholar
  140. 140.
    Kayagaki, N., Yan, M., Seshasayee, D., Wang, H., Lee, W., French, D. M., et al. (2002). BAFF/BLyS receptor 3 binds the B cell survival factor BAFF ligand through a discrete surface loop and promotes processing of NF-kappaB2. Immunity, 17, 515–524.PubMedGoogle Scholar
  141. 141.
    Claudio, E., Brown, K., Park, S., Wang, H., & Siebenlist, U. (2002). BAFF-induced NEMO-independent processing of NF-kappa B2 in maturing B cells. Nature Immunology, 3, 958–965.PubMedGoogle Scholar
  142. 142.
    Sasaki, Y., Casola, S., Kutok, J. L., Rajewsky, K., & Schmidt-Supprian, M. (2004). TNF family member B cell-activating factor (BAFF) receptor-dependent and -independent roles for BAFF in B cell physiology. Journal of Immunology, 173, 2245–2252.Google Scholar
  143. 143.
    Rahman, Z. S., Rao, S. P., Kalled, S. L., & Manser, T. (2003). Normal induction but attenuated progression of germinal center responses in BAFF and BAFF-R signaling-deficient mice. Journal of Experimental Medicine, 198, 1157–1169.PubMedGoogle Scholar
  144. 144.
    Franzoso, G., Carlson, L., Poljak, L., Shores, E. W., Epstein, S., Leonardi, A., et al. (1998). Mice deficient in nuclear factor (NF)-kappa B/p52 present with defects in humoral responses, germinal center reactions, and splenic microarchitecture. Journal of Experimental Medicine, 187, 147–159.PubMedGoogle Scholar
  145. 145.
    Tucker, E., O’Donnell, K., Fuchsberger, M., Hilton, A. A., Metcalf, D., Greig, K., et al. (2007). A novel mutation in the Nfkb2 gene generates an NF-kappa B2 “super repressor”. Journal of Immunology, 179, 7514–7522.Google Scholar
  146. 146.
    Xiao, G., Harhaj, E. W., & Sun, S. C. (2001). NF-kappaB-inducing kinase regulates the processing of NF-kappaB2 p100. Molecular cell, 7, 401–409.PubMedGoogle Scholar
  147. 147.
    He, J. Q., Zarnegar, B., Oganesyan, G., Saha, S. K., Yamazaki, S., Doyle, S. E., et al. (2006). Rescue of TRAF3-null mice by p100 NF-kappa B deficiency. Journal of Experimental Medicine, 203, 2413–2418.PubMedGoogle Scholar
  148. 148.
    Liao, G., Zhang, M., Harhaj, E. W., & Sun, S. C. (2004). Regulation of the NF-kappaB-inducing kinase by tumor necrosis factor receptor-associated factor 3-induced degradation. Journal of Biological Chemistry, 279, 26243–26250.PubMedGoogle Scholar
  149. 149.
    Ni, C. Z., Oganesyan, G., Welsh, K., Zhu, X., Reed, J. C., Satterthwait, A. C., et al. (2004). Key molecular contacts promote recognition of the BAFF receptor by TNF receptor-associated factor 3: Implications for intracellular signaling regulation. Journal of Immunology, 173, 7394–7400.Google Scholar
  150. 150.
    Xu, L. G., & Shu, H. B. (2002). TNFR-associated factor-3 is associated with BAFF-R and negatively regulates BAFF-R-mediated NF-kappa B activation and IL-10 production. Journal of Immunology, 169, 6883–6889.Google Scholar
  151. 151.
    Patke, A., Mecklenbrauker, I., Erdjument-Bromage, H., Tempst, P., & Tarakhovsky, A. (2006). BAFF controls B cell metabolic fitness through a PKC beta- and Akt-dependent mechanism. Journal of Experimental Medicine, 203, 2551–2562.PubMedGoogle Scholar
  152. 152.
    Mecklenbrauker, I., Kalled, S. L., Leitges, M., Mackay, F., & Tarakhovsky, A. (2004). Regulation of B-cell survival by BAFF-dependent PKCdelta-mediated nuclear signalling. Nature, 431, 456–461.PubMedGoogle Scholar
  153. 153.
    Hauser, A. E., Junt, T., Mempel, T. R., Sneddon, M. W., Kleinstein, S. H., Henrickson, S. E., et al. (2007). Definition of germinal-center B cell migration in vivo reveals predominant intrazonal circulation patterns. Immunity, 26, 655–667.PubMedGoogle Scholar
  154. 154.
    Schwickert, T. A., Lindquist, R. L., Shakhar, G., Livshits, G., Skokos, D., Kosco-Vilbois, M. H., et al. (2007). In vivo imaging of germinal centres reveals a dynamic open structure. Nature, 446, 83–87.PubMedGoogle Scholar
  155. 155.
    Allen, C. D., Okada, T., & Cyster, J. G. (2007). Germinal-center organization and cellular dynamics. Immunity, 27, 190–202.PubMedGoogle Scholar
  156. 156.
    Anderson, S. M., Hannum, L. G., & Shlomchik, M. J. (2006). Memory B cell survival and function in the absence of secreted antibody and immune complexes on follicular dendritic cells. Journal of Immunology, 176, 4515–4519.Google Scholar
  157. 157.
    Ahmed, R., & Gray, D. (1996). Immunological memory and protective immunity: Understanding their relation. Science, 272, 54–60.PubMedGoogle Scholar
  158. 158.
    Gray, D., Bergthorsdottir, S., van Essen, D., Wykes, M., Poudrier, J., & Siepmann, K. (1997). Observations on memory B-cell development. Seminars in Immunology, 9, 249–254.PubMedGoogle Scholar
  159. 159.
    Mantchev, G. T., Cortesao, C. S., Rebrovich, M., Cascalho, M., & Bram, R. J. (2007). TACI is required for efficient plasma cell differentiation in response to T-independent type 2 antigens. Journal of Immunology, 179, 2282–2288.Google Scholar
  160. 160.
    Huang, X., Di Liberto, M., Cunningham, A. F., Kang, L., Cheng, S., Ely, S., et al. (2004). Homeostatic cell-cycle control by BLyS: Induction of cell-cycle entry but not G1/S transition in opposition to p18INK4c and p27Kip1. Proceedings of the National Academy of Sciences of the United States of America, 101, 17789–17794.PubMedGoogle Scholar
  161. 161.
    Holcik, M., & Korneluk, R. G. (2001). XIAP, the guardian angel. Nature Reviews. Molecular Cell Biology, 2, 550–556.PubMedGoogle Scholar
  162. 162.
    Qian, Y., Qin, J., Cui, G., Naramura, M., Snow, E. C., Ware, C. F., et al. (2004). Act1, a negative regulator in CD40- and BAFF-mediated B cell survival. Immunity, 21, 575–587.PubMedGoogle Scholar
  163. 163.
    Vora, K. A., Wang, L. C., Rao, S. P., Liu, Z. Y., Majeau, G. R., Cutler, A. H., et al. (2003). Cutting edge: Germinal centers formed in the absence of B cell-activating factor belonging to the TNF family exhibit impaired maturation and function. Journal of Immunology, 171, 547–551.Google Scholar
  164. 164.
    Hase, H., Kanno, Y., Kojima, M., Hasegawa, K., Sakurai, D., Kojima, H., et al. (2004). BAFF/BLyS can potentiate B-cell selection with the B-cell coreceptor complex. Blood, 103, 2257–2265.PubMedGoogle Scholar
  165. 165.
    Scholz, J. L., Crowley, J. E., Tomayko, M. M., Steinel, N., O’Neill, P. J., Quinn, W. J., 3rd, et al. (2008). BLyS inhibition eliminates primary B cells but leaves natural and acquired humoral immunity intact. Proceedings of the National Academy of Sciences of the United States of America, 105, 15517–15522.PubMedGoogle Scholar
  166. 166.
    Treml, L. S., Quinn, W. J., 3rd, Treml, J. F., Scholz, J. L., & Cancro, M. P. (2008). Manipulating B cell homeostasis: A key component in the advancement of targeted strategies. Archivum Immunologiae et Therapiae Experimentalis (Warsz), 56, 153–164.Google Scholar
  167. 167.
    Stohl, W., Xu, D., Kim, K. S., Koss, M. N., Jorgensen, T. N., Deocharan, B., et al. (2005). BAFF overexpression and accelerated glomerular disease in mice with an incomplete genetic predisposition to systemic lupus erythematosus. Arthritis and Rheumatism, 52, 2080–2091.PubMedGoogle Scholar
  168. 168.
    Cambridge, G., Stohl, W., Leandro, M. J., Migone, T. S., Hilbert, D. M., & Edwards, J. C. (2006). 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 and Rheumatism, 54, 723–732.PubMedGoogle Scholar
  169. 169.
    Stohl, W. (2006). Therapeutic targeting of B lymphocyte stimulator (BLyS) in the rheumatic diseases. Endocrine, Metabolic & Immune Disorders Drug Targets, 6, 351–358.Google Scholar
  170. 170.
    Gottenberg, J. E., Busson, M., Cohen-Solal, J., Lavie, F., Abbed, K., Kimberly, R. P., et al. (2005). Correlation of serum B lymphocyte stimulator and beta2 microglobulin with autoantibody secretion and systemic involvement in primary Sjogren’s syndrome. Annals of the Rheumatic Diseases, 64, 1050–1055.PubMedGoogle Scholar
  171. 171.
    Garibyan, L., Lobito, A. A., Siegel, R. M., Call, M. E., Wucherpfennig, K. W., & Geha, R. S. (2007). Dominant-negative effect of the heterozygous C104R TACI mutation in common variable immunodeficiency (CVID). Journal of Clinical Investigation, 117, 1550–1557.PubMedGoogle Scholar
  172. 172.
    Keats, J. J., Fonseca, R., Chesi, M., Schop, R., Baker, A., Chng, W. J., et al. (2007). Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell, 12, 131–144.PubMedGoogle Scholar
  173. 173.
    Annunziata, C. M., Davis, R. E., Demchenko, Y., Bellamy, W., Gabrea, A., Zhan, F., et al. (2007). Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell, 12, 115–130.PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2008

Authors and Affiliations

  • John F. Treml
    • 1
  • Yi Hao
    • 1
  • Jason E. Stadanlick
    • 1
  • Michael P. Cancro
    • 1
  1. 1.Department of Pathology and Laboratory MedicineUniversity of Pennsylvania School of MedicinePhiladelphiaUSA

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