Molecular Mechanisms Regulating Negative Selection in Immature-Stage B-Cells

  • Leslie B. King
  • Peter Sandel
  • Richard A. Sater
  • John G. Monroe
Part of the Contemporary Immunology book series (CONTIM)


Although the tremendous clonal diversity expressed in the B-cell receptor (BCR) repertoire is beneficial for mounting immune responses to foreign antigens, it is simultaneously detrimental in that it may include a multitude of BCRs capable of recognizing self antigens. Therefore, mechanisms must exist to functionally silence these self-reactive B-cells. Negative selection of autoreactive cells has been proposed to occur by clonal elimination or abortion (deletion), clonal silencing (anergy), and clonal alteration (receptor editing). Although there has been a significant advance in our understanding of these various modes of tolerance in recent years, the biochemical mechanisms regulating tolerance remain largely unknown. Rather than present a comprehensive review of the findings in this area, the authors will concentrate on the role of clonal deletion in the tolerization of immature B-cells. In particular, the following questions will be addressed:
  1. 1.

    Which target cell populations are sensitive to deletion?

  2. 2.

    What are the molecular mechanisms responsible for rendering these target populations tolerance sensitive? and

  3. 3.

    Is clonal deletion necessary for the maintenance of B-cell tolerance?



Negative Selection Antigen Receptor Tolerance Induction Clonal Deletion Cell Antigen Receptor 


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  1. 1.
    Lederberg, J. (1959) Genes and antibodies: Do antigens bear instructions for antibody specificity or do they select cell lines that arise by mutation? Science 129, 1649–1653.PubMedCrossRefGoogle Scholar
  2. 2.
    Burnet, F.M. (1959) Clonal Selection Theory of Acquired Immunity Vanderbilt University, Nashville, TN.Google Scholar
  3. 3.
    Metcalf, E. S. and Klinman, N. R. (1976) In vitro tolerance induction of neonatal murine B cells. J. Exp. Med. 143, 1327–1340.Google Scholar
  4. 4.
    Metcalf, E. S. and Klinman, N R (1977) In vitro tolerance induction of bone marrow cells: a marker for B cell maturation. J. Immunol. 118, 2111–2116.PubMedGoogle Scholar
  5. 5.
    Nossal, G. J. V. and Pike, B. L. (1975) Evidence for the clonal abortion theory of B-lymphocyte tolerance. J. Exp. Med. 141, 904–917.PubMedGoogle Scholar
  6. 6.
    Pike, B. L., Kay, T. W., and Nossal., G. J. V. (1980) Relative sensitivity of fetal and newborn mice to induction of hapten-specific B cell tolerance. J. Exp. Med. 152, 1407–1412.PubMedCrossRefGoogle Scholar
  7. 7.
    Raff, M. C., Owen, J. J. T., Cooper, M. D., Lawton, A. D., Megson, M., and Gathings, W. E. (1975) Differences in susceptibility of mature and immature mouse B lymphocytes to antiimmunoglobulin-induced immunoglobulin suppression in vitro: possible implications for B cell tolerance to self. J. Exp. Med. 142, 1052–1064.PubMedCrossRefGoogle Scholar
  8. 8.
    Sidman, C. L. and Unanue, E. R. (1975) Receptor-mediated inactivation of early B lymphocytes. Nature 257, 149–151.PubMedCrossRefGoogle Scholar
  9. 9.
    Roth, P. E. and DeFranco, A. L. (1996) Receptor tails unlock developmental checkpoints for B lymphocytes. Science 272, 1752–1754.PubMedCrossRefGoogle Scholar
  10. 10.
    Rajewsky, K. (1996) Clonal selection and learning in the antibody system. Nature 381, 751–758.PubMedCrossRefGoogle Scholar
  11. 11.
    Goodnow, C. C., Crosbie, J., Adelstein, S., Lavoie, T. B., Smith-Gill, S. J., Brink, R. A., Pritchard-Briscoe, H., Wotherspoon, J. S., Loblay, K. Raphael, R. H., Trent, R. J. and Basten, A. (1988) Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Science 334, 676–682.Google Scholar
  12. 12.
    Nemazee, D. A. and Burki, K. (1989) Clonal deletion of B lymphocytes in a transgenic mouse bearing anti-MHC class I antibody genes. Nature 337, 562–566.PubMedCrossRefGoogle Scholar
  13. 13.
    Kincade, P. W. and Cooper, M. D. (1971) Development and distribution of immunoglobulincontaining cells in the chicken. An immunofluorescent analysis using purified antibodies to mu, gamma and light chains. J. Immunol. 106 371–382.Google Scholar
  14. 14.
    Waldschmidt, T. J. and Vitetta, E. S. (1985) The use ofhaptenated-immunoglobulin molecules to induce tolerance in B cells from neonatal mice. J. Immunol. 134, 1436–1441.PubMedGoogle Scholar
  15. 15.
    Erikson, J., Radic, M. Z., Camper, S. A., Hardy, R. R., Carmack, C., and Weigert, M. (1991) Expression of anti-DNA immunoglobulin trangenes in non-autoimmune mice. Nature 349, 331–334.PubMedCrossRefGoogle Scholar
  16. 16.
    Hartley, S. S., Crosbie, J., Brink, R., Kantor, A. B., Basten, A., and Goodnow, C. C. (1991) Elimination from peripheral lymphoid tissues of self-reactive B lymphocytes recognizing membrane-bound antigens. Nature 353, 765–769.PubMedCrossRefGoogle Scholar
  17. 17.
    Hartley, S. B., Cooke, M. P., Fulcher, D. A., Harris, A. W., Cory, S., Basten, A., and Goodnow, C. C. (1993) Elimination of self-reactive B lymphocytes proceeds in two stages: arrested development and cell death. Cell 72, 325–335.PubMedCrossRefGoogle Scholar
  18. 18.
    Chang, T.-L., Capraro, G., Kleinman, R. E., and Abbas, A. K. (1991) Anergy in immature B lymphocytes. Differential responses to receptor-mediated stimulation and helper T lymphocytes. J. Immunol. 147, 750–756.PubMedGoogle Scholar
  19. 19.
    Yellen, A. J., Glenn, W., Sukhatme, V.P., Cao, X., and Monroe, J. G. (1991) Signaling through surface IgM in tolerance-susceptible immature murine B lymphocytes. J. Immunol. 146, 1446–1454.PubMedGoogle Scholar
  20. 20.
    Allman, D. M., Ferguson, S. E., and Cancro, M. P. (1992) Peripheral B cell maturation. I. Immature peripheral B cells in adults are heat-stable antigenh’ and exhibit unique signaling characteristics. J. Immunol. 149, 2533–2540.PubMedGoogle Scholar
  21. 21.
    Allman, D. M., Ferguson, S. E., Lentz, V. M., and 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. J. Immunol. 151, 4431–4444.PubMedGoogle Scholar
  22. 22.
    Carsetti, R., Kohler, M. P., and Lamers, M. C. (1995) Transitional B cells are the target of negative selection in the B cell compartment. J. Exp. Med. 181, 2129–2140.PubMedCrossRefGoogle Scholar
  23. 23.
    Mason, D. Y., Jones, M., and Goodnow, C. C. (1992) Development and follicular localization of tolerant B lymphocytes in lysozyme/anti-lysozyme IgM/IgD transgenic mice. Int. Immunol. 4, 163–175.PubMedCrossRefGoogle Scholar
  24. 24.
    Carsetti, R., Kohler, G., and Lamers, M. C. (1993) A role for immunoglobulin D: interference with tolerance induction. Eur. J. Immunol. 23, 168–178.PubMedCrossRefGoogle Scholar
  25. 25.
    Chen, C., Nagy, Z., Radic, M. Z., Hardy, R. R., Huszar, D., Camper, S. A., and Weigert, M. (1995) The site and stage of anti-DNA B-cell deletion. Nature 373, 252–255.PubMedCrossRefGoogle Scholar
  26. 26.
    Hertz, M. and Nemazee, D. (1997) BCR ligation induces receptor editing in IgM+IgD- bone marrow cells in vitro. Immunity 6, 429–436.PubMedCrossRefGoogle Scholar
  27. 27.
    Norvell, A. and Monroe, J. G. (1996) Acquisition of surface IgD fails to protect from tolerance-induction. Both surface IgM- and surface IgD-mediated signals induce apoptosis of immature murine B lymphocytes. J. Immunol. 156, 1328–1332.PubMedGoogle Scholar
  28. 28.
    Fulcher, D. A., Lyons, A. B., Korn, S. L., Cook, M. C., Koleda, C., Parish, C., Groth, B. F. D. S., and Basten, A. (1996) The fate of self-reactive B cells depends primarily on the degree of antigen receptor engagement and availability of T cell help. J. Exp. Med. 183, 2313–2328.PubMedCrossRefGoogle Scholar
  29. 29.
    Smith, C. A., Williams, G. T., Kingston, R., Jenkinson, E. J., and Owen, J. J. T. (1989) Antibodies to CD3/T-cell receptor complex induce death by apoptosis in immature T cells in thymic cultures. Nature 337, 181–184.PubMedCrossRefGoogle Scholar
  30. 30.
    Norvell, A., L. Mandik and J. G. Monroe. (1995) Engagement of the antigen-receptor on immature murine B lymphocytes results in death by apoptosis. J. Immunol. 154, 4404–4413.PubMedGoogle Scholar
  31. 31.
    Carman, J. A., Wechsler-Reya, R. J., and Monroe, J. G. (1996) Immature stage B cells enter but do not progress beyond the early GI phase of the cell cycle in response to antigen receptor signaling. J. Immunol. 156, 4562–4569.PubMedGoogle Scholar
  32. 32.
    Monroe, J. G. (1996) Tolerance sensitivity of immature stage B cells: can developmentally regulated B cell antigen receptor (BCR) signal transduction play a role? J. Immunol. 156, 2657–2660.PubMedGoogle Scholar
  33. 33.
    Brink, R., Goodnow, C. C., Crosbie, J., Adams, E., Eris, J., Mason, D. Y., Hartley, S. B., and Basten, A. (1992) Immunoglobulin M and D antigen receptors are both capable of mediating B lymphocyte activation, deletion, or anergy after interaction with specific antigen. J. Exp. Med. 176, 991–1005.PubMedCrossRefGoogle Scholar
  34. 34.
    Nitschke, L., Kosco, M. H., Kohler, G., and Lamers, M. C. (1993) Immunoglobulin D-deficient mice can mount normal immune responses to thymus-independent and -dependent antigens. Proc. Natl. Acad. Sci. USA 90, 1887–1891.PubMedCrossRefGoogle Scholar
  35. 35.
    Roes, J. and Rajewsky, K. (1993) Immunoglobulin D (IgD)-deficient mice reveal an auxiliary receptor function for IgD in antigen-mediated recruitment of B cells. J. Exp. Med. 177, 45–55.PubMedCrossRefGoogle Scholar
  36. 36.
    Bretscher, P. A. and Cohn, M. (1968) Minimal model for the mechanism of antibody induction and paralysis by antigen. Nature 220, 444–448.PubMedCrossRefGoogle Scholar
  37. 37.
    Brines, R. D. and Klaus, G. G. B. (1992) Inhibition of lipopolysaccharide-induced activation of immature B cells by anti-p. and anti-5 antibodies and its modulation by interleukin-4 Int. Immunol. 4, 765–771.PubMedCrossRefGoogle Scholar
  38. 38.
    Wechsler, R. J. and Monroe., J. G. (1995) Immature B lymphocytes are deficient in expression of the src-family kinases p59í and p55/gr. J. Immunol. 154, 1919–1929.PubMedGoogle Scholar
  39. 39.
    Norvell, A., Birkeland, M L, Carman, J., Sillman, A. L., Wechsler-Reya, R., and Monroe, J. G. (1996) Use of isolated immature-stage B cells to understand negative selection and tolerance induction at the molecular level. Immunol. Res. 15, 191–207.PubMedCrossRefGoogle Scholar
  40. 40.
    Sillman, A. L. and Monroe, J. G. (1994) Surface IgM-stimulated proliferation, inositol phospholipid hydrolysis, Cat+ flux, and tyrosine phosphorylation are not altered in B cells from p59IY“-/- mice. J. Leuk. Biol. 56, 812–816.Google Scholar
  41. 41.
    Takata, M., Homma, Y. and Kurosaki, T. (1995) Requirement ofphospholipase C- y2 activation in surface immunoglobulin M-induced B cell apoptosis. J. Exp. Med. 182, 907–914.PubMedCrossRefGoogle Scholar
  42. 42.
    Uckun, F. M., Waddick, K. G., Mahajan, S., Jun, X., Takata, M., Bolen, J., and Kurosaki, T. (1996) BTK as a mediator of radiation-induced apoptosis in DT-40 lymphoma B cells. Science 273, 1096–1100.PubMedCrossRefGoogle Scholar
  43. 43.
    Scheuermann, R. H., Racila, E., Tucker, T., Yefenof, E., Street, N. E., Vitetta, E. S., Picker, L. J., and Uhr., J. W. (1994) Lyn tyrosine kinase signals cell cycle arrest but not apoptosis in B-lineage lymphoma cells. Proc. Natl. Acad. Sci. USA 91, 4048–4052.PubMedCrossRefGoogle Scholar
  44. 44.
    Monroe, J. G., Seyfert, V. L., Owen, C. S., and Sykes, N. (1989) Isolation and characterization of a B lymphocyte mutant with altered signal transduction through its antigen receptor. J. Exp. Med. 169, 1059–1070.PubMedCrossRefGoogle Scholar
  45. 45.
    Fukuda, T., Kitamura, D., Taniuchi, I., Maekawa, Y., Benhamou, L. E., Sarthou, P., and Watanabe, T. (1995) Restoration of surface IgM-mediated apoptosis in an anti-IgM-resistant variant of WEHI-231 lymphoma cells by HS1, a protein-tyrosine kinase substrate. Proc. Nat. Acad. Sci. USA 92, 7302–7306.PubMedCrossRefGoogle Scholar
  46. 46.
    Taniuchi, I., Kitamura, D., Maekawa, Y., Fukuda, T., Kishi, H., and Watanabe, T. (1995) Antigen-receptor induced clonal expansion and deletion of lymphocytes are impaired in mice lacking HS1 protein, a substrate of the antigen-receptor-coupled tyrosine kinases. EMBOJ. 14, 3664–3678.PubMedGoogle Scholar
  47. 47.
    Leitges, M., Schmedt, C., Guinamard, R., Davoust, J., Schaal, S., Stabel, S., and Tarakhovsky, A. (1996) Immunodeficiency in protein kinase c 0-deficient mice. Science 273, 788–791.PubMedCrossRefGoogle Scholar
  48. 48.
    Kerner, J. D., Appleby, M. W., Mohr, R. N., Chien, S., Rawlings, D. J., Maliszewski, C. R., Witte, O. N., and Perlmutter, R. M. (1995) Impaired expansion of mouse B cell progenitors lacking Btk. Immunity 3, 301–312.PubMedCrossRefGoogle Scholar
  49. 49.
    Khan, W. N., Alt, F. W., Gerstein, R. M., Malynn, B. A., Larsson, I., Rathbun, G., Davidson, L., Muller, S., Kantor, A. B., Herzenberg, L. A., Rosen, F.S., and Sideras, P. (1995) Defective B cell development and function in Btk-deficient mice. Immunity 3, 283–299.Google Scholar
  50. 50.
    Yao, L., Kawakami, Y., and Kawakami, T. (1994) The pleckstrin homology domain of Bruton tyrosine kinase interacts with protein kinase C. Proc. Natl. Acad. Sci. USA 91, 9175–9179.PubMedCrossRefGoogle Scholar
  51. 51.
    Sidorenko, S. P., Law, C.-L., Klaus, S. J., Chandran, K. A., Takata, M., Kurosaki, T., and Clark, E. A. (1996) Protein kinase C mu (PKC µ) associates with the B cell antigen receptor complex and regulates lymphocyte signaling. Immunity 5, 353–363.PubMedCrossRefGoogle Scholar
  52. 52.
    Law, C. L., Chandran, K. A., Sidorenko, S. P., and Clark, E. A. (1996) Phospholipase C-gammal interacts with conserved phosphotyrosyl residues in the linker region of Syk and is a substrate for Syk. Mol. Cell. Biol. 16, 1305–1315.PubMedGoogle Scholar
  53. 53.
    Sillman, A. L. and Monroe, J. G. (1995) Association of p72syk with the src homology-2 (SH2) domains of PLCyl in B lymphocytes. J. Biol. Chem. 270, 11,806–11, 811.Google Scholar
  54. 54.
    Gold, M. R., Crowley, M. T., Martin, G. A., McCormick, F., and DeFranco, A. L. (1993) Targets of B lymphocyte antigen receptor signal transduction include the p21ras GTPase-activating protein (GAP) and two GAP-associated proteins. J. Immunol. 150, 377–386.PubMedGoogle Scholar
  55. 55.
    Gold, M. R., Chan, V. W. F., Turck, C. W., and DeFranco, A. L. (1992) Membrane Ig cross-linking regulates phosphatidylinositol 3 kinase in B lymphocytes. J. Immunol. 148, 2012–2022.PubMedGoogle Scholar
  56. 56.
    Marshall, C. J. (1995) Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80, 179–185.PubMedCrossRefGoogle Scholar
  57. 57.
    Xia, Z., Dickens, M., Raingeaud, J., Davis, R. J., and Greenberg, M. E. (1995) Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270, 1326–1331.PubMedCrossRefGoogle Scholar
  58. 58.
    Tsubata, T., Wu, J., and Honjo, T. (1993) B-cell apoptosis induced by antigen receptor crosslinking is blocked by a T-cell signal through CD40. Nature 364, 645–648.PubMedCrossRefGoogle Scholar
  59. 59.
    Sutherland, C. L., Heath, A. W., Pelech, S. L., Young, P. R., and Gold, M. E. (1996) Differential activation of the ERK, JNK, and p38 mitogen-activated protein kinases by CD40 and the B cell antigen receptor. J. Immunol. 157, 3381–3390.PubMedGoogle Scholar
  60. 60.
    Franke, T. F., Kaplan, D. R., Cantley, L. C., and Toker, A. (1997) Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate. Science 275, 665–668.PubMedCrossRefGoogle Scholar
  61. 61.
    Kauffmann-Zeh, A., Rodriguez-Viciana, P., Ulrich, E., Gilbert, C., Coffer, P., Downward, J., and Evan, G. (1997) Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB. Nature 385, 544–548.PubMedCrossRefGoogle Scholar
  62. 62.
    Kennedy, S. G., Wagner, A. J., Conzen, S.D., Jordan, J., Bellacosa, A., Tsichlis, P. N., and Hay, N. (1997) The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal. Genes Dev. 11, 701–713.PubMedCrossRefGoogle Scholar
  63. 63.
    Teale, J. M. and Klinman, N. R. (1984) Membrane and metabolic requirements for tolerance induction of neonatal B cells. J. Immunol. 133, 1811–1817.PubMedGoogle Scholar
  64. 64.
    Sonenshein, G. E. (1997) Down-modulation of c-myc expression induces apoptosis of B lymphocyte models of tolerance via clonal deletion. J. Immunol. 158, 1994–1997.PubMedGoogle Scholar
  65. 65.
    Wu, M., Arsura, M., Bellas, R. E., FitzGerald, M. J., Lee, H., Schauer, S. L., Sherr, D. H. and Sonenshein, G. E. (1996) Inhibition of c-myc expression induces apoptosis of WEHI 231 murine B cells. Mol. Cell. Biol. 16, 5015–5025.PubMedGoogle Scholar
  66. 66.
    Wu, M., Lee, H., Bellas, R. E., Schauer, S. L., Arsura, M., Katz, D., FitzGerald, M. J., Rothstein, T. L., Sherr, D. H., and Sonenshein, G. E. (1996) Inhibition of NF-kappaB/Rel induces apoptosis of murine B cells. EMBO J. 15, 4682–4690.PubMedGoogle Scholar
  67. 67.
    Fearon, D. T. and Carter, R. H. (1995) The CD19/CR2/TAPA-1 complex of B lymphocytes: linking natural to acquired immunity Ann. Rev. Immunol. 13, 127–149.CrossRefGoogle Scholar
  68. 68.
    Justement, L. B., Campbell, K. S., Chien, N., and Cambier, J. C. (1991) Regulation of B cell antigen receptor signal transduction and phosphorylation by CD45. Science 252, 1839–1842.PubMedCrossRefGoogle Scholar
  69. 69.
    Tedder, T. F., Tuscano, J., Sato, S., and Kehrl, J. H. (1997) CD22, a B lymphocyte-specific adhesion molecule that regulates antigen receptor signaling. Ann. Rev. Immunol. 15, 481–504.CrossRefGoogle Scholar
  70. 70.
    Carter, R. H. and Fearon., D. T. (1992) CD19, lowering the threshold for antigen receptor stimulation of B lymphocytes. Science 256, 105–107.PubMedCrossRefGoogle Scholar
  71. 71.
    Dempsey, P. W., Allison, M. E. D., Akkaraju, S., Goodnow, C. C., and Fearon, D. T. (1996) C3d of complement as a molecular adjuvant: bridging innate and acquired immunity Science 271, 348–350.PubMedCrossRefGoogle Scholar
  72. 72.
    Engel, P., Zhou, L. J., Ord, D. C., Sato, S., Koller, B., and Tedder, T. F. (1995) Abnormal B lymphocyte development, activation, and differentiation in mice that lack or overexpress the CD19 signal transduction molecule. Immunity 3, 39–50.PubMedCrossRefGoogle Scholar
  73. 73.
    Rickert, R. C., Rajewsky, K., and Roes, J. (1995) Impairment of T-cell-dependent B-cell responses and B-1 cell development in CD19-deficient mice. Nature 376, 352–355.PubMedCrossRefGoogle Scholar
  74. 74.
    Sato, S., Steeber, D. A., and Tedder, T. F. (1995) The CD19 signal transduction molecule is a response regulator of B-lymphocyte differentiation. Proc. Natl. Acad. Sci. USA 92, 11,558–11, 562.Google Scholar
  75. 75.
    Doody, G. M., Justement, L. B., Delibrias, C. C., Matthews, R. J., Lin, J., Thomas, M. L., and Fearon, D. T. (1995) A role in B cell activation for CD22 and the protein tyrosine phosphatase SHP. Science 269, 242–244.PubMedCrossRefGoogle Scholar
  76. 76.
    Tuscano, J. M., Engel, P., Tedder, T. F., Agarwal, A., and Kehrl, J. H. (1996) Involvement of p72syk kinase, p53/561yn kinase and phosphatidyl inositol-3 kinase in signal transduction via the human B lymphocyte antigen CD22. Eur. J. Immunol. 26, 1246–1252.PubMedCrossRefGoogle Scholar
  77. 77.
    Campbell, M. A. and Klinman, N. R. (1995) Phosphotyrosine-dependent association between CD22 and protein tyrosine phosphatase 1C. Eur. J. Immunol. 25, 1573–1579.PubMedCrossRefGoogle Scholar
  78. 78.
    Lankester, A. C., van Schijndel, G. M., and van Lier, R. A. (1995) Hematopoietic cell phosphatase is recruited to CD22 following B cell antigen receptor ligation. J. Biol. Chem. 270, 20,305–20, 308.Google Scholar
  79. 79.
    Law, C. L., Sidorenko, S. P., Chandran, K. A., Zhao, A., Shen, S. H., Fischer, E. H., and Clark, E. A. (1996) CD22 associates with protein tyrosine phosphatase 1C, Syk, and phospholipase C-71 upon B cell activation. J. Exp. Med. 183, 547–560.PubMedCrossRefGoogle Scholar
  80. 80.
    Shultz, L. D., Schweitzer, P. A., Rajan, T. V., Yi, T., Ihle, J. N., Matthews, R. J., Thomas, M. L., and Beier, D. R. (1993) Mutations at the murine motheaten locus are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene. Cell 73, 1445–1454.PubMedCrossRefGoogle Scholar
  81. 81.
    Tsui, H. W., Siminovitch, K. A., de Souza, L., and Tsui, F. W. (1993) Motheaten and viable motheaten mice have mutations in the haematopoietic cell phosphatase gene. Nat. Gen. 4, 124–129.CrossRefGoogle Scholar
  82. 82.
    Pani, G., Kozlowski, M., Cambier, J. C., Mills, G. B., and Siminovitch, K. A. (1995) Identification of the tyrosine phosphatase PTP1C as a B cell antigen receptor-associated protein involved in the regulation of B cell signaling. J. Exp. Med. 181, 2077–2084.PubMedCrossRefGoogle Scholar
  83. 83.
    Cyster, J. G. and Goodnow, C. C. (1995) Protein tyrosine phosphatase 1C negatively regulates antigen receptor signaling in B lymphocytes and determines thresholds for negative selection. Immunity 2, 13–24.PubMedCrossRefGoogle Scholar
  84. 84.
    Erickson, L. D., Tygrett, L. T., Bhatia, S. K., Grabstein, K. H., and Waldschmidt, T. J. (1996) Differential expression of CD22 (Lyb8) on murine B cells. Int. Immunol. 8, 1121–1129.Google Scholar
  85. 85.
    Nitschke, L., Carsetti, R., Ocker, B., Kohler, G., and Lamers, M. C. (1997) CD22 is a negative regulator of B-cell receptor signalling. Curr. Biol. 7, 133–143.PubMedCrossRefGoogle Scholar
  86. 86.
    O’Keefe, T. L., Williams, G. T., Davies, S. L., and Neuberger, M. S. (1996) Hyperresponsive B cells in CD22-deficient mice. Science 274, 798–801.PubMedCrossRefGoogle Scholar
  87. 87.
    Otipoby, K. L., Andersson, K. B., Drayes, K. E., Klaus, S. J., Farr, A. G., Kerner, J. D., Perlmutter, R. M., Law, C. L., and Clark, E. A. (1996) CD22 regulates thymus-independent responses and the lifespan of B cells. Nature 384, 634–637.PubMedCrossRefGoogle Scholar
  88. 88.
    Sato, S., Miller, A. S., Inaoki, M., Bock, C. B., Jansen, P. J., Tang, M. L., and Tedder, T. F. (1996) CD22 is both a positive and negative regulator of B lymphocyte antigen receptor signal transduction: altered signaling in CD22-deficient mice. Immunity 5, 551–562.PubMedCrossRefGoogle Scholar
  89. 89.
    Kawauchi, K., Lazarus, A. H., Rapoport, M. J., Harwood, A., Cambier, J. C., and Delovitch, T. L. (1994) Tyrosine kinase and CD45 tyrosine phosphatase activity mediate p2lras activation in B cells stimulated through the antigen receptor. J. Immunol. 152, 3306–3316.PubMedGoogle Scholar
  90. 90.
    Pao, L. I., Bedzyk, W. D., Persin, C., and Cambier, J. C. (1997) Molecular targets of CD45 in B cell antigen receptor signal transduction. J. Immunol. 158, 1116–1124.Google Scholar
  91. 91.
    Pao, L. I. and Cambier, J. C. (1997) Syk, but not Lyn, recruitment to B cell antigen receptor and activation following stimulation of CD45- B cells. J. Immunol. 158, 2663–2669.PubMedGoogle Scholar
  92. 92.
    Benatar, T., Carsetti, R., Furlonger, C., Kamalia, N., Mak, T., and Paige, C. J. (1996) Immunoglobulin-mediated signal transduction in B cells from CD45-deficient mice. J. Exp. Med. 183, 329–334.PubMedCrossRefGoogle Scholar
  93. 93.
    Blyth, K. F., Conroy, L. A., Howlett, S., Smith, A. J. H., May, J., Alexander, D. R., and Holmes, N. (1996) CD45-null transgenic mice reveal a positive regulatory role for CD45 in early thymocyte development, in the selection of CD4+CD8+ thymocytes, and in B cell maturation. J. Exp. Med. 183, 1707–1718.Google Scholar
  94. 94.
    Kong, Y.-Y., Kishihara, K., Sumichika, H., Nakamura, T., Kaneko, M., and Nomoto, K. (1995) Differential requirements of CD45 for lymphocyte development and function. Eur. J. Immunol. 25, 3431–3436.PubMedCrossRefGoogle Scholar
  95. 95.
    Cyster, J. G., Healy, J. I., Kishihara, K., Mak, T. W., Thomas, M. L., and Goodnow, C. C. (1996) Regulation of B-lymphocyte negative and positive selection by tyrosine phosphatase CD45. Nature 381, 325–328.PubMedCrossRefGoogle Scholar
  96. 96.
    Hockenbery, D., Nunez, G., Milliman, C., Schreiber, R. D., and Korsmeyer, S. J. (1990) Bc1–2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348, 334–336.PubMedCrossRefGoogle Scholar
  97. 97.
    Oltvai, Z. N., Milliman, C. L., and Korsmeyer, S. J. (1993) Bc1–2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 74, 609–6 19.CrossRefGoogle Scholar
  98. 98.
    Boise, L. H., Gonzalez-Garcia, M., Postema, C. E., Ding, L., Lindsten, T., Turka, L. A., Mao, X., Nunez, G., and Thompson, C. B. (1993) bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 74, 597–608.Google Scholar
  99. 99.
    Yang, E., Zha, J., Jockel, J., Boise, L. H., Thompson, C. B., and Korsmeyer, S. J. (1995) Bad, a heterodimeric partner for Bel-XL and Bcl-2, displaces Bax and promotes cell death. Cell 80, 285–291.PubMedCrossRefGoogle Scholar
  100. 100.
    Lin, E. Y., Orlofsky, A., Berger, M. S., and Prystowsky, M. B. (1993) Characterization of Al, a novel hemopoietic-specific early-response gene with sequence similarity to bcl-2. J. Immunol. 151,(1979–1988.Google Scholar
  101. 101.
    Oltvai, Z. N. and Korsmeyer, S. J. (1994) Checkpoints of dueling dimers foil death wishes. Cell 79, 189–191.PubMedCrossRefGoogle Scholar
  102. 102.
    Li, Y.-S., Hayakawa, K., and Hardy, R. R. (1993) The regulated expression of B lineage associated genes during B cell differentiation in bone marrow and fetal liver. J. Exp. Med. 178, 951–960.PubMedCrossRefGoogle Scholar
  103. 103.
    Merino, R., Ding, L., Veis, D. J., Korsmeyer, S. J., and Nunez, G. (1994) Developmental regulation of the Bel-2 protein and susceptiblity to cell death in B lymphocytes. EMBO J. 13, 683–691.PubMedGoogle Scholar
  104. 104.
    Grillot, D. A. M., Merino, R., Pena, J. C., Fanslow, W. C., Finkelman, F. D., Thompson, C. B., and Nunez, G. (1996) bel-x exhibits regulated expression during B cell development and activation and modulates lymphocyte survival in transgenic mice. J. Exp. Med. 183, 381–391.Google Scholar
  105. 105.
    Choi, M. S., Holmann, M., Atkins, C. J., and Klaus, G. G. (1996) Expression of bel-x during mouse B cell differentiation and following activation by various stimuli. Eur. J. Immunol. 26, 676–682.PubMedCrossRefGoogle Scholar
  106. 106.
    Nakayama, K., Nakayama, K., Negishi, I., Kuida, K., Shinkai, Y., Louie, M. C., Fields, L. E., Lucas, P. J., Stewart, V., Alt, F. W., and Loh, D. Y. (1993) Disappearance of the lymphoid system in Bc1–2 homozygous mutant chimeric mice. Science 261, 1584–1588.Google Scholar
  107. 107.
    Veis, D. J., Sorenson, C. M., Shutter, J. R., and Korsmeyer, S. J. (1993) Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell 75, 229–240.Google Scholar
  108. 108.
    Motoyama, N., Wang, F., Roth, K. A., Sawa, H., Nakayama, K., Nakayama, K., Negishi, I., Senju, S., Zhang, Q., Fujii, S., and Loh, D. Y. (1995) Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice. Science 267, 1506–1510.Google Scholar
  109. 109.
    Knudson, C. M., Tung, K. S., Tourtellotte, W. G., Brown, G. A., and Korsmeyer, S. J. (1995) Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science 270, 96–99.PubMedCrossRefGoogle Scholar
  110. 110.
    Nisitani, S., Tsubata, T., Murakami, M., Okamoto, M., and Honjo, T. (1993) The bc1–2 gene product inhibits clonal deletion of self-reactive B lymphocytes in the periphery but not in the bone marrow. J. Exp. Med. 178, 1247–1254.PubMedCrossRefGoogle Scholar
  111. 111.
    Cyster, J. G., Hartley, S. B., and Goodnow, C. C. (1994) Competition for follicular niches excludes self-reactive cells from the recirculating B cell repertoire. Nature 371 389–395.Google Scholar
  112. 112.
    Strasser, A., Whittingham, S., Vaux, D. L., Bath, M. L., Adams, J. M., Cory, S., and Harris, A. W. (1991) Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease. Proc. Natl. Acad. Sci. USA 88, 8661–8665.PubMedCrossRefGoogle Scholar
  113. 113.
    Smith, C. A., Farrah, T., and Goodwin, R. G. (1994) The TNF receptor superfamily of cellular and viral proteins: activation, costimulation, and death. Cell 76, 959–962.PubMedCrossRefGoogle Scholar
  114. 114.
    Itoh, N., Yonehara, S., Ishii, A, Yonehara, M., Mizushima, S., Sameshima, M., Hase, A., Seto, Y., and Nagata, S. (1991) The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 66, 233–243.PubMedCrossRefGoogle Scholar
  115. 115.
    Suda, T., Takahashi, T., Golstein, P., and Nagata, S. (1993) Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell 75, 1169–1178.PubMedCrossRefGoogle Scholar
  116. 116.
    Singer, G. G. and Abbas, A. K. (1994) The fas antigen is involved in peripheral but not thymic deletion of T lymphocytes in T cell receptor transgenic mice. Immunity 1, 365–371.PubMedCrossRefGoogle Scholar
  117. 117.
    Mandik, L., Nguyen, K.-A. T., and Erikson, J. (1995) Fas receptor expression on B-lineage cells. Eur. J. Immunol. 25, 3148–3154.PubMedCrossRefGoogle Scholar
  118. 118.
    Adachi, M., Suematsu, S., Suda, T., Watanabe, D., Fukuyama, H., Ogasawara, J., Tanaka, T., Yoshida, N., and Nagata, S. (1996) Enhanced and accelerated lymphoproliferation in Fas-null mice. Proc. Nat. Acad. Sci. USA 93, 2131–2136.Google Scholar
  119. 119.
    Rathmell, J. C. and Goodnow, C. C. (1994) Effects of the Ipr mutation on elimination and inactivation of self-reactive B cells. J. Immunol. 153, 2831–2842.PubMedGoogle Scholar
  120. 120.
    Rubio, C. F., Kench, J., Russell, D. M., Yawger, R., and Nemazee, D. (1996) Analysis of central B cell tolerance in autoimmune-prone MRL/lpr mice bearing autoantibody transgenes. J. Immunol. 157, 65–71.PubMedGoogle Scholar
  121. 121.
    Rothstein, T. L., Wang, J. K. M., Panka, D. J., Foote, L. C., Wang, Z., Stanger, B., Cul, H., Ju, S.-T., and Marshak-Rothstein, A. (1995) Protection against Fas-dependent Th 1-mediated apoptosis by antigen receptor engagement in B cells. Nature 374, 163–165.PubMedCrossRefGoogle Scholar
  122. 122.
    Rathmell, J. C., Cooke, M. P., Ho, W. Y., Grein, J., Townsend, S. E., Davis, M. M., and Goodnow, C. C. (1995) CD95 (Fas)-dependent elimination of self-reactive B cells upon interaction with CD4+ T cells. Nature 376, 181–184.Google Scholar
  123. 123.
    Clark, E. A. and Ledbetter, J. A. (1994) How B and T cells talk to each other. Nature 367, 425–428.Google Scholar
  124. 124.
    Choi, M. S., Boise, L. H., Gottschalk, A. R., Quintans, J., Thompson, C. B., and Klaus, G. G. (1995) The role of bcl-XL in CD40-mediated rescue from anti-mu-induced apoptosis in WEHI-231 B lymphoma cells. Eur. J. Immunol. 25, 1352–1357.PubMedCrossRefGoogle Scholar
  125. 125.
    Schauer, S. L., Wang, Z., Sonenshein, G. E., and Rothstein, T. L. (1996) Maintenance of nuclear factor-kappa B/Rel and c-myc expression during CD40 ligand rescue of WEHI 231 early B cells from receptor-mediated apoptosis through modulation of I kappa B proteins. J. Immunol. 157, 81–86.Google Scholar
  126. 126.
    Wang, Z., Karras, J. G., Howard, R. G., and Rothstein, T. L. (1995) Induction of bcl-x by CD40 engagement rescues slg-induced apoptosis in murine B cells. J. Immunol. 155, 3722–3725.PubMedGoogle Scholar
  127. 127.
    Kawabe, T., Naka, T., Yoshida, K., Tanaka, T., Fujiwara, H., Suematsu, S., Yoshida, N., Kishimoto, T., and Kikutani, H. (1994) The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation. Immunity 1, 167–178.PubMedCrossRefGoogle Scholar
  128. 128.
    Opstelten, D. and Osmond, D. G. (1983) Pre-B cells in mouse bone marrow: immunofluorescence stathmokinetic studies of the proliferation of cytoplasmic mu-chain-bearing cells in normal mice. J. Immunol. 131, 2635–2640.PubMedGoogle Scholar
  129. 129.
    Osmond, D. G. (1986) Population dynamics of bone marrow B lymphocytes. Immunol. Rev. 93, 103–124.PubMedCrossRefGoogle Scholar
  130. 130.
    Ellis, R. E., Yuan, J. Y., and Horvitz, H. R. (1991) Mechanisms and functions of cell death. Ann. Rev. Cell Biol. 7, 663–698.PubMedCrossRefGoogle Scholar
  131. 131.
    Lu, L. and Osmond, D. G. (1997) Apoptosis during B lymphopoiesis in mouse bone marrow. J. Immunol. 158, 5136–5145.PubMedGoogle Scholar
  132. 132.
    Gu, H. Tarlinton, D., Muller, W., Rajewsky, K., and Forster, I. (1991) Most peripheral B cells in mice are ligand selected. J. Exp. Med. 173 1357–1371.Google Scholar
  133. 133.
    Torres, R. M., Flaswinkel, H., Reth, M., and Rajewsky, K. (1996) Aberrant B cell development and immune response in mice with a compromised BCR complex. Science 272, 1804–1808.PubMedCrossRefGoogle Scholar
  134. 134.
    Turner, M., Mee, P. J., Costello, P. S., Williams, O., Price, A. A., Duddy, L. P., Furlong, M. T., Geahlen, R. L., and Tybulewicz, V. L. (1995) Perinatal lethality and blocked B-cell development in mice lacking the tyrosine kinase Syk. Nature 378, 298–302.PubMedCrossRefGoogle Scholar
  135. 135.
    Pike, B. L., Boyd, A. W., and Nossal, G. J. V. (1982) Clonal anergy: The universally anergic B lymphocyte. Proc. Natl. Acad. Sci. USA 79, 2013–2017.PubMedCrossRefGoogle Scholar
  136. 136.
    Goodnow, C. C., Crosbie, J., Jorgensen, H., Brink, R. A., and Basten, A. (1989) Induction of self-tolerance in mature peripheral B lymphocytes. Nature 342, 385–391.Google Scholar
  137. 137.
    Cooke, M. P., Heath, A. W., Shokat, K. M., Zeng, Y., Finkelman, F. D., Linsley, P. S., Howard, M., and Goodnow, C. C. (1994) Immunoglobulin signal transduction guides the specificity of B cell-T cell interactions and is blocked in tolerant self-reactive B cells. J. Exp. Med. 179, 425–438.PubMedCrossRefGoogle Scholar
  138. 138.
    Healy, J. I., Dolmetsch, R. E., Timmerman, L. A., Cyster, J. G., Thomas, M. L., Crabtree, G. R., Lewis, R. S., and Goodnow, C. C. (1997) Different nuclear signals are activated by the B cell receptor during positive versus negative signaling Immunity 6, 419–428.Google Scholar
  139. 139.
    Murakami, M., Tsubata, T., Okamoto, M., Shimizu, A., Kumagai, S., Imura, H., and Honjo, T. (1992) Antigen-induced apoptotic death of Ly-1 B cells responsible for autoimmune disease in transgenic mice. Nature 357, 77–80.Google Scholar
  140. 140.
    Fulcher, D. A. and Basten, A. (1994) Reduced life span of anergic self-reactive B cells in a double-transgenic model. J. Exp. Med. 179, 125–134.PubMedCrossRefGoogle Scholar
  141. 141.
    Cyster, J. G. and Goodnow, C. C. (1995) Antigen-induced exclusion from follicles and anergy are separate and complementary processes that influence peripheral B cell fate. Immunity 3, 691–701.PubMedCrossRefGoogle Scholar
  142. 142.
    Radic, M. Z., Erikson, J., Litwin, S., and Weigert, M. (1993) B lymphocytes may escape tolerance by revising their antigen receptors. J. Exp. Med. 177, 1165–1173.PubMedCrossRefGoogle Scholar
  143. 143.
    Tiegs, S. L., Russell, D. M., and Nemazee, D. (1993) Receptor editing in self-reactive bone marrow B cells. J. Exp. Med. 177, 1009–1020.PubMedCrossRefGoogle Scholar
  144. 144.
    Gay, D., Saunders, T., Camper, S., and Weigert, M. (1993) Receptor editing: an approach by autoreactive B cells to escape tolerance. J. Exp. Med. 177, 999–1008.PubMedCrossRefGoogle Scholar
  145. 145.
    Chen, C., Nagy, Z., Prak, E. L., and Weigert, M. (1995) Immunoglobulin heavy chain gene replacement: a mechanism of receptor editing. Immunity 3, 747–755.PubMedCrossRefGoogle Scholar
  146. 146.
    Prak, E. L. and Weigert, M. (1995) Light chain replacement: a new model for antibody gene rearrangement. J. Exp. Med. 182, 541–548.PubMedCrossRefGoogle Scholar
  147. 147.
    Chen, C., Prak, E. L., and Weigert, M. (1997) Editing disease-associated autoantibodies. Immunity 6, 97–105.PubMedCrossRefGoogle Scholar
  148. 148.
    Coleclough, C. (1992) Is expression of the B-cell antigen receptor repertoire chaotic? Res.Immunol. 143, 824–830.PubMedCrossRefGoogle Scholar
  149. 149.
    Andersson, J., F. Melchers and Rolink, A. (1995) Stimulation by T cell independent antigens can relieve the arrest of differentiation of immature auto-reactive B cells in the bone marrow. Scand. J. Immunol.42, 21–33.Google Scholar
  150. 150.
    Adelstein, S., Pritchard-Briscoe, H., Anderson, T. A., Crosbie, J., Gammon, G., Loblay, R. H., Basten, A., and Goodnow, C. C. (1991) Induction of self-tolerance in T cells but not B cells of transgenic mice expressing little self antigen. Science 251, 1223–1225.Google Scholar
  151. 151.
    Chiller, J. M., Habicht, G. S., and Weigle, W. O. (1971) Kinetic differences in unresponsiveness of thymus and bone marrow cells. Science 171, 813–815.Google Scholar
  152. 152.
    Matzinger, P. (1994) Tolerance, danger and the extended family. Annu. Rev. Immunol. 12, 991–1045.PubMedCrossRefGoogle Scholar
  153. 153.
    Yellen-Shaw, A. and Monroe, J. G. (1992) Differential responsiveness of immature-and mature-stage murine B cells to anti-IgM reflects both FcR-dependent and -independent mechanisms. Cell. Immunol. 145, 339–350.PubMedCrossRefGoogle Scholar
  154. 154.
    Parry, S. L., Hasbold, J., Holman, M., and Klaus, G. G. (1994) Hypercross-linking surface IgM or IgD receptors on mature B cells induces apoptosis that is reversed by costimulation with IL-4 and anti-CD40. J. Immunol. 152, 2821–2829.PubMedGoogle Scholar
  155. 155.
    Parry, S. L., Holman, M. J., Hasbold, J., and Klaus, G. G. B. (1994) Plastic-immobilized anti-m or anti-d antibodies induce apoptosis in mature murine B lymphocytes. Eur. J. Immunol. 24, 974–979.PubMedCrossRefGoogle Scholar
  156. 156.
    Finkelman, F. D., Holmes, J. M., Dukhanina, O. I. and Morris, S. C. (1995) Cross-linking of membrane IgD, in the absence of T cell help, kills mature B cells in vivo. J. Exp. Med. 181 515–525.Google Scholar
  157. 157.
    Russell, D. M., Dembic, Z., Morahan, G.J. F., Miller, A. P., Burki, K., and Nemazee, D. (1991) Peripheral deletion of self-reactive B cells. Nature 354, 308–311.Google Scholar
  158. 158.
    Watanabe-Fukunaga, R., C. I. Brannan, N. G. Copeland, J. N. A. Jenkins and S. Nagata. (1992) Lymphoproliferative disorder in mice explained by defects in Fas antigen that mediated apoptosis. Nature 356, 314–317.PubMedCrossRefGoogle Scholar
  159. 159.
    Roark, J. H., Kuntz, C. L., Nguyen, K.-A., Caton, A. J., and Erikson, J. (1995) Breakdown of B cell tolerance in a mouse model of systemic lupus erythematosus. J. Exp. Med. 181, 1157–1167.PubMedCrossRefGoogle Scholar
  160. 160.
    Roark, J. H., Kuntz, C. L., Nguyen, K. A., Mandik, L., Cattermole, M., and Erikson, J. (1995) B cell selection and allelic exclusion of an anti-DNA Ig transgene in MRL-1pr/lpr mice. J. Immunol. 154, 4444–4455.Google Scholar
  161. 161.
    Wang, H. and Shlomchik, M. J. (1997) High affinity rheumatoid factor transgenic B cells are eliminated in normal mice. J. Immunol. 159, 1125–1134.PubMedGoogle Scholar
  162. 162.
    Hannum, L. G., Ni, D., Haberman, A. M., Weigert, M. G., and Shlomchik, M. J. (1996) A disease-related rheumatoid factor autoantibody is not tolerized in a normal mouse: implications for the origins of autoantibodies in autoimmune disease. J. Exp. Med. 184, 1269–1278.Google Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Leslie B. King
  • Peter Sandel
  • Richard A. Sater
  • John G. Monroe

There are no affiliations available

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