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Staging B-Cell Development and the Role of Ig Gene Rearrangement in B Lineage Progression

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Part of the book series: Contemporary Immunology ((CONTIM))

Abstract

As B lymphocytes are generated from hematopoietic stem cells, they pass through several intermediate stages that are characterized by distinctive molecular and functional features. The earliest stage is distinguished by accessibility of the immunoglobulin (Ig) heavy chain locus, indicating chromatin changes preparatory to heavy chain rearrangement. Upon activation of the recombinase complex, first a diversity (D) region segment rearranges to one of four joining (J) segments (usually on both chromosomes), and then one of 50–100 variable (V) region genes rearranges to the D-J segment. If this first attempt fails to generate a productive (inframe) heavy chain protein coding sequence, a second V to DJ rearrangement can occur on the other chromosome. Expression of heavy chain protein in the cytoplasm marks the classical pre-B-cell and signals the cell to progress to the next stage of B-cell differentiation—clonal expansion followed by light chain rearrangement. V to J rearrangement at the light chain locus results in expression of a complete IgM molecule, which is rapidly transported to the surface of the immature B-cell. Further differentiation (and possibly selection) finally generates the IgM+IgD+ mature B-cell.

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References

  1. Coffman, R. L. and Weissman, i. l. (1981) B220: a B cell-specific member of the Y200 glycoprotein family. Nature 289, 681–683.

    Article  PubMed  CAS  Google Scholar 

  2. Hardy, R. R., Kemp, J. D., and Hayakawa, K. (1989) Analysis of lymphoid populations in scid mice: detection of a potential B lymphocyte progenitor population present at normal levels in scid mice by three color flow cytometry with B220 and S7. Curr. Top. Microbiol. Immunol. 152, 19–25.

    Article  PubMed  CAS  Google Scholar 

  3. Bosma, M. J. and Carroll, A. M. (1991) The SCID mouse mutant: definition, characterization and potential uses. Annu. Rev. Immunol. 9, 323–350.

    Article  PubMed  CAS  Google Scholar 

  4. Kay, R., Takei, F., and Humphries, R. K. (1990) Expression cloning of a cDNA encoding M1/69-J11d heat-stable antigens. J. Immunol. 145, 1952–1959.

    PubMed  CAS  Google Scholar 

  5. Symington, F. W. and Hakomori, S.-I. (1984) Hematopoietic subpopulations express cross-reactive, lineage-specific molecules detected by monoclonal antibody. Mol. Immunol. 21, 507.

    Article  PubMed  CAS  Google Scholar 

  6. Hardy, R. R., Carmack, C. E., Shinton, S. A., Kemp, J. D., and Hayakawa, K. (1991) Resolution and characterization of pro-B and pre-pro-B cell stages in normal mouse bone marrow. J. Exp. Med. 173, 1213–1225.

    Article  PubMed  CAS  Google Scholar 

  7. Cooper, M. D., Mulvaney, D., Coutinho, A., and Cazenave, P. A. (1986) A novel cell surface molecule on early B-lineage cells. Nature 321, 616–618.

    Google Scholar 

  8. Ramakrishnan, L., Wu, Q., Yue, A., Cooper, M. D., and Rosenberg, N. (1990) BP-1/6C3 expression defines a differentiation stage of transformed pre-B cells and is not related to malignant potential. J. Immunol. 145, 1603–1608.

    PubMed  CAS  Google Scholar 

  9. Wu, Q., Lahti, J. M., Air, G. M., Burrows, P. D., and Cooper, M. D. (1990) Molecular cloning of the murine BP-1/6C3 antigen: a member of the zinc-dependent metallopeptidase family. Proc. Natl. Acad. Sci. USA 87, 993–997.

    Article  PubMed  CAS  Google Scholar 

  10. Wu, Q., Tidmarsh, G. F., Welch, P. A., Pierce, J. H., Weissman, I. L., and Cooper, M. D. (1989) The early B lineage antigen BP-1 and the transformation-associated antigen 6C3 are on the same molecule. J. Immunol. 143, 3303–3308.

    PubMed  CAS  Google Scholar 

  11. Whitlock, C. A., Tidmarsh, G. F., Muller-Sieburg, C., and Weissman, I. L. (1987) Bone marrow stromal cell lines with lymphopoietic activity express high levels of a pre-B neoplasia-associated molecule. Cell 48, 1009–1021.

    Article  PubMed  CAS  Google Scholar 

  12. Whitlock, C. A. and Witte, O. N. (1982) Long-term culture of B lymphocytes and their precursors from murine bone marrow. Proc. Natl. Acad. Sci. USA 79, 3608–3612.

    Article  PubMed  CAS  Google Scholar 

  13. Alt, F., Rosenberg, N., Lewis, S., Thomas, E., and Baltimore, D. (1981) Organization and reorganization of immunoglobulin genes in A-MULV-transformed cells: rearrangement of heavy but not light chain genes. Cell 27, 381–390.

    Article  PubMed  CAS  Google Scholar 

  14. Alt, F. W., Blackwell, T. K., DePinho, R. A., Reth, M. G., and Yancopoulos, G. D. (1986) Regulation of genome rearrangement events during lymphocyte differentiation. Immunol. Rev. 89, 5–30.

    Article  PubMed  CAS  Google Scholar 

  15. Alt, F. W., Oltz, E. M., Young, F., Gorman, J., Taccioli, G., and Chen, J. (1992) VDJ recombination. Immunol. Today 13, 306–314.

    Article  PubMed  CAS  Google Scholar 

  16. Alt, F. W., Yancopoulos, G. D., Blackwell, T. K., Wood, C., Thomas, E., Boss, M., Coffman, R., Rosenberg, N., Tonegawa, S., and Baltimore, D. (1984) Ordered rearrangement of immunoglobulin heavy chain variable region segments. EMBO J 3, 1209–1219.

    PubMed  CAS  Google Scholar 

  17. Ehlich, A., Schaal, S., Gu, H., Kitamaru, D., Muller, W., and Rajewsky, K. (1993) Immunoglobulin heavy and light chain genes rearrange independently at early stages of B cell development. Cell 72, 695–704.

    Article  PubMed  CAS  Google Scholar 

  18. 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.

    Article  PubMed  CAS  Google Scholar 

  19. Reth, M. G., Ammirati, P., Jackson, S., and Alt, F. W. (1985) Regulated progression of a cultured pre-B-cell line to the B-cell stage. Nature 317, 353–355.

    Article  PubMed  CAS  Google Scholar 

  20. Loffert, D., Schaal, S., Ehlich, A., Hardy, R. R., Zou, Y.-R., Muller, W., and Rajewsky, K. (1994) Early B-cell development in the mouse: insights from mutations introduced by gene targeting. Immunol. Rev. 137, 135–153.

    Article  PubMed  CAS  Google Scholar 

  21. Reichman-Fried, M., Bosma, M. J., and Hardy, R. R. (1993) B-lineage cells in mu-transgenic scid mice proliferate in response to IL-7 but fail to show evidence of immunoglobulin light chain gene rearrangement. Int. Immunol. 5, 303–310.

    Article  PubMed  CAS  Google Scholar 

  22. Spanopoulou, E., Roman, C. A., Corcoran, L. M., Schlissel, M. S., Silver, D. P., Nemazee, D., Nussenzweig, M. C., Shinton, S. A., Hardy, R. R., and Baltimore, D. (1994) Functional immunoglobulin transgenes guide ordered B-cell differentiation in Rag-l-deficient mice. Genes Dey. 8, 1030–1042.

    Article  CAS  Google Scholar 

  23. Reichman-Fried, M., Hardy, R. R., and Bosma, M. J. (1990) Development of B-lineage cells in the bone marrow of scid mice following the introduction of functionally rearranged immunoglobulin transgenes. Proc. Natl. Acad. Sci. USA 87, 2730–2739.

    Article  PubMed  CAS  Google Scholar 

  24. Young, F., Ardman, B., Shinkai, Y., Lansford, R., Blackwell, T. K., Mendelsohn, M., Rolink, A., Melchers, F., and Alt, F. W. (1994) Influence of immunoglobulin heavy-and light-chain expression on B-cell differentiation. Genes Dey. 8, 1043–1057.

    Article  CAS  Google Scholar 

  25. Karasuyama, H., Kudo, A., and Melchers, F. (1990) The proteins encoded by the VpreB and lambda 5 pre-B cell-specific genes can associate with each other and with mu heavy chain. J. Exp. Med. 172, 969–972.

    Article  PubMed  CAS  Google Scholar 

  26. Karasuyama, H., Rolink, A., and Melchers, F. (1993) A complex of glycoproteins is associated with VpreB/lambda 5 surrogate light chain on the surface of mu heavy chain-negative early precursor B cell lines. J. Exp. Med. 178, 469–478.

    Article  PubMed  CAS  Google Scholar 

  27. Sakaguchi, N. and Melchers, F. (1986) X5, a new light-chain-related locus selectively expressed in pre-B lymphocytes. Nature 324, 579–582.

    Article  PubMed  CAS  Google Scholar 

  28. Muller-Sieburg, C. E., Whitlock, C. A., and Weissman, I. L. (1986) Isolation of two early B lymphocyte progenitors from mouse marrow: a committed pre-pre-B cell and a clonogenic Thy-1-lo hematopoietic stem cell. Cell 44, 653–662.

    Article  PubMed  CAS  Google Scholar 

  29. Spangrude, G. J., Heimfeld, S., and Weissman, I. L. (1988) Purification and characterization of mouse hematopoietic stem cells. Science 241, 58–62.

    Article  PubMed  CAS  Google Scholar 

  30. Hombach, J., Leclercq, L., Radbruch, A., Rajewsky, K., and Reth, M. (1988) A novel 34-kd protein co-isolated with the IgM molecule in surface IgM-expressing cells. EMBO J. 7, 3451–3456.

    PubMed  CAS  Google Scholar 

  31. Hombach, J., Lottspeich, F., and Reth, M. (1990) Identification of the genes encoding the IgMalpha and Ig-beta components of the IgM antigen receptor complex by amino-terminal sequencing. Eur. J. Immunol. 20, 2795–2799.

    Article  PubMed  CAS  Google Scholar 

  32. Reth, M. (1993) Antigen receptors on B lymphocytes. Ann. Rev. Immunol. 10, 98–121.

    Google Scholar 

  33. Gilfillan, S., Dierich, A., Lemeur, M., Benoist, C., and Mathis, D. (1993) Mice lacking TdT: Mature animals with an immature lymphocyte repertoire. Science 261, 1175–1178.

    Article  PubMed  CAS  Google Scholar 

  34. Komori, T., Okada, A., Stewart, V., and Alt, F. W. (1993) Lack of N regions in antigen receptor variable region genes of TdT-deficient lymphocytes. Science 261, 1171–1175.

    CAS  Google Scholar 

  35. Landau, N. R., Schatz, D. G., Rosa, M., and Baltimore, D. (1987) Increased frequency of N-region insertion in a murine pre-B-cell line infected with a terminal deoxynucleotidyl transferase retroviral expression vector. Mol. Cell. Biol. 7, 3237–3243.

    PubMed  CAS  Google Scholar 

  36. Wasserman, R., Li, Y.-S., and Hardy, R. R. (1997) Down-regulation of terminal deoxynucleotidyl transferase by Ig heavy chain in B lineage cells. J. Immunol. 158, 1133–1138.

    PubMed  CAS  Google Scholar 

  37. Melchers, F., Karasuyama, H., Haasner, D., Bauer, S., Kudo, A., Sakaguchi, N., Jameson, B., and Rolink, A. (1993) The surrogate light chain in B-cell development. Immunol Today 14, 60–68.

    Google Scholar 

  38. Karasuyama, H., Rolink, A., Shinkai, Y., Young, F., Alt, F. W., and Melchers, F. (1994) The expression of Vpre-B/lambda 5 surrogate light chain in early bone marrow precursor B cells of normal and B cell-deficient mutant mice. Cell 77, 133–143.

    Article  PubMed  CAS  Google Scholar 

  39. Wasserman, R., Li, Y.-S., and Hardy, R. R. (1995) Differential expression of the blk and ret tyrosine kinases during B lineage development is dependent on Ig rearrangement. J. Immunol. 155, 644–651.

    PubMed  CAS  Google Scholar 

  40. 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.

    Article  PubMed  CAS  Google Scholar 

  41. Goodnow, C. C. (1992) Transgenic mice and analysis of B-cell tolerance. Annu. Rev. Immunol. 10, 489–518.

    Article  PubMed  CAS  Google Scholar 

  42. 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.

    Google Scholar 

  43. Nemazee, D. and Burki, K. (1989) Clonal deletion of autoreactive B lymphocytes in bone marrow chimeras. Proc. Natl. Acad. Sci. USA 86, 8039–8043.

    Article  PubMed  CAS  Google Scholar 

  44. Nemazee, D., Russell, D., Arnold, B., Haemmerling, G., Allison, J., Miller, J. F., Morahan, G., and Buerki, K. (1991) Clonal deletion of autospecific B lymphocytes. Immunol. Rev. 122, 117–132.

    Article  PubMed  CAS  Google Scholar 

  45. 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 

  46. 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.

    Google Scholar 

  47. Strasser, A., Harris, A. W., Vaux, D. L., Webb, E., Bath, M. L., Adams, J. M., and Cory, S. (1990) Abnormalities of the immune system induced by dysregulated bc1–2 expression in transgenic mice. Curr. Top. Microbiol. Immunol. 166, 175–181.

    Article  PubMed  CAS  Google Scholar 

  48. Vaux, D. L., Cory, S., and Adams, J. M. (1988) Bc1–2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 335, 440–442.

    Article  PubMed  CAS  Google Scholar 

  49. Merino, R., Ding, L., Veis, D. J., Korsmeyer, S. J., and Nunez, G. (1994) Developmental regulation of the Bc1–2 protein and susceptibility to cell death in B lymphocytes. EMBO J. 13, 683–691.

    PubMed  CAS  Google Scholar 

  50. Fang, W., Mueller, D. L., Pennell, C. A., Rivard, J. J., Li, Y.-S., Hardy, R. R., Schlissel, M. S., and Behrens, T. W. (1996) Frequent aberrant immunoglobulin gene rearrangements in pro-B cells revealed by a Bcl-xL transgene. Immunity 4, 291–299.

    Article  PubMed  CAS  Google Scholar 

  51. Li, Y.-S., Wasserman, R., Hayakawa, K., and Hardy, R. R. (1996) Identification of the earliest B lineage stage in mouse bone marrow. Immunity 5, 527–535.

    Article  PubMed  CAS  Google Scholar 

  52. McKearn, J. P., McCubrey, J., and Fagg, B. (1985) Enrichment of hematopoietic precursor cells and cloning of multipotential B-lymphocyte precursors. Proc. Natl. Acad. Sci. USA 82, 7414–7418.

    Google Scholar 

  53. Cumano, A. and Paige, C. (1992) Enrichment and characterization of uncommitted B-cell precursors from fetal liver at day 12 of gestation. EMBO J 11, 593–601.

    PubMed  CAS  Google Scholar 

  54. Cumano, A., Paige, C. J., Iscove, N. N., and Brady, G. (1992) Bipotential precursors of B cells and macrophages in murine fetal liver. Nature 356, 612–615.

    Article  PubMed  CAS  Google Scholar 

  55. Loken, M. R., Shah, V. O., Hollander, Z., and Civin, C. I. (1988) Flow cytometric analysis of normal B lymphoid development. Pathol. Immunopathol. Res. 7, 357–370.

    Article  PubMed  CAS  Google Scholar 

  56. Chervenak, R., Dempsey, D., Soloff, R., Wolcott, R. M., and Jennings, S. R. (1993) The expression of CD4 by T cell precursors resident in both the thymus and the bone marrow. J. Immunol. 151, 4486–4493.

    Google Scholar 

  57. Fredrickson, G. G. and Basch, R. S. (1989) L3T4 antigen expression by hemopoietic precursor cells. J. Exp. Med. 169, 1473–1478.

    Article  Google Scholar 

  58. Wu, L., Antica, M., Johnson, G. R., Scolly, R., and Shortman, K. (1991) Developmental potential of the earliest precursor cells from the adult mouse thymus. J. Exp. Med. 174, 1617–1627.

    Article  PubMed  CAS  Google Scholar 

  59. Wu, L., Scolly, R., Egerton, M., Pearse, M., Spangrude, G. J., and Shortman, K. (1991) CD4 expressed on earliest T-lineage precursor cells in the adult murine thymus. Nature 349, 71–74.

    Article  PubMed  CAS  Google Scholar 

  60. Alessandrini, A. and Desiderio, S. (1991) Coordination of immunoglobulin DJH transcription and D-to-JH rearrangement by promoter-enhancer approximation. Mol. Cell. Biol. 11, 2096–2107.

    PubMed  CAS  Google Scholar 

  61. Schlissel, M. S., Corcoran, L. M., and Baltimore, D. (1991) Virus-transformed Pre-B cells show ordered activation but not inactivation of immunoglobulin gene rearrangement and transcription. J. Exp. Med. 173, 711–720.

    Article  PubMed  CAS  Google Scholar 

  62. Oettinger, M. A., Schatz, D. G., Gorka, C., and Baltimore, D. (1990) RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science 248, 1517–1523.

    Article  PubMed  CAS  Google Scholar 

  63. Schatz, D. G., Oettinger, M. A., and Baltimore, D. (1989) The V(D)J recombination activating gene, RAG-1. Cell 59, 1035–1048.

    Article  PubMed  CAS  Google Scholar 

  64. Alt, F., Blackwell, T., and Yancopoulos, G. (1987) Development of the primary antibody repertoire. Science 238, 1079–1087.

    Article  PubMed  CAS  Google Scholar 

  65. Schatz, D. G., Oettinger, M. A., and Schlissel, M. S. (1992) V(D)J recombination: molecular biology and regulation. Ann. Rev. Immunol. 10, 359–383.

    Article  CAS  Google Scholar 

  66. Chen, J., Ma, A., Young, F., and Alt, F. W. (1994) IL-2 receptor alpha chain expression during early B lymphocyte differentiation. Int. Immunol. 6, 1265–1268.

    Article  PubMed  CAS  Google Scholar 

  67. Hayakawa, K., Tarlinton, D., and Hardy, R. R. (1994) Absence of MHC class II expression distinguishes fetal from adult B lymphopoiesis in mice. J. Immunol. 152, 4801–4807.

    Google Scholar 

  68. Krop, I. de Fougerolles, A. R., Hardy, R. R., Allison, M., Schlissel, M. S., and Fearon, D. T. (1996) Self-renewal of B-1 lymphocytes is dependent on CD19. Eur. J. Immunol. 26 238–242.

    Google Scholar 

  69. Rolink, A., Grawunder, U., Winkler, T. H., Karasuyama, H., and Melchers, F. (1994) IL-2 receptor alpha chain (CD25, TAC) expression defines a crucial stage in pre-B cell development. Int. Immunol. 6, 1257–1264.

    Article  PubMed  CAS  Google Scholar 

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Hardy, R.R., Shinton, S., Wasserman, R., Li, YS. (1998). Staging B-Cell Development and the Role of Ig Gene Rearrangement in B Lineage Progression. In: Monroe, J.G., Rothenberg, E.V. (eds) Molecular Biology of B-Cell and T-Cell Development. Contemporary Immunology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-4757-2778-4_14

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  • DOI: https://doi.org/10.1007/978-1-4757-2778-4_14

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