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

Part of the Contemporary Immunology book series (CONTIM)


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.


Light Chain Heavy Chain Mouse Bone Marrow Light Chain Gene Stromal Cell Culture 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Coffman, R. L. and Weissman, i. l. (1981) B220: a B cell-specific member of the Y200 glycoprotein family. Nature 289, 681–683.PubMedCrossRefGoogle Scholar
  2. 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.PubMedCrossRefGoogle Scholar
  3. 3.
    Bosma, M. J. and Carroll, A. M. (1991) The SCID mouse mutant: definition, characterization and potential uses. Annu. Rev. Immunol. 9, 323–350.PubMedCrossRefGoogle Scholar
  4. 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.PubMedGoogle Scholar
  5. 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.PubMedCrossRefGoogle Scholar
  6. 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.PubMedCrossRefGoogle Scholar
  7. 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. 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.PubMedGoogle Scholar
  9. 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.PubMedCrossRefGoogle Scholar
  10. 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.PubMedGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 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.PubMedCrossRefGoogle Scholar
  13. 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.PubMedCrossRefGoogle Scholar
  14. 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.PubMedCrossRefGoogle Scholar
  15. 15.
    Alt, F. W., Oltz, E. M., Young, F., Gorman, J., Taccioli, G., and Chen, J. (1992) VDJ recombination. Immunol. Today 13, 306–314.PubMedCrossRefGoogle Scholar
  16. 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.PubMedGoogle Scholar
  17. 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.PubMedCrossRefGoogle Scholar
  18. 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.PubMedCrossRefGoogle Scholar
  19. 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.PubMedCrossRefGoogle Scholar
  20. 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.PubMedCrossRefGoogle Scholar
  21. 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.PubMedCrossRefGoogle Scholar
  22. 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.CrossRefGoogle Scholar
  23. 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.PubMedCrossRefGoogle Scholar
  24. 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.CrossRefGoogle Scholar
  25. 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.PubMedCrossRefGoogle Scholar
  26. 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.PubMedCrossRefGoogle Scholar
  27. 27.
    Sakaguchi, N. and Melchers, F. (1986) X5, a new light-chain-related locus selectively expressed in pre-B lymphocytes. Nature 324, 579–582.PubMedCrossRefGoogle Scholar
  28. 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.PubMedCrossRefGoogle Scholar
  29. 29.
    Spangrude, G. J., Heimfeld, S., and Weissman, I. L. (1988) Purification and characterization of mouse hematopoietic stem cells. Science 241, 58–62.PubMedCrossRefGoogle Scholar
  30. 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.PubMedGoogle Scholar
  31. 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.PubMedCrossRefGoogle Scholar
  32. 32.
    Reth, M. (1993) Antigen receptors on B lymphocytes. Ann. Rev. Immunol. 10, 98–121.Google Scholar
  33. 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.PubMedCrossRefGoogle Scholar
  34. 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.Google Scholar
  35. 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.PubMedGoogle Scholar
  36. 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.PubMedGoogle Scholar
  37. 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. 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.PubMedCrossRefGoogle Scholar
  39. 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.PubMedGoogle Scholar
  40. 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.PubMedCrossRefGoogle Scholar
  41. 41.
    Goodnow, C. C. (1992) Transgenic mice and analysis of B-cell tolerance. Annu. Rev. Immunol. 10, 489–518.PubMedCrossRefGoogle Scholar
  42. 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. 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.PubMedCrossRefGoogle Scholar
  44. 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.PubMedCrossRefGoogle Scholar
  45. 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. 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. 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.PubMedCrossRefGoogle Scholar
  48. 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.PubMedCrossRefGoogle Scholar
  49. 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.PubMedGoogle Scholar
  50. 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.PubMedCrossRefGoogle Scholar
  51. 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.PubMedCrossRefGoogle Scholar
  52. 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. 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.PubMedGoogle Scholar
  54. 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.PubMedCrossRefGoogle Scholar
  55. 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.PubMedCrossRefGoogle Scholar
  56. 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. 57.
    Fredrickson, G. G. and Basch, R. S. (1989) L3T4 antigen expression by hemopoietic precursor cells. J. Exp. Med. 169, 1473–1478.CrossRefGoogle Scholar
  58. 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.PubMedCrossRefGoogle Scholar
  59. 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.PubMedCrossRefGoogle Scholar
  60. 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.PubMedGoogle Scholar
  61. 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.PubMedCrossRefGoogle Scholar
  62. 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.PubMedCrossRefGoogle Scholar
  63. 63.
    Schatz, D. G., Oettinger, M. A., and Baltimore, D. (1989) The V(D)J recombination activating gene, RAG-1. Cell 59, 1035–1048.PubMedCrossRefGoogle Scholar
  64. 64.
    Alt, F., Blackwell, T., and Yancopoulos, G. (1987) Development of the primary antibody repertoire. Science 238, 1079–1087.PubMedCrossRefGoogle Scholar
  65. 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.CrossRefGoogle Scholar
  66. 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.PubMedCrossRefGoogle Scholar
  67. 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. 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. 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.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

There are no affiliations available

Personalised recommendations