Skip to main content
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1993 Oct 1;178(4):1247–1254. doi: 10.1084/jem.178.4.1247

The bcl-2 gene product inhibits clonal deletion of self-reactive B lymphocytes in the periphery but not in the bone marrow

PMCID: PMC2191192  PMID: 8376932

Abstract

To test whether the product of the bcl-2 proto-oncogene blocks clonal deletion of self-reactive B cells, we have generated transgenic mice carrying the bcl-2 gene and the immunoglobulin genes for the anti- erythrocyte 4C8 antibody. In these transgenic mice, clonal deletion of self-reactive immature B cells in the bone marrow was not inhibited in spite of expression of the bcl-2 gene. In contrast, self-antigen- induced clonal deletion of mature self-reactive Ly-1 B (B1) cells in the peritoneal cavity was inhibited in the transgenic mice. These results indicate that the mechanism for clonal deletion of immature self-reactive B cells in the bone marrow differs from that of mature self-reactive B cells in the periphery.

Full Text

The Full Text of this article is available as a PDF (914.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Borzillo G. V., Endo K., Tsujimoto Y. Bcl-2 confers growth and survival advantage to interleukin 7-dependent early pre-B cells which become factor independent by a multistep process in culture. Oncogene. 1992 May;7(5):869–876. [PubMed] [Google Scholar]
  2. Gay D., Saunders T., Camper S., Weigert M. Receptor editing: an approach by autoreactive B cells to escape tolerance. J Exp Med. 1993 Apr 1;177(4):999–1008. doi: 10.1084/jem.177.4.999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Goodnow C. C., Crosbie J., Adelstein S., Lavoie T. B., Smith-Gill S. J., Brink R. A., Pritchard-Briscoe H., Wotherspoon J. S., Loblay R. H., Raphael K. Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature. 1988 Aug 25;334(6184):676–682. doi: 10.1038/334676a0. [DOI] [PubMed] [Google Scholar]
  4. Goodnow C. C., Crosbie J., Jorgensen H., Brink R. A., Basten A. Induction of self-tolerance in mature peripheral B lymphocytes. Nature. 1989 Nov 23;342(6248):385–391. doi: 10.1038/342385a0. [DOI] [PubMed] [Google Scholar]
  5. Goodnow C. C. Transgenic mice and analysis of B-cell tolerance. Annu Rev Immunol. 1992;10:489–518. doi: 10.1146/annurev.iy.10.040192.002421. [DOI] [PubMed] [Google Scholar]
  6. Hartley S. B., Cooke M. P., Fulcher D. A., Harris A. W., Cory S., Basten A., Goodnow C. C. Elimination of self-reactive B lymphocytes proceeds in two stages: arrested development and cell death. Cell. 1993 Feb 12;72(3):325–335. doi: 10.1016/0092-8674(93)90111-3. [DOI] [PubMed] [Google Scholar]
  7. Hartley S. B., Crosbie J., Brink R., Kantor A. B., Basten A., Goodnow C. C. Elimination from peripheral lymphoid tissues of self-reactive B lymphocytes recognizing membrane-bound antigens. Nature. 1991 Oct 24;353(6346):765–769. doi: 10.1038/353765a0. [DOI] [PubMed] [Google Scholar]
  8. Hockenbery D., Nuñez G., Milliman C., Schreiber R. D., Korsmeyer S. J. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature. 1990 Nov 22;348(6299):334–336. doi: 10.1038/348334a0. [DOI] [PubMed] [Google Scholar]
  9. Ishida Y., Agata Y., Shibahara K., Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992 Nov;11(11):3887–3895. doi: 10.1002/j.1460-2075.1992.tb05481.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kinashi T., Inaba K., Tsubata T., Tashiro K., Palacios R., Honjo T. Differentiation of an interleukin 3-dependent precursor B-cell clone into immunoglobulin-producing cells in vitro. Proc Natl Acad Sci U S A. 1988 Jun;85(12):4473–4477. doi: 10.1073/pnas.85.12.4473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Nemazee D. A., Bürki K. Clonal deletion of B lymphocytes in a transgenic mouse bearing anti-MHC class I antibody genes. Nature. 1989 Feb 9;337(6207):562–566. doi: 10.1038/337562a0. [DOI] [PubMed] [Google Scholar]
  12. Nemazee D., Russell D., Arnold B., Haemmerling G., Allison J., Miller J. F., Morahan G., Buerki K. Clonal deletion of autospecific B lymphocytes. Immunol Rev. 1991 Aug;122:117–132. doi: 10.1111/j.1600-065x.1991.tb00600.x. [DOI] [PubMed] [Google Scholar]
  13. Nuñez G., London L., Hockenbery D., Alexander M., McKearn J. P., Korsmeyer S. J. Deregulated Bcl-2 gene expression selectively prolongs survival of growth factor-deprived hemopoietic cell lines. J Immunol. 1990 May 1;144(9):3602–3610. [PubMed] [Google Scholar]
  14. Ohno H., Ogawa M., Nishikawa S., Hayashi S., Kunisada T., Nishikawa S. Conditions required for myelopoiesis in murine spleen. Immunol Lett. 1993 Feb;35(2):197–204. doi: 10.1016/0165-2478(93)90091-f. [DOI] [PubMed] [Google Scholar]
  15. Okamoto M., Murakami M., Shimizu A., Ozaki S., Tsubata T., Kumagai S., Honjo T. A transgenic model of autoimmune hemolytic anemia. J Exp Med. 1992 Jan 1;175(1):71–79. doi: 10.1084/jem.175.1.71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Russell D. M., Dembić Z., Morahan G., Miller J. F., Bürki K., Nemazee D. Peripheral deletion of self-reactive B cells. Nature. 1991 Nov 28;354(6351):308–311. doi: 10.1038/354308a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Sentman C. L., Shutter J. R., Hockenbery D., Kanagawa O., Korsmeyer S. J. bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell. 1991 Nov 29;67(5):879–888. doi: 10.1016/0092-8674(91)90361-2. [DOI] [PubMed] [Google Scholar]
  18. Strasser A., Harris A. W., Cory S. bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship. Cell. 1991 Nov 29;67(5):889–899. doi: 10.1016/0092-8674(91)90362-3. [DOI] [PubMed] [Google Scholar]
  19. Strasser A., Whittingham S., Vaux D. L., Bath M. L., Adams J. M., Cory S., Harris A. W. Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8661–8665. doi: 10.1073/pnas.88.19.8661. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Tiegs S. L., Russell D. M., Nemazee D. Receptor editing in self-reactive bone marrow B cells. J Exp Med. 1993 Apr 1;177(4):1009–1020. doi: 10.1084/jem.177.4.1009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Tsujimoto Y., Cossman J., Jaffe E., Croce C. M. Involvement of the bcl-2 gene in human follicular lymphoma. Science. 1985 Jun 21;228(4706):1440–1443. doi: 10.1126/science.3874430. [DOI] [PubMed] [Google Scholar]
  22. Vaux D. L., Cory S., Adams J. M. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature. 1988 Sep 29;335(6189):440–442. doi: 10.1038/335440a0. [DOI] [PubMed] [Google Scholar]
  23. Yellen-Shaw A. J., Monroe J. G. Developmentally regulated association of a 56-kD member of the surface immunoglobulin M receptor complex. J Exp Med. 1992 Jul 1;176(1):129–137. doi: 10.1084/jem.176.1.129. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Yellen A. J., Glenn W., Sukhatme V. P., Cao X. M., Monroe J. G. Signaling through surface IgM in tolerance-susceptible immature murine B lymphocytes. Developmentally regulated differences in transmembrane signaling in splenic B cells from adult and neonatal mice. J Immunol. 1991 Mar 1;146(5):1446–1454. [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES