Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 Dec 6;91(25):11988–11992. doi: 10.1073/pnas.91.25.11988

Bone marrow declines as a site of B-cell precursor differentiation with age: relationship to thymus involution.

A Ben-Yehuda 1, P Szabo 1, R Dyall 1, M E Weksler 1
PMCID: PMC45361  PMID: 7991570

Abstract

The rearrangement of immunoglobulin genes in B-lymphocyte precursors requires the expression of the recombination activating genes (Rag), which leads to the generation of a highly diverse B-cell repertoire. We can use the level of Rag-1 mRNA in the bone marrow as an index of its capacity to support the maturation of B lymphocytes as all detectable bone marrow Rag-1 mRNA is expressed by B-cell precursors. In mouse bone marrow, Rag-1 mRNA increases during the first 2 months of life to reach its maximal level at 2 months of age. This level is maintained until 5 months of age and thereafter declines to a minimum level by 10 months of age. Thus, bone marrow Rag-1 mRNA is highest at the time when thymic function is maximal in euthymic mice. An association between thymic activity and bone marrow Rag-1 gene expression was supported by showing a low level of bone marrow Rag-1 mRNA in athymic nude mice at an age when this gene is maximally expressed in euthymic mice. Another characteristic of B cells in nude mice is their preferential rearrangement of diversity region (D)-proximal heavy-chain variable region (VH) genes. We demonstrated that injection of syngeneic splenic T cells into nude mice not only stimulates an increase in Rag-1 mRNA in their bone marrow B-cell precursors but also restores their random use of VH genes. Most interestingly, injection of supernatant medium from phytohemagglutinin-activated splenic T-cell cultures from young euthymic mice also induces both Rag-1 mRNA in bone marrow B-cell precursors and random use of VH genes. These findings suggest that thymic function can regulate both Rag-1 gene expression and VH gene use by bone marrow B-cell precursors.

Full text

PDF
11988

Images in this article

11989Image
on p.11989
11990Image
on p.11990
11990Image
on p.11990
11990Image
on p.11990
11991Image
on p.11991

Selected References

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

  1. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  2. Chun J. J., Schatz D. G., Oettinger M. A., Jaenisch R., Baltimore D. The recombination activating gene-1 (RAG-1) transcript is present in the murine central nervous system. Cell. 1991 Jan 11;64(1):189–200. doi: 10.1016/0092-8674(91)90220-s. [DOI] [PubMed] [Google Scholar]
  3. Costa T. E., Suh H., Nussenzweig M. C. Chromosomal position of rearranging gene segments influences allelic exclusion in transgenic mice. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2205–2208. doi: 10.1073/pnas.89.6.2205. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Freitas A. A., Lembezat M. P., Rocha B. Selection of antibody repertories: transfer of mature T lymphocytes modifies VH gene family usage in the actual and available B cell repertories of athymic mice. Int Immunol. 1989;1(4):398–408. doi: 10.1093/intimm/1.4.398. [DOI] [PubMed] [Google Scholar]
  5. Mombaerts P., Iacomini J., Johnson R. S., Herrup K., Tonegawa S., Papaioannou V. E. RAG-1-deficient mice have no mature B and T lymphocytes. Cell. 1992 Mar 6;68(5):869–877. doi: 10.1016/0092-8674(92)90030-g. [DOI] [PubMed] [Google Scholar]
  6. Muegge K., Vila M. P., Durum S. K. Interleukin-7: a cofactor for V(D)J rearrangement of the T cell receptor beta gene. Science. 1993 Jul 2;261(5117):93–95. doi: 10.1126/science.7686307. [DOI] [PubMed] [Google Scholar]
  7. Namen A. E., Lupton S., Hjerrild K., Wignall J., Mochizuki D. Y., Schmierer A., Mosley B., March C. J., Urdal D., Gillis S. Stimulation of B-cell progenitors by cloned murine interleukin-7. Nature. 1988 Jun 9;333(6173):571–573. doi: 10.1038/333571a0. [DOI] [PubMed] [Google Scholar]
  8. Oettinger M. A., Schatz D. G., Gorka C., Baltimore D. RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science. 1990 Jun 22;248(4962):1517–1523. doi: 10.1126/science.2360047. [DOI] [PubMed] [Google Scholar]
  9. Riley R. L., Kruger M. G., Elia J. B cell precursors are decreased in senescent BALB/c mice, but retain normal mitotic activity in vivo and in vitro. Clin Immunol Immunopathol. 1991 May;59(2):301–313. doi: 10.1016/0090-1229(91)90026-7. [DOI] [PubMed] [Google Scholar]
  10. Rolink A., Melchers F. Molecular and cellular origins of B lymphocyte diversity. Cell. 1991 Sep 20;66(6):1081–1094. doi: 10.1016/0092-8674(91)90032-t. [DOI] [PubMed] [Google Scholar]
  11. Schatz D. G., Oettinger M. A., Baltimore D. The V(D)J recombination activating gene, RAG-1. Cell. 1989 Dec 22;59(6):1035–1048. doi: 10.1016/0092-8674(89)90760-5. [DOI] [PubMed] [Google Scholar]
  12. Shinkai Y., Rathbun G., Lam K. P., Oltz E. M., Stewart V., Mendelsohn M., Charron J., Datta M., Young F., Stall A. M. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. 1992 Mar 6;68(5):855–867. doi: 10.1016/0092-8674(92)90029-c. [DOI] [PubMed] [Google Scholar]
  13. Tonegawa S. Somatic generation of antibody diversity. Nature. 1983 Apr 14;302(5909):575–581. doi: 10.1038/302575a0. [DOI] [PubMed] [Google Scholar]
  14. Viale A. C., Chies J. A., Huetz F., Malenchere E., Weksler M., Freitas A. A., Coutinho A. VH-gene family dominance in ageing mice. Scand J Immunol. 1994 Feb;39(2):184–188. doi: 10.1111/j.1365-3083.1994.tb03358.x. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES