Bone Marrow Microenvironmental Changes Underlie Reduced RAG-mediated Recombination and B Cell Generation in Aged Mice
Open accessAbstract
During aging, adaptive immunity is severely compromised, due in part to decreased production of B lymphocytes and loss of immunoglobulin (Ig) diversity. However, the molecular mechanisms that underlie age-associated diminished B cell production remain unclear. Using in vivo labeling, we find that this reduction in marrow pre–B cells reflects increased attrition during passage from the pro–B to pre–B cell pool. Analyses of reciprocal bone marrow chimeras reveal that the magnitude and production rates of pre–B cells are controlled primarily by microenvironmental factors, rather than intrinsic events. To understand changes in pro–B cells that could diminish production of pre–B cells, we evaluated rag2 expression and V(D)J recombinase activity in pro–B cells at the single cell level. The percentage of pro–B cells that express rag2 is reduced in aged mice and is correlated with both a loss of V(D)J recombinase activity in pro–B cells and reduced numbers of pre–B cells. Reciprocal bone marrow chimeras revealed that the aged microenvironment also determines rag2 expression and recombinase activity in pro–B cells. Together, these observations suggest that extrinsic factors in the bone marrow that decline with age are largely responsible for less efficient V(D)J recombination in pro–B cells and diminished progression to the pre–B cell stage.
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Declines in the bone marrow microenvironment, possibly from reduced IL-7 secretion by stromal cells, have been implicated in B cell lineage aging.
“Declines in the bone marrow microenvironment, possibly as a result of decreased IL-7 secretion by stromal cells, have been implicated in B cell lineage aging (36,37).”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [36]
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Cites
Resolution and characterization of pro-B and pre-pro-B cell stages in normal mouse bone marrow.
Hardy, R. R., Carmack, C. E., Shinton, S. A., Kemp, J. D., & Hayakawa, K. (1991) · The Journal of Experimental Medicine · doi:10.1084/jem.173.5.1213 · Cited by 1,604 · see citing works
RAG-1 and RAG-2, Adjacent Genes That Synergistically Activate V(D)J Recombination
Oettinger, M. A., Schatz, D. G., Gorka, C., & Baltimore, D. (1990) · Science · doi:10.1126/science.2360047 · Cited by 1,457 · see citing works
The aging immune system: primer and prospectus
Miller, R. A. (1996) · Science · doi:10.1126/science.273.5271.70 · Cited by 1,165 · see citing works
The V(D)J recombination activating gene, RAG-1
Schatz, D. G., Oettinger, M. A., & Baltimore, D. (1989) · Cell · doi:10.1016/0092-8674(89)90760-5 · Cited by 1,160 · see citing works
Cellular Niches Controlling B Lymphocyte Behavior within Bone Marrow during Development
Tokoyoda, K., Egawa, T., Sugiyama, T., Choi, B.-I., & Nagasawa, T. (2004) · Immunity · doi:10.1016/j.immuni.2004.05.001 · Cited by 796 · see citing works
Allman, D., Ferguson, S. E., Lentz, V. M., & Cancro, M. P. (1993) · The Journal of Immunology · doi:10.4049/jimmunol.151.9.4431 · Cited by 408 · see citing works
Self-citationLymphocyte life-span and memory
Sprent, J., & Tough, D. F. (1994) · Science · doi:10.1126/science.8073282 · Cited by 398 · see citing works
Sigvardsson, M., O’Riordan, M. X., & Grosschedl, R. (1997) · Immunity · doi:10.1016/s1074-7613(00)80507-5 · Cited by 277 · see citing works
The Decline in B Lymphopoiesis in Aged Mice Reflects Loss of Very Early B-Lineage Precursors
Miller, J. P., & Allman, D. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.5.2326 · Cited by 255 · see citing works
Self-citationAllman, D., Ferguson, S. E., & Cancro, M. P. (1992) · The Journal of Immunology · doi:10.4049/jimmunol.149.8.2533 · Cited by 242 · see citing works
Self-citationImmunosenescence and germinal center reaction
Zheng, B. Q., Han, S., Takahashi, Y., & Kelsoe, G. H. (1997) · Immunological Reviews · doi:10.1111/j.1600-065x.1997.tb01028.x · Cited by 229 · see citing works
Unexpected expansions of CD8-bearing cells in old mice.
Callahan, J. E., Kappler, J. W., & Marrack, P. (1993) · The Journal of Immunology · doi:10.4049/jimmunol.151.12.6657 · Cited by 228 · see citing works
Impaired Ability of Bone Marrow Stromal Cells to Support B-Lymphopoiesis With Age
Stephan, R. P., Reilly, C. R., & Witte, P. L. (1998) · Blood · doi:10.1182/blood.v91.1.75 · Cited by 197 · see citing works
Effect of age on humoral immunity, selection of the B‐cell repertoire and B‐cell development
LeMaoult, J., Szabo, P., & Weksler, M. E. (1997) · Immunological Reviews · doi:10.1111/j.1600-065x.1997.tb01032.x · Cited by 183 · see citing works
Opstelten, D., & Osmond, D. G. (1983) · The Journal of Immunology · doi:10.4049/jimmunol.131.6.2635 · Cited by 183 · see citing works
Kline, G. H., Hayden, T. A., & Klinman, N. R. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.162.6.3342 · Cited by 170 · see citing works
Monroe, R. J., Seidl, K. J., Gaertner, F. H., Han, S., Chen, F., Sekiguchi, J., Wang, J. O., Ferrini, R., Davidson, L., Kelsoe, G. H., et al. (1999) · Immunity · doi:10.1016/s1074-7613(00)80095-3 · Cited by 169 · see citing works
A Conserved Transcriptional Enhancer Regulates RAG Gene Expression in Developing B Cells
Hsu, L., Lauring, J. D., Liang, H.-E., Greenbaum, S., Cado, D., Zhuang, Y., & Schlissel, M. S. (2003) · Immunity · doi:10.1016/s1074-7613(03)00181-x · Cited by 159 · see citing works
B-cell development: a comparison between mouse and man
Ghia, P., ten Boekel, E., Rolink, A., et al. (1998) · Immunology Today · doi:10.1016/s0167-5699(98)01330-9 · Cited by 154 · see citing works
Liang, H.-E., Hsu, L., Cado, D., Cowell, L. G., Kelsoe, G. H., & Schlissel, M. S. (2002) · Immunity · doi:10.1016/s1074-7613(02)00448-x · Cited by 153 · see citing works
Coordinate Regulation of RAG1 and RAG2 by Cell Type-Specific DNA Elements 5' of RAG2
Yu, W., Misulovin, Z., Suh, H., Hardy, R. R., Janković, M., Yannoutsos, N., & Nussenzweig, M. C. (1999) · Science · doi:10.1126/science.285.5430.1080 · Cited by 139 · see citing works
Stephan, R. P., Lill-Elghanian, D. A., & Witte, P. L. (1997) · The Journal of Immunology · doi:10.4049/jimmunol.158.4.1598 · Cited by 133 · see citing works
Stage-specific alterations in murine B lymphopoiesis with age
Stephan, R. P., Sanders, V. M., & Witte, P. L. (1996) · International Immunology · doi:10.1093/intimm/8.4.509 · Cited by 126 · see citing works
Borghesi, L., Hsu, L., Miller, J. P., Anderson, M., Herzenberg, L. A., Herzenberg, L. A., Schlissel, M. S., Allman, D., & Gerstein, R. M. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20031800 · Cited by 121 · see citing works
Self-citationDeletion of the RAG2 C terminus leads to impaired lymphoid development in mice
Akamatsu, Y., Monroe, R., Dudley, D. D., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0237043100 · Cited by 107 · see citing works
Anderson, M. T., Tjioe, I., Lorincz, M. C., Parks, D. R., Herzenberg, L. A., Nolan, G. P., & Herzenberg, L. A. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.16.8508 · Cited by 105 · see citing works
Bcmd governs recruitment of new B cells into the stable peripheral B cell pool in the A/WySnJ mouse
Lentz, V. M., Cancro, M. P., Nashold, F. E., et al. (1996) · The Journal of Immunology · doi:10.4049/jimmunol.157.2.598 · Cited by 98 · see citing works
Self-citationRiley, R. L., Kruger, M. G., & Elia, J. (1991) · Clinical Immunology and Immunopathology · doi:10.1016/0090-1229(91)90026-7 · Cited by 91 · see citing works
Klinman, N. R., & Kline, G. H. (1997) · Immunological Reviews · doi:10.1111/j.1600-065x.1997.tb01031.x · Cited by 90 · see citing works
Impaired V(D)J Recombination and Lymphocyte Development in Core RAG1-expressing Mice
Dudley, D. D., Sekiguchi, J., Zhu, C., et al. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20030627 · Cited by 81 · see citing works
Altered VH gene segment utilization in the response to phosphorylcholine by aged mice.
Riley, S. C., Froscher, B. G., Linton, P. J., Zharhary, D., Marcu, K. B., & Klinman, N. R. (1989) · The Journal of Immunology · doi:10.4049/jimmunol.143.11.3798 · Cited by 76 · see citing works
Looney, R. J., Hasan, M. S., Coffin, D., Campbell, D., Falsey, A. R., Kolassa, J. E., Agosti, J. M., Abraham, G. N., & Evans, T. G. (2001) · Journal of Clinical Immunology · doi:10.1023/a:1006736931381 · Cited by 65 · see citing works
Sherwood, E. M., Blomberg, B. B., Xu, W., Warner, C. A., & Riley, R. L. (1998) · PubMed · Cited by 62 · see citing works
Effect of age on the expressed B cell repertoire: role of B cell subsets
Hu, A. C., Ehleiter, D., Ben-Yehuda, A., et al. (1993) · International Immunology · doi:10.1093/intimm/5.9.1035 · Cited by 62 · see citing works
Age-dependent changes in B lymphocyte development in man and mouse
Ghia, P., Melchers, F., & Rolink, A. G. (2000) · Experimental Gerontology · doi:10.1016/s0531-5565(99)00095-9 · Cited by 60 · see citing works
Sherwood, E. M., Blomberg, B. B., Xu, W., Warner, C. A., & Riley, R. L. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.161.9.4472 · Cited by 59 · see citing works
Sherwood, E. M., Xu, W., King, A. M., Blomberg, B. B., & Riley, R. L. (2000) · Mechanisms of Ageing and Development · doi:10.1016/s0047-6374(00)00157-3 · Cited by 57 · see citing works
Maturation of B Cell Precursors Is Impaired in Thymic-Deprived Nude and Old Mice
Szabo, P., Zhao, K., Kirman, I., LeMaoult, J., Dyall, R., Cruikshank, W. W., & Weksler, M. E. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.161.5.2248 · Cited by 56 · see citing works
Ben-Yehuda, A., Szabó, P. E., Dyall, R., & Weksler, M. E. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.25.11988 · Cited by 55 · see citing works
van Dijk‐Härd, I., Söderström, I., Feld, S., Holmberg, D., & Lundkvist, I. (1997) · European Journal of Immunology · doi:10.1002/eji.1830270613 · Cited by 50 · see citing works
Impaired rearrangement of IgH V to DJ segments in bone marrow Pro-B cells from old mice
Szabo, P., Shen, S. S., Telford, W. G., & Weksler, M. E. (2003) · Cellular Immunology · doi:10.1016/s0008-8749(03)00084-4 · Cited by 45 · see citing works
der Put, E. V., Sherwood, E. M., Blomberg, B. B., & Riley, R. L. (2003) · Experimental Gerontology · doi:10.1016/j.exger.2003.07.003 · Cited by 45 · see citing works
Pairs of violet-light-excited fluorochromes for flow cytometric analysis
Anderson, M. T., Baumgarth, N., Haugland, R. P., Gerstein, R. M., Tjioe, T., Herzenberg, L. A., & Herzenberg, L. A. (1998) · Cytometry · doi:10.1002/(sici)1097-0320(19981201)33:4 · Cited by 38 · see citing works
Self-citationSambhara, S. R., Kurichh, A., Miranda, R., James, O., Underdown, B. J., Klein, M. C. A., Tartaglia, J., & Burt, D. S. (2001) · Cellular Immunology · doi:10.1006/cimm.2001.1799 · Cited by 36 · see citing works
The response in old mice: positive and negative immune memory after priming in early age
Sánchez, M., Lindroth, K., Sverremark‐Ekström, E., et al. (2001) · International Immunology · doi:10.1093/intimm/13.10.1213 · Cited by 28 · see citing works
Frasca, D., der Put, E. V., Riley, R. L., & Blomberg, B. B. (2004) · Experimental Gerontology · doi:10.1016/j.exger.2003.09.027 · Cited by 27 · see citing works
Lu, Y.-F., & Černý, J. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.9.4920 · Cited by 25 · see citing works
Borghesi, L., & Gerstein, R. M. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20031802 · Cited by 22 · see citing works
Self-citationLucas, A. H., & Reason, D. C. (1998) · Infection and Immunity · doi:10.1128/iai.66.4.1752-1754.1998 · Cited by 20 · see citing works
Age-associated defects in B lymphocyte development
Szabo, P., Shen, S. S., & Weksler, M. E. (1999) · Experimental Gerontology · doi:10.1016/s0531-5565(99)00023-6 · Cited by 17 · see citing works
Ben‐Yehuda, A., Szabo, P., & Weksler, M. E. (1994) · Immunology Letters · doi:10.1016/0165-2478(94)00067-0 · Cited by 16 · see citing works
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“The output of B cells is severely affected by changes in the microecology of the bone marrow, such as decreased pro-B cell-survival cytokine IL-7 level.(72) The number of B-cell precursors and antibody-producing plasma cells in mouse and human bone marrow decreases with age.”
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- Authors
- Labrie, J. E., Sah, A. P., Allman, D. M., Cancro, M. P., & Gerstein, R. M.
- Affiliations
- University of Massachusetts Chan Medical School (US)
- University of Pennsylvania (US)
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2004-08-16
- Volume
- 200
- Issue
- 4
- Pages
- 411-423
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2211932
- OpenAlex
- W2163109682
- Cited by
- 145
- References
- 51
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 6 · 2023: 4 · 2022: 4 · 2021: 6 · 2020: 2 · 2019: 10 · 2018: 4 · 2017: 7 · 2016: 6 · 2015: 8 · 2014: 3 · 2013: 11 · 2012: 9
- FWCI
- 3.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- eScholarship@UMassChan (submittedVersion)
- Funders
- National Institutes of Health (1r03ag019042-01, 1r03ag015623-01)
- National Institute on Aging (AG19042, AG15623)
- National Institute of Allergy and Infectious Diseases (R01AI043534, AI043534, R56AI043534)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 32520, 5 P30 DK 32520, P30DK032520)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- bone marrow microenvironment, aging, B cell development, V(D)J recombination, RAG2, pro-B cells, pre-B cells, immunosenescence, immunoglobulin diversity, bone marrow chimeras
- MeSH terms
- Aging, Animals, B-Lymphocytes, Bone Marrow, Bromodeoxyuridine, DNA-Binding Proteins, Flow Cytometry, Gene Expression Regulation, Immunity, Cellular, Mice, Inbred Strains, Time Factors, VDJ Recombinases, Mice
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