The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index.
Aging Down-Regulates the Transcription Factor E2A, Activation-Induced Cytidine Deaminase, and Ig Class Switch in Human B Cells
Open accessAbstract
Elderly humans have compromised humoral and cellular immune responses, which lead to reduced protection to infectious agents and to vaccines. Currently, available vaccines suboptimally protect the elderly population. The capacity to class switch the Ig H chain is critical to the effectiveness of humoral immune responses in mice and humans. We have previously shown in mice that the E2A-encoded transcription factor E47, which regulates many B cell functions, is down-regulated in old splenic B cells. This leads to a reduction in the activation-induced cytidine deaminase (AID), which is known to induce class switch recombination and Ig somatic hypermutation. The old activated murine B cells also have less AID and less switched Abs. We have extended our study here to investigate whether aging also affects Ab production and E47 and AID expression in B cells isolated from the peripheral blood of human subjects (18–86 years). Our results obtained with activated CD19+ B cells show that the expression of E47, AID, and Igγ1 circle transcripts progressively decrease with age. We also show an age-related decline in the percentage of switch memory B cells (IgG+/IgA+), an increase in that of naive B cells (IgG−/IgA−/CD27−) for most individuals, and no decrease in that of IgM memory cells in peripheral blood, consistent with our data on the decrease seen in class switch recombination in vitro. Our results provide a possible molecular mechanism for a B cell intrinsic defect in the humoral immune response with aging and suggest avenues for improvement of vaccine response in elderly humans.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“In view of the critical role played by CD4 + T cells in orchestrating the immune response, some of the age-related deficiencies observed in B cells (51,53,54), which include a reduction in the number of plasmablasts that develop in response to influenza vaccination (55) and the production of poor-quality antibodies to carbohydrate antigens (56)(57)(58), may occur secondary to T cell deficiencies.”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [53]
In the citing paper
“Human and murine B cells also exhibit impaired class switch recombination, which has been attributed to decreased induction of activation-induced cytidine deaminase (AID) enzyme (53).”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [53]
In the citing paper
“The reduced E47 and AID mRNA expression levels in B cells from elderly individuals are due to reduced mRNA stability, which is in turn due to the higher expression of the inflammatory micro-RNAs (miRs) 16 and 155, which bind to the 3’-untranslated region of E47 and AID mRNA, respectively, inducing mRNA degradation [115].”
From Aging of the immune system: Focus on inflammation and vaccination (2016) · cites this paper as [115]
In the citing paper
“E47 mRNA expression has also been shown to be decreased in B cells from elderly individuals [115].”
From Aging of the immune system: Focus on inflammation and vaccination (2016) · cites this paper as [115]
In the citing paper
“The reduced E47 and AID mRNA expression levels in B cells from elderly individuals are due to reduced mRNA stability, which is in turn due to the higher expression of the inflammatory micro-RNAs (miRs) 16 and 155, which bind to the 3’-untranslated region of E47 and AID mRNA, respectively, inducing mRNA degradation [115].”
From Aging of the immune system: Focus on inflammation and vaccination (2016) · cites this paper as [115]
In the citing paper
“Using these markers, it has been shown that the percentage of switched memory B cells, the predictors of optimal antibody responses [114], decreases with age [115, 116].”
From Aging of the immune system: Focus on inflammation and vaccination (2016) · cites this paper as [115]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
1 retracted
RETRACTED ARTICLE: DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL
Litinskiy, M. B., Nardelli, B., Hilbert, D. M., He, B., Schaffer, A., Casali, P., & Cerutti, A. (2002) · Nature Immunology · doi:10.1038/ni829 · Cited by 1,252
RetractedMaintenance of Serological Memory by Polyclonal Activation of Human Memory B Cells
Bernasconi, N. L., Traggiai, E., & Lanzavecchia, A. (2002) · Science · doi:10.1126/science.1076071 · Cited by 1,304
Competence and competition: the challenge of becoming a long-lived plasma cell
Radbruch, A., Muehlinghaus, G., Luger, E., Inamine, A., Smith, K. G. C., Dörner, T., & Hiepe, F. (2006) · Nature reviews. Immunology · doi:10.1038/nri1886 · Cited by 1,033
Lifetime of plasma cells in the bone marrow
Manz, R. A., Thiel, A., & Radbruch, A. (1997) · Nature · doi:10.1038/40540 · Cited by 866
Ahmad‐Nejad, P., Häcker, H., Rutz, M., Bauer, S., Vabulas, R. M., & Wagner, H. (2002) · European Journal of Immunology · doi:10.1002/1521-4141(200207)32:7 · Cited by 728
Molecular Mechanism of Class Switch Recombination: Linkage with Somatic Hypermutation
Honjo, T., Kinoshita, K., & Muramatsu, M. (2002) · Annual Review of Immunology · doi:10.1146/annurev.immunol.20.090501.112049 · Cited by 610
The immunology of exceptional individuals: the lesson of centenarians
Franceschi, C., Monti, D., Sansoni, P., & Cossarizza, A. (1995) · Immunology Today · doi:10.1016/0167-5699(95)80064-6 · Cited by 535
AID is required to initiate Nbs1/γ-H2AX focus formation and mutations at sites of class switching
Petersen, S., Casellas, R. C., Reina‐San‐Martin, B., Chen, H. T., Difilippantonio, M. J., Wilson, P. C., Hanitsch, L. G., Celeste, A., Muramatsu, M., Pilch, D. R., et al. (2001) · Nature · doi:10.1038/414660a · Cited by 512
Hoyer, B. F., Moser, K., Hauser, A. E., Peddinghaus, A., Voigt, C., Eilat, D., Radbruch, A., Hiepe, F., & Manz, R. A. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20040168 · Cited by 443
T cells and aging january 2002 update
Pawelec, G. (2002) · Frontiers in bioscience · doi:10.2741/a831 · Cited by 372
Pawelec, G. (1998) · Frontiers in bioscience · doi:10.2741/a266 · Cited by 357
Ku80 is required for immunoglobulin isotype switching
Casellas, R. C., Nussenzweig, A., Wuerffel, R., Pelanda, R., Reichlin, A., Suh, H., Qin, F. X.-F., Besmer, E., Kenter, A., Rajewsky, K., et al. (1998) · The EMBO Journal · doi:10.1093/emboj/17.8.2404 · Cited by 329
Ku70 Is Required for Late B Cell Development and Immunoglobulin Heavy Chain Class Switching
Manis, J. P., Gu, Y., Lansford, R. D., Sonoda, E., Ferrini, R., Davidson, L., Rajewsky, K., & Alt, F. W. (1998) · The Journal of Experimental Medicine · doi:10.1084/jem.187.12.2081 · Cited by 297
Age-related Defects in CD4 T Cell Cognate Helper Function Lead to Reductions in Humoral Responses
Eaton, S. M., Burns, E. M., Kusser, K. L., Randall, T. D., & Haynes, L. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20041395 · Cited by 279
Sigvardsson, M., O’Riordan, M. X., & Grosschedl, R. (1997) · Immunity · doi:10.1016/s1074-7613(00)80507-5 · Cited by 276
Kee, B. L., & Murre, C. (1998) · The Journal of Experimental Medicine · doi:10.1084/jem.188.4.699 · Cited by 267
Human IgM+CD27+ B Cells: Memory B Cells or “Memory” B Cells?
Tangye, S. G., & Good‐Jacobson, K. L. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.1.13 · Cited by 246
E-proteins directly regulate expression of activation-induced deaminase in mature B cells
Sayegh, C. E., Quong, M. W., Agata, Y., & Murre, C. (2003) · Nature Immunology · doi:10.1038/ni923 · Cited by 246
Regulation of Aged Humoral Immune Defense against Pneumococcal Bacteria by IgM Memory B Cell
Shi, Y., Yamazaki, T., Okubo, Y., Uehara, Y., Sugane, K., & Agematsu, K. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.5.3262 · Cited by 229
Romanow, W. J., Langerak, A. W., Goebel, P., Wolvers-Tettero, I. L. M., van Dongen, J. J. M., Feeney, A. J., & Murre, C. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)80429-3 · Cited by 224
Changes in the B-cell repertoire with age
Weksler, M. E. (2000) · Vaccine · doi:10.1016/s0264-410x(99)00497-1 · Cited by 213
Both E12 and E47 Allow Commitment to the B Cell Lineage
Bain, G., Robanus-Maandag, E. C., Riele, H. T., Feeney, A. J., Sheehy, A. M., Schlissel, M. S., Shinton, S. A., Hardy, R. R., & Murre, C. (1997) · Immunity · doi:10.1016/s1074-7613(00)80421-5 · Cited by 204
Lougaris, V., Badolato, R., Ferrari, S., & Plebani, A. (2005) · Immunological Reviews · doi:10.1111/j.0105-2896.2005.00229.x · Cited by 193
Yang, X., Štědra, J., & Cerny, J. (1996) · The Journal of Experimental Medicine · doi:10.1084/jem.183.3.959 · Cited by 179
Paganelli, R., Quinti, I., Fagiolo, U., Cossarizza, A., ORTOLANI, C., GUERRA, E., Sansoni, P., Pucillo, L. P., Scala, E., Cozzi, E., et al. (1992) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.1992.tb07954.x · Cited by 156
Frasca, D., Van der Put, E., Riley, R. L., & Blomberg, B. B. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.4.2155 · Cited by 150
Self-citationWikby, A., Johansson, B., Ferguson, F., & Olsson, J. (1994) · Experimental Gerontology · doi:10.1016/0531-5565(94)90036-1 · Cited by 144
Essential role of Id2 in negative regulation of IgE class switching
Sugai, M., Gonda, H., Kusunoki, T., Katakai, T., Yokota, Y., & Shimizu, A. (2002) · Nature Immunology · doi:10.1038/ni874 · Cited by 139
B cells in the aged: CD27, CD5, and CD40 expression
Colonna-Romano, G., Bulati, M., Aquino, A., Scialabba, G., Candore, G., Lio, D., Motta, M., Malaguarnera, M., & Caruso, C. (2003) · Mechanisms of Ageing and Development · doi:10.1016/s0047-6374(03)00013-7 · Cited by 137 · cited 1×
“Others have shown that the percentage of CD27 memory B cells increase with age but this increase is not significant (20).”
BackgroundQuong, M. W., Harris, D. P., Swain, S. L., & Murre, C. (1999) · The EMBO Journal · doi:10.1093/emboj/18.22.6307 · Cited by 136
Chong, Y. (2005) · International Immunology · doi:10.1093/intimm/dxh218 · Cited by 134
The E Box Motif CAGGTG Enhances Somatic Hypermutation without Enhancing Transcription
Michael, N., Shen, H. M., Longerich, S., Kim, N., Longacre, A., & Storb, U. (2003) · Immunity · doi:10.1016/s1074-7613(03)00204-8 · Cited by 121
Pfister, G., Weiskopf, D., Lazuardi, L., Kovaiou, R. D., Cioca, D., Keller, M., LORBEG, B., Parson, W., & Grubeck‐Loebenstein, B. (2006) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1354.018 · Cited by 118
The effect of age on the cognate function of CD4+ T cells
Haynes, L., & Eaton, S. M. (2005) · Immunological Reviews · doi:10.1111/j.0105-2896.2005.00255.x · Cited by 116
Hodes, R. J. (1997) · Immunological Reviews · doi:10.1111/j.1600-065x.1997.tb01022.x · Cited by 106
Goebel, P., Janney, N., Valenzuela, J. R., Romanow, W. J., Murre, C., & Feeney, A. J. (2001) · The Journal of Experimental Medicine · doi:10.1084/jem.194.5.645 · Cited by 103
EPELDEGUI, M., HUNG, Y., MCQUAY, A., AMBINDER, R., & MARTINEZMAZA, O. (2007) · Molecular Immunology · doi:10.1016/j.molimm.2006.03.018 · Cited by 93
Zhou, C. J., Saxon, A., & Zhang, K. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.4.1887 · Cited by 82
IL‐7Rα and E47: independent pathways required for development of multipotent lymphoid progenitors
Kee, B. L., Bain, G., & Murre, C. (2002) · The EMBO Journal · doi:10.1093/emboj/21.1.103 · Cited by 61
Kolar, G. R., Mehta, D., Wilson, P. C., & Capra, J. D. (2006) · Scandinavian Journal of Immunology · doi:10.1111/j.1365-3083.2006.01817.x · Cited by 52
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
Effect of Age on the Immunoglobulin Class Switch
Frasca, D., Riley, R. L., & Blomberg, B. B. (2004) · Critical Reviews in Immunology · doi:10.1615/critrevimmunol.v24.i5.10 · Cited by 41
Self-citationFrasca, D., der Put, E. V., Landin, A. M., Gong, D., Riley, R. L., & Blomberg, B. B. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.10.6633 · Cited by 39
Self-citationAge-related accumulation of Ig VH gene somatic mutations in peripheral B cells from aged humans
Chong, Y., Ikematsu, H., Yamaji, K., NISHIMURA, M., Kashiwagi, S., & Hayashi, J. (2003) · Clinical & Experimental Immunology · doi:10.1046/j.1365-2249.2003.02185.x · Cited by 38
B cells and aging: gauging the interplay of generative, selective, and homeostatic events
Cancro, M. P. (2005) · Immunological Reviews · doi:10.1111/j.0105-2896.2005.00272.x · Cited by 37
Impact of Age on Hypermutation of Immunoglobulin Variable Genes in Humans
Rosner, K., Winter, D. B., Kasmer, C., Skovgaard, G. L., Tarone, R. E., Bohr, V. A., & Gearhart, P. J. (2001) · Journal of Clinical Immunology · doi:10.1023/a:1011003821798 · Cited by 29
Troutaud, D., Drouet, M., Decourt, Morvan, L., & Cogné, M. (1999) · Immunology · doi:10.1046/j.1365-2567.1999.00779.x · Cited by 25
Stavnezer, J. (2000) · Science · doi:10.1126/science.288.5468.984 · Cited by 24
Antibody class switching: uncoupling S region accessibility from transcription
Kaminski, D. A. (2004) · Trends in Genetics · doi:10.1016/j.tig.2004.06.008 · Cited by 19
Research works printed but not linked: 48
- 1997, Immunol. Rev., 5
- 2000, Vaccine, 1624
- 2004, Crit. Rev. Immunol., 297
- 2004, J. Exp. Med., 1613
- 2005, Immunol. Rev., 220
- 2002, Front. Biosci., d1056
- 1996, J. Exp. Med., 959
- 2005, J. Immunol., 6633
- 2004, J. Immunol., 2155
- 1998, EMBO J., 2404
- 2002, Annu. Rev. Immunol., 165
- 2004, Trends Genet., 337
- 1998, J. Exp. Med., 2081
- 2001, Nature, 660
- 2000, Science, 984
- 2005, Immunol. Rev., 48
- 1995, Immunol. Today, 12
- 1994, Exp. Gerontol., 531
- 2005, J. Immunol., 3262
- 2003, Mech. Ageing Dev., 389
- 2006, Scand. J. Immunol., 314
- 2005, Immunol. Rev., 48
- 2007, Mol. Immunol., 934
- 2007, J. Immunol., 13
- 2005, Int. Immunol., 383
- 2002, Nat. Immunol., 822
- 2002, Science, 2199
- 1992, Clin. Exp. Immunol., 351
- 2003, J. Immunol., 1887
- 2006, Ann. NY Acad. Sci., 152
- 2006, Nat. Rev. Immunol., 741
- 1997, Nature, 133
- 2004, J. Exp. Med., 1577
- 2002, Eur. J. Immunol., 1947
- 2003, Clin. Exp. Immunol., 59
- 2001, J. Clin. Immunol., 102
- 1999, Immunology, 197
- 1997, Eur. J. Immunol., 1381
- 2003, Immunity, 235
- 1999, EMBO J., 6307
- 2003, Nat. Immunol., 25
- 2003, Nat. Immunol., 586
- 1997, Immunity, 145
- 2001, J. Exp. Med., 645
- 2002, EMBO J., 103
- 1998, J. Exp. Med., 699
- 2000, Mol. Cell., 343
- 1997, Immunity, 25
Cited by
Sorted by citations
Understanding immunosenescence to improve responses to vaccines
Goronzy, J. J., & Weyand, C. M. (2013) · Nature Immunology · doi:10.1038/ni.2588 · Cited by 827
Causes, consequences, and reversal of immune system aging
Montecino-Rodriguez, E., Berent-Maoz, B., & Dorshkind, K. (2013) · Journal of Clinical Investigation · doi:10.1172/jci64096 · Cited by 793
“…of the critical role played by CD4 + T cells in orchestrating the immune response, some of the age-related deficiencies observed in B cells (51, 53, 54), which include a reduction in the number of plasmablasts that develop in response to influenza vaccination (55) and the production of…”
Immunosenescence and human vaccine immune responses
Crooke, S. N., Ovsyannikova, I. G., Poland, G. A., & Kennedy, R. B. (2019) · Immunity & Ageing · doi:10.1186/s12979-019-0164-9 · Cited by 530
The aging lung: Physiology, disease, and immunity
Schneider, J. L., Rowe, J. H., Garcia-de-Alba, C., Kim, C. F., Sharpe, A. H., & Haigis, M. C. (2021) · Cell · doi:10.1016/j.cell.2021.03.005 · Cited by 500
“maturation and whose alterations result in a sub-optimal vaccine response (Frasca et al., 2008).”
Human innate immunosenescence: causes and consequences for immunity in old age
Panda, A., Arjona, A., Sapey, E., Bai, F., Fikrig, E., Montgomery, R. R., Lord, J. M., & Shaw, A. C. (2009) · Trends in Immunology · doi:10.1016/j.it.2009.05.004 · Cited by 502
“106 Frasca, D. et al. (2008) Aging down-regulates the transcription factor”
Background
Metadata
- Authors
- Frasca, D., Landin, A. M., Lechner, S. C., Ryan, J. G., Schwartz, R., Riley, R. L., & Blomberg, B. B.
- Affiliations
- University of Miami (US)
- Corresponding author
- Frasca, Daniela
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-04
- Volume
- 180
- Issue
- 8
- Pages
- 5283-5290
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1480510972
- Cited by
- 333
- References
- 49
- Citations by year
- 2026: 13 · 2025: 14 · 2024: 8 · 2023: 24 · 2022: 24 · 2021: 23 · 2020: 23 · 2019: 18 · 2018: 16 · 2017: 18 · 2016: 20 · 2015: 16 · 2014: 14 · 2013: 32 · 2012: 21
- FWCI
- 6.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG-17618, R01AG017618, R37AG023717, AG-28586, AG23717, R21AG028586, R01AG025256, AG-025256)
- National Institute of Allergy and Infectious Diseases (AI 064591, R01AI064591)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Keywords
- immunosenescence, B cell aging, E2A transcription factor, E47, activation-induced cytidine deaminase, class switch recombination, IgG1, naive B cells, humoral immune response, vaccine response in the elderly
- MeSH terms
- AICDA (Activation-Induced Cytidine Deaminase), Adolescent, Adult, Aged, Aged, 80 and over, Aging, B-Lymphocytes, Cells, Cultured, Cytidine Deaminase, Female, Humans, Immunologic Memory, Lymphocyte Activation, Male, Middle Aged, Gene Rearrangement, B-Lymphocyte, Down-Regulation, Immunoglobulin Class Switching, Basic Helix-Loop-Helix Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
