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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.
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“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]
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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
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
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“106 Frasca, D. et al. (2008) Aging down-regulates the transcription factor”
BackgroundAging of the immune system: Focus on inflammation and vaccination
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The ageing immune system: is it ever too old to become young again?
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BackgroundResultInfluentialSasaki, S., Sullivan, M., Narvaez, C. F., Holmes, T. H., Furman, D., Zheng, N.-Y., Nishtala, M., Wrammert, J., Smith, K., James, J. A., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci57834 · Cited by 300
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“, 2006), and others (Frasca et al., 2008; Franceschi et al., 1995) fits well with the expansion of IgG B cells.”
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BackgroundFrasca, D., Diaz, A., Romero, M., Garcia, D., & Blomberg, B. B. (2020) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-011620-034148 · Cited by 232
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Wang, Y., Chen, D., Han, Y., Gu, Z., & Sun, C. C. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.942796 · Cited by 237
“With increasing age, the proportion of peripheral B cells decreases (126).”
BackgroundMaul, R. W., & Gearhart, P. J. (2010) · Advances in immunology · doi:10.1016/s0065-2776(10)05006-6 · Cited by 206
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BackgroundLiver physiology and liver diseases in the elderly
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Erickson, M. A., & Banks, W. A. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20071632 · Cited by 203
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BackgroundB cells and aging: molecules and mechanisms
Cancro, M. P., Hao, Y., Scholz, J. L., Riley, R. L., Frasca, D., Dunn-Walters, D. K., & Blomberg, B. B. (2009) · Trends in Immunology · doi:10.1016/j.it.2009.04.005 · Cited by 198
“BALB/c), it decreases [43].”
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Wang, C., Liu, Y., Xu, L. T., Jackson, K., Roskin, K. M., Pham, T. D., Laserson, J., Marshall, E. L., Seo, K., Lee, J.-Y., et al. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1301384 · Cited by 179
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“We are aware that T cells are also targets of systemic TNF-α, but we have clearly demonstrated that intrinsic B cell defects occur [11].”
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“Copyright © 2017 Wolters Kluwe induced cytidine deaminase is lower [157] and somatic hypermutation and class switch recombination are impaired [158,159].”
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Alterations in Marginal Zone Macrophages and Marginal Zone B Cells in Old Mice
Birjandi, S. Z., Ippolito, J. A., Ramadorai, A. K., & Witte, P. L. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1001271 · Cited by 92
“(37) reported diminished frequency of MZ B cells in old mice.”
BackgroundResultMechanisms for Decreased Function of B Cells in Aged Mice and Humans
Frasca, D., Landin, A. M., Riley, R. L., & Blomberg, B. B. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.5.2741 · Cited by 97
Self-citationAging, immune senescence, and immunotherapy: a comprehensive review
Elias, R., Hartshorn, K., Rahma, O., Lin, N., & Snyder-Cappione, J. E. (2018) · Seminars in Oncology · doi:10.1053/j.seminoncol.2018.08.006 · Cited by 96
Autophagy and Immune Senescence
Zhang, H., Puleston, D. J., & Simon, A. K. (2016) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2016.06.001 · Cited by 95
Aging, inflammaging and immunosenescence as risk factors of severe COVID-19
Tizazu, A. M., Mengist, H. M., & Demeke, G. (2022) · Immunity & Ageing · doi:10.1186/s12979-022-00309-5 · Cited by 96
“Similarly the expression level of (activation-induced cytidine deaminase) an enzyme needed for the initiation of CSR, and its positive regulator, the E47 transcription factor decrease with age [150].”
BackgroundUnique biomarkers for B-cell function predict the serum response to pandemic H1N1 influenza vaccine
Frasca, D., Diaz, A., Romero, M., Phillips, M., Mendez, N. V., Landin, A. M., & Blomberg, B. B. (2012) · International Immunology · doi:10.1093/intimm/dxr123 · Cited by 86
Self-citationKhurana, S., Frasca, D., Blomberg, B., & Golding, H. (2012) · PLoS Pathogens · doi:10.1371/journal.ppat.1002920 · Cited by 85
“transcription factor E47 which activates AID [4].”
BackgroundMethodInfluentialSelf-citationMetabolic requirements of human pro-inflammatory B cells in aging and obesity
Frasca, D., Diaz, A., Romero, M., Thaller, S. R., & Blomberg, B. B. (2019) · PLoS ONE · doi:10.1371/journal.pone.0219545 · Cited by 87
Self-citationAging-Associated Changes in Hematopoiesis and Leukemogenesis: What's the Connection?
Henry, C. J., Marusyk, A., & DeGregori, J. V. (2011) · Aging · doi:10.18632/aging.100351 · Cited by 83
Host Resistance and Immune Aging
Bandaranayake, T., & Shaw, A. C. (2016) · Clinics in Geriatric Medicine · doi:10.1016/j.cger.2016.02.007 · Cited by 88
Silva-Cayetano, A., Foster, W. S., Innocentin, S., Belij-Rammerstorfer, S., Spencer, A. J., Burton, O. T., Fra-Bidó, S., Le Lee, J., Thakur, N., Conceicao, C., et al. (2021) · Med · doi:10.1016/j.medj.2020.12.006 · Cited by 84
Immunomodulatory activity of polyphenols derived from Cassia auriculata flowers in aged rats
John, C. M., Sandrasaigaran, P., Tong, C. K., Adam, A., & Ramasamy, R. (2011) · Cellular Immunology · doi:10.1016/j.cellimm.2011.08.017 · Cited by 81
Buffa, S., Pellicanò, M., Bulati, M., Martorana, A., Goldeck, D., Caruso, C., Pawelec, G., & Colonna‐Romano, G. (2012) · AGE · doi:10.1007/s11357-012-9488-5 · Cited by 83
Impact of Aging and Cytomegalovirus on Immunological Response to Influenza Vaccination and Infection
Merani, S., Pawelec, G., Kuchel, G. A., & McElhaney, J. E. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00784 · Cited by 74
“The B-cell response to vaccination decreases with age (42–44) and the compromised effector function of B-cells in the elderly results in lower antibody production and poor Ig class switching (45).”
BackgroundFrasca, D., Diaz, A., Romero, M., Mendez, N. V., Landin, A. M., Ryan, J., & Blomberg, B. B. (2013) · Vaccine · doi:10.1016/j.vaccine.2013.05.003 · Cited by 79
“AID is our chosen marker for optimal B cell function because we showed it completely correlates with the ability of human B cells to undergo class switch recombination (CSR) [32] and somatic hyper-mutation [42].”
BackgroundMethodResultInfluentialSelf-citationFrasca, D., Diaz, A., Romero, M., Mendez, N. V., Landin, A. M., & Blomberg, B. B. (2013) · Immunity & Ageing · doi:10.1186/1742-4933-10-14 · Cited by 77
Self-citationImpact of aging on viral infections
Leng, J., & Goldstein, D. R. (2010) · Microbes and Infection · doi:10.1016/j.micinf.2010.08.009 · Cited by 81
The impact of age-related syndromes on ICU process and outcomes in very old patients
Vallet, H., Guidet, B., Boumendil, A., de Lange, D. W., Leaver, S. K., Szczeklik, W., Jung, C., Sviri, S., Beil, M., & Flaatten, H. K. (2023) · Annals of Intensive Care · doi:10.1186/s13613-023-01160-7 · Cited by 82
“The total B cells pool decreases [18], with an accumulation of exhausted memory B cells and an impairment of class switch recombination [19].”
BackgroundHaralambieva, I. H., Painter, S. D., Kennedy, R. B., Ovsyannikova, I. G., Lambert, N. D., Goergen, K. M., Oberg, A. L., & Poland, G. A. (2015) · PLoS ONE · doi:10.1371/journal.pone.0122282 · Cited by 76
“, downregulation of the transcription factor E47, and reduction of activation-induced cytidine deaminase/AID, which induces class switch recombination and somatic hypermutation), leading to impaired immune response with reduced antibody specificity and affinity [6,10,11,28,29,30,31,32,33,34,35,36,37,38,39,40,41].”
BackgroundMechanisms underpinning poor antibody responses to vaccines in ageing
Lee, J. L., & Linterman, M. A. (2021) · Immunology Letters · doi:10.1016/j.imlet.2021.11.001 · Cited by 73
Leptin induces immunosenescence in human B cells
Frasca, D., Diaz, A., Romero, M., & Blomberg, B. B. (2019) · Cellular Immunology · doi:10.1016/j.cellimm.2019.103994 · Cited by 74
Self-citationFunctions of double‐negative B cells in autoimmune diseases, infections, and cancers
Chung, M. K. Y., Gong, L., Kwong, D. L., Lee, V. H., Lee, A. W., Guan, X., Kam, N., & Dai, W. (2023) · EMBO Molecular Medicine · doi:10.15252/emmm.202217341 · Cited by 73
“Since AID is an enzyme important for immunoglobulin class-switching for B cells that results in the production of stronger-affinity antibodies (Muramatsu et al , 2000), these B cells have defects in antibody class-switching (Frasca et al , 2008).”
BackgroundHow T follicular helper cells and the germinal centre response change with age
Linterman, M. A. (2014) · Immunology & Cell Biology · doi:10.1038/icb.2013.77 · Cited by 69
Diaz, A., Romero, M., Vazquez, T., Lechner, S. C., Blomberg, B. B., & Frasca, D. (2017) · Vaccine · doi:10.1016/j.vaccine.2017.03.078 · Cited by 71
“We have used activation-induced cytidine deaminase (AID) as a marker for optimal B cell function in these studies because we have shown that it positively and significantly correlates with the ability of B cells to undergo class switch [19] and somatic hypermutation, necessary for affinity maturation of antibodies [20…”
MethodSelf-citationMicroRNAs miR-155 and miR-16 decrease AID and E47 in B cells from elderly individuals
Frasca, D., Diaz, A., Romero, M., Ferracci, F., & Blomberg, B. B. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1500520 · Cited by 69
“E47 is downregulated during aging, leading to reduced AID in human B cells (21).”
BackgroundResultSelf-citationAdipose Tissue Inflammation Induces B Cell Inflammation and Decreases B Cell Function in Aging
Frasca, D., & Blomberg, B. B. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01003 · Cited by 66
“These include a reduction in activation-induced cytidine deaminase (AID), the enzyme necessary for class switch recombination, somatic hypermutation, and IgG production, as well as in E47 (13, 21), a key transcription factor regulating AID (22).”
BackgroundSelf-citationBrazilian green propolis improves immune function in aged mice
Gao, W., Wu, J., Wei, J., Pu, L., Guo, C., Yang, J., Yang, M., & Luo, H. (2014) · Journal of Clinical Biochemistry and Nutrition · doi:10.3164/jcbn.13-70 · Cited by 67
Assessing immune aging in HIV-infected patients
Appay, V., & Sauce, D. (2016) · Virulence · doi:10.1080/21505594.2016.1195536 · Cited by 68
“ferent B cell subsets are altered: it has been shown that na€ıve B cells (IgDC CD27¡) and switched memory B cells (IgD¡ CD27C), predicting optimal antibody responses,(12) decrease with age.(35) Conversely, the antigen-experienced late/exhausted memory B cells (IgD¡ CD27¡) increase with age.”
BackgroundImmune Cell Number, Phenotype, and Function in the Elderly with Sepsis
He, W., Xiao, K., Fang, M., & Xie, L. (2021) · Aging and Disease · doi:10.14336/ad.2020.0627 · Cited by 66
Immunosenescence, Aging, and Systemic Lupus Erythematous
Montoya-Ortiz, G. (2013) · Autoimmune Diseases · doi:10.1155/2013/267078 · Cited by 70
Aging effects on T-bet expression in human B cell subsets
Frasca, D., Diaz, A., Romero, M., D’Eramo, F., & Blomberg, B. B. (2017) · Cellular Immunology · doi:10.1016/j.cellimm.2017.04.007 · Cited by 63
Self-citationReduced EBF expression underlies loss of B‐cell potential of hematopoietic progenitors with age
Lescale, C., Dias, S., Maës, J., Cumano, A., Szabo, P., Charron, D. J., Weksler, M. E., Dosquet, C., Vieira, P., & Goodhardt, M. (2010) · Aging Cell · doi:10.1111/j.1474-9726.2010.00566.x · Cited by 63
“Data from Riley, Bloomberg and colleagues suggest that E2A protein function becomes diminished with age (Van der Put et al., 2004; Riley et al., 2005; Frasca et al., 2008).”
MethodVerma, N., Dimitrova, M., Carter, D. M., Crevar, C. J., Ross, T. M., Golding, H., & Khurana, S. (2012) · Journal of Virology · doi:10.1128/jvi.07085-11 · Cited by 60
“However, age-related immune senescence includes a loss of AID expression in B cells due to impairment of the transcription factor E47 (11).”
BackgroundHow aging impacts vaccine efficacy: known molecular and cellular mechanisms and future directions
Chen, J., Deng, J. C., & Goldstein, D. R. (2022) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2022.09.008 · Cited by 61
B cell function and influenza vaccine responses in healthy aging and disease
Frasca, D., & Blomberg, B. B. (2014) · Current Opinion in Immunology · doi:10.1016/j.coi.2014.05.008 · Cited by 60
Self-citationPerdaens, O., & Pesch, V. V. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2021.811518 · Cited by 62
“This is due to a decrease in antibody class switch and affinity maturation in clonally expanding B cells, related to the downregulation of the E47 transcription factor and activation-induced deaminase (61, 62).”
BackgroundShin, J. H., High, K. P., & Warren, C. A. (2016) · The Journals of Gerontology Series A · doi:10.1093/gerona/glv229 · Cited by 56
“The most significant change with aging in humoral immunity is impairment in the ability to produce high affinity immunoglobulins and undergo immunoglobulin class switch, which allows the production of high affinity IgG, IgA, and IgE (21).”
BackgroundDo natural antibodies compensate for humoral immunosenescence in tropical pythons?
Újvári, B., & Madsen, T. R. L. (2011) · Functional Ecology · doi:10.1111/j.1365-2435.2011.01860.x · Cited by 53
Dysregulated TGF-β Production Underlies the Age-Related Vulnerability to Chikungunya Virus
Uhrlaub, J. L., Pulko, V., DeFilippis, V. R., Broeckel, R. M., Streblow, D. N., Coleman, G. D., Park, B. S., Lindo, J., Vickers, I. E., Anzinger, J. J., et al. (2016) · PLoS Pathogens · doi:10.1371/journal.ppat.1005891 · Cited by 54
Immunesenescence: A Predisposing Risk Factor for the Development of COVID-19?
Hazeldine, J., & Lord, J. M. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.573662 · Cited by 55
“For example, whilst some groups have reported an age-related increase in the percentage or number of circulating CD27 memory B cells (185), others have demonstrated an age-associated decline in this subset (183, 184).”
BackgroundB Cell Responses against Influenza Viruses: Short-Lived Humoral Immunity against a Life-Long Threat
Guthmiller, J. J., Utset, H. A., & Wilson, P. C. (2021) · Viruses · doi:10.3390/v13060965 · Cited by 56
“Funding: This work was funded in part by the National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health grant numbers U19AI082724 (PCW), U19AI109946 (PCW), U19AI057266 (PCW), the NIAID Centers of Excellence for Influenza Research and Surveillance (CEIRS) grant number HHSN272201400005C…”
BackgroundBrown, B. N., Haschak, M. J., Lopresti, S. T., & Stahl, E. C. (2017) · Seminars in Immunology · doi:10.1016/j.smim.2017.05.001 · Cited by 55
The immune system in the aging human
Rymkiewicz, P. D., Heng, Y. X., Vasudev, A., & Larbi, A. (2012) · Immunologic Research · doi:10.1007/s12026-012-8289-3 · Cited by 50
“These studies were confirmed in humans as E47 and activation-induced cytidine deaminase decrease with age [72].”
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
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