Aging Down-Regulates the Transcription Factor E2A, Activation-Induced Cytidine Deaminase, and Ig Class Switch in Human B Cells
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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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Some age-related B cell deficiencies may occur secondary to T cell deficiencies.
“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]
Human and murine B cells show impaired class switch recombination, attributed to reduced induction of the AID enzyme.
“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]
Reduced E47 and AID mRNA expression levels in B cells from elderly individuals are due to reduced mRNA stability.
“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]
E47 mRNA expression is decreased in B cells from elderly individuals.
“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]
Higher expression of inflammatory miRs 16 and 155 causes reduced E47 and AID mRNA stability by binding to their 3'-UTRs and inducing degradation.
“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]
The percentage of switched memory B cells decreases with age.
“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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“Although the output of new B cells, quantified by measuring K deleting recombinant excision circles (KRECs), remains conserved [49], with the peripheral number unchanged, aging is associated with a decline in the frequency of naïve B cells and in the percentage of switch memory B cells [50,51].”
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- 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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