B cells in the aging immune system: time to consider B‐1 cells

Holodick, Nichol E.; Rothstein, Thomas L.

doi:10.1111/nyas.12825

Cited by 43T-cell and B-cell ImmunologyImmune responses and vaccinationsImmune Response and Inflammation

B cells in the aging immune system: time to consider B‐1 cells

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Holodick, Nichol E., Rothstein, Thomas L.·2015·Annals of the New York Academy of Sciences

DOI 10.1111/nyas.12825PMC PMC4679494

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Abstract

The investigation of immune senescence has uncovered many changes in B cell development, maintenance, and function with increasing age. However, most of these studies have focused on conventional B cell subsets in the spleen. The B‐1 cell subset is an essential arm of the innate immune system, which in general has been understudied in terms of immune senescence. Here, we review what is currently known about B cells during aging and go on to describe why B‐1 cell biology is an important component of the aging immune system in the context of diseases that most affect the aged population.

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Changes in immature B cell migration and an increase in age-associated B cells can decrease repertoire diversity.
“Changes in immature B cell migration and an increase in age-associated B cells can decrease repertoire diversity (135).”
From Aging and Lung Disease (2020) · cites this paper as [135]
While the functional ability to produce antibody remains intact, age-associated changes in antibody specificity and antigen affinity result in a diminished ability to mount robust antibody responses in older persons.
“While the functional ability to produce antibody remains intact, age-associated changes in antibody specificity and antigen affinity result in a diminished ability to mount robust antibody responses in older persons (135).”
From Aging and Lung Disease (2020) · cites this paper as [135]
Multiple studies have illustrated an age-associated decline in B cell development, specifically a decreased transition from the presence of naïve to mature B cells.
“Multiple studies have illustrated an age-associated decline in B cell development, specifically a decreased transition from the presence of naïve to mature B cells (135).”
From Aging and Lung Disease (2020) · cites this paper as [135]
Experimental murine studies have demonstrated a decline in the number pro-B, pre-B, and immature B cell subsets present in older animals.
“Specifically, experimental murine studies have demonstrated a decline in the number pro-B, pre-B, and immature B cell subsets present in older animals (135).”
From Aging and Lung Disease (2020) · cites this paper as [135]

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Kantor, A. B. (1996) · Seminars in Immunology · doi:10.1006/smim.1996.0005 · Cited by 25 · see citing works
Old mice retain bone marrow B1 progenitors, but lose B2 precursors, and exhibit altered immature B cell phenotype and light chain usage
Alter-Wolf, S., Blomberg, B. B., & Riley, R. L. (2009) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2009.04.001 · Cited by 23 · see citing works
Aging and neoteny in the B lineage
Melamed, D., & Scott, D. W. (2012) · Blood · doi:10.1182/blood-2012-07-444711 · Cited by 19 · see citing works
Age-related immune response to pneumococcal polysaccharide vaccination: lessons for the clinic
Iyer, A. S., Ohtola, J. A., & Westerink, M. A. J. (2014) · Expert Review of Vaccines · doi:10.1586/14760584.2015.963058 · Cited by 12 · see citing works

Flagged first, then by citations

1 of the 91 references couldn’t be matched to a known paper.

Sorted by citations

Aging and Lung Disease
Cho, S. J., & Stout-Delgado, H. W. (2020) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021119-034610 · Cited by 458 · see citing works
The possible pathophysiology mechanism of cytokine storm in elderly adults with COVID-19 infection: the contribution of “inflame-aging”
Meftahi, G. H., Jangravi, Z., Sahraei, H., & Bahari, Z. (2020) · Inflammation Research · doi:10.1007/s00011-020-01372-8 · Cited by 289 · see citing works
“Production of precursor B lymphocytes in the bone marrow and the number of pro-B and pre-B lymphocytes decreased in aged mice and human [104].”
Background
Targeting immune dysfunction in aging
Borgoni, S., Kudryashova, K. S., Burka, K., & de Magalhães, J. P. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101410 · Cited by 227 · see citing works
“Apart from B-1 changes in number, their ability to secrete IgM is highly impaired, implicating them in increased susceptibility to infection and reduced quality of life (Holodick and Rothstein, 2015; Rodriguez-Zhurbenko et al., 2019).”
Dysbiosis, malnutrition and enhanced gut-lung axis contribute to age-related respiratory diseases
Saint‐Criq, V., Lugo‐Villarino, G., & Thomas, M. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101235 · Cited by 143 · see citing works
“Immunosenescence also impairs B cell development at all stages, leading to a net reduction of the total numbers and diversity of immature B cells (Holodick and Rothstein, 2015).”
Background
Adaptive immune cells shape obesity-associated type 2 diabetes mellitus and less prominent comorbidities
Calvo, S. S.-C., Bharath, L. P., Pugh, G. H., SantaCruz-Calvo, L., Lenin, R. R., Lutshumba, J., Liu, R., Bachstetter, A. D., Zhu, B., & Nikolajczyk, B. S. (2021) · Nature Reviews Endocrinology · doi:10.1038/s41574-021-00575-1 · Cited by 141 · see citing works
The role of B-1 cells in inflammation
Aziz, M., Holodick, N. E., Rothstein, T. L., & Wang, P. (2015) · Immunologic Research · doi:10.1007/s12026-015-8708-3 · Cited by 118 · see citing works
Self-citation
Aging and Mesenchymal Stem Cells: Basic Concepts, Challenges and Strategies
Fraile, M., Eiró, N., Costa, L. A., Martín, A., & Vizoso, F. J. (2022) · Biology · doi:10.3390/biology11111678 · Cited by 76 · see citing works
Oxidation-specific epitopes restrain bone formation
Ambrogini, E., Que, X., Wang, S., Yamaguchi, F., Weinstein, R. S., Tsimikas, S., Manolagas, S. C., Witztum, J. L., & Jilka, R. L. (2018) · Nature Communications · doi:10.1038/s41467-018-04047-5 · Cited by 64 · see citing works
Relationship of Autoantibodies to MDA-LDL and ApoB-Immune Complexes to Sex, Ethnicity, Subclinical Atherosclerosis, and Cardiovascular Events
Prasad, A., Clopton, P., Ayers, C. R., Khera, A., de Lemos, J. A., Witztum, J. L., & Tsimikas, S. (2017) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.117.309101 · Cited by 55 · see citing works
Natural Antibodies as Rheostats for Susceptibility to Chronic Diseases in the Aged
Rothstein, T. L. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00127 · Cited by 50 · see citing works
Self-citation
Dysfunctional peripheral T follicular helper cells dominate in people with impaired influenza vaccine responses: Results from the FLORAH study
Pallikkuth, S., de Armas, L. R., Rinaldi, S., George, V. K., Pan, L., Arheart, K. L., Pahwa, R., & Pahwa, S. G. (2019) · PLoS Biology · doi:10.1371/journal.pbio.3000257 · Cited by 44 · see citing works
Stem cell-derived extracellular vesicles: role in oncogenic processes, bioengineering potential, and technical challenges
Ullah, M., Qiao, Y., Concepcion, W., & Thakor, A. S. (2019) · Stem Cell Research & Therapy · doi:10.1186/s13287-019-1468-6 · Cited by 43 · see citing works
The aging lung: microenvironment, mechanisms, and diseases
Wang, Y., Huang, X., Luo, G., Xu, Y., Deng, X., Lin, Y., Wang, Z., Zhou, S., Wang, S., Chen, H., et al. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1383503 · Cited by 46 · see citing works
Neutralization of oxidized phospholipids attenuates age‐associated bone loss in mice
Palmieri, M., Almeida, M., Nookaew, I., Gómez-Acevedo, H., Joseph, T. E., Que, X., Tsimikas, S., Sun, X., Manolagas, S. C., Witztum, J. L., et al. (2021) · Aging Cell · doi:10.1111/acel.13442 · Cited by 34 · see citing works
“Lipid peroxidation and OxPLs increase with age (Barrera et al., 2018; Liu et al., 2013), while the B- 1 cells that produce natural antibodies against OxPLs decline with age in humans (Griffin et al., 2011; Holodick & Rothstein, 2015; Holodick et al., 2016; Rothstein, 2016).”
Background
B-1 plasma cells require non-cognate CD4 T cell help to generate a unique repertoire of natural IgM
Smith, F. L., Savage, H. P., Luo, Z. L., Tipton, C. M., Lee, F. E.-H., Apostol, A. C., Beaudin, A. E., López, D. A., Jensen, I., Keller, S. M., et al. (2023) · The Journal of Experimental Medicine · doi:10.1084/jem.20220195 · Cited by 28 · see citing works
Potential of Mesenchymal Stem Cells in the Rejuvenation of the Aging Immune System
Yeo, G. E. C., Ng, M. H., Nordin, F., & Law, J. X. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115749 · Cited by 27 · see citing works
Does baseline innate immunity change with age? A multi-year study in great tits
Vermeulen, A., Eens, M., Dongen, S. V., & Müller, W. (2017) · Experimental Gerontology · doi:10.1016/j.exger.2017.03.011 · Cited by 26 · see citing works
“In the case of NAbs, it might be that NAbs play a more important role in long lived animals due to the fact that they have an important role in the elimination of autoantigens, which increase in the elderly (Elkon and Casali, 2008; Holodick and Rothstein, 2015).”
The IgH 3′ regulatory region super-enhancer does not control IgA class switch recombination in the B1 lineage
Issaoui, H., Ghazzaui, N., Saintamand, A., Carrion, C., Oblet, C., & Denizot, Y. (2017) · Cellular and Molecular Immunology · doi:10.1038/cmi.2017.103 · Cited by 22 · see citing works
Nfkbie-deficiency leads to increased susceptibility to develop B-cell lymphoproliferative disorders in aged mice
Della-Valle, V., Roos‐Weil, D., Scourzic, L., Mouly, E., Aid, Z., Darwiche, W., Lécluse, Y., Damm, F., Mémet, S., Mercher, T., et al. (2020) · Blood Cancer Journal · doi:10.1038/s41408-020-0305-6 · Cited by 22 · see citing works
IL-21 enhances influenza vaccine responses in aged macaques with suppressed SIV infection
Kvistad, D., Pallikkuth, S., Sirupangi, T., Pahwa, R., Kizhner, A., Petrovas, C., Villinger, F. J., & Pahwa, S. G. (2021) · JCI Insight · doi:10.1172/jci.insight.150888 · Cited by 18 · see citing works
B Lymphocytes in Alzheimer’s Disease—A Comprehensive Review
Plantone, D., Pardini, M., Locci, S., Nobili, F. M., & Stefano, N. D. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-220261 · Cited by 18 · see citing works
Predicting Clinical Dementia Rating Using Blood RNA Levels
Miller, J. B., Kauwe, J. S. K., & Initiative, F. T. A. D. N. (2020) · Genes · doi:10.3390/genes11060706 · Cited by 13 · see citing works
“Although BCL7A has not previously been directly linked to AD, it is known that B cells are impaired throughout the aging process, which likely compromises the immune system [24], and a compromised peripheral”
Background
Distinct organization of adaptive immunity in the long-lived rodent Spalax galili
Izraelson, M., Metsger, M., Davydov, A. N., Shagina, I. A., Dronina, M. A., Obraztsova, A., Miskevich, D. A., Mamedov, I. Z., Volchkova, L. N., Nakonechnaya, T. O., et al. (2021) · Nature Aging · doi:10.1038/s43587-021-00029-3 · Cited by 13 · see citing works
Identification of a Sensitive Human Immunological Target of Aryl Hydrocarbon Receptor Activation: CD5+ Innate-Like B Cells
Blevins, L. K., Zhou, J., Crawford, R. B., & Kaminski, N. E. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.635748 · Cited by 11 · see citing works
ARID3a expression in human hematopoietic stem cells is associated with distinct gene patterns in aged individuals
Ratliff, M., Garton, J. W., James, J. A., & Webb, C. F. (2020) · Immunity & Ageing · doi:10.1186/s12979-020-00198-6 · Cited by 11 · see citing works
Nanoscale therapeutics for erectile dysfunction: a meta-analysis of stem cell-derived extracellular vesicles as natural nanoparticles in diabetic rat models
Lou, K., Hu, J., Tong, J., & Wang, Z. (2025) · Stem Cell Research & Therapy · doi:10.1186/s13287-025-04389-0 · Cited by 8 · see citing works
The immunoglobulin heavy chain 3′ regulatory region superenhancer controls mouse B1 B-cell fate and late VDJ repertoire diversity
Ghazzaui, N., Issaoui, H., Saintamand, A., Oblet, C., Carrion, C., & Denizot, Y. (2018) · Blood Advances · doi:10.1182/bloodadvances.2017014423 · Cited by 8 · see citing works
Impact of Influenza on Pneumococcal Vaccine Effectiveness during Streptococcus pneumoniae Infection in Aged Murine Lung
Jirru, E., Lee, S. F., Harris, R. M., Yang, J., Cho, S. J., & Stout-Delgado, H. W. (2020) · Vaccines · doi:10.3390/vaccines8020298 · Cited by 6 · see citing works
Deletion of the immunoglobulin heavy chain 3′ regulatory region super-enhancer affects somatic hypermutation in B1 B cells
Issaoui, H., Ghazzaui, N., Boyer, F., Denizot, Y., & Saintamand, A. (2018) · Cellular and Molecular Immunology · doi:10.1038/s41423-018-0091-2 · Cited by 7 · see citing works
Inflammatory immune cells may impair the preBCR checkpoint, reduce new B cell production, and alter the antibody repertoire in old age
Riley, R. L., Khomtchouk, K. M., & Blomberg, B. B. (2018) · Experimental Gerontology · doi:10.1016/j.exger.2018.01.023 · Cited by 6 · see citing works
The transcription factor Bcl11a is essential for B-1a cell maintenance during aging
Xu, S., Huang, L., Liu, X., Zhang, L., Wang, J., Hu, Y., Yang, Y., Shi, X., Liu, C., Wang, R., et al. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2501974122 · Cited by 4 · see citing works
“With advancing age, murine B - 1a cells exhibit functional decline, including reduced natural antibody production and diminished capacity for immune surveillance ( 13 , 18 – 20 ).”
Immunoglobulin: unraveling its complex web in aging
Gu, Q., Wang, Y., Zhu, C., Zhou, X., Ni, L., Zhao, H., Huilin, Y., & Shi, Q. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1690018 · Cited by 4 · see citing works
The New Approach to Treating Erectile Dysfunction: Stem Cell-Derived Extracellular Vesicles
Ping, X., Zhou, H., Zhang, Y., Liu, X., Tao, T., Liu, Q., Feng, S., & Lou, K. (2025) · International Journal of Nanomedicine · doi:10.2147/ijn.s547834 · Cited by 3 · see citing works
“33,34 Broadly, SCs-EVs have been found to perform the following functions: (i) promote the survival of hematopoietic stem cells; (ii) activate monocytes, macrophages, and B cells; (iii) enhance the function of CD4+ regulatory T cells; (iv) inhibit the activity of natural killer cells and CD8+…”
Activation of B-1 Cells
Rothstein, T. L., & Holodick, N. E. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-374279-7.09021-4 · Cited by 3 · see citing works
Self-citation
Therapeutic approaches to delay lung aging: understanding cellular and immune system changes in the older adults
Lin, Y., Yan, M., Shen, L., Wang, Y., He, H., Han, Z., Chen, H., & Liu, A. (2025) · The Journals of Gerontology Series A · doi:10.1093/gerona/glaf149 · Cited by 1 · see citing works
Effect of Age on Xenobiotic-Induced AutoimmunityPreprint
de Ocampo, C., Peiss, A. K., Leung, H. Y., Janssen, L., Kono, D. H., Mayeux, J., & Pollard, K. M. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.05.22.655368 · Cited by 1 · see citing works
“This finding is consistent with the impairment of B2 cell development, the expansion of B1 cells, and a shift from a predominantly adaptive immune response to innate immunity that occurs with age [64, 65].”
PD-L2 regulates natural antibody and IL-10 secretion by B-1 cellsPreprint
Amendt, T., Vanes, L., & Tybulewicz, V. L. J. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.11.693708 · Cited by 1 · see citing works
B Cell Repertoire Changes in Mouse Models of Aging
Scholz, J. L., Hao, Y., Quinn, W. J., & Cancro, M. P. (2017) · Springer eBooks · doi:10.1007/978-3-319-64597-1_20-1
B Cell Repertoire Changes in Mouse Models of Aging
Scholz, J. L., Hao, Y., Quinn, W. J., & Cancro, M. P. (2019) · Springer eBooks · doi:10.1007/978-3-319-99375-1_20
Out of the Shell: Exploring The Phagocytic Capabilities of the B Cell and Isolated Lymphoid Follicle-lie Structures in the Red-Eared Slider, Trachemys Scripta
Ashford, M. A. (2018) · doi:10.30707/etd2018.ashford.m
Exploring the reprogramming potential of B cells and comprehending its clinical and therapeutic perspective
Rani, R., Nayak, M., & Nayak, B. (2023) · Transplant Immunology · doi:10.1016/j.trim.2023.101804
The transcription factor Bcl11a is essential for functional B-1a cell maintenance during agingPreprint
Yu, Y., Xu, S., Huang, L., Zhang, L., Wang, J., Hu, Y., Yang, Y., Shi, X., Liu, C., Wang, R., et al. (2024) · Research Square · doi:10.21203/rs.3.rs-4825323/v1
Geriatric-Specific Considerations in the Care of Older Adults with Pulmonary/Respiratory Diseases
Li, A., & Hunold, K. M. (2025) · Emergency Medicine Clinics of North America · doi:10.1016/j.emc.2024.08.012

Human B-1 Cells and B-1 Cell Antibodies Change With Advancing Age
Rodríguez‐Zhurbenko, N., Quách, T. D., Hopkins, T. J., Rothstein, T. L., & Hernández, A. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00483 · Cited by 111 · see citing works
Self-citation
B Cell Immunosenescence
Frasca, 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 226 · see citing works
The association between human B-1 cell frequency and aging: From cord blood to the elderly
Jazayeri, M. H., Pourfathollah, A. A., Jafari, M. E., Rasaee, M. J., & Dargahi, Z. V. (2013) · Biomedicine & Aging Pathology · doi:10.1016/j.biomag.2013.01.001 · Cited by 12 · see citing works
From lymphopoiesis to plasma cells differentiation, the age-related modifications of B cell compartment are influenced by “inflamm-ageing”
Bulati, M., Caruso, C., & Colonna‐Romano, G. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.04.001 · Cited by 113 · see citing works
B1 Cells for Life
Rothstein, T. L. (2026) · Immunological Reviews · doi:10.1111/imr.70160
Self-citation

Authors: Holodick, N. E., & Rothstein, T. L.
Affiliations: Feinstein Institute for Medical Research (US)
Corresponding author: Holodick, Nichol E.
ORCID: Holodick, Nichol E.
Rothstein, Thomas L.
Venue: Annals of the New York Academy of Sciences
Publisher: Wiley
Published: 2015-07-20
Volume: 1362
Issue: 1
Pages: 176-187
ISSN: 0077-8923 (ISSN-L)
1749-6632
DOI: 10.1111/nyas.12825
PMC: PMC4679494
OpenAlex: W1489280917
Cited by: 43
References: 91
Citations by year: 2025: 8 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 7 · 2020: 6 · 2019: 4 · 2018: 5 · 2017: 4 · 2016: 2 · 2015: 1
FWCI: 0.38
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Annals of the New York Academy of Sciences (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute for Health Research (RO1 AI 029690)
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 › Immune Response and Inflammation
Keywords: immunosenescence, B-1 cells, B cells, aging immune system, innate immunity, B cell development, B cell function
MeSH terms: Aging, Animals, Humans, Immunoglobulin M, Immune System, Immunity, Innate, B-Lymphocyte Subsets

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B cells in the aging immune system: time to consider B‐1 cells

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