B-cell depletion reactivates B lymphopoiesis in the BM and rejuvenates the B lineage in aging

Zohar, Keren; Naor, Shulamit; Nussbaum, Shahar; Golan, Karin; Itkin, Tomer; Sasaki, Yoshiyuki; Schmidt-Supprian, Marc; Lapidot, Tsvee; Melamed, Doron

doi:10.1182/blood-2010-09-307983

Cited by 83 publications

(91 citation statements)

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“…Recently, we showed that depletion of peripheral B cells in old mice reactivates B lymphopoiesis in the BM, thereby supporting the argument that reduction of B lymphopoiesis with aging is an adaptive homeostatic response to the accumulation of long-lived memory B cells in the periphery (19,20). The results shown here further support this argument by showing that in mutated mice, where long-lived B cells do not accumulate, B lymphopoiesis does not significantly change with age, and a high output of B cells from the BM is maintained in aging.…”

Section: Discussionsupporting

confidence: 63%

“…It is important to note that the use of the 3-83Tg model has some disadvantages for repertoire analysis due to the nature of selection and expansion of Tg and non-Tg variant B cells. Thus, although this approach is well accepted (2,10,20), it would be important to confirm these results in a non-Tg system in future studies.…”

Section: Discussionmentioning

confidence: 86%

“…Recently, we showed that depletion of peripheral B cells in old mice stimulated expansion of early progenitors in the BM to reactivate B lymphopoiesis in old mice (20). This study indicated that aging of the B lineage is a reversible process that is subjected to homeostatic regulation.…”

mentioning

confidence: 88%

“…To confirm this, we studied the kinetics of B cell output from the BM. To do so, old and young mice that are either wt or CD19 2/2 were injected with a mixture of Abs to deplete the B cells in vivo and were then followed for reconstitution of the peripheral B cell compartment by analyzing PB samples over time, as we have described (20). The results in Fig.…”

Section: B Lymphopoiesis Does Not Decline In Old Mice With Impaired Bmentioning

confidence: 99%

“…Ab-mediated B cell depletion was performed as we have described (20). Briefly, mice were injected i.p.…”

Section: Depletion Of B Cellsmentioning

confidence: 99%

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Chronic B Cell Deficiency from Birth Prevents Age-Related Alterations in the B Lineage

Zohar

Averbuch

Shahaf

et al. 2011

The Journal of Immunology

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Aging is accompanied by a decline in B lymphopoiesis in the bone marrow and accumulation of long-lived B cells in the periphery. The mechanisms underlying these changes are unclear. To explore whether aging in the B lineage is subjected to homeostatic regulation, we used mutant mice bearing chronic B cell deficiency from birth. We show that chronic B cell deficiency from birth, resulting from impaired maturation (CD19−/− and CD74−/−) or reduced survival (baff-r−/−), prevents age-related changes in the B lineage. Thus, frequencies of early and late hematopoietic stem cells, B lymphopoiesis, and the rate of B cell production do not substantially change with age in these mice, as opposed to wild-type mice where kinetic experiments indicate that the output from the bone marrow is impaired. Further, we found that long-lived B cells did not accumulate and peripheral repertoire was not altered with age in these mice. Collectively, our results suggest that aging in the B lineage is not autonomously progressing but subjected to homeostatic regulation.

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 86%

mentioning

confidence: 88%

Section: B Lymphopoiesis Does Not Decline In Old Mice With Impaired Bmentioning

confidence: 99%

“…Ab-mediated B cell depletion was performed as we have described (20). Briefly, mice were injected i.p.…”

Section: Depletion Of B Cellsmentioning

confidence: 99%

See 3 more Smart Citations

Chronic B Cell Deficiency from Birth Prevents Age-Related Alterations in the B Lineage

Zohar

Averbuch

Shahaf

et al. 2011

The Journal of Immunology

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Aging affects B‐cell antigen receptor repertoire diversity in primary and secondary lymphoid tissues

et al. 2015

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The elderly immune system is characterized by reduced responses to infections and vaccines, and an increase in the incidence of autoimmune diseases and cancer. Age-related deficits in the immune system may be caused by peripheral homeostatic pressures that limit bone marrow B-cell production or migration to the peripheral lymphoid tissues. Studies of peripheral blood B-cell receptor spectratypes have shown that those of the elderly are characterized by reduced diversity, which is correlated with poor health status. In the present study, we performed for the first time high-throughput sequencing of immunoglobulin genes from archived biopsy samples of primary and secondary lymphoid tissues in old (74 ± 7 years old, range 61-89) versus young (24 ± 5 years old, range 18-45) individuals, analyzed repertoire diversities and compared these to results in peripheral blood. We found reduced repertoire diversity in peripheral blood and lymph node repertoires from old people, while in the old spleen samples the diversity was larger than in the young. There were no differences in somatic hypermutation characteristics between age groups. These results support the hypothesis that age-related immune frailty stems from altered B-cell homeostasis leading to narrower memory B-cell repertoires, rather than changes in somatic hypermutation mechanisms. Keywords:Aging r B cells r Bone marrow r Immunoglobulin repertoire r Secondary lymphoid tissues Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe age-related changes in the structure and function of the immune system are usually manifested as increased susceptibility Correspondence: Prof. Ramit Mehr e-mail: ramit.mehr@biu.ac.il to infections (both primary and secondary responses) and cancers, poor responsiveness to new or evolving pathogens, reduced efficacy of vaccination and increased incidence of autoimmune diseases [1][2][3][4][5]. This results in increased disease burdens and health- * These authors contributed equally to this work. * * These authors contributed equally to this work as senior authors.C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2016. 46: 480-492 Molecular immunology 481 care costs [3,6,7]. Intrinsic changes in primary and secondary lymphoid tissue function, including hematopoietic stem cells in the bone-marrow (BM), are associated with aging. Literature on immunosenescence has focused mainly on T-lineage impairments, as thymus involution is probably the most well-studied age-related immune dysfunction. In addition, there are age-related defects in the ability of CD4 + and CD8 + T cells to respond to T-cell receptor engagement, a propensity of CD4 + cells to differentiate into Th17 cells at the expense of Th1 and Th2 differentiation and an increase in regulatory T-cell numbers and function [4,8].In the B-cell lineage, changes were observed in the composition of B-cell subtypes in both BM and periphery that may result from increased B-cell longe...

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Understanding the Mechanisms of Immune System Aging: Immune System Cell Development and Antibody Repertoires

Shahaf

Hazanov

Averbuch

et al. 2014

International Perspectives on Aging

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B-cell depletion reactivates B lymphopoiesis in the BM and rejuvenates the B lineage in aging

Cited by 83 publications

References 50 publications

Chronic B Cell Deficiency from Birth Prevents Age-Related Alterations in the B Lineage

Chronic B Cell Deficiency from Birth Prevents Age-Related Alterations in the B Lineage

Aging affects B‐cell antigen receptor repertoire diversity in primary and secondary lymphoid tissues

Understanding the Mechanisms of Immune System Aging: Immune System Cell Development and Antibody Repertoires

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