B cell maturation and selection at the marrow-periphery interface

Cancro, Michael P.; Allman, David; Hayes, Colleen E.; Lentz, Vicky M.; Fields, Ryan G.; Sah, Alex P.; Tomayko, Mary M.

doi:10.1007/bf02786425

Cited by 25 publications

(24 citation statements)

References 43 publications

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“…7,9,10 Hence, this feedback mechanism may develop with age and may not be relevant to young mice used in the earlier studies. [21][22][23]34 We show here that, when long-lived B cells do not accumulate, B lymphopoiesis does not decrease significantly with age. Moreover, on elimination of peripheral B cells in aged mice, B lymphopoiesis in the BM is reactivated, indicating that the long-lived peripheral B cells mediate the age-related alterations in B lymphopoiesis.…”

mentioning

confidence: 56%

“…This hypothesis stems from earlier studies showing that B lymphopoiesis in the BM of young/adult mice is enhanced after ablating the peripheral B-cell compartment by sublethal irradiation. [21][22][23] A major implication of this hypothesis is that the potential to reactivate B lymphopoiesis exists in old mice, and the recent identification of a subpopulation of HSCs in the BM of old mice that retains an equivalent potential to differentiate into lymphoid and myeloid lineages 24 supports this. Hence, the present study attempts to test the second hypothesis and to determine whether aging in the B lineage is mediated by the accumulating long-lived B cells.…”

Section: Introductionmentioning

confidence: 98%

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

Zohar

Naor

Nussbaum

et al. 2011

Blood

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IntroductionThe aging of the immune system involves many physiologic changes that are collectively referred to as immune senescence. These changes affect both the innate and the adaptive immune system, often resulting in an immunodeficient state that is currently incompletely understood. The most important immunologic manifestations in aging include poor responsiveness to new or evolving pathogens and reduced efficacy of vaccination. 1,2 Primary causes of this immune incompetence are the decline in production of naive lymphocytes in the bone marrow (BM) and thymus, and the expansion and increased survival of antigen-experienced memory lymphocytes. The outcome of these changes is a marked reduction in the diversity of the peripheral B-cell repertoire and in the capacity of the body to mount protective antibody responses. [3][4][5][6][7] Most attempts to enhance vaccination efficacy in aging are based on improving the delivery of antigen but have yielded limited success. 8 Thus, although generation of a memory compartment constitutes an essential process for the function of the immune system throughout life, the expansion of this compartment in aging limits the ability of the immune system to respond to new antigenic challenges.The B lineage undergoes dramatic age-related alterations in its cellular composition. Old mice show a marked decrease in the frequency of precursor B cells and in B-cell production in the BM, whereas in the periphery there is a significant reduction in naive follicular B cells, reduction in B cell diversity, and accumulation of long-lived antigen-experienced B cells. 7,9,10 In addition, intrinsic defects have been shown in the response of B cells from aged mice or humans, including: decreased class switch recombination and expression of activation induced cytidine deaminase and E47, 11 reduced activation and expression of phosphotyrosine kinases and protein kinase C, 12 decreased expansion of B cells in response to antigen, 13 and reduced number and volume of germinal centers. 14 These findings may explain why in aging the antibody response to new antigens is poor in quality and in quantity.The mechanisms underlying the cellular alterations in aging are unclear. Most existing data support the idea that hematopoietic stem cells (HSCs) acquire intrinsic defects with aging that suppress B lymphopoiesis. [15][16][17][18][19] Accordingly, the peripheral B-cell compartment adapts to these changes by accumulating long-lived cells, thus maintaining the peripheral B-cell numbers unchanged. 20 Another hypothesis is that age-related alterations in the B lineage are mediated by the accumulation of long-lived peripheral B cells with age, which suppresses B lymphopoiesis in the BM. This hypothesis stems from earlier studies showing that B lymphopoiesis in the BM of young/adult mice is enhanced after ablating the peripheral B-cell compartment by sublethal irradiation. [21][22][23] A major implication of this hypothesis is that the potential to reactivate B lymphopoiesis exists in old mice, and the recent ...

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mentioning

confidence: 56%

Section: Introductionmentioning

confidence: 98%

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

Zohar

Naor

Nussbaum

et al. 2011

Blood

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“…When B-cell purification was performed, B cells were purified by negative selection with the magnetically activated cell sorting (MACS) B-cell purification kit (Miltenyi Biotech). For comparison of NF-B regulation in transitional B cells between the wild-type and BAFF receptor mutant backgrounds, autoreconstitution studies were initiated by subjecting A/J and AW.Bcmd-2 c mice to 500 rads of sublethal irradiation in order to deplete mature splenic B cells (5). Irradiated mice were then allowed to recover for 13 days, at which point the majority of splenic B cells represented the transitional B cells, as revealed by positive surface staining of C1qRp (previously termed 493 and AA4) (1) and analyzed on a FACScan or FACScalibur using CELLQuest software (data not shown).…”

Section: Methodsmentioning

confidence: 99%

Regulation of Constitutive p50/c-Rel Activity via Proteasome Inhibitor-Resistant IκBα Degradation in B Cells

O’Connor

Shumway

Amanna

et al. 2004

Molecular and Cellular Biology

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Constitutive NF-B activity has emerged as an important cell survival component of physiological and pathological processes, including B-cell development. In B cells, constitutive NF-B activity includes p50/c-Rel and p52/RelB heterodimers, both of which are critical for proper B-cell development. We previously reported that WEHI-231 B cells maintain constitutive p50/c-Rel activity via selective degradation of IB␣ that is mediated by a proteasome inhibitor-resistant, now termed PIR, pathway. Here, we examined the mechanisms of PIR degradation by comparing it to the canonical pathway that involves IB kinase-dependent phosphorylation and ␤-TrCP-dependent ubiquitylation of the N-terminal signal response domain of IB␣. We found a distinct consensus sequence within this domain of IB␣ for PIR degradation. Chimeric analyses of IB␣ and IB␤ further revealed that the ankyrin repeats of IB␣, but not IB␤, contained information necessary for PIR degradation, thereby explaining IB␣ selectivity for the PIR pathway. Moreover, we found that PIR degradation of IB␣ and constitutive p50/c-Rel activity in primary murine B cells were maintained in a manner different from B-cell-activating-factor-dependent p52/RelB regulation. Thus, our findings suggest that nonconventional PIR degradation of IB␣ may play a physiological role in the development of B cells in vivo.NF-B is a family of transcription factors that regulate diverse cellular functions in response to a wide range of stimuli (19). NF-B is typically found as a homo-or heterodimer of p50 (NFB1), p52 (NFB2), RelA (p65), RelB, or c-Rel. Regulation of NF-B is mediated by a family of inhibitor molecules called IB proteins, including IB␣, IB␤, IBε, IB␥/p105, IB␦/p100, and Bcl-3. Most IB proteins associate with NF-B dimers to cause their localization in the cytoplasm. Upon activation by a wide variety of structurally and functionally distinct signals, NF-B dimers regulate the expression of a multitude of genes important for cell survival, inflammatory responses, and immune cell development (31). Thus, the NF-B system serves as an important paradigm for understanding how distinct signals activate gene expression via activation of signal transduction pathways.Inducible NF-B activation through IB␣ degradation has been studied extensively and is identified by several hallmark traits (reviewed in reference 19). Most cell types contain inactive NF-B/IB␣ complexes in their cytoplasm. Upon stimulation with a variety of inducers, including tumor necrosis factor alpha (TNF-␣), bacterial lipopolysaccharide (LPS), and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), IB␣ is phosphorylated by the IB kinase (IKK) complex on the N-terminal residues Ser32 and Ser36 (14, 38). Dually phosphorylated IB␣ is directly recognized by the E3 ligase ␤-transducin repeat-containing protein (␤-TrCP) (60,70,71). Polyubiquitin chain formation on Lys21 and/or Lys22 of IB␣ is then catalyzed by ␤-TrCP and leads to 26S proteasome-dependent degradation of IB␣ and the release of free NF-B heterodimers to direct...

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“…To more carefully examine this, we performed autoreconstitution experiments in which mice were sublethally irradiated to remove peripheral B cells, followed by analyses of the timing of regeneration of peripheral B cell numbers. This assay has been well characterized in terms of the kinetics of peripheral B cell reconstitution, which begins approximately 11 days post-irradiation and is largely achieved by 14 days [11]. There was no difference in kinetics of B cell reconstitution between Vk2-Ik7tg mice and their nontransgenic littermates (Fig.…”

Section: Construction and Expression Of The Ik-7 Transgene In B Cellsmentioning

confidence: 98%

“…The following antibodies were used: anti-CD4 (GK1.5), anti-CD8 (53-6.7), anti-TCRb (H57-597), anti-CD69 (H1-2F3), anti-CD45R/B220 (RA3-6B2), anti-CD62L (MEL-14), anti-CD44 (IM7), anti-IgD (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26), anti-IgM (II/41), anti-MHC class II (M5/114.15.2), anti-CD138,anti-CD22.2 (Cy34.1, BD Pharmingen), anti-CD21 (7G6, BD Pharmingen) and anti-CD23 (B3B4, BD Pharmingen). All antibodies were purchased from eBioscience unless otherwise stated.…”

Section: Antibodies For Flow Cytometric Analysesmentioning

confidence: 99%

Expression of a non‐DNA‐binding Ikaros isoform exclusively in B cells leads to autoimmunity but not leukemogenesis

et al. 2007

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Ikaros is a transcriptional regulator whose function is essential for B cell development. It is expressed in the hematopoietic stem cell (HSC) through the mature B cell stage. Using genetically engineered mice in which the endogenous Ikaros gene is disrupted, it has been shown that a lack of Ikaros leads to a block in B cell development and that its severe diminution results in a hyperresponsive B cell compartment. Ikaros expression within the HSC has led to speculation as to whether the role of Ikaros in B cell biology is largely accomplished prior to B cell specification. In addition, widespread expression of Ikaros in hematopoietic cells leads to the possibility that some or all of the observed defects are not B cell autonomous. In this report, we demonstrate that over-expression of a dominant interfering Ikaros isoform exclusively in B cells has profound effects on mature B cell function. We provide evidence that continued high-level expression of Ikaros is essential for homeostasis of peripheral lymphocytes and maintenance of B cell tolerance. We also show that deregulation of Ikaros activity does not rapidly result in B cell leukemogenesis as it does with 100% penetrance within the T cell lineage.

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B cell maturation and selection at the marrow-periphery interface

Cited by 25 publications

References 43 publications

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

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

Regulation of Constitutive p50/c-Rel Activity via Proteasome Inhibitor-Resistant IκBα Degradation in B Cells

Expression of a non‐DNA‐binding Ikaros isoform exclusively in B cells leads to autoimmunity but not leukemogenesis

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