B Cell Precursors in Bone Marrow: In Vivo Proliferation, Localization, Stimulation by Activated Macrophages and Implications for Oncogenesis

We describe here the development and characterization of the FLS4.1 stromal line derived from 15-day fetal liver of BALB/c embryos and defined culture conditions that efficiently support the cloning and long-term growth of nontransformed B-220+ 14-day fetal liver cells at two stages of B-cell development, namely, pro-B lymphocytes (immunoglobulin [Ig] genes in germ line configuration) and pre-B cells (JH-rearranged genes with both light-chain Ig genes in the germ line state). All B-cell precursor clones require recombinant interleukin-7 (rIL-7) and FLS4.1 stromal cells for continuous growth in culture, but pro-B lymphocyte clones can also proliferate in rIL-3. None proliferate in rIL-1, rIL-2, rIL-4, rIL-5, rIL-6, or leukemia inhibitory factor. FLS4.1 stromal cells synthesize mRNA for Steel factor but not for IL-1 to IL-7; all pro-B and pre-B clones express c-Kit, the receptor for Steel factor, and a c-Kit-specific antibody inhibits the enhanced proliferative response of fetal liver B-220+ B-cell precursors supported by FLS4.1 stromal cells and exogenous rIL-7 but does not affect that promoted by rIL-7 alone. Northern (RNA) blot analysis of the expression of the MB-1, lambda 5, Vpre-B, c mu, RAG-1, and RAG-2 genes in pro-B and pre-B clones show that transcription of the MB-1 gene precedes IgH gene rearrangement and RNA synthesis from c mu, RAG-1, RAG-2, lambda 5, and Vpre-B genes. All clones at the pre-B-cell stage synthesize mRNA for c mu, RAG-1, and RAG-2 genes; transcription of the lambda 5 and Vpre-B genes seems to start after D-to-JH rearrangement in B-cell precursors, indicating that the proteins encoded by either gene are not required for B-cell progenitors to undergo D-to-JH gene rearrangement. These findings mark transcription of the MB-1 gene as one of the earliest molecular events in commitment to develop along the B-lymphocyte pathway. Indeed, both pro-B and pre-B clones can generate in vitro and in vivo B lymphocytes but not T lymphocytes; moreover, these clones do not express the CD3-gamma T-cell-specific gene, nor do they have rearranged gamma, delta, or beta T-cell antigen receptor genes.

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In Vivo Tungsten Exposure Alters B-Cell Development and Increases DNA Damage in Murine Bone Marrow

Toxicological Sciences ◽

10.1093/toxsci/kfs324 ◽

2012 ◽

Vol 131 (2) ◽

pp. 434-446 ◽

Cited By ~ 46

Author(s):

Alexander D. R. Kelly ◽

Maryse Lemaire ◽

Yoon Kow Young ◽

Jules H. Eustache ◽

Cynthia Guilbert ◽

...

Keyword(s):

Bone Marrow ◽

Dna Damage ◽

B Cell ◽

Cell Development ◽

B Cell Development ◽

Murine Bone Marrow

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Benign B-Cell Precursors (Hematogones) Are the Predominant Lymphoid Population in the Bone Marrow of Preterm Infants

Neonatology ◽

10.1159/000079907 ◽

2004 ◽

Vol 86 (4) ◽

pp. 247-253 ◽

Cited By ~ 11

Author(s):

Lisa M. Rimsza ◽

Vonda K. Douglas ◽

Patrick Tighe ◽

Matthew A. Saxonhouse ◽

Darlene A. Calhoun ◽

...

Keyword(s):

Bone Marrow ◽

B Cell ◽

Preterm Infants ◽

B Cell Precursors

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In vivo tracking of transplanted macrophages with near infrared fluorescent dye reveals temporal distribution and specific homing in the liver that can be perturbed by clodronate liposomes

PLoS ONE ◽

10.1371/journal.pone.0242488 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0242488

Author(s):

Satoshi Nishiwaki ◽

Shigeki Saito ◽

Kyosuke Takeshita ◽

Hidefumi Kato ◽

Ryuzo Ueda ◽

...

Keyword(s):

Bone Marrow ◽

Normal State ◽

Near Infrared ◽

Temporal Distribution ◽

Organ Damage ◽

The Other ◽

Acquired Immunity ◽

Activated Macrophages ◽

Clodronate Liposomes

Macrophages play an indispensable role in both innate and acquired immunity, while the persistence of activated macrophages can sometimes be harmful to the host, resulting in multi-organ damage. Macrophages develop from monocytes in the circulation. However, little is known about the organ affinity of macrophages in the normal state. Using in vivo imaging with XenoLight DiR®, we observed that macrophages showed strong affinity for the liver, spleen and lung, and weak affinity for the gut and bone marrow, but little or no affinity for the kidney and skin. We also found that administered macrophages were still alive 168 hours after injection. On the other hand, treatment with clodronate liposomes, which are readily taken up by macrophages via phagocytosis, strongly reduced the number of macrophages in the liver, spleen and lung.

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The influence of a dosage regimen of dexamethasone on detection of normal B-cell precursors in the bone marrow of children with BCP-ALL at the end of induction therapy

Pediatric Hematology/Oncology and Immunopathology ◽

10.24287/1726-1708-2020-19-1-53-57 ◽

2020 ◽

Vol 19 (1) ◽

pp. 53-57

Author(s):

E. V. Mikhailova ◽

T. Yu. Verzhbitskaya ◽

J. V. Roumiantseva ◽

O. I. Illarionova ◽

A. A. Semchenkova ◽

...

Keyword(s):

Bone Marrow ◽

Flow Cytometry ◽

B Cell ◽

Induction Therapy ◽

Therapy Group ◽

Lymphoblastic Leukemia ◽

Leukemic Cells ◽

Intermittent Therapy ◽

Continuous Therapy ◽

B Cell Precursors

Minimal residual disease (MRD) monitoring by flow cytometry at the end of induction therapy is one of the key ways of a prognosis assessment in patients with acute lymphoblastic leukemia (ALL). In B-cell precursor ALL (BCP–ALL), this method of MRD detection is complicated due to the immunophenotypic similarity between leukemic cells and normal B-cell precursors (BCPs). A decrease in intensity of induction therapy can lead to a more frequent appearance of normal BCPs in the bone marrow, which significantly complicates the MRD monitoring. Aim: to assess the incidence of normal BCPs in bone marrow on the 36th day of induction therapy with two different regimens of glucocorticoid (GC) administration according to ALL-MB 2015 protocol. This study was approved by the Independent Ethical Committee and the Academic Council of Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology, Immunology Ministry of Healthcare of Russian Federation. The study included 220 patients with BCP-ALL who were randomized to two types of GC-based induction therapy: a continuous administration of dexamethasone (n = 139) and an intermittent regimen with a 1-week dexamethasone therapy stop (n = 81). On the 36th day of induction therapy, MRD and normal BCPs were quantified in bone marrow samples by flow cytometry. On the 36th day of treatment, 43.2% of BCP(+) samples were established in the intermittent-therapy group, and 27.3% in the continuous-therapy group (p = 0.016). Comparison of the BCP level in BCP(+) samples revealed the more equitable distribution of BCPs at different developmental stages in the intermittent-therapy group, meanwhile mainly the immature BCPs in a quantity of less than 0.01% were found in the continuous-therapy group. Reduced-intensity induction therapy for patients with BCP-ALL leads to a noticeable increase of normal BCPs in bone marrow at the end of this treatment stage. A higher rate of BCP(+) bone marrow samples hinder the MRD detection due to the immunophenotypic similarity of BCPs and leukemic cells.

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Antigen-Specific B Cell Memory

Journal of Experimental Medicine ◽

10.1084/jem.191.7.1149 ◽

2000 ◽

Vol 191 (7) ◽

pp. 1149-1166 ◽

Cited By ~ 135

Author(s):

Louise J. McHeyzer-Williams ◽

Melinda Cool ◽

Michael G. McHeyzer-Williams

Keyword(s):

Bone Marrow ◽

B Cells ◽

B Cell ◽

Memory B Cells ◽

Cell Memory ◽

Specific Memory ◽

B Cell Memory ◽

Cellular Components

The mechanisms that regulate B cell memory and the rapid recall response to antigen remain poorly defined. This study focuses on the rapid expression of B cell memory upon antigen recall in vivo, and the replenishment of quiescent B cell memory that follows. Based on expression of CD138 and B220, we reveal a unique and major subtype of antigen-specific memory B cells (B220−CD138−) that are distinct from antibody-secreting B cells (B220+/−CD138+) and B220+CD138− memory B cells. These nonsecreting somatically mutated B220− memory responders rapidly dominate the splenic response and comprise >95% of antigen-specific memory B cells that migrate to the bone marrow. By day 42 after recall, the predominant quiescent memory B cell population in the spleen (75–85%) and the bone marrow (>95%) expresses the B220− phenotype. Upon adoptive transfer, B220− memory B cells proliferate to a lesser degree but produce greater amounts of antibody than their B220+ counterparts. The pattern of cellular differentiation after transfer indicates that B220− memory B cells act as stable self-replenishing intermediates that arise from B220+ memory B cells and produce antibody-secreting cells on rechallenge with antigen. Cell surface phenotype and Ig isotype expression divide the B220− compartment into two main subsets with distinct patterns of integrin and coreceptor expression. Thus, we identify new cellular components of B cell memory and propose a model for long-term protective immunity that is regulated by a complex balance of committed memory B cells with subspecialized immune function.

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B lymphocytes express and lose syndecan at specific stages of differentiation.

Cell Regulation ◽

10.1091/mbc.1.1.27 ◽

1989 ◽

Vol 1 (1) ◽

pp. 27-35 ◽

Cited By ~ 272

Author(s):

R D Sanderson ◽

P Lalor ◽

M Bernfield

Keyword(s):

Bone Marrow ◽

B Cells ◽

B Cell ◽

B Lymphocytes ◽

B Lymphocyte ◽

Plasma Cells ◽

Receptor Expression ◽

Cell Stage ◽

Precursor B Cells

Lymphopoietic cells require interactions with bone marrow stroma for normal maturation and show changes in adhesion to matrix during their differentiation. Syndecan, a heparan sulfate-rich integral membrane proteoglycan, functions as a matrix receptor by binding cells to interstitial collagens, fibronectin, and thrombospondin. Therefore, we asked whether syndecan was present on the surface of lymphopoietic cells. In bone marrow, we find syndecan only on precursor B cells. Expression changes with pre-B cell maturation in the marrow and with B-lymphocyte differentiation to plasma cells in interstitial matrices. Syndecan on B cell precursors is more heterogeneous and slightly larger than on plasma cells. Syndecan 1) is lost immediately before maturation and release of B lymphocytes into the circulation, 2) is absent on circulating and peripheral B lymphocytes, and 3) is reexpressed upon their differentiation into immobilized plasma cells. Thus, syndecan is expressed only when and where B lymphocytes associate with extracellular matrix. These results indicate that B cells differentiating in vivo alter their matrix receptor expression and suggest a role for syndecan in B cell stage-specific adhesion.

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