scholarly journals TP53INP1 deficiency maintains murine B lymphopoiesis in aged bone marrow through redox-controlled IL-7R/STAT5 signaling

2018 ◽  
Vol 116 (1) ◽  
pp. 211-216 ◽  
Author(s):  
Bochra Zidi ◽  
Christelle Vincent-Fabert ◽  
Laurent Pouyet ◽  
Marion Seillier ◽  
Amelle Vandevelde ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Immune Cell ◽  
B Lymphopoiesis ◽  
Hematopoietic Stem ◽  
Chronic Oxidative Stress ◽  
The Impact ◽  
Deficient Mice

Bone marrow (BM) produces all blood and immune cells deriving from hematopoietic stem cells (HSCs). The decrease of immune cell production during aging is one of the features of immunosenescence. The impact of redox dysregulation in BM aging is still poorly understood. Here we use TP53INP1-deficient (KO) mice endowed with chronic oxidative stress to assess the influence of aging-associated redox alterations in BM homeostasis. We show that TP53INP1 deletion has no impact on aging-related accumulation of HSCs. In contrast, the aging-related contraction of the lymphoid compartment is mitigated in TP53INP1 KO mice. B cells that accumulate in old KO BM are differentiating cells that can mature into functional B cells. Importantly, this phenotype results from B cell-intrinsic events associated with defective redox control. Finally, we show that oxidative stress in aged TP53INP1-deficient mice maintains STAT5 expression and activation in early B cells, driving high Pax5 expression, which provides a molecular mechanism for maintenance of B cell development upon aging.

scholarly journals Roles of activating functions 1 and 2 of estrogen receptor α in lymphopoiesis

2018 ◽  
Vol 236 (2) ◽  
pp. 99-109 ◽  
Author(s):  
Annica Andersson ◽  
Anna E Törnqvist ◽  
Sofia Moverare-Skrtic ◽  
Angelina I Bernardi ◽  
Helen H Farman ◽  
...  
Keyword(s):  
Immune System ◽  
B Cells ◽  
Estrogen Receptors ◽  
B Cell ◽  
Sex Steroids ◽  
Cellular Response ◽  
Immune Cell ◽  
Cell Development ◽  
B Lymphopoiesis ◽  
The Impact

Apart from the role of sex steroids in reproduction, sex steroids are also important regulators of the immune system. 17β-estradiol (E2) represses T and B cell development, but augments B cell function, possibly explaining the different nature of immune responses in men and women. Both E2 and selective estrogen receptors modulators (SERM) act via estrogen receptors (ER). Activating functions (AF)-1 and 2 of the ER bind to coregulators and thus influence target gene transcription and subsequent cellular response to ER activation. The importance of ERαAF-1 and AF-2 in the immunomodulatory effects of E2/SERM has previously not been reported. Thus, detailed studies of T and B lymphopoiesis were performed in ovariectomized E2-, lasofoxifene- or raloxifene-treated mice lacking either AF-1 or AF-2 domains of ERα, and their wild-type littermate controls. Immune cell phenotypes were analyzed with flow cytometry. All E2 and SERM-mediated inhibitory effects on thymus cellularity and thymic T cell development were clearly dependent on both ERαAFs. Interestingly, divergent roles of ERαAF-1 and ERαAF-2 in E2 and SERM-mediated modulation of bone marrow B lymphopoiesis were found. In contrast to E2, effects of lasofoxifene on early B cells did not require functional ERαAF-2, while ERαAF-1 was indispensable. Raloxifene reduced early B cells partly independent of both ERαAF-1 and ERαAF-2. Results from this study increase the understanding of the impact of ER modulation on the immune system, which can be useful in the clarification of the molecular actions of SERMs and in the development of new SERM.

Mobilizing Agents G-CSF, Cyclophosphamide or AMD3100 (Plerixafor) Have Distinct Effects on Osteoblasts, Hematopoietic Stem Cell Niches, and B-Lymphopoiesis,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4005-4005
Author(s):  
Jean-Pierre Levesque ◽  
Linda J. Bendall ◽  
Allison R Pettit ◽  
Liza Raggatt ◽  
Rebecca Jacobsen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
B Cells ◽  
Bone Formation ◽  
B Cell ◽  
Hematopoietic Stem Cell ◽  
B Lymphopoiesis ◽  
Hematopoietic Stem ◽  
Kit Ligand ◽  
Angiopoietin 1

Abstract Abstract 4005 The CXCR4 antagonist AMD3100 is progressively replacing cyclophosphamide as adjuvant to G-CSF to mobilize hematopoietic stem cells (HSC) for autologous transplants in patients who failed prior mobilization with G-CSF alone. We and others have recently demonstrated that G-CSF-induced mobilization and the associated response of HSC niches and bone formation depend on bone marrow (BM) macrophages1–3. Moreover medullar B lymphopoiesis is dependent on bone-forming osteoblasts in vivo. We therefore compared the effects of these three mobilizing agents (6 day course of G-CSF, versus a single injection of cyclophosphamide, versus 6 day course of AMD3100) on endosteal osteoblasts, bone formation, BM macrophages, expression of HSC-supportive cytokines and B lymphopoiesis in the mouse. G-CSF administration significantly reduced the number of endosteal osteoblasts and niche-supporting macrophages. G-CSF also inhibited expression of chemokines and cytokines such as CXCL12, Kit-ligand, angiopoietin-1 and IL-7 in the endosteal region resulting in a profound inhibition of medullar B lymphopoiesis with suppression of pre-pro-B, pro-B, pre-B cells and mature sIgM+ B cells as long as G-CSF was administered and HSC mobilization persisted. Cyclophosphamide also suppressed osteoblasts, niche-supportive macrophages and inhibited endosteal expression of CXCL12 and angiopoietin-1 but did not inhibit KIT-ligand expression. Of note, the down-regulation of CXL12 was more pronounced in response to cyclophosphamide than G-CSF. This could explain the higher mobilizing effect of cyclophosphamide. In contrast to G-CSF, medullar B lymphopoiesis rebounded in synchrony with endosteal IL-7 expression during cyclophosphamide-induced mobilization despite persistent suppression of osteoblasts and bone formation. Despite a marked rebound in the number of immature B cell progenitors in cyclophosphamide-mobilized BM, B cell progenitors could not mature into sIgM+ B cells which remained very depressed in BM, spleen and blood even 10 days after a single cyclophosphamide injection. Finally, while AMD3100 was effective at mobilizing HSC, it did not suppress osteoblasts, cytokine expression at the endosteum or B lymphopoiesis. In conclusion, although G-CSF, cyclophosphamide and AMD3100 efficiently mobilize HSC into the blood, their effects on HSC niches, bone formation and B lymphopoiesis are distinct. Furthermore the contrasted effects of G-CSF, cyclophosphamide and AMD3100 on medullar B lymphopoiesis indicates that grafts mobilized with these three agents may have different immune properties. (1) Winkler IG, Sims NA, Pettit AR, et al. Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs. Blood. 2010;116(23):4815–4828. (2) Christopher MJ, Rao M, Liu F, Woloszynek JR, Link DC. Expression of the G-CSF receptor in monocytic cells is sufficient to mediate hematopoietic progenitor mobilization by G-CSF in mice. J Exp Med 2011;208(2):251–260. (3) Chow A, Lucas D, Hidalgo A, et al. Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. J Exp Med 2011;208(2):261–271. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Transcriptional Repressor Gfi-1 Integrates Cytokine-Receptor Signals Controlling B Cell Differentiation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 204-204 ◽  
Author(s):  
Chozhavendan Rathinam ◽  
Christoph Klein
Keyword(s):  
Bone Marrow ◽  
Transcription Factors ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
B Cell Development ◽  
B Cell Differentiation ◽  
Rt Pcr ◽  
Hematopoietic Stem ◽  
Deficient Mice

Abstract Hematopoietic stem cell differentiation is specified by cytokines and transcription factors but the mechanisms controlling instructive and permissive signalling networks are poorly understood. We provide evidence that common lymphoid progenitor (CLP)-1-dependent IL7-receptor mediated B cell differentiation is critically controlled by the transcriptional repressor Gfi1. Gfi1 is expressed selectively in CLP1 but not in CLP2 cells. Furthermore, in Gfi1-deficient hematopoiesis, CLP1 cells are significantly reduced, while CLP2 cells are present in normal numbers. Hardy fractions B/C, proposed to represent IL7-sensitive stages of early B cell development, are also reduced in Gfi1-deficient bone marrow. In contrast to bone marrow B cells, the phenotype of Gfi1-deficient thymic B cells was comparable to wildtype mice, suggesting that IL7-mediated signalling is perturbed. This hypothesis was further substantiated by a side-by-side comparison of Gfi1- and IL7-deficient mice; both knockout mice revealed a similar B cell phenotype in bone marrow and thymus. In vitro, Gfi1-deficient Sca1+ckit+lin- hematopoietic stem cells did not differentiate into B220+IgM+ B cells in the presence of SCF and IL7, suggesting that instructive IL7-mediated signals are not operative in the absence of Gfi1. Upon retroviral Gfi1 gene transfer, B differentiation was re-established Furthermore, whereas a combination of SCF and IL7 maintained the viability and induced proliferation of Gfi1-deficient HSC, their viability and proliferative capacity was significantly reduced in the presence of IL7 only, suggesting that both trophic and proliferative responses to IL7 depend on Gfi1. In addition, RT-PCR analysis revealed that in early B cell development the coordinated upregulation of the B cell specific transcription factors E2A, EBF, and Pax5 was significantly reduced in sorted Hardy fractions obtained from Gfi1-deficient mice. We reasoned that defective IL7-mediated responses might be due to defective Jak/Stat signalling. Indeed, phosphorylation of STAT5 was almost undectable in Gfi1-deficient B-progenitor cells. This may be due to enhanced expression levels of SOCS3 as determined by RT-PCR and Western Blot analysis. Thus, Gfi1 selectively specifies IL7-dependent development of B cells from CLP1 progenitors, providing clues to the transcriptional networks integrating cytokine signals and lymphoid differentiation.

P6598MicroRNA 21 and Hypoxia Inducible Factor 1 synchronize the impact of B lymphocytes on cardiac function after acute myocardial infarction

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
Y Sun ◽  
C Pinto ◽  
X Loyer ◽  
V Duval ◽  
P Alayrac ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Bone Marrow ◽  
B Cells ◽  
Cardiac Function ◽  
B Cell ◽  
B Lymphocytes ◽  
Cardiac Repair ◽  
Acute Mi ◽  
The Impact ◽  
Deficient Mice

Abstract Background Myocardial infarction (MI) is a severe ischemic disease responsible for heart failure and sudden death. Mature B lymphocytes have been shown to exacerbate tissue injury and deterioration of cardiac function after MI. However, the cellular and molecular mechanisms governing B cell deleterious effects in the ischemic milieu remain to be defined. Purpose In this study, we speculate that endogenous activation of the miR21/HIFα-related pathways mediates the effect of B lymphocytes on post-ischemic cardiac remodeling. Methods Acute MI was induced by permanent ligation of the left anterior descending artery in mice. Cardiac function and remodeling was determined by echocardiography and immunohistochemistry. Inflammatory cell number and phenotype were defined by FACS analysis. To evaluate the role of HIFα isoforms in B cells, we generated mice with B cell lineage specific (Cd79aCre/+) conditional deletion of HIF1α (HIF1αflox/flox), HIF2α (HIF2αflox/flox), or both isoforms (HIF1α-HIF2αflox/flox). Results Acute MI increased miR21 levels in B cells. miR21 deficient mice showed reduced B cell numbers in the spleen, blood and subsequently in the injured cardiac tissue. Transplantation of bone marrow derived cells isolated from miR21-deficient mice (miR21−/−) improved cardiac function and remodeling when compared to administration of wild-type (WT) bone marrow cells. Similarly, in Rag1−/− immunodeficient mice with acute MI, re-supplementation with miR21−/− B lymphocytes restored cardiac repair and function when compared to injection of WT B cells. miR21 abrogated PTEN contents and subsequently enhanced HIF1α levels in cultured B cells. B cell deletion of HIF1α, but not that of HIF2α, reduced B cell accumulation and improved cardiac function after MI. Mice, which were equally deficient in HIF1α and HIF2α, also exhibited abrogation of adverse ventricular remodeling and showed recovery of cardiac function after MI. Toll like receptor agonist, CpG, fostered the release of the monocyte chemo-attractant protein, Ccl7, in cultured WT B cells but not in miR21- or HIF1α- deficient B cells. Ccl7 circulating levels were also reduced in miR21−/− and Cd79aCre/+/HIF1α flox/flox animals after acute MI. Ccl7 down-regulation hampered Ly6Chigh monocyte infiltration in the ischemic myocardium, leading to decreased infarct size and interstitial fibrosis, supporting cardiac repair. Conclusion This work reveals a novel function for miR21/HIF1α related pathways in B lymphocyte dependent effect on cardiac function and remodeling in the setting of acute MI.

scholarly journals Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine.

1995 ◽  
Vol 181 (4) ◽  
pp. 1519-1526 ◽  
Author(s):  
U von Freeden-Jeffry ◽  
P Vieira ◽  
L A Lucian ◽  
T McNeil ◽  
S E Burdach ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Gene Targeting ◽  
B Cell Development ◽  
B Lymphopoiesis ◽  
T And B Cells ◽  
Immature B Cells ◽  
Deficient Mice

Interleukin (IL)-7 is a potent stimulus for immature T and B cells and, to a lesser extent, mature T cells. We have inactivated the IL-7 gene in the mouse germline by using gene-targeting techniques to further understand the biology of IL-7. Mutant mice were highly lymphopenic in the peripheral blood and lymphoid organs. Bone marrow B lymphopoiesis was blocked at the transition from pro-B to pre-B cells. Thymic cellularity was reduced 20-fold, but retained normal distribution of CD4 and CD8. Splenic T cellularity was reduced 10-fold. Splenic B cells, also reduced in number, showed an abnormal population of immature B cells in adult animals. The remaining splenic populations of lymphocytes showed normal responsiveness to mitogenic stimuli. These data show that proper T and B cell development is dependent on IL-7. The IL-7-deficient mice are the first example of single cytokine-deficient mice that exhibit severe lymphoid abnormalities.

scholarly journals Regulated Expression of the Eph-Related Receptor Tyrosine Kinase Hek11 in Early Human B Lymphopoiesis

Blood ◽  
1997 ◽  
Vol 90 (9) ◽  
pp. 3613-3622 ◽  
Author(s):  
Hans-Christian Aasheim ◽  
Leon W.M.M. Terstappen ◽  
Ton Logtenberg
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Expression Patterns ◽  
B Lymphopoiesis ◽  
Fetal Bone ◽  
Degenerate Oligonucleotide ◽  
Regulated Expression ◽  
B Lineage ◽  
B Lineage Cells

Abstract Members of the large Eph family of receptor tyrosine kinases (RTKs) display temporally and spatially restricted expression patterns during embryogenesis, suggesting a role in various developmental processes. We have begun to investigate the expression of members of this receptor family during human hematopoiesis, in particular B lymphopoiesis. Expression of Eph RTKs in cells of the B-lymphoid lineage was assessed by using degenerate oligonucleotide primers based on stretches of conserved nucleic acid sequences in members of the Eph family. First, the content of Eph-family RTKs was assessed in freshly sorted fetal bone marrow pro–B cells. This population was found to harbor transcripts of the Hek8 and Hek11 members of this gene family. Subsequent analysis of expression of these genes in B cells representing various differentiation and ontogenic stages showed that the Hek8 transcript is constitutively present in all fetal and adult B-lineage cells, with high levels of expression in peripheral blood B cells. In contrast, the Hek11 transcript was exclusively found in fetal bone marrow pro–B cells and pre–B cells, but not in more mature fetal B-lineage cells. All adult B-lineage cells, from early pro–B cells to end-stage plasma cells, lacked Hek11 transcripts. The developmentally regulated expression of Hek11 during fetal B lymphopoiesis suggests a role for this gene in pre/pro–B cell expansion and/or differentiation and defines a difference in progenitor B cell populations isolated from fetal versus adult human bone marrow.

RNAi Screening Identifies A Novel Role for A-Kinase Anchoring Protein 12 (AKAP12) in B Cell Development and Function

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 855-855 ◽  
Author(s):  
Mutlu Kartal-Kaess ◽  
Luisa Cimmino ◽  
Simona Infantino ◽  
Mehmet Yabas ◽  
Jian-Guo Zhang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Leukemia Cell ◽  
Cell Development ◽  
B Cell Development ◽  
Leukemia Cell Line ◽  
B Lymphopoiesis ◽  
Catalytic Subunits ◽  
B Cell Leukemia

Abstract Abstract 855 The cAMP signaling pathway has emerged as a key regulator of hematopoietic cell proliferation, differentiation, and apoptosis. Signal specificity is achieved through local activation of signaling enzymes that are anchored to subcellular organelles and membranes. In particular, A-kinase anchoring proteins (AKAPs) coordinate and control cAMP responsive events. AKAPs were originally classified based on their ability to bind cAMP-dependent protein kinase (protein kinase A; PKA). The activity of PKA is regulated by its two regulatory subunits, which from a dimer that binds to the two catalytic subunits. Binding of cAMP to the regulatory dimer dissociates the catalytic subunits and activates PKA. Anchoring of PKA by AKAPs constrains PKA activity to a relevant subset of potential substrates. Thus, AKAPs contribute to the precision of intracellular signaling events by directing anchored enzyme pools to a subset of their physiological substrates at specific subcellular localizations. Using an in vitro short hairpin RNA (shRNA) screen against potentially druggable targets, we have uncovered a requirement for AKAP12 in the proliferation of a cultured pre-B cell leukemia cell line. In the hematopoietic system of mice and humans, expression of AKAP12 is tightly restricted to the pro/pre/immature stages of B lymphopoiesis, suggesting a potential role in pre-B cell receptor (pre-BCR) or BCR signaling. We find that retroviral knockdown or germline knockout of AKAP12 in mice leads to an increase in pre B and immature B cells in the bone marrow. In contrast, B cell numbers in the spleen are significantly reduced, as are recirculating B cells in the bone marrow. Transplantation of AKAP12 null hematopoietic stem and progenitor cells from fetal liver into wildtype recipients demonstrates an autonomous defect in the development of AKAP12−/− B cells. Competitive bone marrow transplantations confirm that this defect is cell autonomous and not due to a defective bone marrow environment or secretion of a B cell inhibitory factor. To identify AKAP12 interaction partners, we overexpressed FLAG-epitope tagged AKAP12 in a pre-B cell leukemia cell line. Affinity purification of AKAP12 showed a repeated co-immunoprecipitation of poorly characterized RIO kinase 1 (RIOK1). Our current efforts are focused on investigating the interaction between RIOK1 and AKAP12 and their role in the control of B cell development and cell cycle progression. Further, we are focusing on a likely role for AKAP12 in the scaffolding of PKA, PKC and phosphodiesterases by analyzing the activation of signaling cascades in cultured primary wildtype and AKAP12−/− pre B cells. Additionally, we are investigating the role of the BCR in vivo by testing if enforced expression of BCR components rescue B cell development in a AKAP12−/− BCR transgenic mouse model (SWHEL mouse). In summary, we have confirmed a novel role for AKAP12 in B lymphopoiesis. Disclosures: No relevant conflicts of interest to declare.

BRAFV600E Mutations Occur In The Hematopoietic Stem Cell Compartment In Hairy Cell Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 816-816
Author(s):  
Stephen S. Chung ◽  
Jae H. Park ◽  
Eunhee Kim ◽  
Young Rock Chung ◽  
Wenhuo Hu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Proliferation ◽  
B Cells ◽  
B Cell ◽  
Bone Marrow Cells ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Hematopoietic Stem ◽  
Mutant Braf

Abstract Hairy cell leukemia (HCL) is a chronic lymphoproliferative disorder recently found to be characterized by somatic BRAFV600E mutations. The malignant cell in HCL exhibits features consistent with a mature B-lymphocyte, including cell-surface expression of the pan-B-cell marker CD19 and monotypic surface immunoglobulins with clonal rearrangements of immunoglobulin heavy and light chains. Despite possessing these stereotypic features, the cell of origin of HCL has been long debated, and no cell type along the continuum of developing B-lymphocytes has been definitively identified as the normal counterpart of HCL cells. We hypothesized that HCL may originate from immature hematopoietic cells, and therefore investigated the hematopoietic-stem/progenitor cell (HSPC) compartment in HCL patients. We found that HCL patients exhibited a significantly increased frequency of immunophenotypically defined long-term hematopoietic stem cells (LT-HSCs; lineage-negative (Lin-neg) CD34+CD38-CD90+CD45RA- cells), pro-B cells (Lin-neg CD10+ cells), and CD34-CD38+ CD10+CD19+ hematogones, as well as a decreased frequency of granulocyte-macrophage progenitor cells (Lin-neg CD34+CD38+CD45RA+CD123+) relative to age-matched normal controls. Sequencing of cDNA from highly pure FACS-sorted cell populations from the bone marrow of HCL patients revealed the presence of the BRAFV600E allele in LT-HSCs and in pro-B cells (Figure). Transplantation of LT-HSCs from the pretreatment bone marrow of HCL patients into NOD/SCID/IL2r-gnull mice resulted in stable human grafts characterized by an expanded B-progenitor population and development of a clonal population of hCD19+hCD103+hCD25+ B cells characteristic of HCL 6 months after transplantation. Together, these data suggest that HCL arises from HSCs that then differentiate into committed B-cells which ultimately give rise to the characteristic clonal B-cell proliferation of HCL. Given the human HSC genetic and functional cell data, we conditionally expressed BRafV600E from its endogenous locus at different stages of hematopoiesis, including in HSPCs and committed B cells. Mice with conditional expression of BRafV600E in Mx1Cre+ BRafV600E knock-in mice died of a lethal hematopoietic malignancy characterized by features of human HCL including splenomegaly, anemia, thrombocytopenia, increased circulating sCD25, and increased clonogenic capacity of B-lineage cells (evidenced by infinite serial replating in the presence of IL-7) (Figure). This disorder was transplantable into lethally-irradiated recipient mice. In contrast, mice with expression of BRafV600E restricted to the B-cell lineage with Cd19 Cre manifested no overt malignant phenotype up to one year of age. Stimulation of these mice with alloantigen through injections of sheep red blood cells resulted in germinal center B-cell hyperplasia, but still did not result in development of a clonal B-cell proliferation. Recent case reports have noted that refractory HCL patients respond to mutant BRAF inhibition with vemurafenib. We investigated the effect of vemurafenib on HSPCs and hematopoiesis in patients treated on a phase II study of the mutant BRAF inhibitor vemurafenib for relapsed/refractory HCL as well as in our in vivo murine models. Flow cytometric analysis of bone marrow cells from vemurafenib treated HCL patients revealed normalization of HSPC frequencies within three months of starting therapy, concomitant with an improvement in peripheral blood counts. Consistent with this, evaluation of the in vitro clonogenic capacity of sorted LT-HSC's from the bone marrow of HCL patients revealed a significant increase in myeloid/erythroid colony formation in HCL patients treated for 3 months with vemurafenib compared to their pretreatment marrows. Likewise, treatment of wildtype mice transplanted with Mx1Cre+ BRafV600E mutant bone marrow cells revealed improvement in anemia and hepatosplenomegaly with in vivo therapy. Overall, these findings link the pathogenesis of HCL to a specific somatic genetic abnormality present in HSCs and provide evidence that mature B-cell malignancies can initiate in the HSC compartment. Moreover, these data suggest that the use of therapies targeting MAP kinase signaling in HCL may lead to durable remissions not only by eliminating the mature leukemic cells but also through targeted inhibition of signaling and survival in HCL initiating cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A monoclonal antibody that recognizes B cells and B cell precursors in mice.

1981 ◽  
Vol 153 (2) ◽  
pp. 269-279 ◽  
Author(s):  
R L Coffman ◽  
I L Weissman
Keyword(s):  
Monoclonal Antibody ◽  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Bone Marrow Cells ◽  
Cell Lineage ◽  
Hematopoietic Stem ◽  
B Cell Precursors

The monoclonal antibody, RA3-2C2, appears to be specific for cells within the B cell lineage. This antibody does not recognize thymocytes, peripheral T cells, or nonlymphoid hematopoietic cells in the spleen or bone marrow. Nor does it recognize the pluripotent hematopoietic stem cells, the spleen colony-forming unit, All sIg+ B cells and most plasma cells are RA3-2C2+. In addition, approximately 20% of nucleated bone marrow cells are RA3-2C2+ but sIg-. This population contains B cell precursors that can give rise to sIg+ cells within 2 d in vitro.

scholarly journals B cells in early and chronic HIV infection: evidence for preservation of immune function associated with early initiation of antiretroviral therapy

Blood ◽  
2010 ◽  
Vol 116 (25) ◽  
pp. 5571-5579 ◽  
Author(s):  
Susan Moir ◽  
Clarisa M. Buckner ◽  
Jason Ho ◽  
Wei Wang ◽  
Jenny Chen ◽  
...  
Keyword(s):  
B Cells ◽  
Antiretroviral Therapy ◽  
Hiv Infection ◽  
B Cell ◽  
Immune Cell ◽  
Memory B Cells ◽  
Early Initiation ◽  
Cell Counts ◽  
The Impact ◽  
Chronic Hiv Infection

Abstract Characterization of lymphocytes including B cells during early versus chronic HIV infection is important for understanding the impact of chronic viremia on immune cell function. In this setting, we investigated B cells before and after reduction of HIV plasma viremia by antiretroviral therapy (ART). At baseline, peripheral blood B-cell counts were significantly lower in both early and chronic HIV-infected individuals compared with uninfected controls. Similar to CD4+ but not CD8+ T cells, B-cell numbers in both groups increased significantly after ART. At baseline, B cells of early HIV-infected individuals were composed of a higher percentage of plasmablasts and resting memory B cells compared with chronic HIV-infected individuals whose B cells were composed of a higher percentage of immature/transitional and exhausted B cells compared with their early infection counterparts. At 1 year after ART, the percentage of resting memory B cells remained higher in early compared with chronic HIV-infected individuals. This difference translated into a better functional profile in that memory B-cell responses to HIV and non-HIV antigens were superior in early- compared with chronic-treated HIV infected individuals. These findings provide new insights on B cells in HIV infection and how early initiation of ART may prevent irreversible immune system damage.

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