scholarly journals Ras Mediates Effector Pathways Responsible for Pre-B Cell Survival, Which Is Essential for the Developmental Progression to the Late Pre-B Cell Stage

2000 ◽  
Vol 192 (2) ◽  
pp. 171-182 ◽  
Author(s):  
Hitoshi Nagaoka ◽  
Yoshimasa Takahashi ◽  
Reiko Hayashi ◽  
Tohru Nakamura ◽  
Kumiko Ishii ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Survival ◽  
Chain Gene ◽  
B Cell Differentiation ◽  
Antigen Receptors ◽  
Cell Stage ◽  
Light Chain Gene ◽  
B Cell Survival ◽  
Effector Pathways

Ras is essential for the transition from early B cell precursors to the pro-B stage, and is considered to be involved in the signal cascade mediated by pre-B cell antigen receptors. To examine the role of p21ras in the late stage of B cell differentiation, we established transgenic mice (TG) expressing a dominant-inhibitory mutant of Ha-ras (Asn-17 Ha-ras) in B lineage cells at high levels after the early B cell precursor stage. Expression of p21Asn-17 Ha-ras was associated with a prominent reduction in the number of late pre-B cells, but had little effect on proliferation of early pre-B cells. Inhibition of p21ras activity markedly reduced the life span of pre-B cells, due, at least in part, to downregulation of the expression of an antiapoptotic protein, Bcl-xL. Thus, the apparent role for p21ras activity in pre-B cell survival may explain the decreased numbers of late pre-B cells in Asn-17 Ha-ras TG. Consistent with this possibility, overexpression of Bcl-2 in Asn-17 Ha-ras TG reversed the reduction in the number of late pre-B cells undergoing immunoglobulin light chain gene (IgL) rearrangement and progressing to immature B cells. These results suggest that p21ras mediates effector pathways responsible for pre-B cell survival, which is essential for progression to the late pre-B and immature B stages.

Constitutive Lymphoid Expression of the Nuclear Form of RNase H1 Is Associated with a Developmental Bottleneck at the Pro-B Cell Stage of B Cell Differentiation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4702-4702
Author(s):  
Lina A. Gugliotti ◽  
Kiran B. Sakhuja ◽  
Hongsheng Wang ◽  
Julia Pinkhasov ◽  
Paul E. Love ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Dna Sequences ◽  
Conflicts Of Interest ◽  
Cell Receptor ◽  
Chain Gene ◽  
B Cell Differentiation ◽  
Loop Formation ◽  
Dna Breaks ◽  
Cell Stage

Abstract Abstract 4702 The development of B lymphocytes and the process of lineage determination are initiated by expression of a set of transcriptional regulators leading to V(D)J recombination events initiated by double-strand DNA breaks. Subsequently, these recombinations form DNAs that permit transcription of immunoglobulin genes and translation of the corresponding mRNAs, first by joining the V(D)J DNA sequences, then by recombination, that generates various isotypes of immunoglobulins by class-switch recombination (CSR). Formation of R-loops, regions containing RNA/DNA hybrid and a displaced single-stranded DNA, have been shown to lead to recombination in bacteria, yeast, HeLa and chick cells. Expression in each of these cases of excess ribonuclease H1 (RNase H1), a class of enzymes that degrade RNA in RNA/DNA hybrids, has ameliorated the deleterious effects and decreased recombinational events associated with R-loop formation. R-loops have been observed following transcription of the switch regions that occurs during CSR. The possibility that R-loops are important in V(D)J recombination has not been addressed, and whether ribonucleases H (RNases H) play a role in this process is still uncertain. Transgenic (TG) mice that overexpress RNase H1 in B and T cells (M27F7) were employed in this study. FACS analysis of hematopoietic cells from TG mice revealed a decrease in pre-B cells in the bone marrow. The data indicate a block at the pro-B to pre-B stage of B cell development, which may be the result of apoptosis due to the failure to generate a productive VH-D-JH rearrangement and expression of the pre-B cell receptor. A few B cells that successfully passed these checkpoints predominately differentiated into marginal zone and B1a cells in the peripheral lymphoid organs of the TG mice. These data suggest that R-loops are important in H chain gene rearrangement. This research is supported by the Intramural Research Program of the National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Allergy and Infectious Diseases. Disclosures: No relevant conflicts of interest to declare.

scholarly journals c-Myb expression is critical to maintain proliferation and glucose metabolism of large pre-B cells

2020 ◽  
Author(s):  
Andrea R. Daamen ◽  
Rowena B. Crittenden ◽  
Timothy P. Bender
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
B Cells ◽  
Glucose Metabolism ◽  
B Cell ◽  
Cell Survival ◽  
Myb Transcription Factor ◽  
Cell Cycle Exit ◽  
Cell Stage ◽  
B Cell Survival

AbstractThe c-Myb transcription factor is required for the differentiation of CD19+ B-lineage cells and plays significant roles from the specification of the B cell lineage to the survival of pro-B cells. c-Myb coordinates the survival of pro-B cells with the expression of genes required for transition to the large pre-B cell stage of differentiation. However, it is not known if c-Myb is important for the proliferative expansion or subsequent differentiation into small pre-B cells. Here we demonstrate that c-Myb expression is important for large pre-B cell survival, proliferation, and differentiation into small pre-B cells. Utilizing genome-wide analysis, we found that c-Myb was important for maintaining glucose uptake and utilization and exogenous expression of Glut1 and Hk1 rescued large pre-B cell recovery and survival. Furthermore, we found that c-Myb is important for repression of Ikaros and Aiolos and our c-Myb-dependent gene signature was enriched in an Ikaros footprint of genes that drive cell cycle exit and the large to small pre-B cell transition. However, upon loss of c-Myb expression, inhibition of Ikaros activity was able to restore certain Ikaros-mediated gene expression changes but was insufficient to rescue recovery of large pre-B cell numbers. We found that c-Myb regulates glucose utilization and glucose-dependent survival through Hk1 in an Ikaros-independent manner. Thus, c-Myb regulation of glucose metabolism is critical to maintain large pre-B cell survival while repression of the Ikaros-mediated gene expression program is critical to prevent premature cell cycle exit and premature differentiation into small pre-B cells.

Differential surrogate light chain expression governs B-cell differentiation

Blood ◽  
2002 ◽  
Vol 99 (7) ◽  
pp. 2459-2467 ◽  
Author(s):  
Yui-Hsi Wang ◽  
Robert P. Stephan ◽  
Alexander Scheffold ◽  
Désirée Kunkel ◽  
Hajime Karasuyama ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Light Chain ◽  
B Cell Receptors ◽  
Chain Gene ◽  
B Cell Differentiation ◽  
Light Chain Gene ◽  
Surrogate Light Chain ◽  
Rag 1

Surrogate light chain expression during B lineage differentiation was examined by using indicator fluorochrome-filled liposomes in an enhanced immunofluorescence assay. Pro-B cells bearing surrogate light chain components were found in mice, but not in humans. A limited subpopulation of relatively large pre-B cells in both species expressed pre-B cell receptors. These cells had reduced expression of the recombinase activating genes, RAG-1 and RAG-2. Their receptor-negative pre-B cell progeny were relatively small, expressed RAG-1 and RAG-2, and exhibited selective down-regulation of VpreB and λ5expression. Comparative analysis of the 2 pre-B cell subpopulations indicated that loss of the pre-B cell receptors from surrogate light chain gene silencing was linked with exit from the cell cycle and light chain gene rearrangement to achieve B-cell differentiation.

scholarly journals Loss of Bim Allows Precursor B Cell Survival But Not Precursor B Cell Differentiation in the Absence of Interleukin 7

2004 ◽  
Vol 200 (9) ◽  
pp. 1179-1187 ◽  
Author(s):  
Paula M. Oliver ◽  
Michael Wang ◽  
Yanan Zhu ◽  
Janice White ◽  
John Kappler ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Cell Survival ◽  
B Cell Differentiation ◽  
Normal Numbers ◽  
Cell Precursor ◽  
Interleukin 7 ◽  
B Cell Survival ◽  
B Cell Precursors

Interleukin (IL)-7 is a stromal cell–derived cytokine required for the survival, proliferation, and differentiation of B cell precursors. Members of the Bcl-2 family of proteins are known to have profound effects on lymphocyte survival, but not lymphocyte differentiation. To distinguish the relative dependence on IL-7 of B cell precursor survival versus B cell differentiation, the combined effects of lack of IL-7 and lack of the proapoptotic Bcl-2 relative, Bim, were studied. Bim is expressed to varying degrees in all B cell precursors and B cells. Lack of Bim compensated for lack of IL-7 in the survival of pro–, pre–, and immature B cells; however, lack of Bim did not substitute for the requirement for IL-7 in B cell precursor differentiation or B cell precursor proliferation. Precursor B cell survival is more dependent on sufficient levels of IL-7 than precursor B cell differentiation because the number of B cells and their precursors were reduced by half in mice heterozygous for IL-7 expression, but were restored to normal numbers in mice also lacking Bim. Hence, Bim and IL-7 work together to control the survival of B cell precursors and the number of B cells that exist in animals.

scholarly journals Receptor Editing and Marginal Zone B Cell Development Are Regulated by the Helix-Loop-Helix Protein, E2A

2004 ◽  
Vol 199 (8) ◽  
pp. 1101-1112 ◽  
Author(s):  
Melanie W. Quong ◽  
Annica Martensson ◽  
Anton W. Langerak ◽  
Richard R. Rivera ◽  
David Nemazee ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Fate ◽  
Gene Rearrangement ◽  
Marginal Zone ◽  
Chain Gene ◽  
Protein Activity ◽  
Cell Stage ◽  
Light Chain Gene ◽  
Marginal Zone B Cells

Previous studies have indicated that the E2A gene products are required to initiate B lineage development. Here, we demonstrate that E2A+/− B cells that express an autoreactive B cell receptor fail to mature due in part to an inability to activate secondary immunoglobulin (Ig) light chain gene rearrangement. Both RAG1/2 gene expression and RS deletion are severely defective in E2A+/− mice. Additionally, we demonstrate that E2A+/− mice show an increase in the proportion of marginal zone B cells with a concomitant decrease in the proportion of follicular B cells. In contrast, Id3-deficient splenocytes show a decline in the proportion of marginal zone B cells. Based on these observations, we propose that E-protein activity regulates secondary Ig gene rearrangement at the immature B cell stage and contributes to cell fate determination of marginal zone B cells. Additionally, we propose a model in which E-proteins enforce the developmental checkpoint at the immature B cell stage.

Combined deficiencies in Bruton tyrosine kinase and phospholipase Cγ2 arrest B-cell development at a pre-BCR+ stage

Blood ◽  
2006 ◽  
Vol 109 (8) ◽  
pp. 3377-3384 ◽  
Author(s):  
Shengli Xu ◽  
Koon-Guan Lee ◽  
Jianxin Huo ◽  
Tomohiro Kurosaki ◽  
Kong-Peng Lam
Keyword(s):  
B Cells ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Cell Development ◽  
B Cell Development ◽  
Chain Gene ◽  
B Cell Differentiation ◽  
Light Chain Gene ◽  
Single Mutant ◽  
Bruton Tyrosine Kinase

Abstract Bruton tyrosine kinase (Btk) and phospholipase Cγ2 (PLCγ2) are 2 key molecules involved in B-cell receptor (BCR) signaling. Biochemical studies have placed them in a linear signaling pathway, with Btk acting upstream of PLCγ2. Consistent with this, mice lacking either molecule display a leaky but similar block in B-cell development. Here, we generated Btk−/−PLCγ2−/− mice and showed that combined deficiencies in Btk and PLCγ2 severely arrested B lymphopoiesis at the large pre–B-cell stage. In contrast to either single mutant, Btk−/−PLCγ2−/− pre–B cells expressed high levels of pre-BCR on their cell surfaces and exhibited reduced immunoglobulin light chain gene rearrangements. Pre-BCR–induced calcium signaling was also drastically compromised in Btk−/−PLCγ2−/− pre–B cells compared with wild-type and single-mutant cells. Interestingly, immunoglobulin heavy chain allelic exclusion remained intact in the absence of Btk and PLCγ2. Overall, our results suggest that Btk and PLCγ2 have combinatorial roles in regulating pre–B cell differentiation.

scholarly journals The anti-apoptotic factor Bcl-2 can functionally substitute for the B cell survival but not for the marginal zone B cell differentiation activity of BAFF

2004 ◽  
Vol 34 (2) ◽  
pp. 509-518 ◽  
Author(s):  
Aubry Tardivel ◽  
Antoine Tinel ◽  
Susanne Lens ◽  
Quynh-Giao Steiner ◽  
Estelle Sauberli ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cell ◽  
Cell Survival ◽  
Marginal Zone ◽  
B Cell Differentiation ◽  
B Cell Survival

Accessibility of the promoter sequence in the J-chain gene is regulated by chromatin changes during B-cell differentiation

1986 ◽  
Vol 6 (11) ◽  
pp. 4031-4038
Author(s):  
M E Minie ◽  
M E Koshland
Keyword(s):  
B Cell ◽  
Early Stage ◽  
Promoter Sequence ◽  
Immunoglobulin M ◽  
Chain Gene ◽  
B Cell Differentiation ◽  
Cell Stage ◽  
J Chain ◽  
Lymphoid Lines ◽  
Nuclease Digestion

The gene for the immunoglobulin M (IgM)-polymerizing protein, the J chain, is activated when the mature B cell is triggered to secrete pentamer IgM. Activation of the gene was found to be associated with chromatin changes in a 240-base-pair region at the 5' end of the gene. Analyses of lymphoid lines showed that the 5' region was resistant to nuclease digestion at the immature B-cell stage; it became slightly more accessible in mature B cells and cells at an early stage in the IgM response and then displayed an open, hypersensitive structure in IgM-secreting cells. In addition, analyses of normal, mitogen-stimulated lymphocytes showed that the open hypersensitive structure was coinducible with J-chain gene expression. These results suggest that the 5' chromatin changes precede transcription, making control sequences within the site accessible to regulatory factors.

scholarly journals B Cell–Activating Factor Promotes B Cell Survival in Ectopic Lymphoid Tissues in Nasal Polyps

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhe-Zheng Wang ◽  
Jia Song ◽  
Hai Wang ◽  
Jing-Xian Li ◽  
Qiao Xiao ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Survival ◽  
Stromal Cells ◽  
Caspase 3 ◽  
Lymphoid Tissues ◽  
B Cell Activating Factor ◽  
B Cell Survival ◽  
Active Caspase

Ectopic lymphoid tissues (eLTs) characterized by B cell aggregation contribute to the local immunoglobulin production in nasal polyps (NPs). B cell-activating factor (BAFF) is vital for B cell survival, proliferation, and maturation. The purpose of this study is to investigate whether BAFF is involved in the B cell survival and eLT formation in NPs. The mRNA and protein levels of BAFF in NP tissues with and without eLTs were detected by PCR and ELISA assay, respectively. The cellular sources of BAFF and active caspase-3-positive B cells in NPs were studied by immunofluorescence staining. B cells purified from NP tissues were stimulated with BAFF and were analyzed by flow cytometry. Stromal cells purified from NP tissues were stimulated with lymphotoxin (LT) α1β2, and BAFF levels in culture supernatants were analyzed by ELISA. Compared with those in control tissues and NPs without eLTs, the BAFF levels were elevated in NPs with eLTs. Abundant BAFF-positive cells and few active caspase-3-positive apoptotic B cells were found in NPs with eLTs, in contrast to those in NPs without eLTs. There was a negative correlation between the numbers of BAFF-positive cells and frequencies of apoptotic B cells in total B cells in NP tissues. BAFF protected nasal polyp B cells from apoptosis in vitro. Stromal cells were an important cellular source of BAFF in NPs with eLTs. LTα1β2 induced BAFF production from nasal stromal cells in vitro. We propose that BAFF contribute to eLT formation in NPs by promoting B cell survival.

Sign in / Sign up

Export Citation Format

Share Document