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Klaus Rajewsky - One of the best experts on this subject based on the ideXlab platform.
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signatures of murine B Cell Development implicate yy1 as a regulator of the germinal center specific program
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Michael R Green, Marc Schmidtsupprian, Stefano Monti, Riccardo Dallafavera, Laura Pasqualucci, Nicole C Walsh, Jeffery L Kutok, Scott J Rodig, Donna Neuberg, Klaus RajewskyAbstract:We utilized gene expression profiling of a comprehensive panel of purified Developmentally defined normal murine B Cells to identify unique transcriptional signatures for each suBset. To elucidate transcription factor activities that function in a stage-specific fashion, we used gene sets that share transcription factor targets and found that germinal center B Cells had a roBust enrichment of up-regulated and down-regulated signatures compared with the other B-Cell suBsets. NotaBly, we found Yy1 and its targets to Be central regulators of the germinal center B (GCB)-specific transcriptional program with Binding of Yy1 to select signature genes in GCB Cells, and translation of the Yy1 signatures to human GCB Cells. We then tested whether our newly generated, stage-specific transcriptional signatures could Be used to link murine lymphoma models to stages of normal B-Cell Development. Although each of the molecularly defined murine lymphoma models conserved certain stage-specific features of normal B-Cell Development, there was a significant alteration of the normal differentiation signature following malignant transformation. These findings offer important tools and insights for elucidating differences Between normal and malignant B Cells.
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preferential use of dh reading frame 2 alters B Cell Development and antigen specific antiBody production
Journal of Immunology, 2008Co-Authors: Robert L Schelonka, Michael Zemlin, Ryoki Kobayashi, Gregory C Ippolito, Yingxin Zhuang, Larry G Gartland, Alexander J Szalai, Kohtaro Fujihashi, Klaus RajewskyAbstract:All jawed verteBrates limit use of D(H) reading frames (RFs) that are enriched for hydrophoBic amino acids. In BALB/c mice, DFL16.1 RF2 encodes valine and isoleucine. To test whether increased use of RF2 affects B Cell function, we examined B Cell Development and AB production in mice with an IgH allele (DeltaD-DmicroFS) limited to use of a single, frameshifted DFL61.1 gene segment. We compared the results of these studies to wild-type mice, as well as those previously oBtained in mice limited to use of either a single normal D(H) or a single inverted D(H) that forces use of arginine in CDR-H3. All three of the mouse strains limited to a single D(H) produced fewer immature B Cells than wild type. However, whereas mice limited to a single normal D(H) achieved normal B Cell numBers in the periphery, mice forced to preferentially use RF2 had reduced numBers of mature B Cells in the spleen and Bone marrow, mirroring the pattern previously oBserved in mice enriched for charged CDR-H3s. There were two exceptions. B Cells in the mice using RF2 normally populated the marginal zone and peritoneal cavity, whereas mice using inverted RF1 had increased numBers of marginal zone B Cells and decreased numBers of B1a Cells. When challenged with several T-dependent or T-independent Ags, Ag-specific AB titers in the mice forced to use RF2 were altered. These findings indicate that B Cell Development and Ag-specific AB production can Be heavily influenced By the gloBal amino acid content of the CDR-H3 repertoire.
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canonical nf κB activity dispensaBle for B Cell Development replaces Baff receptor signals and promotes B Cell proliferation upon activation
Immunity, 2006Co-Authors: Yoshiteru Sasaki, Michael Reth, Klaus Rajewsky, Elias Hobeika, Roberta Pelanda, Emmanuel Derudder, Marc SchmidtsupprianAbstract:The maintenance of mature B Cells hinges on signals emitted from the BAFF-R Cell-surface receptor, But the nature of these signals is incompletely understood. InhiBition of canonical NF-kappaB transcription factor activity through aBlation of the essential scaffold protein NEMO arrests B Cell Development at the same stage as BAFF-R deficiency. Correspondingly, activation of this pathway By constitutively active IkappaB Kinase2 renders B Cell survival independent of BAFF-R:BAFF interactions and prevents proapoptotic PKCdelta nuclear translocation. In addition, canonical NF-kappaB activity mediates differentiation and proper localization of follicular and marginal zone B Cells in the aBsence of BAFF-R, But not CD19. By replacing BAFF-R signals, constitutive canonical NF-kappaB signaling, a hallmark of various B Cell lymphomas, causes accumulation of resting B Cells and promotes their proliferation and survival upon activation, But does not per se induce lymphomagenesis. Therefore, canonical NF-kappaB activity can suBstitute for BAFF-R signals in B Cell Development and pathogenesis.
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c myB is critical for B Cell Development and maintenance of follicular B Cells
Immunity, 2005Co-Authors: Matthew Thomas, Klaus Rajewsky, Christopher S Kremer, Kodi S Ravichandran, Timothy P BenderAbstract:The c-MyB transcription factor is crucial during definitive hematopoiesis. However, the emBryonic lethality of MyB traditional null mutations has precluded analysis of c-MyB function in lymphocytes. Using tissue-specific inactivation at the MyB locus, we demonstrate that loss of MyB causes a partial Block during B Cell Development at the pro-B to pre-B Cell transition, resulting in greatly decreased output of new B Cells from the Bone marrow. Furthermore, we demonstrate that MyB is not essential for the proliferation of splenic B Cells, But that loss of c-MyB function prevents normal B Cell homeostasis due to decreased splenic B Cell survival. Decreased survival is accompanied By hyporesponsiveness to the B Cell survival factor BLyS (also termed BAFF), decreased expression of the BLyS receptor 3 (BR3), and altered regulation of PKCδ nuclear accumulation. Thus, c-MyB is important during multiple stages of B-lymphopoiesis.
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B Cell Development under the condition of allelic inclusion
Immunity, 1997Co-Authors: Eiichiro Sonoda, Yael Pewznerjung, Stephan Schwers, Shinsuke Taki, Steffen Jung, Dan Eilat, Klaus RajewskyAbstract:Mice whose IgH alleles are engineered to encode two distinct antiBody heavy (H) chains generate a normal-sized B Cell compartment in which most Cells staBly express the two heavy chains. This demonstrates that "toxicity" of Bi-allelic H chain expression and Cell-autonomous mechanisms of silencing in-frame IgH gene rearrangements do not significantly contriBute to allelic exclusion at the IgH locus. Notwithstanding, the staBility of the various engineered IgH loci during B Cell Development in the Bone marrow differed suBstantially from each other.
Mark S Schlissel - One of the best experts on this subject based on the ideXlab platform.
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foxo1 directly regulates the transcription of recomBination activating genes during B Cell Development
Nature Immunology, 2008Co-Authors: Rupesh H Amin, Mark S SchlisselAbstract:Regulated expression of the recomBinase RAG-1 and RAG-2 proteins is necessary for generating the vast repertoire of antigen receptors essential for adaptive immunity. Here, a retroviral cDNA liBrary screen showed that the stress-regulated protein GADD45a activated transcription of the genes encoding RAG-1 and RAG-2 in transformed pro-B Cells By a pathway requiring the transcription factor Foxo1. Foxo1 directly activated transcription of the Rag1-Rag2 locus throughout early B Cell Development, and a decrease in Foxo1 protein diminished the induction of Rag1 and Rag2 transcription in a model of receptor editing. We also found that transcription of Rag1 and Rag2 was repressed at the pro-B Cell and immature B Cell stages By the kinase Akt through its 'antagonism' of Foxo1 function. Thus, Foxo1 is a key regulator of Rag1 and Rag2 transcription in primary B Cells.
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a truncated heavy chain protein relieves the requirement for surrogate light chains in early B Cell Development
Journal of Immunology, 1997Co-Authors: Arthur L Shaffer, Mark S SchlisselAbstract:Early B Cell Development depends upon the surface expression of Ig heavy chain protein (mu) in a signaling complex known as the pre-B Cell receptor (pre-BCR). In addition to mu, the pre-BCR consists of the surrogate light chains VpreB and lamBda5 and the transmemBrane signal transduction proteins Ig-alpha and Ig-Beta. Expression of this complex is associated with changes in surface marker expression, gene transcription, and Ig gene rearrangement. Mutations preventing the expression of either mu or lamBda5 result in Developmental arrest, But the precise roles of the various components of the pre-BCR remain unclear. Using mice transgenic for a surface-expressed, But truncated, form of mu that cannot associate with surrogate light chains, we have studied the role of surrogate light chains in B Cell Development. We found that expression of the truncated mu transgene resulted in changes in surface marker expression, germline kappa locus transcription, and V(D)J recomBinase targeting indistinguishaBle from those induced By intact mu protein. These experiments lead us to conclude that surrogate light chains, while necessary for the assemBly of the wild-type pre-BCR, are not directly involved in pre-BCR signaling or otherwise required for early B Cell Development.
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e2a proteins are required for proper B Cell Development and initiation of immunogloBulin gene rearrangements
Cell, 1994Co-Authors: Gretchen Bain, Mark S Schlissel, Els Robanus Maandag, D J Izon, Derk Amsen, Ada M Kruisbeek, Bennett C Weintraub, Ian E Krop, Ann J Feeney, Marian Van RoonAbstract:ABstract E12 and E47 are two helix-loop-helix transcription factors that arise By alternative splicing of the E2A gene. Both have Been implicated in the regulation of immunogloBulin gene expression. We have now generated E2A (−/−) mice By gene targeting. E2A-null mutant mice fail to generate mature B Cells. The arrest of B Cell Development occurs at an early stage, since no immunogloBulin DJ rearrangements can Be detected in homozygous mutant mice. While immunogloBulin germline I μ RAG-1, mB-1 , CD19, and λ5 transcripts are dramatically reduced in fetal livers of E2A (−/−) mice, B29 and μ° transcripts are present, But at lower levels. In addition, we show that Pax-5 transcripts are significantly reduced in fetal livers of E2A (−/−) mice. These data suggest a crucial role for E2A products as central regulators in early B Cell differentiation.
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ig heavy chain protein controls B Cell Development By regulating germ line transcription and retargeting v d j recomBination
Journal of Immunology, 1994Co-Authors: Mark S Schlissel, T MorrowAbstract:The memBrane-associated form of Ig heavy chain (mu) protein has Been implicated as a critical regulator of B Cell Development. Mutant mice unaBle to produce the memBrane form of mu protein fail to produce mature B Cells. Splenic B Cells from mice transgenic for a functionally rearranged Ig mu gene show a marked decrease in endogenous heavy chain gene rearrangement. We have analyzed the effects of a human mu transgene on the regulation of V(D)J recomBination during B Cell Development in the mouse fetal liver. We found that mu transgenic and wild-type littermate mice Begin kappa light chain gene rearrangement at the same time during Development But the transgenic mice show a striking increase in the frequency of kappa gene rearrangement. The transgenic mice also show an increase in the levels of a germ-line kappa gene transcript known to Be associated with kappa gene rearrangement. D-to-JH heavy chain gene rearrangement is unaffected throughout Development By the presence of the mu transgene. Endogenous heavy chain gene V-to-DJH rearrangement occurs with similar frequency in transgenic and nontransgenic fetal livers during midgestation But is reduced in late gestation mu transgenic fetal liver. We show that this decrease in rearrangement is associated with a decrease in unrearranged VH gene transcription. Furthermore, we show that changes in the frequencies of rearranged kappa and mu genes are accompanied By changes in the frequencies of dsDNA Breaks, a V(D)J recomBination reaction intermediate associated with each of these loci. We propose that memBrane-associated mu protein regulates B Cell Development By signaling a change in the pattern of unrearranged Ig gene transcriptional activity, thereBy retargeting the V(D)J recomBinase.
Christopher J Paige - One of the best experts on this subject based on the ideXlab platform.
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the many roles of il 7 in B Cell Development mediator of survival proliferation and differentiation
Seminars in Immunology, 2012Co-Authors: Christopher J Paige, Steven A CorfeAbstract:Interleukin-7 (IL-7) plays several important roles during B Cell Development including aiding in; the specification and commitment of Cells to the B lineage, the proliferation and survival of B Cell progenitors; and maturation during the pro-B to pre-B Cell transition. Regulation and modulation of IL-7 receptor (IL-7R) signaling is critical during B lymphopoiesis, Because excessive or deficient IL-7R signaling leads to aBnormal or inhiBited B Cell Development. IL-7 works together with E2A, EBF, Pax-5 and other transcription factors to regulate B Cell commitment, while also functions to regulate Ig rearrangement By modulating FoxO protein activation and Rag enhancer activity. Suppressor of cytokine signaling (SOCS) proteins are inhiBitors of cytokine activation and, in B Cells, function to fine tune IL-7R signaling; ensuring that appropriate IL-7 signals are transmitted to allow for efficient B Cell commitment and Development.
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characterization of thymic stromal derived lymphopoietin tslp in murine B Cell Development in vitro
European Journal of Immunology, 1996Co-Authors: Robert J Ray, Caren Furlonger, Douglas E Williams, Christopher J PaigeAbstract:B Cell Development is dependent on Both direct interactions with stromal Cells and their secreted cytokines. The precise mechanisms By which these interactions regulate B Cell differentiation are currently unknown. We report here that a novel growth factor thymic stromal-derived lymphopoietin (TSLP) can replace the activity of interleukin-7 (IL-7) in supporting B Cell Development in vitro. TSLP was found to promote the proliferation and differentiation of committed B220+ B Cell progenitors from day 15 fetal liver. Phenotypic analysis of these Cells revealed that they are at the pro-B Cell stage of differentiation and express Cell surface markers characteristic of pro-B Cells cultured in IL-7. TSLP can replace the activity of IL-7 in supporting the progression of B lymphocytes from uncommitted Bipotential precursors. In the aBsence of either TSLP or IL-7, the progeny of Cells that give rise to mature B lymphocytes fail to develop from these Bipotential precursors. Moreover, TSLP can suBstitute for IL-7 in supporting the sustained proliferative response exhiBited By B Cell progenitors from CBA/N mice. Together these results show that TSLP can replace the requirement for IL-7 during in vitro B Cell Development.
Alexander Tarakhovsky - One of the best experts on this subject based on the ideXlab platform.
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essential role of src family protein tyrosine kinases in nf kappaB activation during B Cell Development
Nature Immunology, 2003Co-Authors: Kaoru Saijo, Michael Reth, Christian Schmedt, Hajime Karasuyama, Clifford A Lowell, Takahiro Adachi, Alina Patke, Angela Santana, Alexander TarakhovskyAbstract:The nature of signals that govern the Development of immunogloBulin heavy chain-dependent B Cells is largely unknown. Using mice deficient for the B Cell-expressed Src-family protein tyrosine kinases (SFKs) Blk, Fyn and Lyn, we show an essential role of these kinases in pre-B Cell receptor (pre-BCR)- mediated NF-kappaB activation and B Cell Development. This signaling defect is SFK specific, as a deficiency in Syk, which controls pre-B Cell Development, does not affect NF-kappaB induction. Impaired NF-kappaB induction was overcome By the activation of protein kinase C (PKC)-lamBda, thus suggesting the involvement of PKC-lamBda in pre-BCR-mediated SFK-dependent activation of NF-kappaB. Our data show the existence of a functionally distinct SFK signaling module responsiBle for pre-BCR-mediated NF-kappaB activation and B Cell Development.
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essential role of src family protein tyrosine kinases in nf κB activation during B Cell Development
Nature Immunology, 2003Co-Authors: Kaoru Saijo, Michael Reth, Christian Schmedt, Hajime Karasuyama, Clifford A Lowell, Takahiro Adachi, Alina Patke, Angela Santana, Alexander TarakhovskyAbstract:The nature of signals that govern the Development of immunogloBulin heavy chain-dependent B Cells is largely unknown. Using mice deficient for the B Cell-expressed Src-family protein tyrosine kinases (SFKs) Blk, Fyn and Lyn, we show an essential role of these kinases in pre-B Cell receptor (pre-BCR)– mediated NF-κB activation and B Cell Development. This signaling defect is SFK specific, as a deficiency in Syk, which controls pre-B Cell Development, does not affect NF-κB induction. Impaired NF-κB induction was overcome By the activation of protein kinase C (PKC)-λ, thus suggesting the involvement of PKC-λ in pre-BCR–mediated SFK-dependent activation of NF-κB. Our data show the existence of a functionally distinct SFK signaling module responsiBle for pre-BCR–mediated NF-κB activation and B Cell Development.
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Ezh2 controls B Cell Development through histone H3 methylation and Igh rearrangement
Nature Immunology, 2003Co-Authors: I-hsin Su, Ashwin Basavaraj, Andrew N. Krutchinsky, Oliver Hobert, Axel Ullrich, Brian T. Chait, Alexander TarakhovskyAbstract:PolycomB group protein Ezh2 is an essential epigenetic regulator of emBryonic Development in mice, But its role in the adult organism is unknown. High expression of Ezh2 in developing murine lymphocytes suggests Ezh2 involvement in lymphopoiesis. Using Cre-mediated conditional mutagenesis, we demonstrated a critical role for Ezh2 in early B Cell Development and rearrangement of the immunogloBulin heavy chain gene ( Igh ). We also revealed Ezh2 as a key regulator of histone H3 methylation in early B Cell progenitors. Our data suggest Ezh2-dependent histone H3 methylation as a novel regulatory mechanism controlling Igh rearrangement during early murine B Cell Development.
Christian A J Voshenrich - One of the best experts on this subject based on the ideXlab platform.
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thymic stromal derived lymphopoietin distinguishes fetal from adult B Cell Development
Nature Immunology, 2003Co-Authors: Werner Muller, Christian A J Voshenrich, Ana Cumano, James P Di Santo, Paulo VieiraAbstract:Deletions of interleukin 7 (IL-7) or its receptor components permit fetal But not adult B Cell Development in mice. Mice deficient in IL-7 receptor alpha (IL-7R alpha) had 1% the numBer of B Cells of controls and 10% that of mice deficient in the common gamma chain. As IL-7R alpha is also a receptor for thymic stromal-derived lymphopoietin (TSLP), we assayed the aBility of TSLP to support proliferation of fetal or adult precursor B Cells. Only fetal-derived pro-B Cells were aBle to respond to TSLP, although pre-B Cells from Both origins were TSLP-responsive. Fetal But not adult precursors generated a measuraBle B Cell compartment in the aBsence of IL-7. The residual B Cells found in IL-7R alpha-deficient mice required fetal liver kinase 2 (Flk-2) for their Development. Thus, IL-7R alpha- and Flk-2-mediated signals account for the generation of almost all mouse B lymphocytes.