scholarly journals A Critical Role of the Thy28-MYH9 Axis in B Cell-Specific Expression of the Pax5 Gene in Chicken B Cells

PLoS ONE ◽  
2015 ◽  
Vol 10 (1) ◽  
pp. e0116579 ◽  
Author(s):  
Toshitsugu Fujita ◽  
Fusako Kitaura ◽  
Hodaka Fujii
Keyword(s):  
B Cells ◽  
B Cell ◽  
Critical Role ◽  
Specific Expression ◽  
Pax5 Gene

scholarly journals Ridd Is Required for the Prevention of Chronic Gvhd By Targeting IRE-1a/Xbp-1s Signaling

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1681-1681
Author(s):  
Hee-Jin Choi ◽  
Chih-Hang Anthony Tang ◽  
Linlu Tian ◽  
Yongxia Wu ◽  
Mohammed Hanief Sofi ◽  
...  
Keyword(s):  
T Cells ◽  
Stress Response ◽  
B Cells ◽  
Er Stress ◽  
B Cell ◽  
Critical Role ◽  
Secretory Cells ◽  
Hematopoietic Stem ◽  
Er Stress Response

Abstract Allogeneic hematopoietic stem cell transplantation (allo-HCT) is an effective therapeutic procedure to treat hematological malignancies. However, the benefit of allo-HCT is limited by a major complication, chronic graft-versus-host disease (cGVHD). Since transmembrane and secretory proteins are generated and modified in the endoplasmic reticulum (ER), the ER stress response is of great importance to secretory cells including B cells. By using conditional knock-out (KO) of XBP-1, IRE-1α or both specifically on B cells, we demonstrated that the IRE-1α/XBP-1s pathway, one of the major ER stress response mediators, plays a critical role in B cell pathogenicity on the induction of cGVHD in murine models of allo-HCT. Endoribonuclease activity of IRE-1α not only activates XBP-1s transcription factor by converting unspliced XBP-1 (XBP-1u) mRNA into spliced XBP-1 (XBP-1s) mRNA but also cleaves other ER-associated mRNAs through regulated IRE-1α-dependent decay (RIDD). Besides, it is known that ablation of XBP-1s production leads to unleashed activation of RIDD. Therefore, we hypothesized that RIDD plays an important role in B cells during cGVHD development. In this study, we found that B cells deficient for XBP-1s reduced ability to induce cGVHD, which however was reversed by inactivation of IRE-1α, highlighting the role of RIDD in controlling cGVHD (Fig. A). Activation of RIDD targets IgM mRNA of (Fig. B), a contributor to organ damage and fibrosis in cGVHD, which correlated with dysregulated expression of MHC II and costimulatory molecules such as CD86, CD40, and ICOSL in B cells (Fig. C). Alloreactive T cells need to be primed by APCs to initiate GVHD, and specifically, CD86 and CD40 mediated-costimulation from APCs has been demonstrated to play an essential role in eliciting cGVHD. We demonstrated that alloreactivity of T cells, especially CD4 T cells, can be recovered by suppressing RIDD in XBP-1s-deficient B cells (Fig. D). Since IRE-1α carrying a S729A mutation shows ablated RIDD activity without effect on splicing XBP-1 mRNA, we investigated the contribution of B cells from S729A knock-in mice to confirm the role of RIDD in B cells. We found that B cells from S729A mice increased GVHD severity (Fig. E). S729A B cells showed significant increases in IgM secretion (Fig. F), GC cell differentiation (Fig. G), and the expression levels of MHCII and co-stimulatory factors (Fig. H). In conclusion, these results provide a novel insight on how ER stress response regulates B cell activity after allo-HCT and suggest RIDD is an important mediator for reducing cGVHD pathogenesis. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals A critical role of TAK1 in B-cell receptor–mediated nuclear factor κB activation

Blood ◽  
2009 ◽  
Vol 113 (19) ◽  
pp. 4566-4574 ◽  
Author(s):  
James Schuman ◽  
Yuhong Chen ◽  
Andrew Podd ◽  
Mei Yu ◽  
Hong-Hsing Liu ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Critical Role ◽  
Cell Receptor ◽  
Nuclear Factor Κb ◽  
Cell Development ◽  
B Cell Receptor ◽  
Nuclear Factor

Abstract The kinase TAK1 is essential for T-cell receptor (TCR)–mediated nuclear factor κB (NF-κB) activation and T-cell development. However, the role of TAK1 in B-cell receptor (BCR)–mediated NF-κB activation and B-cell development is not clear. Here we show that B-cell–specific deletion of TAK1 impaired the transition from transitional type 2 to mature follicular (FO) B cells and caused a marked decrease of marginal zone (MZ) B cells. TAK1-deficient B cells exhibited an increase of BCR-induced apoptosis and impaired proliferation in response to BCR ligation. Importantly, TAK1-deficient B cells failed to activate NF-κB after BCR stimulation. Thus, TAK1 is critical for B-cell maturation and BCR-induced NF-κB activation.

scholarly journals Prevention of Chronic Gvhd By Targeting Xbp-1 Genetically or Pharmacologically in Mice

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4541-4541
Author(s):  
Steven D Schutt ◽  
Chih-Hang Anthony Tang ◽  
Yongxia Wu ◽  
David A Bastian ◽  
Juan Del Valle ◽  
...  
Keyword(s):  
T Cells ◽  
Stress Response ◽  
B Cells ◽  
Er Stress ◽  
B Cell ◽  
Chronic Gvhd ◽  
Critical Role ◽  
Conditional Knockout ◽  
Er Stress Response

Abstract Inhibition of the endoplasmic reticulum (ER) stress response via blockade of inositol-requiring enzyme-1α (IRE-1α) is currently a promising therapeutic strategy to treat B-cell leukemia, lymphoma, and myeloma. Because B cells play an important role in the development of chronic graft-versus-host disease (cGVHD), we hypothesize that the ER stress response contributes to B-cell function and pathogenicity in cGVHD. Here, we report that the ER stress response mediated by IRE-1α and its target X-box binding protein-1 (XBP-1) plays a critical role in cGVHD pathophysiology and represents a potential therapeutic target to prevent cGVHD. We tested the role of XBP-1 specifically in B cells by testing XBP-1 conditional knockout B cell grafts (XBP1fl/flCD19Cre+) in two mouse models of cGVHD. In the first model (B6 to BALB/c), recipients given XBP-1-deficient donor grafts showed significantly reduced cGVHD clinical scores, which were associated with reduced frequencies of donor-derived CD4 helper T cells within the lungs compared to the recipients of XBP-1fl/flCD19Cre- littermate donor grafts. XBP-1-deficient B cells produced significantly higher levels of IL-10 compared to WT control B cells after activation ex vivo. In the second model (B6 to B10.BR), the conversion of donor B cells to plasma cells (B220+CD38+CD138+) was reduced in both the spleens and lungs of recipients transplanted with XBP1fl/flCD19Cre+ grafts compared to those of the recipients given XBP1fl/flCD19Cre- grafts. Recipients given XBP1fl/flCD19Cre+ grafts also showed significantly higher total splenocytes and vastly increased splenic B-cell populations when compared with the recipients of XBP1fl/flCD19Cre- grafts. To expand on these findings, we tested if systemic XBP-1 blockade via a novel IRE-1α inhibitor, B-I09, would attenuate cGVHD. In a cutaneous model of cGVHD (B10.D2 to BALB/c), we found that prophylactic administration of B-I09 significantly reduced clinical features of cGVHD compared to vehicle controls (Fig. 1A). Validating these findings, hematoxylin and eosin stained skin sections of B-I09-treated mice had significantly lower pathology scores compared to vehicle controls (Fig. 1B). Isolated skin lymphocytes from recipients treated with B-I09 showed significant reductions in donor derived T cells and DCs compared to those treated with vehicle controls (Fig. 1C and D). Taken together, our findings reveal a novel role of the IRE-1α/XBP-1 pathway of the ER stress response in cGVHD pathophysiology and provide a readily translatable strategy to prevent the development of cGVHD in the clinic. Disclosures No relevant conflicts of interest to declare.

scholarly journals B-Cell Receptor- and Phorbol Ester-Induced NF-κB and c-Jun N-Terminal Kinase Activation in B Cells Requires Novel Protein Kinase C's

2001 ◽  
Vol 21 (19) ◽  
pp. 6640-6650 ◽  
Author(s):  
Daniel Krappmann ◽  
Alina Patke ◽  
Vigo Heissmeyer ◽  
Claus Scheidereit
Keyword(s):  
B Cells ◽  
Protein Kinase ◽  
B Cell ◽  
Phorbol Ester ◽  
Critical Role ◽  
Ectopic Expression ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Novel Protein

ABSTRACT Antigen receptor signaling is known to activate NF-κB in lymphocytes. While T-cell-receptor-induced NF-κB activation critically depends on novel protein kinase C θ (PKCθ), the role of novel PKCs in B-cell stimulation has not been elucidated. In primary murine splenic B cells, we found high expression of the novel PKCs δ and ɛ but only weak expression of the θ isoform. Rottlerin blocks phorbol ester (phorbol myristate acetate [PMA])- or B-cell receptor (BCR)-mediated NF-κB and c-Jun N-terminal kinase (JNK) activation in primary B and T cells to a similar extent, suggesting that novel PKCs are positive regulators of signaling in hematopoietic cells. Mouse 70Z/3 pre-B cells have been widely used as a model for NF-κB activation in B cells. Similar to the situation in splenic B cells, rottlerin inhibits BCR and PMA stimulation of NF-κB in 70Z/3 cells. A derivative of 70Z/3 cells, 1.3E2 cells, are defective in NF-κB activation due to the lack of the IκB kinase (IKKγ) protein. Ectopic expression of IKKγ can rescue NF-κB activation in response to lipopolysaccharides (LPS) and interleukin-1β (IL-1β), but not to PMA. In addition, PMA-induced activation of the mitogen-activated protein kinase JNK is blocked in 1.3E2 cells, suggesting that an upstream component common to both pathways is either missing or mutated. Analysis of various PKC isoforms revealed that exclusively PKCθ was absent in 1.3E2 cells while it was expressed in 70Z/3 cells. Stable expression of either novel PKCθ or -δ but not classical PKCβII in 1.3E2 IKKγ-expressing cells rescues PMA activation of NF-κB and JNK signaling, demonstrating a critical role of novel PKCs for B-cell activation.

scholarly journals Critical Role of B Cell Lymphoma 10 in BAFF-Regulated NF-κB Activation and Survival of Anergic B Cells

2012 ◽  
Vol 189 (11) ◽  
pp. 5185-5193 ◽  
Author(s):  
Mei Yu ◽  
Yuhong Chen ◽  
Yinghong He ◽  
Andrew Podd ◽  
Guoping Fu ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Lymphoma ◽  
Critical Role ◽  
B Cell Lymphoma

Crucial role of FLT3 ligand in immune reconstitution after bone marrow transplantation and high-dose chemotherapy

Blood ◽  
2007 ◽  
Vol 110 (1) ◽  
pp. 424-432 ◽  
Author(s):  
Natalija Buza-Vidas ◽  
Min Cheng ◽  
Sara Duarte ◽  
Hojjatollah Nozad ◽  
Sten Eirik W. Jacobsen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
B Cells ◽  
B Cell ◽  
Crucial Role ◽  
Marrow Transplantation ◽  
Immune Reconstitution ◽  
Critical Role ◽  
B Lymphopoiesis

Almost 5 decades after the first clinical transplantations, delayed immune reconstitution remains a considerable hurdle in bone marrow transplantation, and the mechanisms regulating immune reconstitution after transplantation remain to be established. Whereas adult fms-like tyrosine kinase 3 ligand–deficient (FL−/−) mice have reduced numbers of early B- and T-cell progenitors, they sustain close to normal levels of mature B and T cells. Herein, we demonstrate that adult bone marrow cells fail to reconstitute B-cell progenitors and conventional B cells in lethally irradiated FL−/− recipients, which also display delayed kinetics of T-cell reconstitution. Similarly, FL is essential for B-cell regeneration after chemotherapy-induced myeloablation. In contrast, fetal progenitors reconstitute B lymphopoiesis in FL−/− mice, albeit at reduced levels. A critical role of FL in adult B lymphopoiesis is further substantiated by an age-progressive decline in peripheral conventional B cells in FL−/− mice, whereas fetally and early postnatally derived B1 and marginal zone B cells are sustained in a FL-independent manner. Thus, FL plays a crucial role in sustaining conventional B lymphopoiesis in adult mice and, as a consequence, our findings implicate a critical role of FL in promoting immune reconstitution after myeloablation and bone marrow transplantation.

scholarly journals Role of the Cyclic AMP Response Element in the bcl-2 Promoter in the Regulation of Endogenous Bcl-2 Expression and Apoptosis in Murine B Cells

2006 ◽  
Vol 26 (22) ◽  
pp. 8599-8606 ◽  
Author(s):  
Hong Xiang ◽  
Jinghong Wang ◽  
Linda M. Boxer
Keyword(s):  
B Cells ◽  
Cyclic Amp ◽  
B Cell ◽  
Critical Role ◽  
Response Element ◽  
B Cell Survival ◽  
Cyclic Amp Response Element ◽  
Induced Apoptosis

ABSTRACT We have previously shown for B-cell lines that the cyclic AMP response element (CRE) is a major positive regulatory site in the bcl-2 promoter. However, the role of the CRE in the regulation of endogenous bcl-2 expression in vivo has not been characterized. We used gene targeting to generate knock-in mice in which a mutated CRE was introduced into the bcl-2 promoter region (mutCRE-bcl2 mice). Quantitative chromatin immunoprecipitation assays revealed that mutation of the CRE abolished the binding of CREB/ATF and CBP transcription factors to the bcl-2 promoter and greatly diminished the binding of NF-κB factors. The mutant CRE significantly reduced the expression of Bcl-2 in B cells and rendered them susceptible to surface immunoglobulin- and chemotherapeutic agent-induced apoptosis. The low levels of Bcl-2 were not changed with activation of the cells. The numbers of pre-B, immature B, and mature B cells in the bone marrow were decreased, as were the numbers of splenic B cells in mutCRE-bcl2 mice. Our findings indicate that the CRE in the bcl-2 promoter has an important functional role in the regulation of endogenous Bcl-2 expression and plays a critical role in the coordination of signals that regulate B-cell survival.

scholarly journals The mast cell–B cell axis in lung vascular remodeling and pulmonary hypertension

2017 ◽  
Vol 312 (5) ◽  
pp. L710-L721 ◽  
Author(s):  
Siegfried Breitling ◽  
Zhang Hui ◽  
Diana Zabini ◽  
Yijie Hu ◽  
Julia Hoffmann ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Mast Cell ◽  
Immune System ◽  
B Cells ◽  
Mast Cells ◽  
B Cell ◽  
Vascular Remodeling ◽  
Critical Role ◽  
Cell Axis

Over past years, a critical role for the immune system and, in particular, for mast cells in the pathogenesis of pulmonary hypertension (PH) has emerged. However, the way in which mast cells promote PH is still poorly understood. Here, we investigated the mechanisms by which mast cells may contribute to PH, specifically focusing on the interaction between the innate and adaptive immune response and the role of B cells and autoimmunity. Experiments were performed in Sprague-Dawley rats and B cell-deficient JH-KO rats in the monocrotaline, Sugen/hypoxia, and the aortic banding model of PH. Hemodynamics, cell infiltration, IL-6 expression, and vascular remodeling were analyzed. Gene array analyses revealed constituents of immunoglobulins as most prominently regulated mast cell-dependent genes in the lung in experimental PH. IL-6 was shown to link mast cells to B cells, as 1) IL-6 was upregulated and colocalized with mast cells and was reduced by mast-cell stabilizers and 2) IL-6 or mast cell blockade reduced B cells in lungs of monocrotaline-treated rats. A functional role for B cells in PH was demonstrated in that either blocking B cells by an anti-CD20 antibody or B-cell deficiency in JH-KO rats attenuated right ventricular systolic pressure and vascular remodeling in experimental PH. We here identify a mast cell–B cell axis driven by IL-6 as a critical immune pathway in the pathophysiology of PH. Our results provide novel insights into the role of the immune system in PH, which may be therapeutically exploited by targeted immunotherapy.

The Role of the BCR Class Expressed by Eμ-TCL1tg Mice and Human CLL

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 182-182
Author(s):  
Marcus Dühren-von Minden ◽  
Thomas Wossning ◽  
Hassan Jumaa ◽  
Hendrik Veelken
Keyword(s):  
B Cells ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
Operating Characteristics ◽  
Lymphoma Cells ◽  
Mutational Status ◽  
Significant Difference ◽  
Single Positive

Abstract Abstract 182 The B-cell antigen receptor (BCR) plays a critical role in the development and progression of B-cell lymphomas. In chronic lymphocytic leukemia (CLL), the existence of stereotyped heavy-chain complementarity determining regions (HCDR3) suggested that binding of external antigens might play a role in CLL pathogenesis. In contrast, we recently reported that BCRs derived from both human CLL patients and from Eμ-TCL1tg mice have the unique function to induce antigen-independent signaling. This capacity is mediated by the HCDR3 through binding to a BCR internal motif in adjacent BCRs on the same cell (Dühren-von Minden et al., Nature 2012). Mature B cells as well as CLL B cells co-express IgM and IgD with the same HCDR3. In this study, we address the respective roles of these expressed BCR classes in lymphoma pathogenesis in Eμ-TCL1tg mice and in human CLL. By mating Eμ-TCL1tg-mice with IgM−/− mice, which lacks the μ constant heavy domain (μCH) and instead expresses IgD in all developmental stages, we demonstrate a significantly lower frequency of CD19+CD5+IgM+IgDlow lymphoma cells in heterozygous IgM+/−TCL1 mice compared to conventional IgM+/+TCL1 mice (p=0.007). Furthermore, IgM+/−TCL1 mice show a delayed or slowed disease progression compared to TCL1tg mice carrying both IgM alleles. In both TCL1tg mice strains, lymphoma development was exclusively linked to expression of surface IgM, since no IgD single positive lymphoma was detected in IgM+/−TCL1 mice (n=12). TCL1tg mice that lack both μCH alleles showed an accumulation of CD19+CD5+ cells in the spleen at the age of 6 months. According to the genotype of these mice, this population was indeed IgD single positive. However, no further progression could be observed during follow-up to an age of 8 months, indicating a benign form of lymphoproliferation. In contrast to BCRs derived from Eμ-TCL1 mice, analysis of the signaling properties of BCRs derived from IgM−/−TCL1 mice failed to show any autonomous signaling capacity, even when they were expressed as IgM. To address whether IgD in general is able to mediate autonomous signaling reported for TCL1tg- and CLL-derived BCRs, we tested these receptors for autonomous signaling capacity when expressed as IgD. However, expression as IgD led to a complete loss of autonomous signaling capacity in all cases (n=10). In conclusion, whereas autonomous signaling is a characteristic feature of TCL1tg- and CLL-derived BCRs, the pathogenesis of CLL is dependent on the expression of their BCR as the IgM isotype. Expression of IgD-BCRs leads to loss of autonomous signaling capacity, and mice that lack μCH fail to develop malignant lymphoproliferation. To address the question if differential expression of IgD and IgM also had an impact on the clinical behavior of human CLL, we measured the relative expression levels of surface IgD and IgM on circulating lymphoma cells from 67 CLL patients by flow cytometry with simultaneous staining. According to previous reports (Mockridge et al., Blood 2007), unmutated (UM-CLL) cases (n=22) had a higher level of total surface Ig compared to mutated CLL (M-CLL) cases (n=45). Based on our results that IgM is more potent to drive lymphoproliferation, we calculated the ratio of mean fluorescence intensities for IgD over IgM, further called DvM-Score, for every case. A significant difference in the expression pattern as represented by the DvM-Score was observed for UM-CLL and M-CLL (p=0.003) as well as for ZAP70+ and ZAP70- cases (p=0.0002). Both UM-CLL cases as well as ZAP70+ cases show a higher amount of IgM compared to IgD represented by a DvM-Score of <1, whereas the majority of M-CLL and ZAP70− cases express less IgM than IgD and show a DvM-Score of >1. Based on receiver operating characteristics, an DvM cut-off value of 1.15 was identified to optimally discriminate mutational status (AUC: 0.72) and ZAP70 expression (AUC: 0.78). Preliminary data show that CLL samples with a DvM-Score <1.15 had a more aggressive disease course as indicated by a median time to first treatment (TTFT) of 39 months, whereas cases with a DvM-Score of >1.15 show a median TTFT of 154 months (log rank test, p=0.0014). In summary, our results demonstrate an important role of the BCR class, especially with respect to the pathogenetic role of autonomously active IgM BCRs expressed by CLL B cells, for the outcome of the disease. In addition, the DvM score may represent a convenient and novel prognostic marker for CLL. Disclosures: No relevant conflicts of interest to declare.

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