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1
Lin, Wai, Joanne Hildebrand, and Gail Bishop. "New insights into TRAF-mediated regulation of BAFF receptor signals (P1110)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 64.2. http://dx.doi.org/10.4049/jimmunol.190.supp.64.2.
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Abstract BAFF receptor (BAFFR), a member of the TNFR superfamily, binds to the pro-survival cytokine BAFF to promote B cell development and survival, and deficiencies of either BAFFR or BAFF result in inhibition of B cell development. BAFF-R engagement recruits TRAFs 2, 3 and 6 and activates the non-canonical NF-κB2 pathway. Current models propose that TRAF3 mediates degradation of the NF-κB activating kinase NIK, concluding that BAFFR-mediated TRAF3 degradation is necessary and sufficient for NF-κB2 activation. However, our recent studies of a mutant BAFFR indicate that this model is inadequate to fully explain how BAFFR activates the NF-κB2 pathway. The A/WySnJ mouse harbors a spontaneous mutation of BAFFR in which 8 residues of the cytoplasmic tail are replaced by 22 amino acids from a viral genome. Engagement of this mutant BAFF-R fails to activate the NF-κB2 pathway, and A/WySnJ mice have a substantial B cell deficiency. However, the mutant BAFF-R shows no decrease in recruitment or receptor-mediated degradation of TRAF3, demonstrating that TRAF3 degradation is not sufficient to allow NF-κB2 activation. Our recent data instead suggest that recruitment of TRAFs 2 and 6 and the signaling protein Act1 may play important roles in BAFFR-mediated NF-κB2 activation.
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Wang, Xiuli, Zhenyuan Dong, Wen-Chung Chang, Wesley Cheng, Vibhuti Vyas, Dennis Awuah, Soung-chul Cha, et al. "CD19/BAFF-R Dual-Targeted CAR T Cells for the Treatment of Mixed Antigen-Negative Variants of Acute Lymphoblastic Leukemia." Blood 138, Supplement 1 (November 5, 2021): 2783. http://dx.doi.org/10.1182/blood-2021-151293.
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Abstract The results of clinical trials evaluating CD19-targeting chimeric antigen receptor (CAR) T cells are impressive, with overall response rates of up to 90% in B cell acute lymphoblastic leukemia (ALL) and 50-80% in lymphoma. Despite initial responses, antigen-negative relapse is common following treatment with CD19-targeted therapies and is estimated to occur in up to 39% of patients. One approach of addressing this problem is to utilize dual-targeting CAR T cells, a strategy that has recently been applied to CD19/CD22 for ALL, CS1/BCMA, and BCMA/GPRC5D for multiple myeloma. Dual-targeting CARs can simultaneously target two tumor antigens and, therefore, potentially eradicate heterogeneous tumors. The initial response to dual-targeted CAR T cells is expected to provide greater tumor coverage compared to single-targeted therapy, and can potentially circumvent antigen escape. Moreover, if one tumor antigen becomes downregulated during treatment, the second targeting domain will continue to be reactive to tumors. Therefore, it is critical to identify novel targets that can be combined with CD19 in a dual-targeted immunotherapeutic platform. To expand the potential for dual targeting of ALL, we developed a CAR T cell therapy against a novel target, B-cell activating factor receptor (BAFF-R), based on the remarkable specificity of anti-BAFF-R antibodies that we previously generated. BAFF-R is expressed almost exclusively on B cells, including in patients with CD19-negative relapse, making it an ideal immunotherapeutic target. Studies demonstrate that the role of BAFF-R in B cell function and survival is conclusive, an important feature that may mitigate the tumor's ability to escape therapy through antigen loss, particularly if a non-redundant role for BAFF-R is confirmed. BAFF-R-CAR T cells demonstrate in vitro effector function and in vivo therapeutic efficacy in CD19-negative models, including patient-derived xenograft models, and are currently being evaluated clinically for the treatment of ALL (NCT04690595). We hypothesized that simultaneous targeting of CD19 and BAFF-R in a bispecific CAR platform could confer a therapeutic advantage and avoid the challenges of sequential administration of CD19 and BAFF-R monospecific CAR T cells. We leveraged our experience with CD19- and BAFF-R-CAR T cells to develop a dual-targeting, bispecific CAR with a 41BB costimulatory domain (CD19/BAFF-R dual CAR). Here, we identified the optimal orientation of the single-chain variable fragment (loop scFv) domains within the dual construct and tested the CD19/BAFF-R dual CAR T cells for their in vitro effector function and in vivo anti-leukemia activity. To evaluate the specific targeting to CD19 and BAFFR, we developed Nalm-6-BAFF-R-knockout (KO) and Nalm-6-CD19-KO cell lines. CD19/BAFF-R dual CAR T cells specifically released IFN-g following incubation with Nalm-6 CD19-/- or BAFF-R-/- cells (P<0.001) compared with un-transduced mock T cells. Both CD4+ and CD8+ CAR T cell populations exhibited effector function. To evaluate the antigen-dependent targeting of the CD19/BAFF-R dual CAR T cells in vivo, we utilized a mixed B-cell leukemia model that simulates clinical tumor heterogeneity. NOD-scid IL2Rgammanull (NSG) mice were inoculated with 2-3x10 5 of mixed Nalm-6 BAFF-R-/- and CD19-/- cells at a 1:1 ratio with a single injection. 1x10 6 CD19/BAFF-R dual CAR, CD19, or BAFF-R single CAR-T cells were administered intravenously 9-10 days later. Tumor growth was monitored by bioluminescent imaging weekly. We observed superior tumor eradication (P<0.01) and survival (P<0.01) (Figure 1) by CD19/BAFF-R dual CAR T cells compared to either single-targeting CAR and mock T cells. The adoptively transferred CD19/BAFF-R dual CAR T cells were able to persist in vivo. Our unique CD19/BAFF-R dual-targeting CAR T cells will be the first to target this combination of tumor-associated antigens. Our study demonstrated the reliability of bispecific CD19/BAFF-R dual CAR T cell therapy in inducing remission in ALL consisting of CD19-/- and BAFF-R-/- tumors. We hypothesize that simultaneous immunotherapy targeting of heterogeneous leukemic cell populations may diminish the likelihood of antigen escape and may have a significant impact on leukemia treatment by improving the therapeutic benefits of CAR T cell therapy. Figure 1 Figure 1. Disclosures Wang: Pepromene Bio, Inc.: Consultancy. Forman: Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company. Kwak: Pepromene Bio, Inc.: Consultancy, Current equity holder in publicly-traded company. Qin: Pepromene Bio, Inc.: Consultancy, Current equity holder in publicly-traded company.
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Secreto, Frank J., Michelle K. Manske, Tammy Price-Troska, Steven C. Ziesmer, Stephen M. Ansell, James R. Cerhan, and Anne J. Novak. "A Lymphoma-Associated Mutation in BAFF-R Drives Constitutive PI3K Signaling and Increased Expression of Pro-Survival Genes." Blood 118, no. 21 (November 18, 2011): 2642. http://dx.doi.org/10.1182/blood.v118.21.2642.2642.
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Abstract Abstract 2642 BAFF is essential for B cell maturation, and a lack of either BAFF or its primary receptor, BAFF-R, results in a severe depletion of T2 marginal zone and follicular B cells. Elevated serum BAFF levels have been correlated with an increased risk of developing non-Hodgkin's lymphoma (NHL), along with a more aggressive phenotype. A growing body of genetic evidence points toward an association between the development of human disease and variation in genes encoding BAFF and its receptors. Recently, we characterized a novel lymphoma-associated mutation in TNFRSF13C, the gene encoding BAFF-R. This mutation (BAFF-R H159Y) encodes a His159Tyr substitution in the C-terminus of BAFF-R adjacent to the TRAF3 binding motif. Signaling through BAFF-R H159Y results in increased NF-κB activity, elevated immunoglobulin production and increased association with TRAF2, TRAF3 and TRAF6 compared to wild type (WT) BAFF-R. We have detected this mutation in 6% of total NHL cases (n=129), and in 10% of follicular lymphoma (FL) cases (n=41) evaluated thus far. We previously reported that BAFF-R H159Y expressing mouse B cells exhibited significantly more resistance to Fas ligand (FasL) induced apoptosis compared to their cells expressing BAFF-R WT, and we propose here that BAFF-R H159Y mediated increases in PI3K activity may explain such an enhanced anti-apoptotic response. In this study we now show that BAFF stimulated HEK 293 cells stably expressing BAFF-R H159Y not only display significantly increased Akt phosphorylation when compared to BAFF-R WT expressing cells, but also demonstrate robust Akt phosphorylation in the absence of BAFF. BAFF-R H159Y-dependent Akt activation also led to activation of the downstream Akt targets mTOR and GSK3β and their phosphorylation was inhibited following treatment with the PI3- kinase inhibitor wortmannin. We next examined the impact of the BAFF-R H159Y mutation on expression of BAFF-target genes. Quantitative PCR analyses revealed that BAFF-R H159Y cells exhibited a pattern of gene expression indicative of promoting cell survival, displaying significantly higher levels of BCL2, BCL2L1 and PIN1, while down-regulating expression of the pro-apoptotic gene BIM. We recently reported that TRAF6 associates with BAFF-R, and that such binding is more pronounced in cells expressing BAFF-R H159Y. In order to investigate the role TRAF6 plays in mediating BAFF-R-dependent PI3K activity, we silenced TRAF6 expression in HEK 293 and Karpas 422 lymphoma cells using TRAF6 shRNA. Reduced TRAF6 protein expression resulted in a parallel decrease in BAFF-R WT mediated phosphorylation of mTOR in Karpas 422 cells and phosphorylation of both Akt and GSK3β was markedly reduced in BAFF-R H159Y expressing HEK 293 cells. Interestingly, TRAF6 knock-down did not affect NF-kB2 activation in either Karpas 422 or HEK BAFF-R expressing cells suggesting that Akt does not play a role in BAFF-R mediated activation of non-canonical NF-kB. Finally, preliminary co-precipitation studies indicate that Akt can be recruited to BAFF-R itself, and our initial observations suggest that such an association is significantly reduced in cells expressing BAFF-R H159Y. Taken together, these studies suggest that the BAFF-R H159Y mutation confers enhanced BAFF-R-dependent PI3K signaling and pro-survival gene expression independent of BAFF. Moreover, such enhanced P13K activation is partly dependent upon TRAF6, and decreased recruitment of Akt to BAFF-R H159Y may function to increase the amount of this PI3K target for activation. Thus, BAFF-R H159Y likely contributes to BAFF signaling irregularities in NHL patients harboring this mutation, and may predispose individuals to developing lymphoma regardless of their serum BAFF concentration. Disclosures: No relevant conflicts of interest to declare.
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Hildebrand, Joanne M., Zhenghua Luo, Michelle K. Manske, Tammy Price-Troska, Steven C. Ziesmer, Wai Lin, Bruce S. Hostager, et al. "A BAFF-R mutation associated with non-Hodgkin lymphoma alters TRAF recruitment and reveals new insights into BAFF-R signaling." Journal of Experimental Medicine 207, no. 12 (November 1, 2010): 2569–79. http://dx.doi.org/10.1084/jem.20100857.
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The cytokine B cell activating factor (BAFF) and its receptor, BAFF receptor (BAFF-R), modulate signaling cascades critical for B cell development and survival. We identified a novel mutation in TNFRSF13C, the gene encoding human BAFF-R, that is present in both tumor and germline tissue from a subset of patients with non-Hodgkin lymphoma. This mutation encodes a His159Tyr substitution in the cytoplasmic tail of BAFF-R adjacent to the TRAF3 binding motif. Signaling through this mutant BAFF-R results in increased NF-κB1 and NF-κB2 activity and increased immunoglobulin production compared with the wild-type (WT) BAFF-R. This correlates with increased TRAF2, TRAF3, and TRAF6 recruitment to His159Tyr BAFF-R. In addition, we document a requirement for TRAF6 in WT BAFF-R signaling. Together, these data identify a novel lymphoma-associated mutation in human BAFF-R that results in NF-κB activation and reveals TRAF6 as a necessary component of normal BAFF-R signaling.
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Hildebrand, Joanne M., Zhenghua Luo, Michelle Manske, Steven Ziesmer, Tammy Price-troska, Wai Lin, Bruce Hostager, et al. "A BAFF-R Mutation Associated with Non-Hodgkin Lymphoma Exhibits Altered TRAF Binding and Reveals New Insights Into Proximal BAFF-R Signaling." Blood 116, no. 21 (November 19, 2010): 468. http://dx.doi.org/10.1182/blood.v116.21.468.468.
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Abstract Abstract 468 The requirement for BAFF and BAFF-R in normal human and murine B cells is well studied, but there is also significant evidence to suggest that BAFF plays an important role in malignant B cell proliferation and survival. Serum BAFF levels are elevated in patients with non-Hodgkin lymphoma (NHL) and high BAFF levels correlate with aggressive disease and a poor response to therapy. There is also increasing genetic evidence suggesting an association between the development of human disease and genetic variation in genes encoding BAFF and its receptors. Mutations in TNFRSF13B (TACI) were identified in patients with familial common variable immunodeficiency (CVID) and IgA deficiency and we have found that single nucleotide polymorphisms (SNP) in TNFSF13B (BAFF) are associated with elevated BAFF levels and risk for developing NHL. To build upon these findings we sequenced BAFF and its receptors; TNFSF13B, TNFRSF13B, TNFRSF17(BCMA), and TNFRSF13C (BAFF-R) in NHL patients to identify novel genetic variants that may be associated with NHL risk. Among 40 individual samples (20 controls and 20 follicular lymphoma (FL) cases) that were bi-directionally sequenced we identified a heterozygous cytosine to thymidine transition in 1 patient specimen at position 475 (C475T) of TNFRSF13C. The C475T transition encodes a missense substitution of tyrosine for histidine in codon 159 (H159Y) in the highly conserved cytoplasmic tail of BAFF-R, adjacent to the TRAF3 binding motif PVPAT. We next expanded our analysis of BAFF-R H159Y and analyzed NHL tumor biopsies for the presence of the mutation. 4/41 (10%) follicular lymphomas (FL), 2/42 (5%) diffuse large B cell lymphomas, 1/22 (5%) lymphoplasmacytic lymphomas (LPL), and 1/24 (4%) mucosal associate lymphoid tissue lymphomas carried the heterozygous mutation. The BAFF-R H159Y mutation was not detected in any of the normal control DNA from healthy donors (n=100). Given its close proximity to the TRAF3 binding site in the cytoplasmic domain of BAFF-R we first wanted to determine if the H159Y mutation altered BAFF induced signaling. We generated cell lines that express HA-tagged wildtype BAFF-R, BAFF-R with the H159Y mutation, or BAFF-R with an ablated TRAF3 binding site as a negative control. Analysis of cells expressing H159Y BAFF-R demonstrates that this mutation results in increased BAFF-R-mediated NFκB1 and NF-κB2 activation. The enhanced signal activated by BAFF-R H159Y is coupled with a several fold increase in TRAF3, TRAF2, and TRAF6 recruitment to BAFF-R and increased IgM production. We further demonstrate that recruitment of TRAF6 to BAFF-R is not unique to the mutant H159Y BAFF-R, but is also an important and necessary feature of BAFF-R signaling in normal B cells. Collectively, our data identify a novel lymphoma-associated mutation in BAFF-R and describe exciting new aspects of BAFF-R signaling that are important for understanding normal B cell homeostasis and function, as well as pathogenic BAFF-R contributions to human disease. Disclosures: No relevant conflicts of interest to declare.
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Mulazzani, Matthias, Xíaolan Zhou, Wenlong Zhang, Andreas Straube, and Louisa von Baumgarten. "TMOD-33. THE ROLE OF BAFF-R SIGNALING IN THE GROWTH OF PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA." Neuro-Oncology 22, Supplement_2 (November 2020): ii235. http://dx.doi.org/10.1093/neuonc/noaa215.983.
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Abstract Primary CNS lymphoma (PCNSL) is an aggressive brain tumor. Despite improvements in therapeutic algorithms, long-term survival remains rare, illustrating an urgent need for novel therapeutic targets. BAFF-R is a pro-survival receptor expressed on most malignant B cells, including PCNSL. To date, its role in PCNSL growth remains elusive. Here, we created a BAFF-R knockout lymphoma cell line (BAFF-R-KO) using CRISPR-Cas9. In serum-starved conditions, BAFF-R-KO cells exhibit decreased viability in vitro compared to BAFF-R+ cells. Combining an orthotopic mouse model of PCNSL with chronic cranial windows and intravital microscopy, we demonstrate a significant delay in tumor growth in mice inoculated with BAFF-R-KO cells compared to BAFF-R+ PCNSL. Additionally, median survival of BAFF-R-KO mice was significantly prolonged. Altogether, our results indicate a potential of BAFF-R as a novel treatment target for PCNSL.
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Hildebrand, Joanne, and Gail Bishop. "TRAF6, a new member of the proximal signaling complex recruited by BAFFR and TACI in B lymphocytes (34.1)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 34.1. http://dx.doi.org/10.4049/jimmunol.184.supp.34.1.
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Abstract The cytokines BAFF (B-cell activating factor of the TNF family, BLyS) and APRIL (a proliferation-inducing ligand) activate several major signaling cascades responsible for B-cell survival and homeostasis. Made primarily by myeloid cells, BAFF binds and activates three cell membrane receptors; BCMA (B-cell maturation antigen), TACI (transmembrane activator and CAML interactor), and BAFF-R (BAFF Receptor, BR3), while APRIL binds TACI and BCMA. Studies of genetically altered mice demonstrate that TACI and BCMA perform niche roles in B-cell Ig isotype switching and plasma cell maintenance. In contrast, BAFF-R deletion in mice results in greater than 90% loss of mature B-cells, revealing it as an essential mediator of B-cell maturation and survival beyond the immature transitional (T1) stage. TNF receptor family proteins utilize characteristic combinations of TNF receptor associated factors (TRAFs) to bridge receptor activation with a multitude of downstream signaling pathways. To date, studies of TRAF recruitment by TACI and BAFFR and their roles in signaling have been limited, and TRAF3 was the only TRAF thought to associate with these receptors. Here we present the novel finding that TRAF6 is directly recruited by TACI and BAFFR in B-cells, and that it forms an essential link to the initiation of the canonical NF-kB pathway and other pro survival signals.
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Bossen, Claudia, Teresa G. Cachero, Aubry Tardivel, Karine Ingold, Laure Willen, Max Dobles, Martin L. Scott, et al. "TACI, unlike BAFF-R, is solely activated by oligomeric BAFF and APRIL to support survival of activated B cells and plasmablasts." Blood 111, no. 3 (February 1, 2008): 1004–12. http://dx.doi.org/10.1182/blood-2007-09-110874.
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Abstract The cytokine BAFF binds to the receptors TACI, BCMA, and BAFF-R on B cells, whereas APRIL binds to TACI and BCMA only. The signaling properties of soluble trimeric BAFF (BAFF 3-mer) were compared with those of higher-order BAFF oligomers. All forms of BAFF bound BAFF-R and TACI, and elicited BAFF-R–dependent signals in primary B cells. In contrast, signaling through TACI in mature B cells or plasmablasts was only achieved by higher-order BAFF and APRIL oligomers, all of which were also po-tent activators of a multimerization-dependent reporter signaling pathway. These results indicate that, although BAFF-R and TACI can provide B cells with similar signals, only BAFF-R, but not TACI, can respond to soluble BAFF 3-mer, which is the main form of BAFF found in circulation. BAFF 60-mer, an efficient TACI agonist, was also detected in plasma of BAFF transgenic and nontransgenic mice and was more than 100-fold more active than BAFF 3-mer for the activation of multimerization-dependent signals. TACI supported survival of activated B cells and plasmablasts in vitro, providing a rational basis to explain the immunoglobulin deficiency reported in TACI-deficient persons.
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Fu, Lingchen, Yen-Chiu Lin-Lee, Archito Tamayo, Linda Yoshimura, and Richard J. Ford. "BAFF-R Receptor Also Functions in the Nucleus of Normal and Neoplastic Human B Lymphocytes." Blood 108, no. 11 (November 1, 2006): 2368. http://dx.doi.org/10.1182/blood.v108.11.2368.2368.
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Abstract B-lymphocyte stimulator (BLyS) is a relatively newly described tumor necrosis factor (TNF) superfamily cytokine involved in cell survival and proliferation in normal and neoplastic B cells, particularly in the aggressive B cell non-Hodgkin’s lymphomas (NHL-B). BLyS binds to three receptors: BAFF-R (or BR3), BCMA and TACI. However, recent studies have shown that BLyS regulates B cell survival and proliferation predominately through BAFF-R. Mice with mutant BAFF-R show significant decrease in the peripheral blood B-lymphocyte compartment, similar to the phenotype of BLyS knockout mice. BLyS/BAFF-R signaling functions through activation of the critical transcription factor NF-kB pathways, especially the NF-kB2 pathway, which mainly involves the p52/ rel-B complex. Our previous studies have shown that BLyS is constitutively expressed in aggressive NHL-B cells leading to increased survival and proliferation of the malignant B cells. In this study, we found by western blotting and confocal microscopy that BAFF-R, the major B cell associated cell membrane receptor for BLyS, was also present in the B cell nucleus, in addition to its location in plasma membrane and cytoplasm in both normal peripheral blood B lymphocytes and NHL-B cells. Nuclear presence can be increased by anti-IgM and soluble CD154 treatment in normal peripheral blood B lymphocytes, and is constitutively expressed in aggressive NHL-B. Inhibition of BLyS expression by specific BLyS siRNA decreases nuclear BAFF-R level and survival in LBCL cells. Immunostaining experiments show that in the cytoplasm of normal and neoplastic B cells, BAFF-R interacts with the improtin a and b which are members of the classic karypherin pathway. A candidate nuclear localization sequence (NLS) was also identified in the BAFF-R protein sequence, and mutation of this putative NLS can block BAFF-R entering nucleus, which is consistent with our hypothesis that BAFF-R undergoes nuclear translocation. To further investigate the functional role of BAFF-R in nucleus, we performed confocal immunostaining analysis and co-immunoprecipitation, that shows that BAFF-R co-localizes with some NF-kB family members such as c-rel in the B cell nucleus. We also found that nuclear BAFF-R/c-rel complex can bind to the NF-kB binding site on the promoters of NF-kB target genes such as BLyS, CD154, Bcl-xL and Bfl-1 /A1 by chromatin immnoprecipitation (ChIP) assay. Luciferase reporter assays show that BAFF-R has transactivation activity on these NF-kB target genes. Furthermore, NLS mutant BAFF-R decreases NF-kB target gene promoter activity, compared to wild type BAFF-R, and NHL-B cell proliferation. These findings indicates that in addition to activating NF-kB pathways at the plasma membrane, BAFF-R may also promote survival and proliferation of both normal and NHL-B cell in the nucleus by directly regulating transcriptional activity of key NF-kB target genes and may functions as a transcriptional co- factor with NF-kB.
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Castigli, Emanuela, Stephen A. Wilson, Sumi Scott, Fatma Dedeoglu, Shengli Xu, Kong-Peng Lam, Richard J. Bram, Haifa Jabara, and Raif S. Geha. "TACI and BAFF-R mediate isotype switching in B cells." Journal of Experimental Medicine 201, no. 1 (January 3, 2005): 35–39. http://dx.doi.org/10.1084/jem.20032000.
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The tumor necrosis factor family members BAFF and APRIL induce Ig isotype switching in human B cells. We analyzed the ability of BAFF and APRIL to induce isotype switching in murine B cells to IgG1, IgA, and IgE. APRIL and BAFF each engage two receptors, transmembrane activator and calcium-modulator and cytophilin ligand interactor (TACI) and B cell maturation antigen (BCMA), on B cells. In addition, BAFF engages a third receptor on B cells, BAFF-R. To determine the role of these receptors in isotype switching, we examined B cells from mice deficient in TACI, BCMA, and BAFF-R. The results obtained indicate that both TACI and BAFF-R are able to transduce signals that result in isotype switching.
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Proust, Alexis, Idir Adrar, Patricia Rince, Virginie Mercier, Thierry Lazure, Martine Raphael, and Loïc Garçon. "Expression of the BAFF-R (BR3) Is Positive in a Minority of Diffuse Large B Cell Lymphomas and Does Not Correlate with the Germinal Center or Non Germinal Center Origin of Lymphomatous Cells." Blood 106, no. 11 (November 16, 2005): 4711. http://dx.doi.org/10.1182/blood.v106.11.4711.4711.
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Abstract BAFF, a member of the TNF family, has been shown to be implicated in B cell maturation and survival through an interaction with its three receptors, BCMA, TACI and BAFF-R. Recent data revealed that it also plays a role in B cell malignancies. For exemple, an autocrine activation of the BAFF receptors could participate to oncogenesis during multiple myeloma or chronic lymphocytic leukemia. BAFF-R, the sole BAFF specific receptor, is expressed in a subset of Diffuse Large B Cell Lymphomas (DLBCL). Since BAFF-R activation in B cells leads to cell proliferation and survival, expression of this receptor in DLBCL could correlate with more aggressive lymphomas. DLBCL can be divided into prognostically important subgroups with germinal center B cell-like (GCB), activated B cell-like (ABC) and type 3 gene expression profiles using a cDNA microarray. The germinal center origin of malignant B cells in DLBCL can also be characterized by immunohistochemistry (IHC) according to CD10, Bcl6 CD138 and MUM1 expression. In this work, we investigated whether expression of BAFF-R in DLBCL correlate or not with the GCB vs non GCB phenotype of lymphomatous cells. Lymph nodes biopsies from 23 DLBCL (among whom 3 post-transplantation lymphomas and 1 AIDS-related DLBCL) were analyzed. In a first step, we characterized by IHC the precise phenotype of each DLBCL: CD10+/Bcl6+ DLBCL were classified into the germinal center (GCB) group (n=9), whereas CD10-/BCL6-/MUM1+ lymphomas defined the non germinal center (NGCB) one (n=14). Each DLBCL was then analyzed for BAFF-R expression by IHC. In agreement with a recent report, most of the DLBCL were found to be negative for BAFF-R expression (16 out of 23). Interestingly, 4 of the 9 GCB DLBCL were found to be BAFF-R positive (44%), whereas only 3 out of 14 (21%) in the NGCB group. Although the difference did not reach statistical significance, we concluded from this observation that a consequent percentage of GCB DLBCL express the specific receptor BAFF-R. Thus, we actually analyze the clinical and biological characteristics of BAFF-R positive DLBCL and investigate whether expression of BAFF-R could represent a bad prognosis factor in term of clinical outcome and response to treatment.
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Qin, Hong, Zhenyuan Dong, Xiuli Wang, Wesley Cheng, Diane Lynne Smith, Joo Y. Song, Ibrahim Aldoss, Markus Muschen, Stephen J. Forman, and Larry W. Kwak. "Novel BAFF-R CAR T-Cell Therapy for CD19 Antigen-Loss Relapsed B Cell Tumors." Blood 132, Supplement 1 (November 29, 2018): 1411. http://dx.doi.org/10.1182/blood-2018-99-117513.
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Abstract Background: Chimeric antigen receptor (CAR) T cells against CD19 have shown great potential in treatment of B cell malignancies. However, tumor relapse from antigen loss can limit efficacy. B-cell activating factor-receptor (BAFF-R), a tumor necrosis factor receptor superfamily protein (TNFRSF13C), is another potential B-cell specific target of B cell malignancies. BAFF-R is an especially interesting alternative to CD19 as BAFF-R signaling is a driver of B-cell survival, which may limit the capacity of clonal B-cell tumors to escape therapy by down-regulation of antigen expression. However, while the BAFF/BAFF-R axis has been successfully targeted for autoimmune diseases, the promise for cancer therapy has not yet been fulfilled. Methods and Results: A humanized, single-chain variable fragment (scFv) derivative of an anti-human BAFF-R antibody (Qin et al. Clin Can Res 2018;24:1114-1123) was engineered onto a second generation CAR construct containing 4-1BB costimulatory and CD3ζ intracellular signaling domains. BAFF-R-CAR T cells demonstrated cytotoxicity against human lymphoma and acute lymphocytic leukemia (ALL) lines. Adoptively transferred BAFF-R-CAR T cells eradicated 10-day pre-established tumor xenografts after a single treatment and were superior to CD19-CAR T cells (not shown) and retained efficacy against xenografts deficient in CD19 expression, including one primary patient-derived xenograft (PDX). Specifically, we modeled disease relapse due to the loss of CD19 by generating CRISPR CD19 gene knock-out of the ALL (Nalm-6) cell line and a gRNA-silenced CD19 gene knock-down of an ALL PDX. We confirmed the absence of CD19 and presence BAFF-R expression, which was unaffected, on the resulting cell lines by surface staining (Fig. 1A). Using transduced CD8 TN cells, we found that CD19-CAR T cells demonstrated cytotoxicity only against wild-type tumor cells, while BAFF-R-CAR T cells maintained significant cytotoxicity against both wild-type and CD19-negative tumors in vitro (Fig. 1B). The therapeutic efficacy of BAFF-R-CAR T cells was tested against human ALL Nalm-6-CD19 deficient xenografts established in NSG mice following IV tumor challenge on day 0 with luciferase-expressing cells. A single dose of 2.5 x 106 CD4 TN + 106 CD8 TN BAFF-R- or CD19-CAR T cells/mouse infused IV on day 11 post tumor implantation completely eliminated established Nalm-6-CD19KO ALL tumors and conferred long-term survival. In contrast, treatment with PBS or identical mixtures of CD19-CAR T cells or non-transduced T cells from the same donor were associated with progressive tumor growth and 100% mortality by Day 60 (Fig. 1C). Finally, four relapsed, antigen loss primary ALLs obtained after CD19-directed therapy retained BAFF-R expression and activated BAFF-R-, but not CD19-CAR T cells. Specifically, cell surface staining demonstrated CD19 and BAFF-R expression in tumors obtained prior to CD19-targeted therapy. However, post-treatment samples exhibited clear down-regulation of CD19, while retaining positive BAFF-R expression (Fig. 1D, results from a single representative patient shown). The ability of the primary tumor samples to activate either CD19- or BAFF-R-CAR T cells was determined by expression of the degranulation marker CD107a on the CAR T cells. Cryopreserved ALL samples were co-cultured with BAFF-R or CD19 CAR-T cells derived from the same healthy donor in the presence of anti-CD107a antibody for 6 h. Non-transduced T cells (non-CAR) from the same donor were used as a negative control. Activation of CD19-CAR T cells by all four CD19-negative post-blinatumomab therapy tumors was significantly reduced, compared with BAFF-R-CAR T cells and with corresponding available CD19-positive pre-therapy tumors, while BAFF-R-CAR T cells were equally activated by pre- and post-CD19-targeted therapy tumors (Fig.1E-F). We observed similar trends for both CD19- and BAFF-R-CAR T cell activation by pre- and post-CD19-targeted therapy tumors, as measured by specific intracellular CAR T-cell TNF-α and IFN-γ production (not shown). Conclusion: Taken together, our data suggest that BAFF-R is amenable to CAR T-cell therapy and that targeting it may add to existing alternative strategies to overcome relapse from CD19 antigen loss, such as CD22 CAR T cells. Future strategies combining dual targeting of CD19 and BAFF-R may also be effective. Disclosures Wang: Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.
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Qin, Hong, Zhenyuan Dong, Xiuli Wang, Wesley Cheng, Diane Lynne Smith, Joo Y. Song, Ibrahim Aldoss, Stephen J. Forman, and Larry W. Kwak. "Overcoming CD19 Antigen Loss in B-Cell Malignancies with CAR T Cells Targeting BAFF-R." Blood 134, Supplement_1 (November 13, 2019): 3871. http://dx.doi.org/10.1182/blood-2019-129228.
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Background: The current success in treating hematological malignancies with CD19 targeted chimeric antigen receptor (CAR) T cells is diminished by tumor relapse from target antigen loss. The B-cell activating factor-receptor (BAFF-R), a tumor necrosis factor receptor superfamily protein (TNFRSF13C), is a particularly interesting alternative target in CD19 relapsed disease and in B cell malignancies in general. BAFF-R null mice exhibit greatly reduced normal B-cell numbers and mouse strains expressing a mutant BAFF-R exhibited decreased B-cell life spans and a dramatically reduced peripheral B-cell compartment. Thus, BAFF-R signaling is a driver of B-cell survival, which may limit the capacity of clonal B-cell tumors to escape therapy by down-regulation of antigen expression. We have exploited the potential of the BAFF/BAFF-R axis and developed a proprietary BAFF-R targeting CAR T cell using a single-chain variable fragment (scFv) of a humanized anti-human BAFF-R antibody engineered into a second generation CAR construct containing 4-1BB costimulatory and CD3ζ intracellular signaling domains (Qin et al. Sci. Transl. Med., In Press). BAFF-R CAR T cells were cytotoxic against a panel of human leukemia and lymphoma lines. Adoptively transferred BAFF-R-CAR T cells eradicated 10-day pre-established tumor xenografts after a single treatment and retained efficacy against xenografts deficient in CD19 expression, including CD19-negative variants within a background of CD19-positive lymphoma cells. BAFF-R-, but not CD19-CAR T cells, also demonstrated antitumor effects against an additional CD19 antigen loss primary patient-derived xenograft (PDX) in vivo. Methods and Results: A first-in-human clinical trial of this BAFF-R CAR T cell in B-ALL is planned. To this end, we cloned the BAFF-R CAR construct into a previously FDA approved clinical lentiviral vector (Figure, part A), and produced BAFF-R CAR T cells using both the research prototype and clinical vectors for head-to-head analysis. We observed comparable cytotoxic T lymphocyte activity against previously established leukemia and lymphoma models in vitro. In vivo, NSG mice challenged with Nalm-6 human B-ALL tumors were randomized (n=5/group) for treatment with either BAFF-R CAR produced from the research prototype or clinical vectors. The two experimental groups were indistinguishable in their antitumor efficacy (data not shown). Further, to advance IND enabling studies we also compared clinical CAR T cell manufacturing strategies. We used an early stage TN/MEM subset for CAR T cell production, as used in previous CAR T cell trials at our institution, and using TN/MEM isolated from healthy donor PBMCs achieved 36% transduction efficiency, comparable to clinical experience at City of Hope. Finally, we assessed the therapeutic effects of BAFF-R CAR TN/MEM cells in vivo. We challenged NSG mice on day 0 with 1 x 105 Nalm-6-CD19 deficient (Nalm-6-CD19KO) human ALL tumor cells and randomized them (n=5/group) to receive a single infusion of either low dose (1 x 106) or high dose (2 x 106) BAFF-R-CAR TN/MEM cells on day 10. Because transduction efficiency was 36%, 2.8 or 5.6 x 106 total T cells were infused to yield 1 or 2 x106 BAFF-R-CAR TN/MEM, respectively. Non-transduced T cells from the same donor were used as allogeneic controls (non-CAR). Tumors were monitored by bioluminescent imaging on the days indicated. Both the low and the high dose BAFF-R CAR T cell groups demonstrated complete Nalm-6 CD19KO tumor regressions, compared with controls (Figure, part B). Conclusions: Our studies support the clinical development of BAFF-R CAR T cells and a pending clinical trial of BAFF-R CAR T cell therapy in relapsed/refractory B-ALL patients who have failed prior CD19-targeted immunotherapy. Targeting BAFF-R may thereby add to existing alternative strategies to overcome relapse from CD19 antigen loss. While BAFF-R antigen loss by tumor cells is unlikely, because its expression is critically required for normal B-cell survival, this hypothesis can only be established by clinical testing. Disclosures Qin: InnoLifes: Consultancy, Equity Ownership; Pepromene Bio: Consultancy, Equity Ownership. Aldoss:AUTO1: Consultancy; Helocyte: Consultancy, Honoraria, Other: travel/accommodation/expenses; Jazz Pharmaceuticals: Honoraria, Other: travel/accommodation/expenses, Speakers Bureau; Agios: Consultancy, Honoraria. Kwak:Pepromene Bio: Consultancy, Equity Ownership, Research Funding; InnoLifes: Consultancy, Equity Ownership; Xeme BioPharma, Inc: Consultancy, Equity Ownership; Enzychem LifeSciences: Consultancy; Celltrion, Inc.: Consultancy; Celltrion Healthcare: Consultancy.
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Mihalcik, Stephen A., and Diane F. Jelinek. "C-Rel in the Regulation of BAFF-R Expression in Malignant Human B Cells." Blood 114, no. 22 (November 20, 2009): 2400. http://dx.doi.org/10.1182/blood.v114.22.2400.2400.
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Abstract Abstract 2400 Poster Board II-377 Tumor necrosis factor superfamily member BAFF-R has been shown to transduce a powerful survival signal in B lineage cells upon ligation by BAFF, its soluble high affinity ligand. The availability of BAFF in lymphoid organs and its detectable levels in the blood suggest that it is the control of receptor expression by the B cell rather than ligand production by supportive cells that limits the activity of this survival signal. The presence of BAFF-R on the surface of B cells from the transitional stages of development through maturity mirrors the expression of BAFF-R on the malignancies thought to arise from these various developmental stages and may enable B lineage malignancies to receive an anti-apoptotic signal from BAFF that reinforces and supports the expansion of the malignant cells. This additional survival signal may be crucial in indolent malignancies like chronic lymphocytic leukemia (CLL), a cancer characterized more by the prolonged survival of the cancerous cells than by their abundant proliferation. While there are ongoing efforts to thwart this survival pathway with antibody-based therapeutics directed toward BAFF and BAFF-R, understanding the regulation of BAFF-R expression may open a more proximal, potent, and novel therapeutic avenue. Rel/NF-kB family member c-Rel is an appealing candidate BAFF-R regulator, since its nuclear localization and expression within B lineage cells roughly correlate with BAFF-R expression, predominating at nuclear kB sites as a dimer with p50 in mature B cells and declining in plasma cells. Recently published evidence has shown that B cell receptor (BCR)-induced c-Rel expression can modulate BAFF-R in murine transitional B cells, providing a critical increase in BAFF-R expression and thus, BAFF-responsiveness, during B cell development (Castro, I. J Immunol. 2009; 182(12): 7729). A role for the BCR is especially provocative in the context of CLL, which is commonly characterized by lower levels of surface BAFF-R despite a generally activated phenotype and, in the unmutated subtype, typically increased expression of genes downstream of the BCR. In related studies, we have analyzed BAFF-R promoter activity in BAFF-R expressing B cells vs. myeloma cell lines, which generally lack expression of this receptor, and have indeed demonstrated differential promoter activity of the region directly upstream of the BAFF-R gene. The goal of our current study was to focus on the role of the transcription factor, c-Rel, in regulating BAFF-R expression. While in silico tools identifying transcription factor binding sites in the three kilobases upstream of the BAFF-R gene found numerous possible c-Rel binding sites, only three c-Rel sites remained under the most stringent search conditions. An initial chromatin immunoprecipitation (ChIP) experiment with an anti-c-Rel antibody suggested that the binding site within the first five hundred bases upstream of the transcriptional start site may be bound by c-Rel: ChIP with RAMOS B cells showed a 6-fold increase in the precipitated DNA of the region over the isotype-matched antibody control. Electrophoretic mobility shift assays (EMSAs) using peripheral blood (PB) B cell nuclear extracts both from normal donors and CLL patients as well as malignant cell lines, demonstrate the different levels of binding to the putative c-Rel sites identified in silico and support the hypothesis that c-Rel directly regulates BAFF-R expression in these cells. These assays, which demonstrated the affinity of c-Rel for the putative promoter sites upstream of the BAFF-R gene, led to the transfection of new luciferase reporter constructs into malignant B and plasma cell lines, which demonstrate the effects both of amplifying and of mutating the c-Rel binding sites in our reporter assays. We supplemented these assays with experiments measuring the production of c-Rel in these cells both by quantitative RT-PCR, which demonstrated a twenty-fold decrease in plasma cell line ALMC-1 and a two-fold decrease in CLL cell c-Rel mRNA as compared to normal PB B cells, and by Western blot. Finally, we used a c-Rel expression vector to directly increase BAFF-R expression in the malignant cell lines. By identifying c-Rel expression and activation as a possible mechanism of direct control of BAFF-R expression in human B cells, we reveal a critical new rationale for the use of NF-kB inhibitors as chemotherapeutic adjuvants in B cell cancers. Disclosures: No relevant conflicts of interest to declare.
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Tschumper, Renee C., Jaime R. Darce, Xiaosheng Wu, Stephen A. Mihalcik, and Diane F. Jelinek. "Comprehensive Analysis of BAFF Binding Receptor Profiles and Receptor Occupancy in B Cell Chronic Lymphocytic Leukemia: Identification of Discrete Phenotypic Subgroups." Blood 110, no. 11 (November 16, 2007): 1135. http://dx.doi.org/10.1182/blood.v110.11.1135.1135.
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Abstract B cell-activating factor (BAFF) is known to regulate normal B cell development and homeostasis primarily by signaling through the high affinity receptor, BAFF-R, one of three BAFF binding receptors (BBRs). BAFF also binds two other receptors, BCMA and TACI with lesser affinity. We have recently shown that normal peripheral blood (PB) B cells express high levels of prebound soluble BAFF, which is lost upon B cell activation. Because of BAFF’s activity on normal B cells, we have been interested in the roles of BAFF and BBRs in B cell chronic lymphocytic leukemia (B-CLL). We and others have demonstrated that BAFF promotes primary CLL B cell survival and that serum BAFF levels are elevated in some patients. Although CLL B cells are known to express BBRs, a comprehensive and quantitative analysis of BBR levels and CLL B cell capacity to bind BAFF has not yet been done. We began this study by characterizing the level of soluble BAFF bound to freshly isolated CLL B cells, measured by both western blot analysis and flow cytometry. To assess receptor occupancy, cells were incubated with or without exogenous BAFF before assessing anti-BAFF reactivity and changes in median fluorescence intensity (ΔMFI; defined by dividing the MFI of the anti-BAFF antibody by the MFI of the isotype matched control antibody) were calculated. Normal B cells have higher detectable levels of bound BAFF with a ΔMFI ranging from 16 to 35 (mean=22.2). Upon addition of exogenous BAFF, the ΔMFI range increased to 27–96.6 (mean=49.1; n=8). Thus, despite evidence of prebound BAFF, clearly not all BBRs were occupied on normal PB B cells. By contrast, the levels of prebound BAFF on CLL B cells were significantly lower with a ΔMFI ranging from 1 to 13.1 (mean=2.7; n=36). Of note, 10/36 patients did not exhibit increased anti-BAFF reactivity upon incubation with exogenous BAFF (mean fold induction=0.8) whereas 26/36 patients displayed a mean fold induction of anti-BAFF reactivity of 3.5. These observations prompted us to next quantitate CLL B cell BBR expression. All patient CLL B cells expressed BAFF-R but at significantly lower levels than observed in normal B cells (p=0.0009). When CLL patients were categorized into IGHV mutated (M; n=22) and unmutated (UM; n=24), UM patients were observed to express higher levels of BAFF-R (ΔMFI =8.9) than M patients (ΔMFI =5.24). Regarding TACI, we previously demonstrated that normal memory B cells uniformly express TACI (ΔMFI =12.7; n=10) and there is a small population of activated naïve B cells that express TACI at lower levels (ΔMFI =8.3; n=10). In our CLL cohort, 14/22 M patients were TACI+ (ΔMFI =7.0) and 19/24 UM patients were TACI+ (ΔMFI =4.7). Finally, whereas normal PB B cells completely lack BCMA expression, 7/22 M and 4/22 UM patients expressed BCMA. Thus, using the BBR profile and analysis of expression levels relative to normal PB B cells, the following subgroups of B-CLL can be defined: BAFF-R+; BAFF-R/TACI+; BAFF-R/BCMA+; BAFF-R/TACI/BCMA+. It remains to be determined if these BBR profiles correlate with aspects of clinical disease. In addition, given the putative importance of BAFF in this disease, it is interesting to note that in general, CLL B cells display overall lower levels of prebound BAFF. Current studies are focused on determining whether this reflects CLL B cell activation status, increased competition for BAFF, and/or reduced levels of BBR expression.
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Hu, Shanshan, Rui Wang, Mei Zhang, Kangkang Liu, Juan Tao, Yu Tai, Weijie Zhou, Qingtong Wang, and Wei Wei. "BAFF promotes T cell activation through the BAFF-BAFF-R-PI3K-Akt signaling pathway." Biomedicine & Pharmacotherapy 114 (June 2019): 108796. http://dx.doi.org/10.1016/j.biopha.2019.108796.
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Hikida, Masaki, Sachiko Johmura, Ari Hashimoto, Mayuko Takezaki, and Tomohiro Kurosaki. "Coupling Between B Cell Receptor and Phospholipase C-γ2 Is Essential for Mature B Cell Development." Journal of Experimental Medicine 198, no. 4 (August 11, 2003): 581–89. http://dx.doi.org/10.1084/jem.20030280.
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Two signaling pathways known to be essential for progression from immature to mature B cells are BAFF receptor (BAFF-R) and the B cell receptor (BCR). Here, we first show that phospholipase C (PLC)-γ2 is required for a BAFF-R–mediated survival signal. Then, we have examined the question of whether the reduced number of mature B cells in PLC-γ2−/− mice is caused by a defect in either BCR or BAFF-R signaling. We find that a PLC-γ2 SH2 mutant, which inhibits coupling between BCR and PLC-γ2, fails to restore B cell maturation, despite supporting BAFF-dependent survival. Therefore, our data suggest that the BAFF-R–mediated survival signal, provided by PLC-γ2, is not sufficient to promote B cell maturation, and that, in addition, activation of PLC-γ2 by BCR is required for B cell development.
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Hakim, Frances T., Najibah Rehman, John Dickinson, Sivasubramanian Baskar, Christoph M. Rader, Edward W. Cowen, Steven Z. Pavletic, and Ronald E. Gress. "Elevated BAFF Is Correlated with Inflammatory Processes in Chronic Graft Versus Host Disease and Supports Increases in Transitional B Cells." Blood 112, no. 11 (November 16, 2008): 465. http://dx.doi.org/10.1182/blood.v112.11.465.465.
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Abstract B Cell Activating Factor of the TNF Family (BAFF) plays a critical role in the survival, activation and function of B cells. Elevated levels of BAFF in plasma, however, have been reported in systemic autoimmune disorders and in chronic graft versus host disease (CGVHD). We similarly observed elevated plasma BAFF levels in 98 patients in an ongoing NCI CGVHD natural history protocol, with a median of 2653 pg/ml (range 92 to 14907), as compared to 556 pg/ml (range 75 to 1834) in 18 normal donors. Furthermore, in a subset of 40 patients in which severity of cutaneous CGVHD could be assessed by the presence of marked erythema or sclerosis, BAFF levels correlated with total percentage body surface area involvement (p<0.02). We then explored the factors that might contribute to elevated BAFF levels. In recipients recovering from either autologous or allogeneic transplant (without GVHD) we observed the highest BAFF levels at day 0 (median of 10534 and 12240 pg/ml respectively), when B cells were severely depleted. As B cell populations recovered to normal levels post transplant, plasma BAFF concentrations declined (Spearman r = −.80 and r = −.60, respectively), consistent with homeostatic cytokine-consumption dynamics. Despite comparably high levels of BAFF (median of 11342 pg/ml) at transplant day 0 in 16 patients who later developed CGHVD, BAFF levels in the cross-sectional, natural history patient population were only moderately correlated with the degree of post transplant B cell recovery (r = −.46). Since inflammatory triggers can induce elevated BAFF production, we assessed plasma levels of cytokines indicative of an inflammatory process. In 98 patients, the plasma levels of IP-10 and sTNFRII correlated positively with BAFF levels (r = +.579 and r = +.396, respectively), consistent with active inflammatory processes in those CGVHD patients with elevated BAFF levels. In a multi-step regression model, the levels of circulating B cells, plasma IP-10 and sTNFRII combined to strongly predict BAFF levels (R =.704). These findings suggest that both homeostatic recovery of B cell populations consuming BAFF and inflammatory cytokine cascades initiated by donor-anti-host reactivity combine to regulate BAFF levels post transplant. Although a broad range of autoimmune symptoms have been described in CGVHD, the mechanisms by which donor-anti-host reactivity can result in autoimmunity remains poorly understood. In murine models, elevated BAFF levels have been associated with increased survival of the transitional B cell population, altering the normal processes of B cell negative selection, and resulting in failure to eliminate auto-reactive B cells. We therefore assessed whether elevated BAFF levels were associated with increased frequencies of transitional CD21− T1 B cells in CGVHD patients. In 79 CGVHD patients, the median percentage of CD19+CD21− transitional B cells was 6.13% (range 1% to 39.4%) as compared to 2.24% (range 0.66% to 7.44%) in 40 healthy adult donors. Furthermore, the frequency of CD21− transitional B cells was significantly higher in those patients with higher BAFF levels (p<.002). Finally, the expression (mean fluorescent intensity (MFI)) of the BAFF receptor (BAFF-R) was reduced in patients with CGVHD compared with normal donors, consistent with down-regulation upon BAFF consumption; among CGVHD patients, receptor MFI was inversely correlated with BAFF levels (Spearman r = −.44). Elevated BAFF levels in CGVHD therefore may both reflect the inflammatory processes initiated by donor-anti-host reactivity and contribute to the later generation of pathologic autoantibodies by dysregulation of B cell negative selection.
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Qin, Hong, Zhenyuan Dong, Xiuli Wang, Wesley A. Cheng, Feng Wen, Weili Xue, Han Sun, et al. "CAR T cells targeting BAFF-R can overcome CD19 antigen loss in B cell malignancies." Science Translational Medicine 11, no. 511 (September 25, 2019): eaaw9414. http://dx.doi.org/10.1126/scitranslmed.aaw9414.
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CAR T cells targeting CD19 provide promising options for treatment of B cell malignancies. However, tumor relapse from antigen loss can limit efficacy. We developed humanized, second-generation CAR T cells against another B cell–specific marker, B cell activating factor receptor (BAFF-R), which demonstrated cytotoxicity against human lymphoma and acute lymphoblastic leukemia (ALL) lines. Adoptively transferred BAFF-R-CAR T cells eradicated 10-day preestablished tumor xenografts after a single treatment and retained efficacy against xenografts deficient in CD19 expression, including CD19-negative variants within a background of CD19-positive lymphoma cells. Four relapsed, primary ALLs with CD19 antigen loss obtained after CD19-directed therapy retained BAFF-R expression and activated BAFF-R-CAR, but not CD19-CAR, T cells. BAFF-R-CAR, but not CD19-CAR, T cells also demonstrated antitumor effects against an additional CD19 antigen loss primary patient–derived xenograft (PDX) in vivo. BAFF-R is amenable to CAR T cell therapy, and its targeting may prevent emergence of CD19 antigen loss variants.
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Kim, Seok Jin, Hwa Jung Sung, Chul Won Choi, In Sun Kim, Byung Soo Kim, Soo-Young Yoon, Jong-Ho Won, and Jun Suk Kim. "Serum B-Cell Activating Factor (BAFF) in Diffuse Large B-Cell Lymphoma: Its Prognostic Significance in the Rituximab Era." Blood 110, no. 11 (November 16, 2007): 1575. http://dx.doi.org/10.1182/blood.v110.11.1575.1575.
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Abstract The introduction of rituximab, a chimeric monoclonal antibody against the CD20 antigen has significantly improved the treatment outcome of diffuse large B-cell lymphoma (DLBCL). However, not all patients with DLBCL respond to rituximab plus CHOP (R-CHOP) chemotherapy. Thus, resistant clones of DLBCL remain a significant clinical problem. Although the underlying mechanisms of this resistance are still not clear, considering that the dysregulation of the balance between cell survival and programmed cell death is a central feature of lymphomagenesis, a factor promoting survival of lymphoma cells may be associated with resistance of DLBCL to rituximab. B-cell activating factor (BAFF), a member of the tumor necrosis factor (TNF) superfamily has shown to be a key mediator in the formation and regulation of normal B-cell response. BAFF is usually expressed by monocytes and macropahges, and is promoting cell survival and preventing apoptosis. Therefore, we performed this study to determine the clinical impact of serum BAFF on the treatment outcome of DLBCL treated with R-CHOP. 48 patients diagnosed as DLBCL were enrolled, and all the patients were treated with R-CHOP every 3 weeks. Before treatment and every two cycles of R-CHOP, their serum was taken and cryopreserved. The level of BAFF was measured by ELSA method (Human BAFF immunoassay, R&D systems, USA). We also analyzed the expression of BAFF receptor in tumor sections by immunohistochemistry (Polyclonal antibody to BAFF receptor, Abcam, UK). Median age of the patients was 56 years old (range 21–79). 20 patients were stage I/II, and 28 were stage III/IV. Rituximab was administered at the dosage of 375mg/m2 on day1, and CHOP chemotherapy was combined with rituximab until 6 – 8 cycles. The mean level of BAFF at the time of diagnosis was 2284.54pg/mL, and the median was 1326.60pg/mL (138.80–13537.92pg/mL). When the patients were dichotomized into high and low BAFF group based on the median value, 21 patients showed complete response in low BAFF group, however, only 3 patients showed complete response in high BAFF group (p=0.011). Among 16 patients showing relapse, 11 patients belonged to high BAFF group. The expression of BAFF receptor was also increased in relapsed patients compared to non-relapse group (p < 0.05). In the analysis of relapse-free survival, low BAFF group did not reach the median value as yet while high BAFF group showed 379 days (p=0.046). Thus, baseline serum BAFF may be associated with response of DLBCL to R-CHOP. When we serially checked the level of serum BAFF, the level of BAFF was increased during treatment (After the 2nd cycle 6448.56pg/mL, and after 4th cycle 7421.28pg/mL). In conclusion, serum B-cell activating factor may be a useful indicator predicting response to R-CHOP and prognosis in patients with DLBCL. Figure Figure
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Kim, Kwang Soo, Ilo Jou, and Sang Myun Park. "Functional Implication of BAFF Synthesis and Release in Gmix-stimulated Microglia (B174)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): LB36. http://dx.doi.org/10.4049/jimmunol.178.supp.b174.
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Abstract BAFF (B-cell activating factor) is a recently identified member of TNF ligand superfamily that plays a critical role in B cell differentiation, survival, and regulation of immunoglobulin production. It exerts its effect by binding to three receptors: BAFF-R (BAFF receptor), TACI (transmembrane activator and CAML interactor), and BCMA (B-cell maturation antigen) which was known to be primarily expressed in B-lineage cells. In this present study, we examined whether or not BAFF is also expressed in microglia and the synthesis and release of BAFF is regulated by stimuli. BAFF is expressed and released in primary rat microglia as well as BV-2 cells, mouse microglial cell line and the expression and release of BAFF is increased by Gmix-stimuli in microglia. The expression and release of BAFF is regulated by JAK-STAT, especially STAT1 and STAT3-dependent signaling pathway. Interestingly, SP600125, and SB203580, inhibitors of p38 and JNK, respectively, did not inhibit BAFF expression, but inhibit the release of BAFF by soluble form. It suggested that p38 and JNK signaling pathway regulate the release, not the synthesis of BAFF in microglia. In BV-2 cells, only BAFF-R is expressed in cytoplasm and cell-surface. However, in primary rat microglia of microglia, BAFF-R and TACI are expressed in cytoplasm and cell-surface. Recombinant BAFF increases cytokines release, especially, IL-6 and IL-10 in primary rat microglia as well as BV-2 cells. It was suggested that BAFF, secreted by microglia may play important roles in CNS inflammation through regulating microglia as well as infiltrated B cells.
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Dong, Zhenyuan, Wesley A. Cheng, D. Lynne Smith, Brian Huang, Tiantian Zhang, Wen-Chung Chang, Xiuli Wang, Stephen J. Forman, Larry W. Kwak, and Hong Qin. "Antitumor efficacy of BAFF-R targeting CAR T cells manufactured under clinic-ready conditions." Cancer Immunology, Immunotherapy 69, no. 10 (May 25, 2020): 2139–45. http://dx.doi.org/10.1007/s00262-020-02614-8.
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Abstract B-cell malignancies can potentially be cured by CD19 chimeric antigen receptor (CAR) T-cell therapy. Although clinical response rates can be up to 93% in acute lymphoblastic leukemia, treatment-related antigen loss and lack of therapeutic persistence contribute to disease relapse. These shortcomings of current CAR T-cell therapy indicate the need for biologically relevant target selection and for improving the efficacy and persistence of the CAR T cells, which we have addressed by developing a novel B-cell activating factor receptor (BAFF-R) CAR T-cell therapy with improved therapeutic persistence. BAFF-R is a B-cell survival receptor and highly expressed in B-cell malignancies. We developed a prototype CAR T cell that efficiently and specifically eliminated BAFF-R expressing human B-cell tumors in several xenogeneic mouse models, including models of CD19 antigen loss. We proceeded with translational development and validation of BAFF-R CAR T cells produced under current good manufacturing practices (cGMP). cGMP-grade BAFF-R CAR T cells underwent in vitro and in vivo validation in established models to confirm that the potency and efficacy of our original research modeling was replicated. Food and Drug Administration required release testing was performed to ensure our BAFF-R CAR T cells meet specifications for new drug products. Completing and exceeding these requirements, the data fully support the initiation of a first-in-human Phase 1 trial for BAFF-R-positive relapsed/refractory (r/r) B-ALL.
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Sarantopoulos, Stefanie, Kristen E. Stevenson, Haesook T. Kim, Nazmim S. Bhuiya, Corey S. Cutler, Robert J. Soiffer, Joseph H. Antin, and Jerome Ritz. "BAFF/Blys Levels Correlate with Disease Activity and Alter Peripheral B Cell Subsets in Patients with Chronic GVHD." Blood 108, no. 11 (November 16, 2006): 41. http://dx.doi.org/10.1182/blood.v108.11.41.41.
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Abstract Patients with chronic graft versus host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) have been found to have high titers of allo-reactive antibodies, but a role for B cells in the pathology of this disease remains undefined. B Cell Activating Factor, BAFF/Blys (BAFF), promotes differentiation and expansion of antigen-activated B cells and contributes to loss of B cell tolerance in animal models. We hypothesized that the BAFF/BAFF receptor (BAFF-R) pathway may perpetuate potentially allo- or auto-reactive antigen-experienced CD27+ B cells in patients with cGVHD after HSCT. Soluble BAFF was measured in plasma from 104 patients after HSCT. Median BAFF levels were statistically different when groups were compared using a two-sided Wilcoxon-Rank-Sum test (see Table below). Logistic regression analysis revealed that higher BAFF levels were associated with active cGVHD after adjusting for other GVHD prognostic factors (p=0.0007). Patients with ≥10ng/ml BAFF levels had ten-fold increased odds of having cGVHD compared to patients with BAFF levels of <10ng/ml (OR of 10.8, p=<0.0001). High dose prednisone reduced median plasma BAFF levels (3.8ng/ml in patients receiving ≥30mg daily prednisone versus 14ng/ml for those receiving <30mg or no prednisone). Serial BAFF measurements revealed peak BAFF levels at 6 months post-HSCT in patients who later developed limited cGVHD. 81% of patients with BAFF levels >10ng/ml at 6 months subsequently developed cGVHD (median BAFF was 20ng/ml) compared to 39% of patients with BAFF levels <10ng/ml at 6 months (p=0.002). We also found that BAFF-R expression on B cells was down-regulated in vitro in the presence of BAFF. Consistent with this finding flow cytometry revealed very low BAFF-R expression on B cells in patients with active cGVHD. BAFF-R expression on peripheral B cells correlated with BAFF levels (p=0.0001), suggesting that BAFF signals via BAFF-R in cGVHD. We used 5-color FACS to characterize peripheral B cell subsets in 68 post-HSCT patients. Compared to patients without cGVHD, the proportion of antigen-experienced CD27+ B cells was increased in patients with limited cGVHD (n=20, p=0.04). The extensive cGVHD patient group was smaller (n=11) with greater variability in CD27+ B cell frequency resulting in no statistical difference (p=0.27). The proportion of CD27+ post-germinal center B cells was also increased in patients with active cGVHD (p=0.04 and p=0.03 extensive and limited cGVHD, respectively). High BAFF levels correlated with increased total numbers of CD27+ B cells (p=0.05), but not with total or naïve B cell numbers, suggesting that BAFF plays a role in perpetuation of circulating antigen-experienced and memory B cells in cGVHD patients. Our results suggest that high levels of BAFF after HSCT help break peripheral B cell tolerance and contribute to cGVHD pathobiology. Comparison of BAFF Levels Between Extensive/Limited versus Inactive/No cGVHD Groups cGVHD Type N Median BAFF (ng/ml) p-value vs. inactive p-value vs. no Extensive 15 11.5 0.14 0.02 Limited 33 9.0 0.02 0.0004 Inactive 27 5.7 - 0.02 No 29 4.4 0.16 - Normal 26 1.9 0.0002 0.004
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de la Torre, Inmaculada, Rita A. Moura, Maria J. Leandro, Jonathan Edwards, and Geraldine Cambridge. "B-cell-activating factor receptor expression on naive and memory B cells: relationship with relapse in patients with rheumatoid arthritis following B-cell depletion therapy." Annals of the Rheumatic Diseases 69, no. 12 (June 25, 2010): 2181–88. http://dx.doi.org/10.1136/ard.2010.131326.
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ObjectivesTo examine the expression of B-cell-activating factor receptor (BAFF-R) on naive CD27− and memory CD27+ B cells in normal individuals and patients with rheumatoid arthritis (RA) undergoing B-cell depletion therapy with rituximab.Patients and MethodsBAFF-R expression on B-cell subsets was determined in normal controls (NC; n=11), active patients with RA pre-rituximab (pre-RX; n=15), relapsing patients either concordant for B-cell repopulation (C-R, n=13) or discordant, with relapse more than 3 months after repopulation (D-R, n=11) and patients in remission over 3 months postrepopulation (discordant non-relapsing (D-NR), n=5). Serum BAFF was measured by ELISA and analysed using Mann–Whitney.ResultsThere was no significant difference between NC, pre-RX and D-NR patients in %BAFF-R-positive B cells or mean fluorescence intensity (MFI) in naive and memory B cells. Relapsing patients had significantly lower MFI and %BAFF-R-positive cells in both naive and memory compartments from NC and pre-RX (C-R and D-R; p<0.01). BAFF levels in pre-RX patients were within the normal range and did not correlate with BAFF-R expression in any patient group. D-NR patients had relatively lower proportions of pre and postswitch CD27+ B cells than pre-RX patients (D-NR vs pre-RX; p<0.05 for both) and also lower numbers of postswitch B cells than D-R patients (D-NR vs D-R, p<0.05).ConclusionBAFF-R expression was significantly reduced on both naive and memory B cells in patients at relapse, regardless of the relationship with B-cell repopulation or serum BAFF levels. Re-establishment of active disease was also associated with an increase in class-switch recombination. Factors responsible for lower levels of BAFF-R may relate to altered thresholds for autoreactive B-cell generation at relapse in patients with RA.
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Chiu, April, Xugang Qiao, Bing He, Elizabeth Hyjjek, Joong Lee, Ethel Cesarman, Amy Chadburn, Daniel M. Knowles, and Andrea Cerutti. "The TNF Family Members BAFF and APRIL Play an Important Role in Hodgkin Lymphoma." Blood 106, no. 11 (November 16, 2005): 22. http://dx.doi.org/10.1182/blood.v106.11.22.22.
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Abstract Introduction. B cell-activating factor of the TNF family (BAFF) and a proliferation-inducing ligand (APRIL), a BAFF-related molecule, play a key role in the survival and proliferation of mature B cells. In addition, BAFF and APRIL cooperate with IL-4 to induce class switch DNA recombination (CSR) from IgM (or IgG) to IgG, IgA or IgE. This process requires activation-induced-cytidine deaminase (AID), a DNA-editing enzyme involved also in Ig somatic hypermutation and lymphomagenesis. BAFF and APRIL are usually produced by myeloid cells, including dendritic cells, macrophages and granulocytes, and engage three receptors preferentially expressed on B cells, including transmembrane activator and calcium modulator and cyclophylin ligand interactor (TACI), B cell maturation antigen (BCMA), and BAFF receptor (BAFF-R). Our previous studies show that BAFF and APRIL are EBV-inducible molecules implicated in B cell non-Hodgkin’s lymphoma (NHL). The scope of the present studies was to elucidate the expression and function of BAFF, APRIL, TACI, BCMA and BAFF-R in Hodgkin lymphoma (HL). Methods. Tissue sections from 5 primary EBV+ HL cases and 5 primary EBV− HL cases were analyzed for BAFF, APRIL, TACI, BCMA, and BAFF-R expression through immunohistochemistry. RS cells from 6 primary cases were microdissected and analyzed for the expression of AID and CSR byproducts by RT-PCR. The expression of BAFF, APRIL, TACI, BCMA, BAFF-R, AID, and CSR byproducts was also analyzed in 5 HL cell lines cultured in the presence or absence of recombinant BAFF, APRIL and cytokines as previously described1,2,3. Results. We found that the reactive infiltrate of primary HL tumors comprises non-malignant elements, such as macrophages, granulocytes and plasma cells, expressing BAFF and APRIL. Also a variable proportion of malignant CD30+ Reed-Sternberg (RS) cells from both EBV+ and EBV− HL cases express BAFF and APRIL. Unlike NHL B cells, which usually express BAFF-R, primary RS cells and RS cell lines lack BAFF-R, but express TACI and BCMA. In the presence of BAFF or APRIL, RS cell lines are rescued from spontaneous or induced apoptosis. This effect is associated with activation of NF-κB through a classical pathway. Increased RS cell survival is also associated with up-regulation of the pro-survival BCL-2 and BCL-XL proteins, and down-regulation of the pro-apoptotic BAX protein. Finally, in the presence of BAFF or APRIL and IL-4, RS cell lines up-regulate AID expression and increase their spontaneous CSR activity. Of note, AID expression extends to primary RS cells and is associated with ongoing CSR. Conclusions. Our studies indicate that BAFF and APRIL stimulate malignant RS cells through both autocrine and paracrine pathways. Engagement of TACI and BCMA receptors by BAFF and APRIL may enhance the expansion of RS cells by attenuating apoptosis through a mechanism involving NF-κB and BCL family proteins. By up-regulating AID, signals emanating from TACI and BCMA receptors might also introduce genomic instability. Finally, considering that TACI, BCMA and AID are B cell-specific molecules and that CSR is a process confined to B cells, our findings consolidate the notion that RS cells derive from a B cell precursor.
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Birnbaum, Tobias, Sigrid Langer, Sigrun Roeber, Louisa Von Baumgarten, and Andreas Straube. "Expression of B-cell activating factor, a proliferating inducing ligand and its receptors in primary central nervous system lymphoma." Neurology International 5, no. 1 (March 21, 2013): 4. http://dx.doi.org/10.4081/ni.2013.e4.
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B-cell activating factor belonging to the tumor necrosis factor family (BAFF) and a proliferating inducing ligand (APRIL) might play an important role in the pathogenesis of systemic B-cell malignancies. However, the BAFF/APRIL system has not been systematically evaluated in primary central nervous system lymphoma (PCNSL) to date. We assessed the expression of BAFF, APRIL and its receptors BAFF-R (BAFF receptor), BCMA (B-cell maturation antigen) and TACI (transmembrane activator and calcium modulator cyclophilin ligand interactor) in five PCNSL specimens by immunohistochemical staining. We found extensive expression of BAFF and weak to moderate expression of APRIL, BAFF-R, BCMA, and TACI in all specimens. CD20 positive cells showed expression of both ligands and receptors at the same time. Our results indicate that autocrine stimulation of the BAFF/APRIL system might be involved in the pathogenesis of PCNSL.
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Hamzaoui, Agnès, Hanene Chelbi, Fayçal Hai Sassi, and Kamel Hamzaoui. "Release of B Cell-Activating Factor of the TNF Family in Bronchoalveolar Lavage from Behçet Disease with Pulmonary Involvement." Oxidative Medicine and Cellular Longevity 3, no. 2 (2010): 122–28. http://dx.doi.org/10.4161/oxim.3.2.11149.
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Pulmonary artery aneurysms, arterial and venous thrombosis, pulmonary infarction, recurrent pneumonia, bronchiolitis obliterans organized pneumonia, and pleurisy are the main features of pulmonary involvement in Behçet disease. The objective of this study was to investigate the production of B-cell-activating factor of the TNF family (BAFF), an important regulator of B-cell survival and immunoglobulin class-switch recombination, in bronchoalveolar lavage (BAL) fluid from BD patients having pulmonary manifestation. Bronchoalveolar lavage (BAL) was performed in 15 BD patients with pulmonary manifestation and 18 BAL from healthy controls. Concentrations of B-cell-active cytokines, including BAFF, IL-6 and IL-13, were measured by using specific ELISA and cytometric bead array assays. Levels of BAFF protein were significantly increased in BAL fluid from active BD (109 ± 21.78 pg/mL) compared with those oh healthy controls (4.83 ± 1.75 pg/mL; p < 0.0001). In the BAL fluid, BAFF levels were significantly correlated with absolute numbers of total cells (r = 0.823; p < 0.0001), lymphocytes (r = 0.709; p < 0.0001), neutrophils (r = 0.809; p < 0.0001) and macrophages (r = 0.742; p < 0.0001). Normalization to albumin indicated that BAFF production occurred locally in the airways. BAFF levels were also significantly correlated with the other B-cell-activating cytokines IL-6 (r= 0.882, p < 0.001) and IL-13 (r= 0.659, p < 0.001). The antigen-induced production of BAFF in the lung of active BD with pulmonary manifestations might contribute to immunoglobulin synthesis by B-cells. The cells residing in the lung might affect each other through BAFF.
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Mihalcik, Stephen A., Renee C. Tschumper, and Diane F. Jelinek. "Molecular Mechanisms Regulating BAFF and APRIL Receptor Expression in B Cells: Promoter Structure and Epigenetics." Blood 112, no. 11 (November 16, 2008): 4765. http://dx.doi.org/10.1182/blood.v112.11.4765.4765.
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Abstract Throughout differentiation, mature B cells express distinct combinations of the BAFF and APRIL receptors, BAFF-R, TACI, and BCMA. The patterns of B lineage cell receptor expression reflect their stage of differentiation and impart the ability to respond to ligands, in some cases delivering a powerful anti-apoptotic signal. B cell malignancies arise from each stage of differentiation, typically exhibit the patterns of receptor expression that reflect their cell of origin, and have been shown to exploit the generally anti-apoptotic effects of BAFF and/or APRIL. For example, there is evidence for a role for BAFF in mature B cell cancers, including B cell chronic lymphocytic leukemia (B-CLL). As the majority of circulating CLL B cells are quiescent cells, prolonged survival is a significant hallmark, a trait that signals through BAFF-R could initiate or reinforce. Therapeutic strategies designed to interrupt this pro-survival pathway have thus far primarily focused on blocking ligand binding. Therapeutic modalities impacting receptor expression may be similarly effective. However, despite the apparent precise activation stage-dependent orchestration of B cell BAFF-R, TACI, and BCMA expression, the genetic mechanisms regulating expression of the three receptors remain undefined, and the question of whether each receptor governs expression of the other two remains unanswered. In agreement with previous studies in our own lab and others, analyses of the receptor profiles of CLL B cells continue to show BAFF-R surface expression, albeit at lower levels than seen on normal peripheral B cells, and the curious variable presence of BCMA and TACI. Similarly, multiple myeloma (MM) plasma cells (PCs), like normal PCs, uniformly lack BAFF-R expression, express BCMA, and variably express TACI. Our current study explores the mechanisms of receptor regulation in B cells, with an emphasis on BAFF-R, the receptor that is most consistently expressed on the CLL B cell population and that has the most clearly defined survival function. We began by analyzing the BAFF-R gene’s genomic context. We identified a possible regulatory element 2 kb upstream of the first exon with significant homology across seven mammalian species that overlapped a cluster of B cell lineage transcription factor binding sites, and, thus, we called the 2.5 kb directly upstream of the gene the putative BAFF-R promoter. We cloned the region and created promoter-reporter vectors in which the full-length promoter and 0.5 kb 5’ truncations thereof drive firefly luciferase production. While studies of primary B cells continue, studies with malignant B cell lines suggest that we have successfully cloned a powerful positive regulatory region. Specifically, B cell lines that express surface BAFF-R show positive inductions of firefly to control renilla luciferase activity in all of the promoter constructs over the empty construct with the greatest promoter activity in the longest constructs: 6-, 18-, and 3-fold inductions with the 2.5 kb promoter in RAJI, Loukes, and MEC-1 cells, respectively. To further test the promoter specificity, we transfected malignant PC lines, ALMC-1, ALMC-2, and KAS-6/1, which are negative by RT-PCR and surface staining for BAFF-R. These lines showed little promoter activity over baseline, with fold inductions between 0.5 and 2.5 for all of the promoter constructs. These results suggest that the MM lines no longer express the transcription factors required to drive BAFF-R expression and underscore our conclusion that we have identified the BAFF-R promoter. At the same time, investigations into epigenetic modification may reveal a crucial level of control. The transcriptional start site of the BAFF-R gene falls within a region of high CG content, and may be a possible CpG island. Upon treatment with the methyltransferase inhibitor, 5-azacytidine, primary blood B cells and MM cells showed no change in receptor expression. However, in CLL B cells, treatment of cultured cells caused a slight (9%) decrease in BAFF-R expression and prevented TACI upregulation in cells stimulated with CpG (a 76% increase fell to 36%). This evidence suggests that methylation indirectly suppresses expression of BAFF-R and TACI. It is essential to understand the regulation of survival receptors critical to normal B lineage cell survival, which may also be crucial for their malignant counterparts, in order to target those mechanisms as therapy.
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Luo, Yan, Kaihin Lui, Tommy T. To, Andrew liu, Farah Yassine, Mohamed A. Kharfan Dabaja, Martha E. Gadd, and Hong Qin. "Abstract 2855: Antitumor activity of BAFF-R targeting CAR T-cells on chronic lymphocytic leukemia." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2855. http://dx.doi.org/10.1158/1538-7445.am2022-2855.
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Abstract B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in adults with CD19-targeting CAR T-cell therapy showing an excellent initial curative response. However, 10-20% of patients who receive anti-C19 CAR T-cell treatment experience relapse due to CD19 antigen loss. B-cell activating factor receptor (BAFF-R) that is expressed on the surface of normal and neoplastic B cells mediates the survival of mature peripheral B cells along with the B-cell receptor. Since B-CLL is characterized by apoptotic disruption and subsequent accumulation of mature B cells, BAFF-R is a logical, novel target for CAR T-cell therapy directed against B-CLL, especially if CD19 antigen loss occurs. In this study, we first manufactured BAFF-R CAR T-cells by infecting healthy donor Tnaïve/memory (Tn/mem) cells with BAFF-R CAR lentivirus before evaluating the antitumor activity of BAFF-R CAR T-cells on wild type MEC-1 (a B-CLL cell line), modified MEC-1, and primary cell lines. Antigen-specific cytotoxicity and activation of the BAFF-R CAR T-cells or control CD19 CAR T-cells were determined upon incubation with B-CLL cell lines and patient-derived primary B-CLL by measuring degranulation and IFN-γ release, respectively. BAFF-R CAR T-cells demonstrated substantial cytotoxicity against MEC-1, CD19-deficient MEC-1, and primary B-CLL cell lines; CD19 CAR T-cells showed no effect on CD19-deficient MEC-1 cells but did show effects with primary B-CLL and MEC-1 cells. Similarly, the release of IFN-γ was greater when BAFF-R CAR T-cells were co-cultured with CD19-deficient MEC-1 or primary B-CLL compared to CD19 CAR T-cells co-cultured with CD19-deficient MEC-1. In summary, BAFF-R CAR T-cells exert significant antitumor properties not only on patient-derived primary B-CLL cells but also on a CD19-deficient B-CLL cell line. We, therefore, assert BAFF-R-targeting CAR T-cells to be a novel therapeutic avenue for patients newly diagnosed with B-CLL and patients experiencing relapsed B-CLL after anti-CD19 therapy. Citation Format: Yan Luo, Kaihin Lui, Tommy T. To, Andrew liu, Farah Yassine, Mohamed A. Kharfan Dabaja, Martha E. Gadd, Hong Qin. Antitumor activity of BAFF-R targeting CAR T-cells on chronic lymphocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2855.
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McWilliams, Emily M., Carolyn Cheney, Jeffrey A. Jones, Joseph M. M. Flynn, Kami Maddocks, Leslie A. Andritsos, Heather Huet, et al. "B-1239, a Novel Anti-BAFF-R Afucosylated Human Antibody, Promotes Potent Natural Killer Cell- Mediated Antibody Dependent Cellular Cytotoxicity In Chronic Lymphocytic Leukemia Cells In- Vitro and Depletion Of Circulating Leukemic CLL B Cells In-Vivo." Blood 122, no. 21 (November 15, 2013): 4185. http://dx.doi.org/10.1182/blood.v122.21.4185.4185.
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Abstract B-cell activating factor (BAFF) belongs to the TNF ligand superfamily of cytokines involved in B cell survival and maturation. BAFF is produced by diverse cell types including innate immune cells like monocytes and dendritic cells as well as T cells, activated B cells, and bone marrow stromal cells. BAFF binds to the BAFF receptor (BAFF-R) with high affinity compared to the other BAFF receptors, BCMA and TACI. While BAFF is known to regulate normal B-cell development and proliferation, it also contributes to survival in chronic lymphocytic leukemia (CLL). We observed expression of BAFF-R on virtually all B cells from CLL patients. B-CLL cells have strong up-regulation of BAFF and BAFF-R compared to normal healthy B cells. We describe here the in-vitro and in-vivo evaluation in CLL of B-1239, a fully human anti-BAFF-R monoclonal IgG1 antibody. B-1239 is devoid of fucose residues in its Fc domain, resulting in enhanced binding to FCgammaRIIIa activating receptor on Natural Killer (NK) cells. While B-1239 failed to induce direct or complement mediated cytotoxicity, binding of B-1239 to CLL cells resulted in enhanced antibody dependent cellular cytotoxicity (ADCC) with allogeneic or autologous NK effector cells in-vitro. Indeed, at a therapeutically relevant concentration of 10 ug/mL B-1239 shows more than 30% increased relative cytotoxic activity over current CLL antibody therapeutic Rituximab. Dilutions of B-1239 down to 0.01 ug/mL showed similar cytotoxicity to the 10 ug/mL concentration. At 0.0001 ug/mL B-1239 has a 40% cytotoxic effect on CLL cells in ADCC assays while antibody therapeutic controls, like Rituximab, show virtually no cytotoxic activity. Furthermore, B-1239 mediated antibody-dependent cellular phagocytosis (ADCP) by monocyte-derived macrophages and mediated activation of monocytes and macrophages as detected by TNF-alpha production. Consistent with the cross reactivity to murine BAFF-R, flow cytometric analysis revealed binding of B-1239 to CD5+CD19+ leukemic B cells from Eu-Tcl-1 transgenic mouse CLL cells. A single dose of B-1239 by i.v injection into Eu-Tcl-1 mice resulted in dramatic reduction in circulating CD5+CD19+ leukemic B cells in all three B-1239 injected mice. In contrast, we observed continued increase of leukemic CD5+CD19+ populations in the two vehicle treated mice. Ongoing studies are focused on determining how targeting BAFF-R on CLL B-cells depletes the leukemic population both in-vitro and in-vivo and the downstream effects of targeting through this receptor. Collectively, these results demonstrate that targeting BAFF-R on CLL cells provides a B-cell specific approach for rapid and robust depletion of leukemic CLL cells and provides evidence for a strong therapeutic advantage in BAFF-R targeted therapies in CLL. Disclosures: Huet: Novartis: Employment, Employment Related Perks Other. Gram:Novartis: Employment, Employment Related Perks Other. Baeck:Novartis: Employment, Employment Related Perks Other.
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Fu, Lingchen, Yen-Chiu Lin-Lee, Lan Pham, Archie Tamayo, and Richard J. Ford. "BAFF-R Receptor Functions in Transcription Regulation in Genes Critical to Survival and Proliferation in Normal and Neoplastic Human B Lymphocytes." Blood 112, no. 11 (November 16, 2008): 4478. http://dx.doi.org/10.1182/blood.v112.11.4478.4478.
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Abstract B-lymphocyte stimulator (BLyS also called BAFF), is a potent cell survival factor expressed in many hematopoietic cells. However, many aspects of BLyS signaling pathway remain unclear. In order to investigate BLyS signaling pathway, we studied the function of BAFF-R (also called BR3), a major BLyS receptor, in normal and neoplastic B cell survival and proliferation. In our initial study, we found that BAFF-R was also present in nucleus, in addition to its presence in the plasma membrane of B cells. A candidate nuclear localization sequence was identified in the BAFF-R protein sequence. We also found BAFF-R mediated transcriptional activity, that could be increased through over expression of a NF-κB family member c-rel. Further study showed that BAFF-R co-localized with, c-rel in the nucleus and bound to the NF-κB binding site on the promoters of NF-κB target genes such as BLyS, CD154, Bcl-xL, Bfl-1/A1 and IL-8. The IκB kinase (IKK) protein complex is critical for regulating NF-κB pathway activation. The IKK complex includes three important subunits: the catalytic subunits IKKα and IKKβ (also known as IKK1 and IKK2) and the regulatory subunit IKKγ (also known as NEMO). In the cytoplasm, activation of the IKK complex induces processing of precursors p105 and p100 into p50 and p52 respectively, resulting in NF-κB subunit dimeric partners that migrate from the cytoplasm into the nucleus. In recent studies, IKKα has also been identified in the cell nucleus, functioning in histone H3 phosphorylation. Although IKKβ was also previously observed in the cell nucleus, its nuclear function has been obscure. Besides functioning as a transcriptional co-factor with c-rel, we also found BAFF-R interacted with IKKβ in the nucleus of normal and neoplastic (lymphoma) B cells, enhancing histone H3 phosphorylation through IKKβ by immuno precipitation experiments and in vitro kinase assays. Inhibition of BAFF-R entry into the nucleus by BAFF-R NLS mutant transfection, decreased the level of phosphorylated histone H3 compared to the controls in NHL-B cells. These findings not only demonstrate a novel nuclear function of IKKβ, but also determine a new mechanism of how BAFF-R promotes survival and proliferation of normal B cells and NHL-B cells. In addition to activating NF-κB pathways in the plasma membrane, BAFF-R also functions as a transcriptional regulator binding to NF-κB targeted gene promoters possibly through a chromatin remodeling mechanism(s).
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Chiu, April, Weifeng Xu, Bing He, Paul Santini, Stacey R. Dillon, Amy Chadburn, Daniel M. Knowles, and Andrea Cerutti. "Splenic Sinusoids Stimulate the Survival and Proliferation of Hairy Cell Leukemia B Cells through BAFF, APRIL and Heparan-Sulphate Proteoglycans." Blood 108, no. 11 (November 16, 2006): 4959. http://dx.doi.org/10.1182/blood.v108.11.4959.4959.
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Abstract Introduction. Hairy cell leukemia (HCL) is a rare chronic B cell lymphoproliferative disorder characterized by massive infiltration of the spleen by cells displaying a unique “hairy” morphology and surface phenotype. The ontogeny of hairy cells (HCs) and the mechanism underlying their accumulation in the spleen remain elusive. Growing evidence indicates that B cell-activating factor of the TNF family (BAFF) and a proliferation-inducing ligand (APRIL) play important roles in malignant B cells. BAFF and APRIL are usually produced by myeloid cells and engage three receptors on B cells known as transmembrane activator and calcium modulator and cyclophylin ligand interactor (TACI), B cell maturation antigen (BCMA), and BAFF receptor (BAFF-R). APRIL binding to TACI and BCMA is reinforced by cell-anchored and matrix-associated heparan-sulphate proteoglycans (HSPGs). In this study we verified the role of BAFF and APRIL in HCL. Methods. Splenic tissue sections and B cells from 5 healthy donors and 5 HCL patients were analyzed for expression of BAFF, APRIL, TACI, BCMA, BAFF-R and other molecules through immunohistochemistry, immunofluorescence, flow cytometry, immunoblotting and quantitative real-time RT-PCR. HCs were also cultured with umbilical vein or splenic endothelial cells in the presence or absence of BAFF and APRIL inhibitors, including soluble TACI-Ig decoy receptor, small interfering RNAs (siRNAs) and HSPG-modifying agents, such as heparinitase. HC proliferation, survival and signaling as induced by recombinant BAFF or APRIL were evaluated through standard assays. Results. We found that splenic sinusoids surrounding HCs were comprised of endothelial cells expressing APRIL and, to a lesser extent, BAFF. Endothelial cells up-regulated BAFF and APRIL upon exposure to HC-derived cytokines, including TNF-α. Unlike naïve, germinal center, memory and plasmacytoid B cells but similar to splenic marginal zone B cells, HCs expressed high levels of TACI, BCMA, BAFF-R and HSPGs together with CD1c, CD11c, CD27, CD83, CD123, endocytic receptors, and carbohydrate receptors. Preliminary data indicated that endothelial cells stimulated HCs through a mechanism involving BAFF, APRIL and HSPGs as pretreatment of endothelial cells with BAFF and APRIL small interfering RNAs or heparinitase attenuated the growth and survival of HCs in co-cultures. TACI-Ig, which binds to and neutralizes BAFF and APRIL, had a similar inhibitory effect. Conversely, BAFF, APRIL as well as TACI, BCMA or BAFF-R cross-linking stimulated HC growth. This stimulation was associated with NF-κB activation as well as up-regulation of various pro-survival and growth-inducing intracellular proteins. Conclusions. The present findings suggest that HCs may derive from a splenic marginal zone B cell precursor. In addition, our studies indicate that splenic sinusoids form a BAFF-APRIL-HSPG-rich niche that promotes HC expansion via TACI, BCMA and BAFF-R. Finally, our data suggest that blocking BAFF and APRIL through TACI-Ig, siRNAs and HSPG-modifying agents could have therapeutic value in HCL.
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McWilliams, Emily M., Christopher R. Lucas, Timothy Chen, Bonnie K. Harrington, Ronni Wasmuth, Amanda Campbell, Kerry A. Rogers, et al. "Anti–BAFF-R antibody VAY-736 demonstrates promising preclinical activity in CLL and enhances effectiveness of ibrutinib." Blood Advances 3, no. 3 (February 8, 2019): 447–60. http://dx.doi.org/10.1182/bloodadvances.2018025684.
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Abstract The Bruton tyrosine kinase inhibitor (BTKi) ibrutinib has transformed chronic lymphocytic leukemia (CLL) therapy but requires continuous administration. These factors have spurred interest in combination treatments. Unlike with chemotherapy, CD20-directed antibody therapy has not improved the outcome of BTKi treatment. Whereas CD20 antigen density on CLL cells decreases during ibrutinib treatment, the B-cell activating factor (BAFF) and its receptor (BAFF-R) remain elevated. Furthermore, BAFF signaling via noncanonical NF-κB remains elevated with BTKi treatment. Blocking BAFF interaction with BAFF-R by using VAY-736, a humanized defucosylated engineered antibody directed against BAFF-R, antagonized BAFF-mediated apoptosis protection and signaling at the population and single-cell levels in CLL cells. Furthermore, VAY-736 showed superior antibody-dependent cellular cytotoxicity compared with CD20- and CD52-directed antibodies used in CLL. VAY-736 exhibited in vivo activity as a monotherapy and, when combined with ibrutinib, produced prolonged survival compared with either therapy alone. The in vivo activity of VAY-736 is dependent upon immunoreceptor tyrosine–based activation motif (ITAM)–mediated activation of effector cells as shown by using an ITAM-deficient mouse model. Collectively, our findings support targeting the BAFF signaling pathway with VAY-736 to more effectively treat CLL as a single agent and in combination with ibrutinib.
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Fu, Lingchen, Yen-Chiu Lin-Lee, Lan V. Pham, Archito T. Tamayo, Linda C. Yoshimura, and Richard J. Ford. "BAFF-R promotes cell proliferation and survival through interaction with IKKβ and NF-κB/c-Rel in the nucleus of normal and neoplastic B-lymphoid cells." Blood 113, no. 19 (May 7, 2009): 4627–36. http://dx.doi.org/10.1182/blood-2008-10-183467.
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Abstract BLyS and its major receptor BAFF-R have been shown to be critical for development and homeostasis of normal B lymphocytes, and for cell growth and survival of neoplastic B lymphocytes, but the biologic mechanisms of this ligand/receptor-derived intracellular signaling pathway(s) have not been completely defined. We have discovered that the BAFF-R protein was present in the cell nucleus, in addition to its integral presence in the plasma membrane and cytoplasm, in both normal and neoplastic B cells. BAFF-R interacted with histone H3 and IKKβ in the cell nucleus, enhancing histone H3 phosphorylation through IKKβ. Nuclear BAFF-R was also associated with NF-κB/c-Rel and bound to NF-κB targeted promoters including BLyS, CD154, Bcl-xL, IL-8, and Bfl-1/A1, promoting the transcription of these genes. These observations suggested that in addition to activating NF-κB pathways in the plasma membrane, BAFF-R also promotes normal B-cell and B-cell non-Hodgkin lymphoma (NHL-B) survival and proliferation by functioning as a transcriptional regulator through a chromatin remodeling mechanism(s) and NF-κB association. Our studies provide an expanded conceptual view of the BAFF-R signaling, which should contribute a better understanding of the physiologic mechanisms involved in normal B-cell survival and growth, as well as in the pathophysiology of aggressive B-cell malignancies and autoimmune diseases.
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Wright, Jacqueline, Iris Castro, Bazarragchaa Damdinsuren, Kristen Hoek, Gianluca Carlesso, Nicholas Shinners, Rachel Gerstein, Robert Woodland, Ranjan Sen, and Wasif Khan. "BCR mediated c-Rel induction facilitates NF-κB2 and RelB expression (84.22)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 84.22. http://dx.doi.org/10.4049/jimmunol.184.supp.84.22.
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Abstract B cell receptor (BCR) and B cell activating factor receptor (BAFF-R) signaling are critical for the generation of mature splenic B cells. BCR expressing Transitional type 1 (T1) cells migrate from the bone marrow to the spleen where they must successfully pass BCR mediated checkpoints to become Transitional type 2 (T2) cells and subsequently mature follicular B (FoB) cells. T1 and T2 cells are fundamentally different in their response to BCR or BAFF-R stimulation; T1 cells do not survive whereas T2 cells do when triggered through BCR or BAFF-R. Our results demonstrate that Bruton’s tyrosine kinase (Btk) plays a critical role in both BCR and BAFF-R mediated T2 and mature B cell survival. These results suggest that a potential mechanism that provides T2 cells with a survival advantage is their ability to sustain c-Rel expression in response to BCR engagement via mechanisms involving Btk. The increased c-Rel expression coincides precisely with the up-regulation of anti-apoptotic members of the Bcl-2 family as well as BAFF-R and its substrate p100 (NF-κB2). Thus, BCR indirectly enhances the survival function of BAFF-R in part through c-Rel. Consistent with a supporting role for BCR/c-Rel signaling in the activation of alternative NF-κB pathway, c-Rel-deficient B cells are impaired for BCR-induced expression of p100 as well as RelB.
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Kern, Catherine, Jean-François Cornuel, Christian Billard, Ruoping Tang, Danielle Rouillard, Virginie Stenou, Thierry Defrance, et al. "Involvement of BAFF and APRIL in the resistance to apoptosis of B-CLL through an autocrine pathway." Blood 103, no. 2 (January 15, 2004): 679–88. http://dx.doi.org/10.1182/blood-2003-02-0540.
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Abstract Tumor necrosis factor (TNF) superfamily members BAFF, or B-cell activation factor of the TNF family, and APRIL, a proliferation-inducing ligand, are involved in normal B-cell survival and differentiation. They interact with 3 receptors: BAFF-R, specific to BAFF; and TACI and BCMA, which are shared by BAFF and APRIL. We tested the potential role of these proteins in B-cell chronic lymphocytic leukemia (B-CLL) resistance to apoptosis. TACI and BAFF-R mRNAs were found in leukemic B cells. BAFF and APRIL mRNAs and proteins were detected in B-CLL leukemic cells and normal blood or tonsil-derived B lymphocytes. Yet, in contrast to normal B lymphocytes, BAFF and APRIL were expressed at the membranes of leukemic cells. Adding soluble BAFF or APRIL protected B-CLL cells against spontaneous and drug-induced apoptosis and stimulated NF-κB activation. Conversely, adding soluble BCMA-Fc or anti-BAFF and anti-APRIL antibodies enhanced B-CLL apoptosis. Moreover, a soluble form of BAFF was detected using surface-enhanced laser desorption/ionization–time-of-flight mass spectrometry (SELDI-TOF MS) in the sera of B-CLL patients but not of healthy donors. Taken together, our results indicate that B-CLL cells can be rescued from apoptosis through an autocrine process involving BAFF, APRIL, and their receptors. Inhibiting BAFF and APRIL pathways may be of therapeutic value for B-CLL treatment.
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Lougaris, Vassilios, Massimiliano Vitali, Manuela Baronio, Giacomo Tampella, and Alessandro Plebani. "BAFF-R mutations in Good's syndrome." Clinical Immunology 153, no. 1 (July 2014): 91–93. http://dx.doi.org/10.1016/j.clim.2014.04.002.
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Badr, Gamal, Gwenoline Borhis, Eric A. Lefevre, Nada Chaoul, Frederique Deshayes, Valérie Dessirier, Genevieve Lapree, Andreas Tsapis, and Yolande Richard. "BAFF enhances chemotaxis of primary human B cells: a particular synergy between BAFF and CXCL13 on memory B cells." Blood 111, no. 5 (March 1, 2008): 2744–54. http://dx.doi.org/10.1182/blood-2007-03-081232.
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B-cell–activating factor of the TNF family, (BAFF), and a proliferation-inducing ligand (APRIL) regulate B-lymphocyte survival and activation. We report that BAFF, but not APRIL, increased the chemotactic response of primary human B cells to CCL21, CXCL12, and CXCL13. The BAFF-induced increase in B-cell chemotaxis was totally abolished by blockade of BAFF-R and was strongly dependent on the activation of PI3K/AKT, NF-κB, and p38MAPK pathways. BAFF had similar effects on the chemotaxis of naive and memory B cells in response to CCL21 but increased more strongly that of memory B cells to CXCL13 than that of naive B cells. Our findings indicate a previously unreported role for the BAFF/BAFF-R pair in mature B-cell chemotaxis. The synergy between CXCL13 and BAFF produced by stromal cells and follicular dendritic cells may have important implications for B-cell homeostasis, the development of normal B-cell areas, and for the formation of germinal center–like follicles that may be observed in various autoimmune diseases.
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Ferrer, Gerardo, Kate E. Hodgson, Pau Abrisqueta, Aina Pons, Sonia Jansa, Bernat Gel, Xavier Filella, et al. "BAFF and APRIL in Chronic Lymphocytic Leukemia: Clinico-Biological Correlates and Prognostic Significance." Blood 114, no. 22 (November 20, 2009): 1235. http://dx.doi.org/10.1182/blood.v114.22.1235.1235.
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Abstract Abstract 1235 Poster Board I-257 BAFF (B-cell activating factor) and APRIL (a proliferation-inducing ligand) are TNF family proteins that upregulate anti-apoptotic genes through the NF-kB pathway. Studies in vitro suggest that BAFF and APRIL protect neoplastic B cells from apoptosis in chronic lymphoproliferative disorders (CLPD) including chronic lymphocytic leukemia (CLL). Serum BAFF levels have been previously shown to be lower in CLL than in other CLPD or normal subjects. To contribute to a better understanding of their role in CLL, we analyzed BAFF and APRIL at mRNA and protein serum levels and their receptors [transmembrane activator and CAML interactor (TACI), B-cell maturation antigen (BCMA) and BAFF receptor (BAFF-R)] by flow cytometry, in 82 patients with CLL, 36 with other CLPD and 35 age- and sex-matched controls. mRNA BAFF and APRIL levels were calculated as a the percentage of expression referred to an internal control and the receptor expression as the ratio between the mean fluorescence intensity (MFI) of the receptor antibody and the MFI of the isotype control. Patients with CLL showed significantly lower median BAFF and APRIL levels (0.63 μg/ml and 3.18 μg/ml) than those with other CLPD (1.27 μg/ml and 5.51 μg/ml) (p<0.05). Moreover, BAFF but not APRIL was lower in CLL than in healthy subjects (0.63 μg/ml vs. 0.77 μg/ml; p<0.0001). Serum BAFF levels and blood lymphocyte counts were inversely correlated. Likewise, in follicular lymphoma patients who had circulating neoplastic B cells, median BAFF levels was 0.84 μg/ml vs. 1.46 μg/ml in those without detectable neoplastic cells in blood (p<0.05). We also examined the expression of BAFF and APRIL in purified CD19+ cells from 19 CLL patients and 10 healthy controls. All CLL and normal B cells expressed BAFF and APRIL although heterogeneously. Nevertheless, BAFF and APRIL were lower in CLL than in normal B cells (median: 6.24% and 12.73% in CLL vs. 11.54% and 42.26% in controls). In CLL, mRNA BAFF expression inversely correlated with BAFF serum levels. As far as BAFF and APRIL receptors are concerned, BAFF-R was the one most highly expressed in CLL and normal B cells (MFI ratios of 167.3 and 157.2, respectively). TACI and BCMA were also expressed in all CLL cells and normal B cells (MFI ratios TACI: 1.70 and 2.41; BCMA: 9.51 and 4.72, respectively), but at a significantly lower level than BAFF-R (p<0.001). Furthermore, whereas BCMA MFI ratio was significantly higher in CLL than in normal B cells (p<0.05), no differences were observed in the expression of TACI and BAFF-R. TACI expression was heterogenous in CLL cells. BAFF-R inversely correlated with BAFF and APRIL serum levels. From a clinical standpoint, there is some indication that BAFF and APRIL serum levels as well as their expression in CLL cells may correlate with clinical and biological characteristics of the disease. No significant relationship was observed between BAFF and APRIL and IGVH mutational status, ZAP-70, CD38 or cytogenetics. However, an inverse correlation was observed between BAFF serum levels and blood lymphocyte counts as well as advanced clinical stage (p<0.05). In contrast, APRIL serum levels were only correlated with CD38 expression, the higher the expression of CD38 the higher the APRIL. Although blood lymphocyte counts and BAFF serum levels are correlated, a multivariate analysis showed that these two variables along with poor risk cytogenetics were independent predictors of progression (poor risk cytogenetics RR=11.699, p<0.05; high blood lymphocyte count RR=9.780, p<0.05 and low serum BAFF RR= 6.098, p<0.05). In summary this study confirms that BAFF and APRIL serum levels are lower in CLL than in other CLPD. In patients with CLL, BAFF serum and mRNA levels correlate with blood lymphocyte count and advanced clinical stage but not with other well known prognostic factors. Finally, although BAFF correlates with blood lymphocyte counts, our results suggest that BAFF serum levels have independent prognostic significance. Disclosures No relevant conflicts of interest to declare.
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Jacque, Emilie, Edina Schweighoffer, Victor L. J. Tybulewicz, and Steven C. Ley. "BAFF activation of the ERK5 MAP kinase pathway regulates B cell survival." Journal of Experimental Medicine 212, no. 6 (May 18, 2015): 883–92. http://dx.doi.org/10.1084/jem.20142127.
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B cell activating factor (BAFF) stimulation of the BAFF receptor (BAFF-R) is essential for the homeostatic survival of mature B cells. Earlier in vitro experiments with inhibitors that block MEK 1 and 2 suggested that activation of ERK 1 and 2 MAP kinases is required for BAFF-R to promote B cell survival. However, these inhibitors are now known to also inhibit MEK5, which activates the related MAP kinase ERK5. In the present study, we demonstrated that BAFF-induced B cell survival was actually independent of ERK1/2 activation but required ERK5 activation. Consistent with this, we showed that conditional deletion of ERK5 in B cells led to a pronounced global reduction in mature B2 B cell numbers, which correlated with impaired survival of ERK5-deficient B cells after BAFF stimulation. ERK5 was required for optimal BAFF up-regulation of Mcl1 and Bcl2a1, which are prosurvival members of the Bcl-2 family. However, ERK5 deficiency did not alter BAFF activation of the PI3-kinase–Akt or NF-κB signaling pathways, which are also important for BAFF to promote mature B cell survival. Our study reveals a critical role for the MEK5-ERK5 MAP kinase signaling pathway in BAFF-induced mature B cell survival and homeostatic maintenance of B2 cell numbers.
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Ferrer, Gerardo, Kate E. Hodgson, Victor Ciria, Gael Roue, Dolors Colomer, Emili Montserrat, and Carol Moreno. "B Cell Stimulation through BCR and CD40 Modulates the Response of Chronic Lymphocytic Leukemia Cells to BAFF and APRIL." Blood 116, no. 21 (November 19, 2010): 1361. http://dx.doi.org/10.1182/blood.v116.21.1361.1361.
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Abstract Abstract 1361 The two TNF family proteins (B-cell activating factor [BAFF] and a proliferation-inducing ligand [APRIL]) and their three receptors (transmembrane activator and CAML interactor [TACI], B-cell maturation antigen [BCMA], and BAFF receptor [BAFF-R]) play a critical role in the process of differentiation, maturation and survival of normal B cells. Additionally, recent studies indicate that activation or inhibitory signals can modulate the sensitivity of normal B cells to BAFF and APRIL through the regulation of their receptors. In chronic lymphocytic leukemia (CLL), BAFF and APRIL have been shown to increase survival of neoplastic B cells in vitro. We investigated whether stimulation of CLL cells through the B cell receptor (BCR) or CD40 ligation could regulate the expression of BAFF-R, TACI and BCMA and enhance BAFF and APRIL sensitivity. Purified B cells were obtained from 23 CLL patients and nine healthy controls. Receptor expression was measured by flow cytometry at baseline and at 48 hours after stimulation with F(ab’)2 antihuman IgM (10 μg/ml) and CD40L (500ng/ml) plus IL-4 (20ng/ml). Cell activation and viability, as assessed by labeling CD69 and Annexin V/TO-PRO-3, were evaluated at 48, and at 72 hours after co-stimulation with either soluble BAFF (100ng/ml) or APRIL (500ng/ml). Baseline analyses showed that BAFF-R was the most highly expressed receptor in CLL cells and normal B cells (Mean fluorescence intensity (MFI) ratios, 213.5 and 185.8, respectively). TACI and BCMA were also expressed in all CLL cells and normal B cells (MFI ratios TACI: 2.5 and 1.9; BCMA: 14.8 and 6.6, respectively), but at a significantly lower level than BAFF-R (p<0.001). Furthermore, BCMA MFI ratio was significantly higher in CLL than in normal B cells (p=0.015). After 48h of culture, an increase of all three receptors was observed in normal B cells in response to either BCR stimulation or CD40 ligation. In contrast, in CLL cells BCR stimulation induced almost no variation in the receptors expression in all cases. This was accompanied by a failure of cell activation and a significant decreased viability of CLL cells (from 36% to 24% p=0.013). By contrast, CD40 ligation in CLL cells induced a significant upregulation of TACI expression (p=0.007) and a significant reduction of BCMA (p=0.007), which correlated with an increase of CLL cell activation and viability (p<0.001). BAFF-R levels did not change. The addition of exogenous soluble BAFF or APRIL showed increase in the viability of normal B cells at 72 hours independently of whether cells were unstimulated or stimulated through the BCR or by CD40 ligation. In CLL cells, however, the viability was significantly increased in CD40-stimulated cells whereas in either unstimulated or BCR-stimulated CLL cells, the addition of BAFF and APRIL had a modest effect on viability (Table). These findings indicate that stimulation of CLL cells through the BCR and CD40 modifies the sensitivity of CLL cells to respond to BAFF and APRIL which reflects the regulation of BCMA, TACI and BAFF-R. In contrast to normal B cells, CD40-ligation in CLL cells upregulated only TACI expression. The fact that the addition of CD40L plus IL-4 and BAFF increased viability in CLL cells while BAFF alone had almost no effect may be related to the ability of CD40 ligation to increase TACI expression. Although BCR stimulation failed to increase the expression of the receptors, co-stimulation by BAFF plus BCR increased viability in CLL cells. Disclosures: No relevant conflicts of interest to declare.
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Vicioso, Yorleny M., Rose Beck, Herman Gram, Keman Zhang, Abhishek Asthana, Derek Wong, John Letterio, and Reshmi Parameswaran. "A new Natural Killer cell therapy to target relapse Acute Lymphoblastic Leukemia." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 241.43. http://dx.doi.org/10.4049/jimmunol.204.supp.241.43.
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Abstract Acute Lymphoblastic Leukemia (ALL) is the most common childhood cancer. Drug resistance and relapse are two major problems in ALL. Pre-B ALL cells express B-cell activating factor receptor (BAFF-R) on their surface, which is not present on normal pre-B cells. This makes it an attractive therapeutic target for ALL. We used a BAFF-R antibody optimized for antibody dependent cell cytotoxicity (ADCC) to enhance NK cell mediated killing of drug resistant and relapsed ALL cells, which are difficult to treat by conventional chemotherapy. We found that anti-BAFF-R antibody enhanced NK cell mediated killing of drug resistant ALL cells in vitro. Early treatment with anti-BAFF-R antibody and NK cells significantly reduced disease burden in xenograft ALL models and increased overall mice survival. However, in advanced disease, the efficacy of NK cells to mediate ADCC is reduced. ALL cells are known to produce TGF beta, a cytokine that causes NK cell dysfunction. We found that ALL cells produce TGF-β and co-culturing ALL cells with NK cells lead to a decrease in CD16 expression on NK cells, which is reversible by addition of EW-7197, a potent TGF-beta receptor I inhibitor. We found that EW-7197 treatment improved anti-BAFF-R antibody mediated ADCC of drug resistant ALL cells, in vivo, even if treatment is started late. Our data validate this novel BAFF-R antibody as a very promising tool for pre-B ALL therapy.
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Sarantopoulos, Stefanie, Kristen E. Stevenson, Haesook T. Kim, Nazmim S. Bhuiya, Corey S. Cutler, Robert J. Soiffer, Joseph H. Antin, and Jerome Ritz. "Chronic GVHD Is Associated with a BAFF Driven BCR-Activated B Cell Repertoire." Blood 110, no. 11 (November 16, 2007): 166. http://dx.doi.org/10.1182/blood.v110.11.166.166.
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Abstract We recently showed that high levels of B cell Activating Factor (BAFF) after allogeneic hematopoietic stem cell transplantation (HSCT) correlate with chronic GVHD development. BAFF promotes survival and differentiation of human BCR-activated (CD27+) B cells into Ig-secreting cells (ISC). To examine whether BAFF drives ISC in cGVHD, CD27+ peripheral B subsets and plasma BAFF levels were examined in 57 patients ≥ 12 months after HSCT. Significantly higher BAFF levels were found in active and inactive cGVHD groups compared to control patients with no cGVHD. Patients with cGVHD had a relative reduction in naive B cells compared to controls, resulting in a preponderance of CD27+ B cells (Table 1). Both pre-germinal center [pre-GC (IgD+)] and post-GC (IgDLo) subsets had significantly increased CD27+ in active cGVHD (Table 2). When BAFF levels were compared with cell number, only active disease patients had a positive correlation between BAFF and plasmablasts (r=+0.51, p-value=0.013), suggesting CD27+ post-GC B cells are highly BAFF-dependent in cGVHD. Active and inactive cGVHD patients had a positive correlation between BAFF and number of CD27+ pre-GC cells (r=+0.5, r=+0.49, respectively, p-value=0.02 each). In vitro analysis of these infrequent B subpopulations was accomplished using a large-volume lymphocyte donation from an untreated active cGVHD patient. Plasmablast and pre-GC purified populations had distinctly higher apoptotic rates attenuated in vitro by BAFF. CD27+ pre-GC B cells were induced by BAFF to differentiate into post-GC plasmablasts, indicating that survival and differentiation effects likely explain the correlations between BAFF and pre and post-GC CD27+ B subsets in patients. Increased BAFF levels in patients with inactive disease also correlated with lower total B (r=−0.59, p=0.003) and memory subset numbers (r=−0.57, p=0.005) suggesting that simultaneous B cell turnover and reconstitution may occur as disease becomes inactive. Thus, peripheral CD27+ B cells differentiate into potentially alloreactive ISC in presence of excess BAFF without need for further antigen stimulation. These results implicate BAFF and BCR-activated B cells in cGVHD and provide a rationale for therapeutic use of BAFF antagonists in this disease. Median BAFF Levels & Relative Increase in CD27+ BCR-activated B cells in cGVHD Disease Status & Median Time post-HSCT (months) BAFF (ng/ml) p-value vs. none Naive B # (x 106 p-value vs. none CD27 of B cells (%) p-value vs. none Active, n=22 (21 mo.) 7.0 0.0003 79.8 0.0009 19.0 0.06 Inactive, n=23 (31mo.) 5.5 0.02 99.1 0.0005 8.4 0.21 None, n=12 (27 mo.) 3.0 260.5 6.1 Healthy, n=33 (no HSCT) 1.9 0.003 89.5 0.0004 27.3 <0.0001 Median CD27 expression on B cell subsets in cGVHD Disease Status CD27 on IgDHiCD38HiB (Pre-GC%) p-value vs. none CD27 on IgDLoCD38Lo B (Memory%) p-value vs. none CD27 on IgDLoCD38Hi (Plasmablast%) p-value vs. none Active (n=22) 41.3 0.06 20.4 0.04 86.9 0.03 Inactive (n=23) 9.7 0.42 18.4 0.06 66.4 0.23 None (n=12) 4.4 10.9 36.7 Healthy, no HSCT (n=33) 4.7 0.65 32.8 <0.0001 40.7 0.79
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Zhu, Xiao-juan, Yan Shi, Jun Peng, Cheng-shan Guo, Ning-ning Shan, Ping Qin, Xue-bin Ji, and Ming Hou. "The effects of BAFF and BAFF-R-Fc fusion protein in immune thrombocytopenia." Blood 114, no. 26 (December 17, 2009): 5362–67. http://dx.doi.org/10.1182/blood-2009-05-217513.
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Abstract Elevated level of B-cell activating factor (BAFF) has been implicated in the pathogenesis of some autoimmune diseases. Blockade of receptor and ligand binding by decoy receptor has demonstrated a clinical benefit in both oncologic and immunologic diseases. In this report, we have detected plasma BAFF and BAFF mRNA expression in immune thrombocytopenia (ITP) patients by enzyme-linked immunosorbent assay (ELISA) and real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR). The effects of recombinant human BAFF (rhBAFF) and BAFF-R-Fc fusion protein (BR3-Fc) on B cells, T cells, platelets, secretion of interferon γ (IFNγ), and interleukin-4 (IL-4) were measured by flow cytometry and ELISA. Patients with active disease had higher levels of plasma BAFF and BAFF mRNA than patients in remission and controls. In in vitro assays, rhBAFF promoted the survival of CD19+ and CD8+ cells, and increased the apoptosis of platelets and the secretion of IFN-γ. BR3-Fc successfully corrected the effects of rhBAFF on lymphocytes, platelets, and cytokines. These findings suggest that BAFF may play a pathogenic role in ITP by promoting the survival of CD19+ and CD8+ cells, and increasing the apoptosis of platelets and the secretion of IFN-γ. Blockade of BAFF by BR3-Fc might be a promising therapeutic approach for ITP.
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Yang, Shu, Jian-Yong Li, and Wei Xu. "Role of BAFF/BAFF-R axis in B-cell non-Hodgkin lymphoma." Critical Reviews in Oncology/Hematology 91, no. 2 (August 2014): 113–22. http://dx.doi.org/10.1016/j.critrevonc.2014.02.004.
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Thompson, J. S. "BAFF-R, a Newly Identified TNF Receptor That Specifically Interacts with BAFF." Science 293, no. 5537 (August 16, 2001): 2108–11. http://dx.doi.org/10.1126/science.1061965.
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Chiu, April, Weifeng Xu, Bing He, Stacey R. Dillon, Jane A. Gross, Eric Sievers, Xugang Qiao, et al. "Hodgkin lymphoma cells express TACI and BCMA receptors and generate survival and proliferation signals in response to BAFF and APRIL." Blood 109, no. 2 (September 7, 2006): 729–39. http://dx.doi.org/10.1182/blood-2006-04-015958.
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Abstract Hodgkin lymphoma (HL) originates from the clonal expansion of malignant Hodgkin and Reed-Sternberg (HRS) cells. These B-cell–derived elements constitute less than 10% of the tumoral mass. The remaining tissue is comprised of an inflammatory infiltrate that includes myeloid cells. Myeloid cells activate B cells by producing BAFF and APRIL, which engage TACI, BCMA, and BAFF-R receptors on the B cells. Here, we studied the role of BAFF and APRIL in HL. Inflammatory and HRS cells from HL tumors expressed BAFF and APRIL. Unlike their putative germinal center B-cell precursors, HRS cells lacked BAFF-R, but expressed TACI and BCMA, a phenotype similar to that of plasmacytoid B cells. BAFF and APRIL enhanced HRS cell survival and proliferation by delivering nonredundant signals via TACI and BCMA receptors through both autocrine and paracrine pathways. These signals caused NF-κB activation; Bcl-2, Bcl-xL, and c-Myc up-regulation; and Bax down-regulation, and were amplified by APRIL-binding proteoglycans on HRS cells. Interruption of BAFF and APRIL signaling by TACI-Ig decoy receptor, which binds to and neutralizes BAFF and APRIL, or by small-interfering RNAs targeting BAFF, APRIL, TACI, and BCMA inhibited HRS cell accumulation in vitro and might attenuate HL expansion in vivo.
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Proust, Alexis, Patricia Rince, Rita Creidy, Thierry Lazure, Monique Fabre, Irène Joab, Catherine Guettier, and Martine Raphael. "P52 Activation in Monomorphic B-Cell Post-Transplant Lymphoproliferative Disorders without BAFF-R Expression." Blood 114, no. 22 (November 20, 2009): 2932. http://dx.doi.org/10.1182/blood.v114.22.2932.2932.
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Abstract Abstract 2932 Poster Board II-908 Post-transplant lymphoproliferative disorders (PTLD) are one of the worse prognostic complications after solid organ or bone marrow stem cells transplantation. Most of them are associated to EBV known to activate NF-kB pathway especially by constitutive p65 expression. BAFF cytokine, a B cell-activating factor belonging to the tumour necrosis factor (TNF) family, have been described to modulate cell growth and survival in non Hodgkin lymphomas. However, little is known on the association between EBV, BAFF/BAFF-R signalling and canonical and non canonical NF-kB pathways expression in PTLD. Thus, we intend to study the role of EBV, NF-κB and BAFF/BAFF-R expression in PTLD.Our study has been investigated in two different contexts of diffuse large B-cell lymphoma (DLBCL). 20 cases of DLCBL resulting from immunocompetent patients (DLBCL/IC) and 13 from post-transplant recipients (DLBCL/PTLD) were compared. Indeed, all cases were characterized by histology and immunohistochemistry (IHC) was used to detect B-cell markers and to identify their germinal center (GC) or non GC (NGC) origin. EBV was detected by in situ Hybridisation (ISH) using EBER probe. Latent proteins LMP1 and EBNA2 as well as replicative protein ZEBRA were also detected by IHC. In addition, p50 and p52 proteins expression was carried out to study NF-kB pathway activation. We showed in DLBCL/IC, regardless of the ontogenic profile GC/NGC, that BAFF-R is expressed in 40% of cases, while in DLBCL/PTLD NGC pattern, BAFF-R is expressed in only one case out of 13 (7,7%) (p<0,05). Moreover, there was no significant difference in p50 expression between the categories of DLBCL studied. In contrast, we have shown a significant expression of p52 in DLBCL/PTLD (8 out of 13 cases) compared to DLBCL/IC (4 out of 20 cases) (p<0.005). In DLBCL/PTLD, there was no expression of BAFF-R ; this pattern could be related to the presence of EBV and LMP1 since p52 expression is mostly observed in EBV+ DLBCL/PTLD (5 out of 7 p52+ cases). In conclusion, the activation profile of DLBCL/PTLD is mostly not associated with BAFF/BAFF-R expression while NF-kB2 pathway is activated. Disclosures: No relevant conflicts of interest to declare.
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Feng, Guo-dong, Xiao-chang Xue, Mei-li Gao, Xian-feng Wang, Zhen Shu, Nan Mu, Yuan Gao, et al. "Therapeutic Effects of PADRE-BAFF Autovaccine on Rat Adjuvant Arthritis." BioMed Research International 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/854954.
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B cell activating factor (BAFF) is a cytokine of tumor necrosis factor family mainly produced by monocytes and dendritic cells. BAFF can regulate the proliferation, differentiation, and survival of B lymphocytes by binding with BAFF-R on B cell membrane. Accumulating evidences showed that BAFF played crucial roles and was overexpressed in various autoimmune diseases such as systemic lupus erythematous (SLE) and rheumatoid arthritis (RA). This suggests that BAFF may be a therapeutic target for these diseases. In the present study, we developed a BAFF therapeutic vaccine by coupling a T helper cell epitope AKFVAAWTLKAA (PADRE) to the N terminus of BAFF extracellular domains (PADRE-BAFF) and expressed this fusion protein inEscherichia coli. The purified vaccine can induce high titer of neutralizing BAFF antibodies and ameliorate the syndrome of complete Freund’s adjuvant (CFA) induced rheumatoid arthritis in rats. Our data indicated that the BAFF autovaccine may be a useful candidate for the treatment of some autoimmune diseases associated with high level of BAFF.
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Erdő-Bonyár, Szabina, Judit Rapp, Dávid Szinger, Tünde Minier, Gábor Kumánovics, László Czirják, Timea Berki, and Diána Simon. "Ligation of TLR Homologue CD180 of B Cells Activates the PI3K/Akt/mTOR Pathway in Systemic Sclerosis and Induces a Pathological Shift in the Expression of BAFF Receptors." International Journal of Molecular Sciences 23, no. 12 (June 17, 2022): 6777. http://dx.doi.org/10.3390/ijms23126777.
Full textAbstract:
The phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) pathways are known to play a key role in B-cell activation and fibrosis in systemic sclerosis (SSc). Receptors of B-cell activator factor (BAFF) utilize these pathways, which can be influenced by Toll-like receptors (TLRs), as TLRs can alter the expression of BAFF-binding receptors. Our results show that B-cell stimulation via TLR homologue CD180 phosphorylates Akt in diffuse cutaneous SSc (dcSSc) to a lower extent than in healthy controls (HCs). We found basal downregulated BAFF receptor (BAFF-R) and enhanced transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) expression in dcSSc B cells, which might enhance the formation of autoantibody-secreting plasma cells. Moreover, this pathological shift was observed in naive B cells, emphasizing the importance of their increase in SSc. Additionally, we measured higher serum levels of autoantibodies to BAFF in dcSSc patients, suggesting that an imbalance in the complex system of BAFF/anti-BAFF autoantibodies/BAFF-binding receptors may contribute to the development of SSc. Anti-CD180 antibody treatment had opposite effects on the expression of BAFF-R and TACI in HC B cells, resulting in similar levels as observed in SSc B cells without stimulation, which argues against the usefulness of such therapy in SSc.