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1
Scapini, Patrizia, Bernardetta Nardelli, Gianpaolo Nadali, Federica Calzetti, Giovanni Pizzolo, Cesare Montecucco, and Marco A. Cassatella. "G-CSF–stimulated Neutrophils Are a Prominent Source of Functional BLyS." Journal of Experimental Medicine 197, no. 3 (January 27, 2003): 297–302. http://dx.doi.org/10.1084/jem.20021343.
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B lymphocyte stimulator (BLyS) is a novel member of the TNF ligand superfamily that is important in B cell maturation and survival. We demonstrate that human neutrophils, after incubation with G-CSF or, less efficiently, IFNγ, express high levels of BLyS mRNA and release elevated amounts of biologically active BLyS. In contrast, surface expression of the membrane-bound BLyS was not detected in activated neutrophils. Indeed, in neutrophils, uniquely among other myeloid cells, soluble BLyS is processed intracellularly by a furin-type convertase. Worthy of note, the absolute capacity of G-CSF–stimulated neutrophils to release BLyS was similar to that of activated monocytes or dendritic cells, suggesting that neutrophils might represent an important source of BLyS. In this regard, we show that BLyS serum levels as well as neutrophil-associated BLyS are significantly enhanced after in vivo administration of G-CSF in patients. In addition, serum obtained from two of these patients induced a remarkable accumulation of neutrophil-associated BLyS in vitro. This effect was neutralized by anti–G-CSF antibodies, indicating that G-CSF, present in the serum, stimulated neutrophils to produce BLyS. Collectively, our findings suggest that neutrophils, through the production of BLyS, might play an unsuspected role in the regulation of B cell homeostasis.
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Goenka, Radhika, Andrew H. Matthews, Bochao Zhang, Patrick J. O’Neill, Jean L. Scholz, Thi-Sau Migone, Warren J. Leonard, William Stohl, Uri Hershberg, and Michael P. Cancro. "Local BLyS production by T follicular cells mediates retention of high affinity B cells during affinity maturation." Journal of Experimental Medicine 211, no. 1 (December 23, 2013): 45–56. http://dx.doi.org/10.1084/jem.20130505.
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We have assessed the role of B lymphocyte stimulator (BLyS) and its receptors in the germinal center (GC) reaction and affinity maturation. Despite ample BLyS retention on B cells in follicular (FO) regions, the GC microenvironment lacks substantial BLyS. This reflects IL-21–mediated down-regulation of the BLyS receptor TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) on GC B cells, thus limiting their capacity for BLyS binding and retention. Within the GC, FO helper T cells (TFH cells) provide a local source of BLyS. Whereas T cell–derived BLyS is dispensable for normal GC cellularity and somatic hypermutation, it is required for the efficient selection of high affinity GC B cell clones. These findings suggest that during affinity maturation, high affinity clones rely on TFH-derived BLyS for their persistence.
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Chang, Sook Kyung, Bonnie K. Arendt, Jaime R. Darce, Xiaosheng Wu, and Diane F. Jelinek. "A role for BLyS in the activation of innate immune cells." Blood 108, no. 8 (October 15, 2006): 2687–94. http://dx.doi.org/10.1182/blood-2005-12-017319.
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AbstractB-lymphocyte stimulator (BLyS) is a member of the tumor necrosis factor (TNF) ligand superfamily. Although BLyS costimulates adaptive immune cells, the ability of BLyS to stimulate innate immune cells has not been described. Here, we show that BLyS strongly induces human monocyte survival, and activation as measured by proinflammatory cytokine secretion and up-regulation of costimulatory molecule expression. In addition, monocytes cultured with BLyS differentiated into macrophage-like cells. Regarding BLyS receptor(s) expression, freshly isolated monocytes bound low levels of exogenous BLyS and expressed primarily intracellular TACI, and cell surface TACI levels increased following monocyte activation. Of interest, bone marrow monocytes from some multiple myeloma patients expressed significant levels of cell surface TACI at isolation. Our findings indicate that BLyS plays a role in activating innate immune cells. Moreover, this study may explain more clearly why high BLyS production is often correlated with certain inflammatory autoimmune diseases and B-lymphocyte malignancies.
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Elsawa, Sherine F., Anne J. Novak, Deanna M. Grote, Steven C. Ziesmer, Thomas E. Witzig, Robert A. Kyle, Stacey R. Dillon, Brandon Harder, Jane A. Gross, and Stephen M. Ansell. "B-lymphocyte stimulator (BLyS) stimulates immunoglobulin production and malignant B-cell growth in Waldenström macroglobulinemia." Blood 107, no. 7 (April 1, 2006): 2882–88. http://dx.doi.org/10.1182/blood-2005-09-3552.
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AbstractWaldenström macroglobulinemia (WM) is a serious and frequently fatal B-cell malignancy associated with an elevated monoclonal IgM protein in the serum. Many of the mechanisms leading to this disease are not yet known. B-lymphocyte stimulator (BLyS) is a TNF family member that is critical for maintenance of normal B-cell development and homeostasis. BLyS is overexpressed in a variety of B-cell malignancies and has been shown to inhibit apoptosis in malignant B cells. It also regulates immunoglobulin secretion by normal B cells. To determine the relevance of BLyS in WM, we examined the role of BLyS in WM patient samples. Malignant B cells were found to bind soluble BLyS and variably express the receptors BAFF-R, TACI, and BCMA. We also found expression of BLyS in bone marrow specimens by immunohistochemistry and elevated serum BLyS levels in patients with WM. BLyS, alone or in combination with cytokines that induce immunoglobulin production, was found to increase IgM secretion by malignant B cells. Furthermore, BLyS was found to increase the viability and proliferation of malignant B cells from WM patients. Due to the role of BLyS in WM, strategies to inhibit BLyS may potentially have therapeutic efficacy in these patients.
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Novak, Anne J., Deanna M. Grote, Mary Stenson, Steven C. Ziesmer, Thomas E. Witzig, Thomas M. Habermann, Brandon Harder, et al. "Expression of BLyS and its receptors in B-cell non-Hodgkin lymphoma: correlation with disease activity and patient outcome." Blood 104, no. 8 (October 15, 2004): 2247–53. http://dx.doi.org/10.1182/blood-2004-02-0762.
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Abstract BLyS, recently shown to be critical for survival of normal B cells, has been found to be elevated in a number of immune disease models. A role for BLyS in the survival of malignant B cells has also been revealed and we therefore sought to identify a role for BLyS and its receptors in non-Hodgkin lymphoma (NHL). We found that tumor cells from all NHL histologic subtypes expressed one or more of 3 known receptors (BCMA, TACI, and BAFF-R) for BLyS; however, the pattern of expression was variable. We provide evidence that BLyS is expressed in tumors from patients with NHL and that BLyS levels increase as tumors transform to a more aggressive phenotype. Additionally, we provide evidence that serum BLyS levels are elevated in a subgroup of patients with NHL. In patients with de novo large B-cell lymphoma, a high BLyS level correlated with a poorer median overall survival, the presence of constitutional symptoms, and elevated values of lactic dehydrogenase. When BLyS levels were correlated with response to therapy in all patients, responding patients had a significantly lower BLyS level than those with progressive disease. In summary, we found that BLyS and its receptors represent a potentially important therapeutic target in B-cell lymphoma.
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Nardelli, Bernardetta, Ornella Belvedere, Viktor Roschke, Paul A. Moore, Henrik S. Olsen, Thi Sau Migone, Svetlana Sosnovtseva, et al. "Synthesis and release of B-lymphocyte stimulator from myeloid cells." Blood 97, no. 1 (January 1, 2001): 198–204. http://dx.doi.org/10.1182/blood.v97.1.198.
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Abstract B-lymphocyte stimulator (BLyS) is a recently identified novel member of the tumor necrosis factor ligand superfamily shown to exist in a membrane-bound and soluble form. BLyS was found to be specifically expressed on cells of myeloid lineage and to selectively stimulate B-lymphocyte proliferation and immunoglobulin production. The expression of a cytokine involved in potentiation of humoral immune responses, such as BLyS, is expected to be strictly controlled. The goal of the present study was to examine regulation of BLyS levels in monocytic cells in response to cytokines and during their differentiation to macrophages and dendritic cells. The presence of BLyS on the cell surface and in the culture medium of both normal blood monocytes and on tumor cells of myelomonocytic origin was demonstrated. BLyS gene expression and levels of membrane-associated and soluble BLyS were found to be regulated by cytokines, in particular interferon (IFN)-γ and to a lesser extent interleukin-10 (IL-10). The expression of BLyS on monocyte membranes was retained following differentiation into macrophages, but detection on the surface of monocyte-derived dendritic cells required stimulation with IFN-γ. Both IFN-γ and IL-10 enhanced the release of soluble BLyS that was active in B-cell proliferation assays. Cells transfected with BLyS complementary DNA mutated in a predicted cleavage site failed to release BLyS into the culture medium, thereby suggesting that soluble BLyS was derived from the membrane form. These results provide further support for an important role for BLyS expressed in myeloid cells in B-cell expansion and antibody responses.
7
Ansell, Stephen M., Deanna M. Grote, Steven C. Ziesmer, Thomas E. Witzig, Robert A. Kyle, and Anne J. Novak. "B-Lymphocyte Stimulator (BLyS) Is Highly Expressed in Waldenstrom’s Macroglobulinemia." Blood 104, no. 11 (November 16, 2004): 2291. http://dx.doi.org/10.1182/blood.v104.11.2291.2291.
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Abstract Waldenstrom’s macroglobulinemia is a serious and frequently fatal illness, however many of the mechanisms leading to this disease are not yet known. It is clear, however, that there is dysregulation of the balance between cell proliferation and programmed cell death. BLyS (B-lymphocyte stimulator) is a newly identified TNF family member expressed by monocytes, macrophages, and dendritic cells. BLyS has been shown to be critical for maintenance of normal B cell development and homeostasis, and has been found to stimulate lymphocyte growth. BLyS is overexpressed in a variety of B-cell malignancies and has been shown to inhibit apoptosis in malignant B-cells. Studies of the effects of BLyS on B cell physiology have shown that it also regulates immunoglobulin secretion. To determine the relevance of the BLyS receptor-ligand system in Waldenstrom’s macroglobulinemia, we examined malignant B cells from 5 patients with Waldenstrom’s macroglobulinemia for their ability to bind soluble BLyS and for the expression of the known BLyS receptors, TACI, BAFF-R, or BCMA. The malignant B cells were found to bind BLyS and express BAFF-R and TACI. BCMA expression was undetectable. We then determined the expression of BLyS in bone marrow specimens from 5 patients with Waldenstrom’s macroglobulinemia by immunohistochemistry and compared it to the expression in 5 normal bone marrow specimens. The lymphoplasmacytic cell infiltrate in the bone marrow of patients with Waldenstrom’s macroglobulinemia showed significantly increased BLyS expression. We further determined the serum BLyS levels by ELISA in stored serum specimens from patients with Waldenstrom’s macroglobulinemia (n=20), and compared them to serum BLyS levels in other patients with lymphoplasmacytic lymphoma without elevated immunoglobulin levels (n=10) and to serum levels in normal controls (n=50). Serum BLyS levels in Waldenstrom’s patients (mean: 49.6ng/ml) as well as those in patients with lymphoplasmacytic lymphoma (mean; 46.7ng/ml) were significantly higher than normal controls (mean 12.6ng/ml). In conclusion, we have demonstrated that malignant B cells from patients with Waldenstrom’s macroglobulinemia express the receptors for BLyS and can bind soluble BLyS. Furthermore, we have found that serum BLyS levels are significantly elevated in patients with Waldenstrom’s macroglobulinemia when compared to controls. Strategies to inhibit BLyS may potentially have significant therapeutic efficacy in Waldenstrom’s macroglobulinemia.
8
Weitzman, Jonathan B. "Absolute BlyS." Genome Biology 2 (2001): spotlight—20010822–01. http://dx.doi.org/10.1186/gb-spotlight-20010822-01.
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Novak, Anne J., Deanna M. Grote, Steven C. Ziesmer, Thomas E. Witzig, Shanafelt Tait, Timothy Call, Neil E. Kay, Diane F. Jelinek, James R. Cerhan, and Stephen M. Ansell. "Elevated BLyS Levels in Patients with Familial and Sporadic B-CLL: Correlation with BLyS Polymorphisms." Blood 104, no. 11 (November 16, 2004): 964. http://dx.doi.org/10.1182/blood.v104.11.964.964.
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Abstract Serum BLyS levels have been found to be elevated in a number of immune disease models and there is increasing evidence that this may correlate with pathogenesis of various B cell related disorders including B cell malignancies. While it is clear that BLyS expression is required for normal B cell development and homeostasis, the exact source of BLyS in these scenarios and definition of the mechanisms that control BLyS expression remain to be fully elucidated. Serum BLyS levels are elevated in a number of B cell malignancies known to have a familial incidence. Therefore, we sought to determine if there was any correlation between serum BLyS levels and family history of B cell cancers. In our initial studies we examined the serum BLyS levels in patients with sporadic vs. familial B-cell chronic lymphocytic leukemia (B-CLL; near relative with B-CLL, multiple myeloma, or non-Hodgkin lymphoma), and normal age-matched controls. In the normal controls (n=50), the mean serum BLyS level was 12.7 ng/ml, and we found that 4/50 (8%) had BLyS levels exceeding 20 ng/ml. In the sporadic CLL cohort (n=52), the mean serum BLyS level was 18.3 ng/ml, and we found that 5/52 (10%) had BLyS levels exceeding 20 ng/ml. In striking contrast, in the familial CLL cohort (n=24), the mean serum BLyS levels was 33.4 ng/ml, and we found that 11/24 (46%) had BLyS levels exceeding 20 ng/ml. The percentage of patients with elevated BLyS levels, as well as the mean BLyS levels in the familial CLL cohort compared to the normal controls, was significantly higher (mean, p=0.002) and suggests that elevated BLyS levels may correlate with familial CLL. Because of the correlation between BLyS levels and family history B cell malignancies, we next wanted to determine if there was a common underlying genetic event influencing BLyS expression in this group of patients. We began by sequencing the BLyS promoter in 19 patients with B-CLL and 11 normal controls. We identified 2 sites that were polymorphic, −661 A/G and −871 C/T. The −871 T/T genotype has been previously reported to be expressed at increased frequency in SLE patients and is associated with elevated BLyS mRNA levels. Using RFLP analysis we examined the presence of the two polymorphisms in our control, sporadic, and familial CLL cohorts. In the control group (n=50) we found that at −871, C/C (wildtype) was expressed in 24%, C/T in 54%, and T/T in 22% of patients. Similarily, in the sporadic CLL group (n=35) we found that at −871, C/C was expressed in 29%, C/T in 57%, and T/T in 14%. In the familial group (n=24) we found that at −871, C/C was expressed in only 8%, C/T in 67%, and T/T in 25%. These data suggest a decreased representation of −871 C/C in the familial group. No significant changes were observed between the three groups at the −661 A/G locus. Additionally, we found that none of the patients with BLyS levels exceeding 20 ng/ml expresses C/C at −871. In summary, our data suggest that BLyS levels are elevated in patients with familial CLL relative to both normal controls and individuals with sporadic CLL and that elevated BLyS levels may correlate with the presence of a T at −871 in the BLyS promoter.
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Elsawa, Sherine F., Anne J. Novak, Deanna M. Grote, Steven C. Zeismer, Thomas E. Witzig, Robert A. Kyle, and Stephen M. Ansell. "Role of B-Lymphocyte Stimulator (BLyS) in Waldenstrom’s Macroglobulinemia." Blood 106, no. 11 (November 16, 2005): 601. http://dx.doi.org/10.1182/blood.v106.11.601.601.
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Abstract Waldenstrom’s macroglobulinemia (WM) is a serious and frequently fatal disorder characterized by the production of a monoclonal IgM protein, a lymphoplasmacytic infiltrate in the bone marrow, and associated symptoms including anemia, lymphadenopathy and hyperviscosity. Many of the mechanisms leading to this disease are not yet known. It is clear, however, that there is dysregulation of the balance between cell proliferation and programmed cell death. BLyS (B-lymphocyte stimulator) is a TNF family member expressed by monocytes, neutrophils, macrophages, and dendritic cells. BLyS has been shown to be critical for maintenance of normal B cell development and homeostasis, and has been found to stimulate lymphocyte growth. BLyS is overexpressed in a variety of B-cell malignancies and has been shown to inhibit apoptosis in malignant B-cells. Studies of the effects of BLyS on B cell physiology have shown that it also regulates immunoglobulin secretion. In previous work, we have shown that malignant B cells from patients with WM are able to bind soluble BLyS and variably express the BLyS receptors, BAFF-R, TACI and BCMA. We also found expression of BLyS in bone marrow specimens by immunohistochemistry and elevated serum BLyS levels in patients with WM. The goal of this study was to determine the functional role of BLyS-receptor ligand system in Waldenstrom’s macroglobulinemia and its relevance to the increased immunoglobulin production seen in this disease. Using cells from WM patients, we first examined the ability of BLyS to increase the secretion of IgM by malignant B cells. BLyS, alone or in combination with cytokines that induce plasmacytic differentiation and immunoglobulin production (IL-2, IL-6, IL-10 and IL-12), was found to increase IgM secretion by malignant B cells. Mean baseline IgM levels significantly increased in cells treated with BLyS (p=0.03), cytokines (p=0.0002) and a combination of BLyS and cytokines (p<0.0001). We then determined the effect of BLyS on the survival of malignant B cells using Annexin-V/PI staining. Compared to cells cultured in media alone, BLyS was found to increase viability of malignant B cells from WM patients. Cell viability was normalized relative to the media-alone control and the median relative viability increased significantly compared to controls (median increase 41.2%; range 8 – 46%). Next, we examined the ability of BLyS to modulate cell proliferation using thymidine incorporation. Using WM patient samples, BLyS was found to significantly enhance the proliferation of malignant B cells (p=0.0002). Furthermore, addition of anti-Ig antibody further enhanced the ability of BLyS to promote the proliferation of malignant B cells (p<0.0001). In summary, we have demonstrated that BLyS enhances IgM secretion by malignant B cells from patients with Waldenstrom’s macroglobulinemia. We have also demonstrated the ability of BLyS to enhance the survival and proliferation of malignant B cells. Strategies to inhibit BLyS may potentially have therapeutic efficacy in Waldenstrom’s macroglobulinemia.
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Goenka, Radhika, Andrew Mathews, Patrick O'Neill, Jean Scholz, Warren Leonard, William Stohl, and Michael Cancro. "Positive selection during affinity maturation relies on T cell derived BLyS (61.3)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 61.3. http://dx.doi.org/10.4049/jimmunol.186.supp.61.3.
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Abstract Protective humoral immunity relies on high affinity B cell clones that are generated and selected during the germinal center (GC) reaction. To determine whether BLyS family member(s) play a role in this process, we assessed their distribution within the GC. We show that majority of the GC is devoid of BLyS despite the presence of ample BLyS in the adjacent follicular regions. The paucity of BLyS correlates with down-regulation of TACI receptor on GC B cells and likewise follicular B cells in TACI-deficient mice bind less BLyS. TACI down-regulation on follicular B cells is mediated by IL-21 in a surrogate thymus-dependent stimulation. Furthermore, some BLyS staining is detectable in the light zone associated by T Follicular Helper cells (TFH). The expression of BLyS by TFH is crucial for appropriate GC evolution, since efficient affinity maturation fails in mixed bone marrow chimeras where T cells are deficient in BLyS. We conclude that positive selection during affinity maturation relies on restricted sources of BLyS on GC TFH that provide survival signals to preserve high affinity clones.
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Crowley, Jenni E., Jason E. Stadanlick, John C. Cambier, and Michael P. Cancro. "FcγRIIB signals inhibit BLyS signaling and BCR-mediated BLyS receptor up-regulation." Blood 113, no. 7 (February 12, 2009): 1464–73. http://dx.doi.org/10.1182/blood-2008-02-138651.
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Abstract These studies investigate how interactions between the BCR and FcγRIIB affect B lymphocyte stimulator (BLyS) recep-tor expression and signaling. Previous studies showed that BCR ligation up-regulates BLyS binding capacity in mature B cells, reflecting increased BLyS receptor levels. Here we show that FcγRIIB coaggregation dampens BCR-induced BLyS receptor up-regulation. This cross-regulation requires BCR and FcγRIIB coligation, and optimal action relies on the Src-homology-2 (SH2)–containing inositol 5 phosphase-1 (SHIP1). Subsequent to FcγRIIB/BCR coaggregation, the survival promoting actions of BLyS are attenuated, reflecting reduced BLyS receptor signaling capacity in terms of Pim 2 maintenance, noncanonical NF-κB activation, and Bcl-xL levels. These findings link the negative regulatory functions of FcγRIIB with BLyS-mediated B-cell survival.
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Fu, Lingchen, Yen-Chiu Lin-Lee, Lan V. Pham, Archito Tamayo, Linda Yoshimura, and Richard J. Ford. "Constitutive NF-κB and NFAT activation leads to stimulation of the BLyS survival pathway in aggressive B-cell lymphomas." Blood 107, no. 11 (June 1, 2006): 4540–48. http://dx.doi.org/10.1182/blood-2005-10-4042.
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AbstractB-lymphocyte stimulator (BLyS), a relatively recently recognized member of the tumor necrosis factor ligand family (TNF), is a potent cell-survival factor expressed in many hematopoietic cells. BLyS binds to 3 TNF-R receptors, TACI, BCMA, BAFF-R, to regulate B-cell survival, differentiation, and proliferation. The mechanisms involved in BLYS gene expression and regulation are still incompletely understood. In this study, we examined BLYS gene expression, function, and regulation in B-cell non-Hodgkin lymphoma (NHL-B) cells. Our studies indicate that BLyS is constitutively expressed in aggressive NHL-B cells, including large B-cell lymphoma (LBCL) and mantle cell lymphoma (MCL), playing an important role in the survival and proliferation of malignant B cells. We found that 2 important transcription factors, NF-κB and NFAT, are involved in regulating BLyS expression through at least one NF-κB and 2 NFAT binding sites in the BLYS promoter. We also provide evidence suggesting that the constitutive activation of NF-κB and BLyS in NHL-B cells forms a positive feedback loop associated with lymphoma cell survival and proliferation. Our findings indicate that constitutive NF-κB and NFAT activations are crucial transcriptional regulators of the BLyS survival pathway in malignant B cells that could be therapeutic targets in aggressive NHL-B.
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Woodland, Robert T., Casey J. Fox, Madelyn R. Schmidt, Peter S. Hammerman, Joseph T. Opferman, Stanley J. Korsmeyer, David M. Hilbert, and Craig B. Thompson. "Multiple signaling pathways promote B lymphocyte stimulator–dependent B-cell growth and survival." Blood 111, no. 2 (January 15, 2008): 750–60. http://dx.doi.org/10.1182/blood-2007-03-077222.
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We investigated the mechanism by which B lymphocyte stimulator (BLyS)/BAFF, a tumor necrosis factor superfamily ligand, promotes B-cell survival and resistance to atrophy. BLyS stimulation activates 2 independent signaling pathways, Akt/mTOR and Pim 2, associated with cell growth and survival. BLyS blocks the cell volume loss (atrophy) that freshly isolated B cells normally undergo when maintained in vitro while concurrently increasing glycolytic activity and overall metabolism. This atrophy resistance requires Akt/mTOR. We used a genetic approach to resolve the contributions of Akt/mTOR and Pim kinase pathways to BLyS-mediated survival. Pim 2–deficient B cells are readily protected from death by BLyS stimulation, but this protection is completely abrogated by treatment with the mTOR inhibitor rapamycin. Furthermore, rapamycin treatment in vivo significantly reduces both follicular and marginal zone B cells in Pim-deficient but not healthy hosts. BLyS-dependent survival requires the antiapoptotic protein Mcl-1. Mcl-1 protein levels rise and fall in response to BLyS addition and withdrawal, respectively, and conditional deletion of the Mcl-1 gene renders B cells refractory to BLyS-mediated protection. Because BlyS is required for the normal homeostasis of all B cells, these data suggest a therapeutic strategy simultaneously inhibiting mTOR and Pim 2 could target pathogenic B cells.
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Landau, D.-A., M. Rosenzwajg, D. Saadoun, D. Klatzmann, and P. Cacoub. "The B lymphocyte stimulator receptor–ligand system in hepatitis C virus-induced B cell clonal disorders." Annals of the Rheumatic Diseases 68, no. 3 (April 23, 2008): 337–44. http://dx.doi.org/10.1136/ard.2007.085910.
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Objective:The study aim was to examine the B lymphocyte stimulator (BLyS) receptor–ligand system in hepatitis C virus (HCV)-induced B lymphocyte clonal disorders.Methods:94 patients with chronic HCV (including 35 with HCV+ mixed cryoglobulinaemia (MC)-vasculitis and nine with HCV+ B cell non-Hodgkin’s lymphoma (B-NHL)) and 15 healthy volunteers were included.Results:A twofold serum BLyS increase was associated with HCV-induced MC-vasculitis, and a threefold increase with HCV-induced B-NHL, compared with patients that were HCV+, but without vasculitis, or healthy controls (p<0.05). Lower membrane BLyS expression in HCV-induced MC-vasculitis was observed. CD19+ BLyS binding and BLyS receptor 3 (BR3) staining showed a stepwise decrease with highest values in healthy controls and who were HCV+ without MC, and lowest in B-NHL (p<0.05, p<0.0001, respectively) with a further decrease in VH1-69+ clonal B cells. BLyS anti-apoptotic effects were maintained despite this decrease in BR3 staining. Complete clinical remission after antiviral treatment was associated with a decrease in serum BLyS, and an increase in BR3 staining. Rituximab treatment was associated with a fivefold increase in serum BLyS (p<0.001), mirroring the depletion of CD19+ cells. BR3 staining in repopulating B cells was significantly decreased (p<0.005).Conclusions:The BLyS ligand–receptor activity is increased in HCV-induced B cell clonal disorders, indicating a possible role for treatment targeting the BLyS receptor–ligand system.
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Scholz, Jean, Bapi Pahar, Joanna B. Madej, Martina Soldemo, Wendy Lala Trunch, Javier Guenaga, Arpita Myles, et al. "Effects of temporary BLyS treatment of rhesus macaques." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 215.19. http://dx.doi.org/10.4049/jimmunol.198.supp.215.19.
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Abstract BLyS is a survival cytokine that regulates peripheral B cell numbers and transitional B cell throughput. In mice, exogenous BLyS administration yields elevated pre-immune B cell numbers, an increased proportional representation of transitional B cells, and shifts in repertoire composition (1–3). Consistent with these observations, BLyS pretreatment alters the quality of antibody responses to HIV gp140 in mice, yielding enhanced neutralizing responses (4). While it is assumed that BLyS plays analogous roles in other species, similar studies in nonhuman primates are lacking. Accordingly, we have assessed the effects of exogenous BLyS treatment in rhesus macaques. Here we treated juvenile rhesus macaques with 0.05 mg/kg recombinant human BLyS over ten days. Physical exams and blood cell counts indicate no adverse effects of treatment except a decrease in lymphocyte counts during the treatment periods. We find that the numbers and proportional representation of transitional B cells (CD20+ IgM+ CD10+) increase during and immediately following BLyS treatment, returning to pre-treatment levels within 20–30 days. There is a small increase in plasma anti-dsDNA antibody, and a significant increase in anti-recombinant human BLyS antibody indicating immunogenicity in this species. Together, these results indicate that BLyS plays similar roles in rodents and primates. They further suggest that deliberate manipulation of BLyS may be an effective approach in rhesus macaques for expanding B cell repertoire diversity and altering the quality of antibody responses.
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Crowley, Jenni Eileen, Jean L. Scholz, Thi-Sau Migone, and Michael P. Cancro. "Primary and memory B cells occupy independent homeostatic niches (B20)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): LB4. http://dx.doi.org/10.4049/jimmunol.178.supp.b20.
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Abstract The cytokines BLyS (B lymphocyte stimulator) and APRIL (a proliferation-inducing ligand) interact with three receptors – BR3, TACI, and BCMA – to regulate peripheral B cell homeostasis. Experimental evidence indicates that the BLyS-BR3 interaction governs the size and composition of primary B cell subsets by controlling the proportion of transitional (TR) cells that complete differentiation and determining the lifespan of follicular (FO) and marginal zone (MZ) B cells. The role of the BLyS family in the regulation and maintenance of memory B cell subsets remains less understood. Accordingly, we have directly tested the role of BLyS in the maintenance of memory B cells in vivo using a neutralizing anti-BLyS antibody. Mice injected with anti-BLyS show profoundly reduced numbers of TR, FO, and MZ B cells within two weeks following treatment, as well as significantly reduced serum BLyS levels. However, for mice previously immunized with NP-CGG and injected with anti-BLyS, this treatment, while similarly reducing primary B cell pools, has no effect on NP-specific memory B cell numbers. Further, upon rechallenge, the expansion of NP specific memory B cells and serum anti-NP antibody levels are similar to controls that did not receive anti-BLyS. Together, these findings indicate that memory B cells are largely independent of BLyS availability, and therefore occupy a separate homeostatic niche from primary B cells. Supported by USPHS AI054488 to MPC and T32-AI-055428 to JEC
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Novak, Anne J., Deanna M. Grote, Steven C. Ziesmer, Michael P. Kline, Michelle K. Manske, Susan Slager, Thomas E. Witzig, et al. "Elevated Serum B-Lymphocyte Stimulator Levels in Patients With Familial Lymphoproliferative Disorders." Journal of Clinical Oncology 24, no. 6 (February 20, 2006): 983–87. http://dx.doi.org/10.1200/jco.2005.02.7938.
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Purpose Serum B-lymphocyte stimulator (BLyS) levels have been found to be elevated in a number of immune disease models. Therefore, we sought to establish whether BLyS levels were elevated in patients with B-cell lymphoproliferative disorders and to determine whether elevated BLyS levels correlated with clinical characteristics of the disease. Patients and Methods Specimens were collected from the peripheral blood of individuals diagnosed with B-cell chronic lymphocytic leukemia (B-CLL; n = 70) or from age- and sex-matched patients seen at the same institution (n = 41). Serum BLyS levels were determined by enzyme-linked immunosorbent assay, and sequencing of the BLyS promoter was performed by conventional methods and confirmed by restriction fragment length polymorphism analysis. Results We found that elevated BLyS levels were more common in patients with familial B-CLL than individuals with sporadic B-CLL or normal controls. Because of this association, we sequenced the BLyS promoter in patients with B-CLL and normal controls and identified a polymorphic site, −871 C/T. We found that the wild-type sequence was significantly underrepresented in patients with familial B-CLL (4%) compared with patients with sporadic B-CLL (30%; P = .01) or controls (24%; P = .04). Furthermore, using a luciferase reporter under control of the BLyS promoter containing either a C or a T at position −871, we found that the reporter construct containing a T at −871 had a 2.6-fold increase in activity (P = .004). Conclusion Our data suggest serum BLyS levels are elevated in patients with familial B-CLL and that elevated BLyS levels correlate with the presence of a T at −871 in the BLyS promoter.
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Oki, Yasuhiro, Georgios V. Georgakis, Thi-Sau Migone, Larry W. Kwak, and Anas Younes. "Serum BLyS Level as a Prognostic Marker in Patients with Lymphoma." Blood 106, no. 11 (November 16, 2005): 1926. http://dx.doi.org/10.1182/blood.v106.11.1926.1926.
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Abstract Background: BLyS is a TNF family member which was recently shown to play a critical role for survival of normal and malignant B cells. BLyS is expressed by monocytes, macrophages, dendritic cells as well as lymphoma cells, where its expression levels increase as tumors transform to a more aggressive phenotype. Previous small studies suggested that serum BLyS level is elevated in some proportion of patients with aggressive non-Hodgkin lymphoma (NHL). Little is known if serum BLyS level has prognostic value in patients with lymphoma. Thus, we determined serum soluble BLyS levels in 191 samples obtained from patients with various forms of lymphoma, and correlated them with the clinical characteristics and the prognosis. Materials and Methods: We analyzed serum BLyS level with ELISA in normal individuals and patients with newly diagnosed or relapsed lymphoma. Patients’ histopathological diagnosis, stage, presence of bulky disease, serum LDH, serum beta-2 microglobulin (b2m), IPI score, FLIPI score, progression free survival (PFS) and overall survival (OS) were correlated with serum BLyS levels. For survival analysis. Results: The sensitivity of the ELISA assay was 0.4 ng/ml. Serum samples from 93 normal individuals,135 newly diagnosed patients with lymphoma, and 56 patients with relapsed lymphoma were examined for serum soluble BLyS levels. Median serum BLyS levels were <0.4ng/ml (range 0–0.5) in normal individuals, 1.8ng/ml (0–60.0) in Hodgkin lymphoma (HL), <0.4ng/ml (0–28.5) in small lymphocytic lymphoma, <0.4ng/ml (0–0.94) in marginal zone lymphoma, 1.43ng/ml (0–26.2) in follicular grade 1/2, 1.3ng/ml (0–32.1) in follicular grade 3, 1.9ng/ml (0–6.9) in diffuse large B cell lymphoma, 1.4ng/ml (0–2.8) in immunoblastic lymphoma, <0.4ng/ml (0–14.7) in mantle cell lymphoma. BLyS levels did not correlate with stage, presence of bulky disease, serum LDH, serum b2m, IPI score, FLIPI score. Elevated BLyS levels (>=2ng/ml) were observed more frequently in patients with relapsed lymphomas (42/56, 75%) than in patients with newly diagnosed lymphomas (46/136, 45%, p<0.0001) (Table). BLyS levels were more frequently elevated in relapsed HL than relapsed NHL (p=0.02). Elevated serum BLyS levels were associated with shorter PFS in all patients with relapsed lymphoma (median 2.4 vs 13.4 month, p=0.03, by Wilcoxon), and in patients with relapsed aggressive NHL (1.1 month vs 40.5 months, p=0.02). Patients with elevated BLyS levels had shorter OS in all patients with relapsed lymphoma (median 14.8 vs 49.3 months, p=0.01). Elevated BLyS levels in patients with newly diagnosed lymphoma had no significant impact on PFS or OS in our study. Conclusion: Serum BLyS levels are frequently elevated in patients with lymphoma, especially HL. Serum BLyS level is particularly higher in patients with relapsed disease, and is associated with poor prognosis in those patients group. Our study suggests the promising role of BLyS in the prognostication of patients with lymphoma, particularly aggressive NHL and HL.
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Novak, Anne J., Susan L. Slager, Steven C. Ziesmer, Alice H. Wang, James R. Cerhan, Stacey R. Dillon, and Stephen M. Ansell. "Polymorphisms in the BLyS Gene Are Associated with an Increased Risk of Developing B-Cell Non-Hodgkin Lymphoma." Blood 110, no. 11 (November 16, 2007): 564. http://dx.doi.org/10.1182/blood.v110.11.564.564.
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Abstract Background: Elevated serum BLyS levels have been found in patients with both malignant and autoimmune diseases when compared to those of healthy donors, suggesting that BLyS may play a pathogenic role. While it is clear that BLyS expression is required for normal B cell development and homeostasis, the mechanistic details underlying control of BLyS expression remain to be defined. In previous work we found that a single nucleotide polymorphisms (SNP) in the BLyS promoter (−871C→T) resulted in increased BLyS transcription suggesting that genetic variation in the BLyS gene may influence its expression. Because elevated BLyS levels have been detected in patients with NHL we wanted to determine if additional SNPs in the BLyS gene were associated with high serum BLyS levels and risk of developing of NHL. Methods: We genotyped 9 tagSNPs within the BLyS gene in a clinic-based study of 441 incident Caucasian NHL cases and 475 frequency matched Caucasian controls seen at the Mayo Clinic from 2002–2005. We evaluated the association of individual SNPs as well as haplotypes from the BLyS gene with risk of NHL. We also jointly tested the main effects for all independent (r2<0.25) SNPs using a multivariate logistic regression (MLR) model. As a secondary analysis, for those SNPs showing significant results (< 5% significance), we evaluated associations between those who had all high risk alleles at the SNPs of interest compared to those who had all low risk alleles at the SNPs of interest. Additionally, we evaluated serum BLyS levels by ELISA in these same subjects. Serum BLyS levels were detemined by ELISA. Results: In the individual single SNP logistic regression analysis, 3 of the 9 tagSNPs were significant at p<0.05. Haplotype and MLR results were nonsignificant. However, when we categorized participants into low and high risk groups based on risk alleles at the three statistically significant SNPs, we found the high risk variant had an odds ratio (OR) of 2.086 (p=0.0001) for risk of B-cell NHL. When the analysis was restricted by histologic subtype we found that diffuse large B-cell lymphoma or follilcular lymphoma grade 3 had an OR of 3.163 (p=0.01), follicular lymphoma grade I/II had an OR= 2.547 (p=0.046), and chronic lymphocytic leukemia (CLL) had an OR=1.238 (p=0.13). Because there was not a significant correlation of the high risk variant with CLL, we performed an additional analysis in which we included all B cell NHL cases excluding CLL and the OR was 2.799 (p=0.0001). We next wanted to determine if serum BLyS levels correlated with either the high or low risk variant. The mean serum BLyS level in those individuals (untreated cases and controls) who carried the low risk variant at all three SNPs was significantly lower (p=0.0061) at 1.3 ng/ml (n=25, range: undetectable-4.4 ng/ml) compared to 4.3 ng/ml in those with the high risk variant (n=74, range: undetectable- 66.8 ng/ml). Conclusions: In summary, we have found that genetic variation in the BLyS gene is significantly associated with an increased risk of developing B-cell NHL, particularly follicular and large B-cell lymphoma. Further, we found that genetic variation is also associated with an increase in serum BLyS levels.Taken together, our data further highlight the role of the BLyS gene in B cell malignancies and characterization of the precise genetic and environmental mechanisms that regulate BLyS may have significant clinical impact.
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Kyrtsonis, Marie-Christine, Katerina Sarris, Efstathios Koulieris, Dimitrios Maltezas, Eftychia Nikolaou, Maria K. Angelopoulou, Vassiliki Bartzis, et al. "Serum Soluble TACI, a BLyS Receptor, Is a Powerful Prognostic Marker of Outcome in Chronic Lymphocytic Leukemia." BioMed Research International 2014 (2014): 1–5. http://dx.doi.org/10.1155/2014/159632.
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BLyS is involved in CLL biology and its low soluble serum levels related to a shorter time to first treatment (TFT). TACI is a BLyS receptor and can be shed from cells’ surface and circulate in soluble form (sTACI). We investigated the impact of serum BLyS and sTACI levels at diagnosis in CLL patients and their relationship with disease parameters and patients’ outcome. Serum BLyS was determined in 73 patients, while sTACI in 60. Frozen sera drawn at diagnosis were tested by ELISA. sTACI concentrations correlated with BLyS (P=-0.000021), b2-microglobulin (P=0.005), anemia (P=-0.03), thrombocytopenia (P=0.04), Binet stage (P=0.02), and free light chains ratio (P=0.0003). Soluble BLyS levels below median and sTACI values above median were related to shorter TFT (P=0.0003and 0.007). During a ten-year followup, sTACI levels, but not BLyS, correlated with survival (P=0.048). In conclusion, we confirmed the prognostic significance of soluble BLyS levels with regard to TFT in CLL patients, and, more importantly, we showed for the first time that sTACI is a powerful prognostic marker, related to parameters of disease activity and staging and, more importantly, to TFT and OS.
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Briones, J. "BLyS and BLyS receptor expression in non-Hodgkin's lymphoma." Experimental Hematology 30, no. 2 (February 2002): 135–41. http://dx.doi.org/10.1016/s0301-472x(01)00774-3.
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Fu, Lingchen, Tamayo Archito, Yen-Chiu Lin-Lee, Lan Pham, Linda Yoshimura, and Richard J. Ford. "The BLyS Survival Pathway in NHL-B Cells: Constitutive NF-kB and NFAT Lead to Activation." Blood 104, no. 11 (November 16, 2004): 2279. http://dx.doi.org/10.1182/blood.v104.11.2279.2279.
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Abstract B-cell non-Hodgkin’s Lymphomas (NHL-B), neoplasms of the immune system have shown a significant increase in incidence in the USA over the last three decades. While the pathophysiology of the NHL-B is still unclear, the need to identify the relevant genes and critical signaling pathways, and their involvement in the disease processes in NHL-B have begun to be elucidated. Recently, B Lymphocyte Stimulator (BLyS) has been described as a relatively new member of the TNF ligand family, as a potent cell survival factor that is expressed in many hematopoietic cells, including neoplastic B cells. BLyS can bind to three receptors: TACI, BCMA, BAFF-R, and plays a critical role in B cell maturation, differentiation and proliferation. Relatively high levels of BLyS has been found in the serum of NHL-B patients as well as of the patients with autoimmune disease. The mechanisms of BLyS gene expression and regulation is still unclear, but we have recently found that BLyS is constitutively expressed in several NHL-B cell lines and patient tumor samples by RT-PCR, confocal microscopy, realtime PCR and flow cytometry (FCM). We detected high levels and differential expression of BLyS receptors (TACI, BCMA, BAFF-R) in several NHL-B cell lines by flow cytometry, RT-PCR and realtime PCR in both NHL-B cell lines and patient tumor samples. We have identified a single binding site for NF-kB and two binding sites for NFAT in the BLyS promoter. We also show in aggressive lymphoma B cells that constitutive NF-kB and NFAT binds to the BLyS promoter constitutively. Inhibiting NF-kB/NFAT activity levels, using the NF-kB inhibitors, BAY-11 or Velcade (PS-341), can decrease NF-kB binding activity in the BLyS promotor by EMSA. These inhibitors also decrease BLyS and BAFF-R mRNA and protein levels by realtime PCR and flow cytometry. Similarly, when NHL-B cells were transfected with dominant negative NFAT or NF-kB constructs, there is a 50% decrease in BLyS and BAFF-R expressions, demonstrating that both the ligand (BLyS) and the receptor (BAFF-R) expression are regulated by NFAT and NF-kB. Interestingly, follicular (low grade) lymphoma cells do not express constitutive NF-kB/NFAT activation, and barely detectable mRNA and protein levels of BlyS, but can be activated with exogenous CD154/anti IgM in vitro, activating NF-kB/NFAT and promoting binding to the BLyS promoter by EMSA. This results in a significant increase of BLyS protein level by flow cytometry. Our studies indicate that constitutive NF-kB and NFAT are critical transcriptional regulators of the BLyS survival pathway in malignant B cells that may provide a future therapeutic target in the aggressive NHL-B.
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Do, Richard K. G., Eunice Hatada, Hayyoung Lee, Michelle R. Tourigny, David Hilbert, and Selina Chen-Kiang. "Attenuation of Apoptosis Underlies B Lymphocyte Stimulator Enhancement of Humoral Immune Response." Journal of Experimental Medicine 192, no. 7 (September 25, 2000): 953–64. http://dx.doi.org/10.1084/jem.192.7.953.
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B lymphocyte stimulator (BLyS) is a newly identified monocyte-specific TNF family cytokine. It has been implicated in the development of autoimmunity, and functions as a potent costimulator with antiimmunoglobulin M in B cell proliferation in vitro. Here we demonstrate that BLyS prominently enhances the humoral responses to both T cell–independent and T cell–dependent antigens, primarily by attenuation of apoptosis as evidenced by the prolonged survival of antigen-activated B cells in vivo and in vitro. BLyS acts on primary splenic B cells autonomously, and directly cooperates with CD40 ligand (CD40L) in B cell activation in vitro by protecting replicating B cells from apoptosis. Moreover, although BLyS alone cannot activate the cell cycle, it is sufficient to prolong the survival of naive resting B cells in vitro. Attenuation of apoptosis by BLyS correlates with changes in the ratios between Bcl-2 family proteins in favor of cell survival, predominantly by reducing the proapoptotic Bak and increasing its prosurvival partners, Bcl-2 and Bcl-xL. In either resting or CD40L-activated B cells, the NF-κB transcription factors RelB and p50 are specifically activated, suggesting that they may mediate BLyS signals for B cell survival. Together, these results provide direct evidence for BLyS enhancement of both T cell–independent and T cell–dependent humoral immune responses, and imply a role for BLyS in the conservation of the B cell repertoire. The ability of BLyS to increase B cell survival indiscriminately, at either a resting or activated state, and to cooperate with CD40L, further suggests that attenuation of apoptosis underlies BLyS enhancement of polyclonal autoimmunity as well as the physiologic humoral immune response.
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Scholz, Jean L., Jenni E. Crowley, Patrick J. O’Neill, Yun Hee Cho, Chris Ward, Thi-Sau Migone, and Michael P. Cancro. "The effect of BLyS neutralization on primary B cell compartments and responses (B31)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): LB6—LB7. http://dx.doi.org/10.4049/jimmunol.178.supp.b31.
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Abstract B lymphocyte stimulator (BLyS) controls the proportion of transitional B cells completing differentiation and the longevity of most primary B cells. These key roles in B cell selection, survival and homeostasis make BLyS and its receptors attractive candidates for targeted B cell therapeutics. Here we have used a neutralizing hamster anti-mouse BLyS antibody to assess how BLyS depletion influences developing and primary B cell subsets, as well as how this treatment impacts primary TD and TI immune responses. Mice treated with 10F4 show rapid and substantial reductions in the transitional, follicular, and marginal zone pools which persist for ~40 days. In contrast, the only bone marrow subset affected is the mature recirculating B cell fraction. Interestingly, splenic B1 cells, but not peritoneal B1 cells, are reduced as well. Following the recovery of serum BLyS levels, peripheral reconstitution occurs gradually, such that normal B cell numbers return by day 70–80. Mice challenged with T-dependent or T-independent antigen at day 30 post-treatment with anti-BLyS mount attenuated humoral responses compared with untreated mice. Together, our results show that BLyS neutralization ablates most primary B cells but spares B lineage progenitors; and indicate that these populations, as well as BLyS per se, may be required for unabridged primary immune responses.
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Santos, Daniel Ditzel, Olivier Tournilhac, Lian Xu, Hatjiharrisi Evdoxia, Zachary Hunter, Andrew Branagan, Robert Manning, Kenneth C. Anderson, Iqbal Grewal, and Steven P. Treon. "B-Lymphocyte Stimulator Protein (BLYS) Is Expressed by Bone Marrow Mast and Lymphoplasmacytic Cells in Waldenstrom’s Macroglobulinemia, and Provides Signaling for Growth, Survival and IgM Secretion." Blood 104, no. 11 (November 16, 2004): 3358. http://dx.doi.org/10.1182/blood.v104.11.3358.3358.
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Abstract B-lymphocyte stimulator protein (BLYS) is a member of the tumor necrosis family of ligands which is expressed by monocytes and neutrophils and regulates B-cell homeostasis and immunoglobulin production through its receptors BCMA, TACI and BAFF-R. In recent studies, we have shown that bone marrow (BM) mast cells (MC) are increased in WM patients and support tumor cell growth. We therefore evaluated sorted WM BM MC (CD117+FceRI+) and lymphoplasmacytic cells (LPC) for BLYS, BCMA, TACI AND BAFF-R by multicolor flow cytometry and RT-PCR. Results were as follows: Flow Cytometry RT-PCR WM MC WM MC BLYS 5/7 (71%) 8/15 (53%) 25/26 (96%) 20/23 (61%) BCMA 4/6 (66%) 7/8 (87%) 20/20 (100%) 8/13 (61%) TACI 15/16 (93%) 7/7 (100%) 20/20 (100%) 12/15 (80%) BAFF-R 11/16 (68%) 5/8 (62%) 20/20 (100%) 11/11 (100%) By RT-PCR, BLYS was detected in MC from 5/7 normal donors. However, in contrast to MC from WM patients, BLYS was not expressed on the cell surface of MC from 7 normal donors using multicolor flow cytometry (p=0.02). Importantly, recombinant human BLYS stimulated proliferation, enhanced survival and/or induced IgM secretion of WM LPC at concentrations of up to 1 ug/mL. Paradoxically, at higher concentrations (5, 10 ug/mL) BLYS induced apoptosis of WM LPC. These studies therefore demonstrate that MC and LPC in WM patients express BLYS and BLYS receptors, and provide the framework for specific targeting of MC-LPC interactions in WM.
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Nimmanapalli, Ramadevi, Mi-Ae Lyu, Min Du, Michael J. Keating, Michael G. Rosenblum, and Varsha Gandhi. "The growth factor fusion construct containing B-lymphocyte stimulator (BLyS) and the toxin rGel induces apoptosis specifically in BAFF-R–positive CLL cells." Blood 109, no. 6 (November 21, 2006): 2557–64. http://dx.doi.org/10.1182/blood-2006-08-042424.
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Abstract The cytokine B lymphocyte stimulator (BLyS) mediates its effect through cell-surface receptors BAFF-R, TACI, and BCMA. BLyS receptors are expressed only on B cells and not present in other normal cells including normal T lymphocytes. Chronic lymphocytic leukemia (CLL) is a B-cell disease and CLL lymphocytes express BLyS receptors. Gelonin, a type 1 ribosome-inactivating toxin, lacks cell membrane binding domain and hence is nontoxic to intact cells. We generated a construct of recombinant gelonin (rGel) fused to BLyS to specifically target quiescent B-CLL lymphocytes. The construct rGel/BLyS specifically binds and internalizes through BAFF-R into CD19+ B-CLL lymphocytes and induces apoptosis at nanomolar concentrations. In contrast, rGel alone was not able to internalize into these leukemic lymphocytes. Mechanistically, the rGel/BLyS construct inhibits protein synthesis with an IC50 of less than 3 nM compared with more than 5000 nM for rGel toxin alone. This rGel/BLyS-mediated decrease in protein synthesis was associated with a decline in short-lived proteins such as MCL-1 and XIAP, the 2 survival proteins in B-CLL. There was a strong relationship between a decrease in these proteins and the cleavage of PARP, a hallmark feature of apoptosis. Taken together, these data suggest that the rGel/BLyS fusion toxin may have potential therapeutic efficacy for B-CLL patients.
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Chang, Sook Kyung, and Diane F. Jelinek. "BLyS Regulates Human Myeloma Cell IL-6 Expression." Blood 104, no. 11 (November 16, 2004): 1412. http://dx.doi.org/10.1182/blood.v104.11.1412.1412.
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Abstract Multiple myeloma (MM) is a malignant disease of plasma cells that accumulate in the bone marrow. The survival mechanisms of myeloma cells are still not fully understood. There are several cytokines that are known to support the survival and growth of myeloma cells, such as IL-6, IGF-I, TNF-a, and IL-1β. Recent evidence has also shown that the TNF family member, B lymphocyte stimulator (BLyS), is critical for normal B cell development and homeostasis, as well as for survival of malignant B cells, including MM. However, it should be noted that the precise mechanisms by which BLyS promotes the survival of MM cells remain uncertain. Our group has already reported that MM cell lines and primary myeloma cells can express BLyS and its receptors. Thus, exogenous BLyS augmented the survival of MM cells, including the IL-6 dependent MM cell line, KAS-6/1. To better study the mechanism underlying BLyS-mediated survival of myeloma cells, we sought to establish a KAS-6/1 cell line variant which was solely dependent on exogenous BLyS for growth and survival. We have previously reported that KAS-6/1 cells do not appear to express autocrine IL-6, and therefore are highly dependent on exogenous IL-6 for survival. To establish a BLyS-dependent KAS-6/1 variant, cells were cultured long-term in RPMI containing 0.5% BSA or 1% FCS in the absence of exogenous IL-6, and in the presence or absence of exogenous BLyS. KAS-6/1 cells cultured in the absence of cytokines were non-viable after two weeks of culture, whereas KAS-6/1 cells cultured with BLyS alone remained viable and proliferated, albeit at a lower rate than parental KAS-6/1 cells maintained with IL-6. We next focused on identifying the mechanisms of BLyS-dependent survival of the KAS-6/1/BLyS (KAS-6/B) variant cell line. Of interest, KAS-6/B cells placed in short term culture exhibited cytokine independent survival and proliferation and this was completely inhibited using a neutralizing IL-6 antibody. These results therefore suggested that the mechanism underlying BLyS-mediated survival and proliferation of the KAS-6/B cells is induction of an autocrine IL-6 pathway. This notion is further supported by the ability of BLyS to induce IL-6 expression at the transcriptional level, and at the protein level as revealed by an IL-6 specific ELISA. Consistent with the concept that BLyS induced autocrine IL-6 expression in the KAS-6/B cells, we also observed that STAT-3 was constitutively activated in these cells. In addition, we tested the ability of BLyS-conditioned media obtained from KAS-6/B cells to stimulate the proliferation of a different IL-6 dependent MM cell line, JMW. Whereas BLyS alone failed to stimulate JMW cell proliferation, BLyS-conditioned media obtained from the KAS-6/B cells stimulated proliferation, and in a manner that was inhibited by a neutralizing IL-6 antibody. Finally, BLyS stimulation of primary patient MM cells similarly resulted in increased IL-6 expression. IL-6 is known to play a major role in the malignant progression of MM by regulating the growth and survival of tumor cells. IL-6 levels often increase during disease progression, and it has been demonstrated that IL-6 may derive from the tumor cells themselves or from other cell types in the bone marrow. Because of this, it is important to fully understand what signals are capable of inducing IL-6 expression in this disease. In summary, our results demonstrate for the first time the ability of BLyS to maintain myeloma cell survival via the induction of an autocrine IL-6 pathway. Our results underscore the importance of IL-6 in this disease, and further demonstrate the complexity of the deregulated cytokine network in this disease.
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Dolff, S., and J. Menke. "BLyS und Belimumab." Der Nephrologe 9, no. 3 (April 27, 2014): 233–35. http://dx.doi.org/10.1007/s11560-013-0812-6.
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Bath, Natalie M., Bret M. Verhoven, Nancy A. Wilson, Weifeng Zeng, Weixiong Zhong, Lauren Coons, Arjang Djamali, and Robert R. Redfield. "APRIL/BLyS deficient rats prevent donor specific antibody (DSA) production and cell proliferation in rodent kidney transplant model." PLOS ONE 17, no. 10 (October 13, 2022): e0275564. http://dx.doi.org/10.1371/journal.pone.0275564.
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APRIL (A proliferation inducing ligand) and BLyS (B Lymphocyte Stimulator) are two critical survival factors for B lymphocytes and plasma cells, the main source of alloantibody. We sought to characterize the specific effects of these cytokines in a kidney transplant model of antibody mediated rejection (AMR). We engineered APRIL-/- and BLyS-/- Lewis rats using CRISPR/Cas9. APRIL-/- and BLyS-/- rats were sensitized with Brown Norway (BN) blood (complete MHC mismatch). Twenty-one days following sensitization, animals were harvested and collected tissues were analyzed using flow cytometry, ELISPOT, and immunohistochemistry. Flow cross match and a 3 day mixed lymphocyte reaction (MLR) was performed to assess donor specific antibody (DSA) production and T-cell proliferation, respectively. Sensitized dual knock out Lewis rats (APRIL-/-/BLyS-/-) underwent kidney transplantation and were sacrificed on day 7 post-transplant. Sensitized BLyS-/- had significant decreases in DSA and cell proliferation compared to WT and APRIL-/- (p<0.02). Additionally, BLyS-/- rats had a significant reduction in IgG secreting cells in splenic marginal zone B lymphocytes, and in cell proliferation when challenged with alloantigen compared to WT and APRIL-/-. Transplanted APRIL-/-/BLyS-/- rodents had significantly less DSA and antibody secreting cells compared to WT (p<0.05); however, this did not translate into a significant difference in AMR seen between groups. In summary, our studies suggest that APRIL and BLyS play a greater role in DSA generation rather than AMR, highlighting the role of cellular pathways that regulate AMR.
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Landau, Dan Avi, Michelle Rosenzwajg, David Saadoun, David Klatzmann, and Patrice Cacoub. "The BLyS/BAFF Receptor-Ligand System in HCV Induced B-Cell Clonal Disorders." Blood 110, no. 11 (November 16, 2007): 3866. http://dx.doi.org/10.1182/blood.v110.11.3866.3866.
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Abstract The study aim was to examine the B-Lymphocytes Stimulator (BLyS) receptor-ligand system in HCV induced B lymphocyte clonal disorders. 94 patients with chronic HCV [including 35 HCV+ mixed cryoglobulinemia (MC)-vasculitis and 9 HCV+ B-non Hodgkin’s lymphoma (B-NHL) patients] and 15 healthy volunteers were included. A 2-fold serum BLyS increase was associated with HCV-induced MC-vasculitis, and a three-fold increase with HCV-induced B-NHL, compared with HCV+ patients without vasculitis or healthy controls (p<0.05). Lower mBLyS expression in HCV-induced MC vasculitis was observed. CD19+ BLyS binding and BR3 staining showed a step wise decrease with highest values in healthy controls and HCV+ without MC, and lowest in B-NHL (p<0.05, p<0.0001, respectively) with a further decrease in Vh1-69+ (heavy chain rearrangement often found in clonal disorders associated with HCV) clonal B-cells. BLyS anti-apoptotic effects were maintained despite this decrease in BR3 staining. Complete clinical remission after anti-viral treatment was associated with a decrease in serum BLyS, and an increase in BR3 staining. Rituximab treatment was associated with a five-fold increase in serum BLyS (p<0.001), mirroring the depletion of CD19+ cells. BR3 staining in repopulating B-cells was significantly decreased (p<0.005). In conclusion, the BLyS ligand-receptor activity is increased in HCV induced B-cell clonal disorders, indicating a possible role for treatment targeting the BLyS receptor-ligand system. Figure Figure Figure Figure
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Scapini, Patrizia, Antonio Carletto, Bernardetta Nardelli, Federica Calzetti, Viktor Roschke, Flavia Merigo, Nicola Tamassia, et al. "Proinflammatory mediators elicit secretion of the intracellular B-lymphocyte stimulator pool (BLyS) that is stored in activated neutrophils: implications for inflammatory diseases." Blood 105, no. 2 (January 15, 2005): 830–37. http://dx.doi.org/10.1182/blood-2004-02-0564.
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Abstract We have recently shown that granulocyte–colony-stimulating factor (G-CSF)– and interferon-γ (IFN-γ)–activated human neutrophils accumulate and release remarkable amounts of soluble B-lymphocyte stimulator (BLyS) in vitro. In this study, we provide evidence that neutrophils migrating into skin window exudates (SWEs) developed in healthy volunteers and in patients with rheumatoid arthritis (RA), synthesized, and released BLyS in response to locally produced G-CSF. Accordingly, the concentrations of soluble BLyS in SWEs were significantly more elevated than in serum. Because the levels of SWE BLyS, but not SWE G-CSF, were higher in patients with RA than in healthy subjects, we examined the effect of CXCL8/IL-8, C5a, and other proinflammatory mediators that dramatically accumulate in RA SWEs and in inflamed synovial fluids. We show that CXCL1/GROα, CXCL8/IL-8, C5a, immune complexes, tumor necrosis factor-α (TNF-α), leukotriene B4, N-formyl-methionyl-leucyl-phenylalanine (fMLP), and lipopolysaccharide (LPS), which by themselves do not induce BLyS de novo synthesis, act as potent secretagogues for BLyS, which is mainly stored in Golgi-related compartments within G-CSF–treated neutrophils, as determined by immunogold electron microscopy. This action is pivotal in greatly amplifying neutrophil-dependent BLyS release in SWEs of patients with RA compared with healthy subjects. Collectively, our data uncover a novel mechanism that might dramatically exacerbate the release of BLyS by neutrophils during pathologic inflammatory responses.
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Scholz, Jean L., Jenni E. Crowley, Mary M. Tomayko, Natalie Steinel, Patrick J. O'Neill, William J. Quinn, Radhika Goenka, et al. "BLyS inhibition eliminates primary B cells but leaves natural and acquired humoral immunity intact." Proceedings of the National Academy of Sciences 105, no. 40 (October 1, 2008): 15517–22. http://dx.doi.org/10.1073/pnas.0807841105.
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We have used an inhibiting antibody to determine whether preimmune versus antigen-experienced B cells differ in their requisites for BLyS, a cytokine that controls differentiation and survival. Whereas in vivo BLyS inhibition profoundly reduced naïve B cell numbers and primary immune responses, it had a markedly smaller effect on memory B cells and long-lived plasma cells, as well as secondary immune responses. There was heterogeneity within the memory pools, because IgM-bearing memory cells were sensitive to BLyS depletion whereas IgG-bearing memory cells were not, although both were more resistant than naïve cells. There was also heterogeneity within B1 pools, as splenic but not peritoneal B1 cells were diminished by anti-BLyS treatment, yet the number of natural antibody-secreting cells remained constant. Together, these findings show that memory B cells and natural antibody-secreting cells are BLyS-independent and suggest that these pools can be separately manipulated.
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Doshi, Bhavya S., Robert J. Davidson, and Valder R. Arruda. "The Un-BLyS-Ful State: Blocking Factor VIII Inhibitor Development with BLyS Depletion." Blood 132, Supplement 1 (November 29, 2018): 138. http://dx.doi.org/10.1182/blood-2018-99-114795.
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Abstract The development of neutralizing alloantibodies (inhibitors) to infused factor VIII (FVIII) remains the most significant complication of therapy in hemophilia A (HA). Despite some insights into genetic and environmental risk factors associated with inhibitor development, the immunological mechanisms behind this complication remain incompletely understood. Given that infused FVIII is likely encountered in the periphery, transitional B cell response to FVIII may regulate inhibitor development. Transitional B cell survival, maturation and proliferation are tightly regulated by the cytokine BLyS (B-lymphocyte stimulator). Elevated levels of BLyS have been described in both auto- and allo-immune disease processes and may be genetically determined in a subset of patients with lupus and multiple sclerosis. In prior experiments, we noted that BLyS levels are higher in HA patients with inhibitors as opposed to 10 other pro- and anti-inflammatory cytokines. However, BLyS levels normalized amongst those who underwent successful immune tolerance induction. Thus, we hypothesized that BLyS may regulate FVIII inhibitor development or persistence. Here, we present results from animal studies aimed at 1) preventing inhibitor development in naïve HA mice and 2) maintaining long-term tolerance. For prevention experiments, HA C57Bl/6 mice (n=8-10/group) were given a single dose of anti-BLyS neutralizing antibody (Sandy-2, Adipogen) or PBS control one week prior to immunization with recombinant human FVIII (rhFVIII) at 80 IU/kg via tail vein injection every 14 days for four injections (Fig 1). Plasma samples were obtained at baseline and 7 days after last immunization and analyzed for FVIII antibody by Bethesda assay, anti-FVIII IgG by ELISA, and BLyS levels by ELISA. To test long-term tolerance, 22 weeks after initial anti-BLyS antibody injection, mice without inhibitors were challenged with 4 additional rhFVIII intravenous infusions and plasma obtained 7 days following each injection (Fig 1). Data was analyzed using Prism and is reported as median (IQR) with Mann-Whitney test for two-group comparisons and Mantel-Cox log-rank test for Kaplan-Meier survival analysis. Anti-BLyS treated mice achieved nadir BLyS levels at 14 days post-injection compared to control (0.2 [0.09-0.3] vs 8.2 [7.3-8.5] ng/ml, respectively, p < 0.0001), and levels equalized by day 28 between groups. Only 2 of 9 mice in the anti-BLyS treated group developed inhibitors to FVIII (0 [0-12.5] BU) compared to 9 of 10 in the treated group (21.1 [2.5-157.3] BU) with a significant log-rank survival of 0.0007 and favorable hazard ratio of 0.16 (95% CI 0.05-0.56) after initial immunization. Total anti-FVIII IgG was lower in the treated group (4.7 [1.1-11.5] mcg/ml) compared to control mice (27.6 [24-42] mcg/ml) with p of 0.003. Of the anti-BLyS treated inhibitor-free mice that have been challenged with rhFVIII, no inhibitors were detected until after the fourth rhFVIII injection. In these mice, there was a trend towards lower inhibitor titers compared to controls with a range of 1-1.8 BU vs. 85.6-1016 BU and lower FVIII IgG (23 [20.9-25.2] vs 69.9 [65.1-129.9] mcg/ml), respectively. Here, we demonstrate that BLyS depletion prior to FVIII exposure in naïve HA mice can prevent antibody development and may result in long-term sustained FVIII tolerance. As BLyS is central to the survival and maturation of transitional B cells, including marginal zone B cells which have recently been demonstrated to be important in inhibitor formation, this may provide a strategy for both antibody prevention and eradication in HA patients. Notably, the anti-BLyS monoclonal antibody belimumab is already FDA approved for the treatment of patients with lupus. Further studies to confirm the duration of immune tolerance obtained with anti-BLyS therapy in animal models may allow for translation of this strategy to provide long-lasting FVIII tolerance to patients with high risk of inhibitor development. Disclosures Doshi: Bayer Hemophilia Awards Program: Research Funding.
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Novak, Anne J., Richard J. Bram, Neil E. Kay, and Diane F. Jelinek. "Aberrant expression of B-lymphocyte stimulator by B chronic lymphocytic leukemia cells: a mechanism for survival." Blood 100, no. 8 (October 15, 2002): 2973–79. http://dx.doi.org/10.1182/blood-2002-02-0558.
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B-cell chronic lymphocytic leukemia (B-CLL) is defined by the accumulation of CD5+ B cells in the periphery and bone marrow. This disease is not characterized by highly proliferative cells but rather by the presence of leukemic cells with significant resistance to apoptosis and, therefore, prolonged survival. B-lymphocyte stimulator (BLyS) is a newly identified tumor necrosis factor (TNF) family member shown to be critical for maintenance of normal B-cell development and homeostasis and it shares significant homology with another TNF superfamily member, APRIL. The striking effects of BLyS on normal B-cell maintenance and survival raises the possibility that it may be involved in pathogenesis and maintenance of hematologic malignancies, including B-CLL. In this study, we investigated the status of APRIL and BLyS expression, as well as their receptors, in this disease. All B-CLL patient cells studied expressed one or more of 3 known receptors for BLyS; however, the pattern of expression was variable. In addition, we demonstrate for the first time that B-CLL cells from a subset of patients aberrantly express BLyS and APRIL mRNA, whereas these molecules were not detectable in normal B cells. Furthermore, we provide in vitro evidence that BLyS protects B-CLL cells from apoptosis and enhances cell survival. Because these molecules are key regulators of B-cell homeostasis and tumor progression, leukemic cell autocrine expression of BLyS and APRIL may be playing an important role in the pathogenesis of this disease.
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Adamia, Sophia, Lian Xu, Antonio Sacco, and Steven Treon. "Identification Genetic Variations (GVs) Causing Splicing of TNF Family Members and Adaptor Proteins That Modulate NFkB Pathways in Waldenstrom’s Maroglobulinemia (WM)." Blood 110, no. 11 (November 16, 2007): 2516. http://dx.doi.org/10.1182/blood.v110.11.2516.2516.
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Abstract The TNF ligand-receptor superfamily and their adaptor proteins regulate important B-cell signaling pathways, including CD40L-CD40 and APRIL/BLYS-TACI through adaptor protein TRAF2. These pathways promote B-cell differentiation and immunoglobulin heavy chain class switching. Defects in immunoglobulin heavy chain class switching and presence of constitutive IgA and IgG hypogammaglobulinemia in patients with WM have previously been reported by us (Hunter et al, ASH2006). In WM patients we identified several novel splice variants of TNF-family members CD40 and BLYS, and their adaptor protein TRAF2. Cloning, sequencing and alignment analysis document that aberrant splice transcripts of CD40, CD40-Va, Vb and Vc, and BLYS, BLYS-Va and Vb, result from partial exon skipping (CD40Va and Vc) and entire or partial intron retention (CD40-Vb, BLYS-Va and Vb), while the TRAF2 variant is a result of exon skipping only. Using RT-PCR DNA fragment analysis, malignant and normal B-cells from the bone marrow of 25 WM patients and 6 healthy donors (HDs) were screened for the expression of CD40, BLYS and TRAF2 splice transcripts. This analysis identified overexpression of CD40-Vb (15/25WM vs. 0/6HD; P=0.01), CD40-Vc (21/25WM vs. 0/6HD; P=0.0003), BLYS-Vb (18/25WM vs. 0/6HD; P=0.002) and TRAF2-V (21/25WM vs. 1/6HD; P=0.004) in WM patients. The expression of other splice variants CD40-Va (18/25WM vs.2/4HD; P=0.09) and BLYS-Va (23/25WM vs. 4/6HD P=0.2) in the same group of WM patients were not significant. We hypothesized that these aberrations are consequences of genetic variations (GVs) distributed in the vicinity of splicing elements of these genes, as well as, alterations may have occurred in the repertoire of splicing factors (SFs) with respect of their expression levels. To address these issues, we started sequencing CD40, BLYS, and TRAF2 gene segments that are subjected to aberrant splicing. Sequencing analysis of the CD40 gene from WM B cells revealed 6 recurrent genetic variations (GVs-defined as mutations occurring more than one patients) that include 2 missense (on exon 3) and 3 silent substitutions (on exons 3-4-5), and 1 frame-shift deletion on exon 5. These substitutions lead to amino acid changes on CD40 gene, while the frame-shift deletion may cause truncation of wild-type CD40 protein. We also identified recurrent GVs on introns 4 and 5. All these GVs detected on exons and introns are distributed in the vicinity of key splicing elements that create and/or activate a new splice site in precisely the position required for the splicing events to create CD40 variants. Also, using TaqMan low density array (TaqMan-LDA) we evaluated levels of major SFs and other TNF family members involved in CD40 and BLYS signaling. These analyses showed that patients expressing aberrant splice variants of CD40 and BLYS overexpress not only other members of TNF family but also major SFs: SF2/ASF (a proto-oncogene), U2, hNRPA1 and SRP55. TaqMan-LDA analysis suggests that these SFs may play a significant role in CD40, BLYS and TRAF2 splicing in WM patients since these transcripts were upregulated (1.2-2.2 fold higher) only in those patients which expressed CD40, BLYS and TRAF2 variants. In conclusion, presence of GVs in the vicinity of splicing elements and upregulation of SFs collectively may promote aberrant CD40, BLYS and TRAF2 splicing and thus modulate TNF family pathways supportive of B-cell differentiation and immunoglobulin heavy chain class switching in patients with WM.
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Fontaine, Julie, Josiane Chagnon-Choquet, Han Sang Valcke, Johanne Poudrier, and Michel Roger. "High expression levels of B lymphocyte stimulator (BLyS) by dendritic cells correlate with HIV-related B-cell disease progression in humans." Blood 117, no. 1 (January 6, 2011): 145–55. http://dx.doi.org/10.1182/blood-2010-08-301887.
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AbstractIn view of assessing the possible contribution of dendritic cells (DCs) to HIV-related B-cell disorders, we have longitudinally measured B lymphocyte stimulator (BLyS) surface expression by myeloid DCs (mDCs) and concentrations of B-cell growth factors in the blood of subjects undergoing primary HIV infection with different rates of disease progression. We report that BLyS surface expression by mature mDCs and precursors as well as blood levels of BLyS, a proliferation-inducing ligand (APRIL), interleukin-6 (IL-6), and IL-10 increased above normal levels in both rapid and normal HIV progressors as quickly as in the acute phase of infection and persisting throughout the course of disease despite successful therapy. Consequently, hyperglobulinemia and high blood levels of circulating activated mature B cells and precursor/activated marginal zone (MZ)–like B cells were found throughout follow-up for both rapid and normal progressors. In contrast, mDC cell-surface expression of BLyS as well as blood levels of BLyS, immunoglobulin, activated mature B cells, and precursor/activated MZ-like B cells in aviremic slow progressors were similar to those observed in healthy donors. Interestingly, the levels of mature MZ B cells were significantly reduced in slow progressors. Our results suggest that DCs might modulate the outcome of the HIV-related B-cell disease progression through the expression of BLyS.
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Zekavat, Ghazal, Thi-Sau Migone, Robert E. Roses, Michael P. Cancro, Ali Naji, and Hooman Noorchashm. "The Impact of B Lymphocyte Depletion on the Pathogenesis of Autoimmune Diabetes (131.28)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S243. http://dx.doi.org/10.4049/jimmunol.178.supp.131.28.
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Abstract NOD B cell development is characterized by a defective homeostatic checkpoint in B cell maturation and selection. Having demonstrated that the progression of autoimmune diabetes requires antigen presentation by B-lymphocytes, we hypothesized that B cell depletion may prevent diabetes progression in NOD mice. Here, we employed two distinct approaches for in vivo B lymphocyte depletion: a cohort of adult hCD20 Tg NOD mice were treated with the B lymphocyte depleting mAb, Rituximab (anti-CD20) anda cohort of adult NOD mice were treated with a neutralizing Hamster anti-mouse mAb specific for the B cell survival factor, BLyS/BAFF. Treatment with both Rituximab (2mg/injection x3doses) and anti-BLyS mAb (100?g/injection x2 doses) led to B cell depletion within 10 days. BLyS/BAFF neutralization, using anti-BLyS, caused a profound depletion of mature/recirculating B cells in these mice and lasted for >30 days. Diabetes occurred within 2 weeks in all Rituximab treated female hCD20 Tg NOD mice (n=4); despite their early backcross generations (i.e., N4-6F1) onto the NOD genetic background. Conversely, adult female NOD/LtJ mice (n=20), B cell depleted using anti-BLyS/BAFF did not progress to diabetes for >30 days following treatment. Collectively, these results indicate that BLyS/BAFF neutralization may be required for the prevention of autoimmune diabetes following B lymphocyte depletion.
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Novak, Anne J., Jaime R. Darce, Bonnie K. Arendt, Brandon Harder, Kathy Henderson, Wayne Kindsvogel, Jane A. Gross, Philip R. Greipp, and Diane F. Jelinek. "Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival." Blood 103, no. 2 (January 15, 2004): 689–94. http://dx.doi.org/10.1182/blood-2003-06-2043.
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Abstract Multiple myeloma (MM) is a progressive disease that is thought to result from multiple genetic insults to the precursor plasma cell that ultimately affords the tumor cell with proliferative potential despite its differentiated phenotype and resistance to undergoing apoptosis. Altered expression of antiapoptotic factors as well as growth factors have been described in a significant number of patients. However, the key regulatory elements that control myeloma development and progression remain largely undefined. Because of the knowledge that B-lymphocyte stimulator (BLyS), a tumor necrosis factor (TNF) family member shown to be critical for maintenance of normal B-cell development and homeostasis, promotes the survival of malignant B cells, we began a coordinated study of BLyS and its receptors in MM. All MM cells studied expressed one or more of 3 known receptors (B-cell maturation antigen [BCMA], transmembrane activator and CAML interactor [TACI], and B-cell activating factor receptor [BAFF-R]) for BLyS; however, the pattern of expression was variable. Additionally, we provide evidence that BLyS can modulate the proliferative capacity and survival of MM cells. Finally, we provide evidence that BLyS is expressed by MM cells and is present in the bone marrow of patients with MM. Expression of BCMA, TACI, and BAFF-R by MM taken together with the ability of BLyS to support MM cell growth and survival has exciting implications because they may be potential therapeutic targets.
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Varfolomeev, Eugene, Frank Kischkel, Flavius Martin, Dhaya Seshasayee, Hua Wang, David Lawrence, Christine Olsson, et al. "APRIL-Deficient Mice Have Normal Immune System Development." Molecular and Cellular Biology 24, no. 3 (February 1, 2004): 997–1006. http://dx.doi.org/10.1128/mcb.24.3.997-1006.2004.
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ABSTRACT APRIL (a proliferation-inducing ligand) is a member of the tumor necrosis factor (TNF) superfamily. APRIL mRNA shows high levels of expression in tumors of different origin and a low level of expression in normal cells. APRIL shares two TNF receptor family members, TACI and BCMA, with another TNF homolog, BLyS/BAFF. BLyS is involved in regulation of B-cell activation and survival and also binds to a third receptor, BR3/BAFF-R, which is not shared with APRIL. Recombinant APRIL and BLyS induce accumulation of B cells in mice, while BLyS deficiency results in severe B-cell dysfunction. To investigate the physiological role of APRIL, we generated mice that are deficient in its encoding gene. APRIL−/− mice were viable and fertile and lacked any gross abnormality. Detailed histological analysis did not reveal any defects in major tissues and organs, including the primary and secondary immune organs. T- and B-cell development and in vitro function were normal as well, as were T-cell-dependent and -independent in vivo humoral responses to antigenic challenge. These data indicate that APRIL is dispensable in the mouse for proper development. Thus, BLyS may be capable of fulfilling APRIL's main functions.
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Hondowicz, B. D., S. T. Alexander, W. J. Quinn, A. J. Pagan, M. H. Metzgar, M. P. Cancro, and J. Erikson. "The role of BLyS/BLyS receptors in anti-chromatin B cell regulation." International Immunology 19, no. 4 (February 20, 2007): 465–75. http://dx.doi.org/10.1093/intimm/dxm011.
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Liu, Mei-Yun, Wei Han, Yan-Li Ding, Tian-Hong Zhou, Rui-Yang Tian, Sheng-Li Yang, Hui Liu, and Yi Gong. "Generation and Characterization of C305, a Murine Neutralizing scFv Antibody That Can Inhibit BLyS Binding to Its Receptor BCMA." Acta Biochimica et Biophysica Sinica 37, no. 6 (June 1, 2005): 415–20. http://dx.doi.org/10.1111/j.1745-7270.2005.00059.x.
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Abstract B-lymphocyte stimulator (BLyS) is a member of the tumor necrosis factor (TNF) family and a key regulator of B cell response. Neutralizing single-chain fragment variable (scFv) antibody against BLyS binding to its receptor BCMA has the potential to play a prominent role in autoimmune disease therapy. A phage display scFv library constructed on pIII protein of M13 filamentous phage was screened using BLyS. After five rounds of panning, their binding activity was characterized by phage-ELISA. Nucleotide sequencing revealed that at least two different scFv gene fragments (C305 and D416) were obtained. The two different scFv gene fragments were expressed to obtain the soluble scFv antibodies, then the soluble scFv antibodies were characterized by means of competitive ELISA and in vitro neutralization assay. The results indicated that C305 is the neutralizing scFv antibody that can inhibit BLyS binding to its receptor BCMA.
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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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Scholz, Jean, Martina Soldemo, Pia Dosenovic, Martin Naradikian, Lin Zhou, Richard Wilson, Richard Wyatt, Andrew Lackner, Gunilla Karlsson Hedestam, and Michael Cancro. "Potentially neutralizing B cell clonotypes are eliminated at peripheral selection checkpoints (LYM6P.768)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 131.5. http://dx.doi.org/10.4049/jimmunol.192.supp.131.5.
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Abstract B lymphocyte stimulator (BLyS) signals via BR3 mediate selection and survival in the transitional, mature, and germinal center B cell pools. We have previously shown that treatment of mice with exogenous BLyS prior to immunization with HIV-1 envelope (Env) trimers improves neutralizing antibody breadth and potency. We are therefore investigating the hypothesis that broadly neutralizing B cell clonotypes are rare because of counter-selection at the transitional or germinal center checkpoints. Here we show that Env-specific murine B cells in pre-immune, germinal center, and memory B cell subsets can be visualized and tracked by flow cytometry using a biotinylated Env probe. Initial results indicate loss of Env+ B cells at both the transitional developmental stage and in the germinal center following immunization. As a first step in testing the feasibility of a BLyS pre-immunization treatment approach in nonhuman primates, we show that BLyS enhances survival of quiescent and dividing rhesus macaque B cells in vitro.
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Li, Xinrui, Kaihong Su, Alexander J. Szalai, Tong Zhou, Robert P. Kimberly, and Jeffrey C. Edberg. "Immune opsonins modulate BLyS/BAFF release in a receptor-specific fashion (53.6)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S104. http://dx.doi.org/10.4049/jimmunol.178.supp.53.6.
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Abstract TNF ligand superfamily member 13B (B lymphocyte stimulator (BLyS), B cell activating factor (BAFF)) promotes primary B cell proliferation and immunoglobulin production. It exists in both membrane-bound and soluble forms. Because the soluble form is thought to be the primary biologically active form, we investigated factors that might regulate its cleavage and processing. In both myeloid cell lines and primary human monocytes, the shedding of membrane BLyS can be regulated by CRP and IgG. Within 10 minutes, both of these opsonins trigger significant shedding of BLyS (up to 52.2±3.0%, p=0.003) by engaging FcγRs. In U937 cells, a primary role of FcγRI is demonstrated both by direct receptor cross-linking (FcγRI 45.69±2.05% verses FcγRIIa 2.11±1.33%) and by the lack of enhanced cleavage when FcγRI and FcγRIIa are co-crosslinked. The shed BLyS is biologically functional since it promotes B cell survival. The generation of a B cell proliferation and survival factor by Fcγ receptor engagement, especially FcγRI, which can also enhance antigen uptake and presentation mediated by ligands of both innate and adaptive immune systems, provides a unique opportunity to facilitate antibody production. These functions suggest that Fcγ receptors may provide a link between immune complex mediated autoimmune diseases and elevations in circulating BLyS in autoimmune disease patients. Supported by NIH R01AR042476 and R01AR033062.
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Woodland, Robert T., Madelyn R. Schmidt, and Craig B. Thompson. "BLyS and B cell homeostasis." Seminars in Immunology 18, no. 5 (October 2006): 318–26. http://dx.doi.org/10.1016/j.smim.2006.06.001.
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O'Connor, Brian P., Vanitha S. Raman, Loren D. Erickson, W. James Cook, Lehn K. Weaver, Cory Ahonen, Ling-Li Lin, George T. Mantchev, Richard J. Bram, and Randolph J. Noelle. "BCMA Is Essential for the Survival of Long-lived Bone Marrow Plasma Cells." Journal of Experimental Medicine 199, no. 1 (January 5, 2004): 91–98. http://dx.doi.org/10.1084/jem.20031330.
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Long-lived humoral immunity is manifested by the ability of bone marrow plasma cells (PCs) to survive for extended periods of time. Recent studies have underscored the importance of BLyS and APRIL as factors that can support the survival of B lineage lymphocytes. We show that BLyS can sustain PC survival in vitro, and this survival can be further enhanced by interleukin 6. Selective up-regulation of Mcl-1 in PCs by BLyS suggests that this α-apoptotic gene product may play an important role in PC survival. Blockade of BLyS, via transmembrane activator and cyclophilin ligand interactor–immunoglobulin treatment, inhibited PC survival in vitro and in vivo. Heightened expression of B cell maturation antigen (BCMA), and lowered expression of transmembrane activator and cyclophilin ligand interactor and BAFF receptor in PCs relative to resting B cells suggests a vital role of BCMA in PC survival. Affirmation of the importance of BCMA in PC survival was provided by studies in BCMA−/− mice in which the survival of long-lived bone marrow PCs was impaired compared with wild-type controls. These findings offer new insights into the molecular basis for the long-term survival of PCs.
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Stadanlick, Jason E., Jean L. Scholz, Juli P. Miller, and Michael P. Cancro. "BCR Signaling Generates NF-kB2 (p100) For BR3-Mediated Processing And Survival (83.2)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S112. http://dx.doi.org/10.4049/jimmunol.178.supp.83.2.
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Abstract Signaling through both the B cell receptor (BCR) and the BLyS receptor, BR3, are required for primary B cell survival. Therefore, understanding how the downstream signaling pathways from these receptors interact should help reveal the molecular mechanisms underlying primary B cell selection and survival. The classical and non-classical NF-kB pathways are an attractive starting point for interrogation, since its members operate downstream of several key B cell signaling systems. Accordingly we have examined BLyS-mediated signaling and survival both in isolation as well as in the context of signals derived form the BCR. In NH3T3 cells expressing BR3, as well as in primary splenic B cells, we find that BLyS signaling via BR3 predominantly activates the non-classical pathway. This is evidenced by an increase in p52 levels and the corresponding diminution of the p100 pool upon BLyS treatment. In contrast, while BCR signaling potently upregulates p100 levels, it does not result in processing to the active p52 form. However, simultaneous BCR and BR3 signaling yields both p52 accumulation and sustained p100 availability. These findings suggest a model whereby BCR signaling is required to maintain available substrate for the viability-promoting BR3 pathway. In support of this model, blockade of proximal BCR signaling with a Syk kinase inhibitor leads to the depletion of p100 stores and the failure of BLyS-mediated survival. Together, these findings lead us to propose a model whereby BCR signaling rations a key survival pathway substrate, thus governing selection and homeostasis.
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Hunter, Zachary R., Xavier Leleu, Daniel D. Santos, Susannah Hamilton, Sigitas Verselis, Edward A. Fox, Iqbal Grewal, and Steven Treon. "Sequence Analysis in the BLYS and APRIL Receptor TACI Reveals Novel Variants with a Potential Pathogenetic Role in Waldenstrom’s Macroglobulinemia (WM)." Blood 106, no. 11 (November 16, 2005): 991. http://dx.doi.org/10.1182/blood.v106.11.991.991.
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Abstract B-lymphocyte stimulator protein (BLYS) and a proliferation inducing ligand (APRIL) are members of the tumor necrosis family of ligands which play an important role in normal and malignant human B-cell homeostasis through their receptors BCMA, TACI (for BLYS and APRIL) and BAFF-R (for BLYS only). We previously demonstrated via multicolor flow cytometric and RT-PCR analysis the expression of BLYS and APRIL, along with BCMA, TACI and BAFF-R on lymphoplasmacytic cells (LPC) as well as mast cells, which provide LPC growth support in patients with Waldenstrom’s Macroglobulinemia (WM) (Blood 104:917a). Based on these studies, we performed sequence analysis for BLYS, APRIL, BCMA, TACI and BAFF-R from DNA obtained from CD19+ selected bone marrow LPC from 15 patients with the consensus panel diagnosis of WM, who also demonstrated active disease. These studies demonstrated multiple variants in exons 3 and 5 of TACI in 5/15 patients, and exon 1 of BAFF-R in 2/15 patients. The finding of genetic variants in the TACI gene in WM patients is of particular interest given its recently described role as a potential tumor suppressor gene, and potential involvement in the generation of autoimmunity (Immunity2003; 8:279–88), which is a common complication in patients with WM. Moreover, variants in TACI have been reported in patients with common variable immunodeficiency (CVID) (Nat Genet2005;37:820–8), a finding significant to patients with WM who chronically demonstrate IgA and IgG hypogammaglobulinemia, even following successful therapeutic intervention as we recently reported (Blood 104:306b). The results of these studies suggest that variants in TACI, and possibly BAFF-R may play a significant role in the pathogenesis of WM.
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Chaparro, Alejandra, Víctor Beltrán, Daniel Betancur, Ye-Han Sam, Haniyeh Moaven, Ali Tarjomani, Nikolaos Donos, and Vanessa Sousa. "Molecular Biomarkers in Peri-Implant Health and Disease: A Cross-Sectional Pilot Study." International Journal of Molecular Sciences 23, no. 17 (August 29, 2022): 9802. http://dx.doi.org/10.3390/ijms23179802.
Full textAbstract:
Background: The aim of this feasibility study was to investigate the concentration level of CCL-20/MIP-3α, BAFF/BLyS, IL-23, RANKL, and Osteoprotegerin in the Peri-Implant Crevicular Fluid (PICF), from patients diagnosed with peri-implant mucositis and peri-implantitis, and to compare them with PICF from patients with healthy implants. Methods: Participants with at least one dental implant with healthy peri-implant tissues, peri-implant mucositis, or peri-implantitis were included. PICF was collected using paper strips from healthy and diseased peri-implant sites (n = 19). Biomarker levels were analyzed using a custom Multiplex ELISA Assay Kit. Results: In comparison to peri-implant health, the peri-implant mucositis group showed an increased concentration of CCL-20 MIP-3α, BAFF/BLyS, IL-23, RANKL, and Osteoprotegerin. The peri-implantitis group had the lowest median concentration of Osteoprotegerin (1963 ng/mL); this group had a similar concentration of RANKL (640.84 ng/mL) when compared to the peri-implant health group. BAFF/BLyS (17.06 ng/mL) showed the highest concentration in the peri-implantitis group. Conclusions: This feasibility study suggests that IL-23 and RANKL may help to elucidate the pathogenesis during the conversion from peri-implant health to peri-implantitis. Further research is required in BAFF/BLyS for the early diagnosis of peri-implantitis.