Articoli di riviste: "BAFF"

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Krejsek, Jan, Martina Koláčková, Irena Lindrová, Radovan Slezák e Ctirad Andrýs. "Increase of Intracellular BAFF in B Cells of Sjögren’s Patients Is Not Affected by Decrease of BAFFR". Acta Medica (Hradec Kralove, Czech Republic) 58, n. 1 (2015): 25–31. http://dx.doi.org/10.14712/18059694.2015.88.

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The presence of a broad spectrum of autoantibodies in Sjögren’s syndrome (SjS) patients is the result of abnormal B-cell regulation that can be at least partially explained by abnormal BAFF/BAFFR regulation. The objective of this study was to determine both membrane and intracellular expression of BAFF/BAFFR in monocytes and B-cells in peripheral blood of 19 primary Sjögren’s syndrome patients and 20 healthy controls using flow cytometry. We also measured sBAFF in serum. Compared to healthy controls, both surface and intracellular expression of BAFF was significantly increased in monocytes and B-cells of SjS patients. Also serum sBAFF level was elevated. Expression of BAFFR on B-cells of SjS patients was surprisingly decreased, but there was no clear increase or decrease within monocytes. Our results indicate that activated monocytes communicate with B-cells via BAFF and BAFFR, so that B-cells are stimulated, but BAFF is also produced to stimulate cells in autocrine way. The decrease of BAFFR expression in SjS patients suggests that there is the mechanism that attempts to take over in order to balance the high level of BAFF.

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Saidoune, F., N. Charles, J. Chezel, B. Escoubet, T. Papo, A. Nicoletti e K. Sacre. "AB0140 BAFF NEUTRALIZATION HAS JANUS-FACED EFFECT ON ATHEROSCLEROSIS ASSOCIATED WITH SYSTEMIC LUPUS ERYTHEMATOSUS". Annals of the Rheumatic Diseases 79, Suppl 1 (giugno 2020): 1370.3–1370. http://dx.doi.org/10.1136/annrheumdis-2020-eular.988.

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Background:Cardiovascular diseases (CVD) are the leading cause of death in systemic lupus erythematosus (SLE). B cells play a key role in the pathogenesis of lupus and anti-BAFF therapy has been approved in SLE. Since mature B cells also promote atherosclerosis, BAFF neutralization is expected to have an atheroprotective effect in SLE.Objectives:The aim of our study was to test this hypothesis using a new mouse model with a mix susceptibility to lupus and atherosclerosis that received or not an anti-BAFF treatment, and in a cohort of SLE patients in whom we monitored carotid plaques, the B cell compartment and BAFF levels.Methods:The effect of BAFF on atherosclerosis associated with lupus was investigated in the atherosclerosis- and lupus-proneApoe°D227Kmouse model and in a cohort of SLE patients. Mice were treated with a blocking anti-BAFF monoclonal antibody (Ab), while fed with a standard chow diet. Carotid plaque and carotid intima media thickness were assessed by ultrasound at baseline and during follow-up in SLE patients asymptomatic for CVD.Results:Anti-BAFF Ab inApoe°D227Kmice i/ induced a B cell depletion, ii/ efficiently treated lupus, iii/improved atherosclerosis lesions in mice that had low plasma cholesterol levels but worsened the lesions in mice with high cholesterol levels. In that case, the atheroprotective effect of the BAFF-BAFFR signaling inhibition on B cells was counterbalanced by the proatherogenic effect of the BAFF-TACI signaling inhibition on macrophages. In SLE patients, BAFF blood levels were associated with subclinical atherosclerosis. Anti-BAFF Ab treatment had a differential effect on the intima media thickness progression in SLE patients depending on the body mass indexConclusion:Depending on the balance between metabolic- and B cell-induced proatherogenic conditions, anti-BAFF could be respectively detrimental or beneficial on atherosclerosis development in SLEAcknowledgments:Guillaume Even, Yasmine Lamri, Anh-Thu Gaston,Disclosure of Interests:Fanny Saidoune Grant/research support from: supported by a research partnerships between the academic and GlaxoSmithKline France.Anti-BAFF mAb (IgG1, clone 10F4B) in mice was provided by Glaxosmithkline, Nicolas Charles: None declared, Julie Chezel: None declared, Brigitte Escoubet: None declared, Thomas Papo: None declared, Antonino Nicoletti: None declared, karim sacre: None declared

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Alexaki, Vassilia-Ismini, Vassiliki Pelekanou, George Notas, Maria Venihaki, Marilena Kampa, Valérie Dessirier, Sanaa Sabour-Alaoui, Efstathios N. Stathopoulos, Andreas Tsapis e Elias Castanas. "B-Cell Maturation Antigen (BCMA) Activation Exerts Specific Proinflammatory Effects in Normal Human Keratinocytes and Is Preferentially Expressed in Inflammatory Skin Pathologies". Endocrinology 153, n. 2 (1 febbraio 2012): 739–49. http://dx.doi.org/10.1210/en.2011-1504.

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TNFα is known to be expressed in human skin, regulating immune-related responses. Here we report that human normal skin keratinocytes express the members of the TNF superfamily members A proliferation-inducing ligand (APRIL; TNFSF13), B cell-activating factor (BAFF; TNFSF13B), and their receptors, B cell maturation antigen (BCMA; TNFRSF17) and transmembrane activator, calcium-modulator, and cyclophilin ligand interactor (TACI; TNFRSF13B), in a distinct spatial pattern. Our data show a differential expression of these molecules within epidermal layers and skin appendages, whereas the BAFF-specific receptor BAFFR (TNFRSF13C) is absent. Importantly, APRIL and BCMA but not BAFF or TACI are up-regulated in inflammatory skin lesions of psoriasis and squamous cell carcinomas. To explore the functional significance of this system in the skin, we assayed these receptors and ligands in cultured primary keratinocytes and HaCaT cells. We show that both cell types express BAFF, APRIL, BCMA, and TACI. Furthermore, APRIL and/or BAFF trigger nuclear factor-κB activation and IL-6 and granulocyte macrophage colony-stimulating factor (GM-CSF) expression through functional BCMA receptors, an activation inhibited by anti-BCMA short hairpin RNA. However, BAFF and/or APRIL do not induce IL-8 or TNFα production. Our data advance BCMA as an inflammation-related TNFSFR member in keratinocytes, of potential importance in the management of inflammatory skin conditions.

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Xu, Haifeng C., Jun Huang, Vishal Khairnar, Vikas Duhan, Aleksandra A. Pandyra, Melanie Grusdat, Prashant Shinde et al. "Deficiency of the B Cell-Activating Factor Receptor Results in Limited CD169+Macrophage Function during Viral Infection". Journal of Virology 89, n. 9 (11 febbraio 2015): 4748–59. http://dx.doi.org/10.1128/jvi.02976-14.

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ABSTRACTThe B cell-activating factor (BAFF) is critical for B cell development and humoral immunity in mice and humans. While the role of BAFF in B cells has been widely described, its role in innate immunity remains unknown. Using BAFF receptor (BAFFR)-deficient mice, we characterized BAFFR-related innate and adaptive immune functions following infection with vesicular stomatitis virus (VSV) and lymphocytic choriomeningitis virus (LCMV). We identified a critical role for BAFFR signaling in the generation and maintenance of the CD169+macrophage compartment. Consequently,Baffr−/−mice exhibited limited induction of innate type I interferon production after viral infection. Lack of BAFFR signaling reduced virus amplification and presentation following viral infection, resulting in highly reduced antiviral adaptive immune responses. As a consequence, BAFFR-deficient mice showed exacerbated and fatal disease after viral infection. Mechanistically, transient lack of B cells inBaffr−/−animals resulted in limited lymphotoxin expression, which is critical for maintenance of CD169+cells. In conclusion, BAFFR signaling affects both innate and adaptive immune activation during viral infections.IMPORTANCEViruses cause acute and chronic infections in humans resulting in millions of deaths every year. Innate immunity is critical for the outcome of a viral infection. Innate type I interferon production can limit viral replication, while adaptive immune priming by innate immune cells induces pathogen-specific immunity with long-term protection. Here, we show that BAFFR deficiency not only perturbed B cells, but also resulted in limited CD169+macrophages. These macrophages are critical in amplifying viral particles to trigger type I interferon production and initiate adaptive immune priming. Consequently, BAFFR deficiency resulted in reduced enforced viral replication, limited type I interferon production, and reduced adaptive immunity compared to BAFFR-competent controls. As a result, BAFFR-deficient mice were predisposed to fatal viral infections. Thus, BAFFR expression is critical for innate immune activation and antiviral immunity.

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Prieto-Peña, D., S. Remuzgo Martinez, F. Genre, V. Pulito-Cueto, B. Atienza-Mateo, B. Sevilla, J. Llorca et al. "POS0113 BAFF-APRIL-BAFFR PATHWAY ON THE PATHOGENESIS OF IMMUNOGLOBULIN-A VASCULITIS". Annals of the Rheumatic Diseases 80, Suppl 1 (19 maggio 2021): 267.2–268. http://dx.doi.org/10.1136/annrheumdis-2021-eular.707.

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Background:BAFF, APRIL and BAFFR are genes that encode cytokines with a key role in the development and survival of B-lymphocytes [1-4]: The B cell-activating factor (BAFF, also known as BLyS), a proliferation-inducing ligand (APRIL) and BAFF receptor (BAFF-R), respectively. Previous genetic studies have revealed that the BAFF-APRIL-BAFFR pathway is implicated in the genetic predisposition to several immune-mediated diseases [5].Objectives:To determine whether the BAFF-APRIL-BAFFR pathway represents a novel genetic risk factor for the pathogenesis of Immunoglobulin-A vasculitis (IgAV), an inflammatory disease in which IgA deposits and B-lymphocytes are crucial [6, 7].Methods:A functional BAFF polymorphism (rs374039502) and two tag variants within APRIL (rs11552708 and rs6608) and BAFFR (rs7290134 and rs77874543) were genotyped in 386 Caucasian IgAV patients (the largest series of Caucasian patients with IgAV ever assessed for genetic studies) and 806 sex and ethnically matched healthy controls by TaqMan assays.Results:No statistically significant differences in the genotype and allele frequencies between patients with IgAV and healthy controls were observed when each genetic variant of BAFF APRIL and BAFFR was analyzed independently (Table 1). Likewise, no statistically significant differences in genotype and allele frequencies of BAFF APRIL or BAFFR were found when patients with IgAV were stratified according to the age at disease onset or to the presence/absence of gastrointestinal or renal manifestations. Similar results were disclosed when haplotype frequencies of APRIL and BAFFR were compared between patients with IgAV and healthy controls as well as patients with IgAV stratified according to the age at disease onset or to the presence/absence of gastrointestinal or renal manifestations.Conclusion:Our results suggest that the BAFF-APRIL-BAFFR pathway does not contribute to the genetic network underlying IgAV.References:[1]J Exp Med 1999;190:1697-710; [2] Science 1999;285:260-3; [3] Nat Genet 2005;37:829-34; [4] Nat Immunol 2002;3:822-9; [5] N Engl J Med 2017;376:1615-26; [6] N Engl J Med 2013;368:2402-14; [7] Autoimmun Rev 2018;17:301-315.Table 1.Genotype and allele frequencies of BAFF, APRIL and BAFFR genes in patients with IgA vasculitis and healthy controls.PolymorphismLocus1/2Data set1/11/22/212rs374039502BAFFT/APatients91.9 (353)8.1 (31)095.9 (737)4.1 (31)Controls91.5 (733)8.1 (65)0.4 (3)95.6 (1531)4.4 (71)rs11552708APRILG/APatients78.1 (299)20.6 (79)1.3 (5)88.4 (677)11.6 (89)Controls77.9 (625)20.4 (1641.6 (13)88.1 (1414)11.9 (190)rs6608APRILC/TPatients71.9 (277)26.0 (100)2.1 (8)84.9 (654)15.1 (116)Controls70.0 (561)27.6 (221)2.5 (20)83.7 (1343)16.3 (261)rs7290134BAFFRA/GPatients58.0 (224)36.3 (140)5.7 (22)76.2 (588)23.8 (184)Controls57.2 (459)36.4 (292)6.5 (52)75.3 (1210)24.6 (396)rs77874543BAFFRG/CPatients82.7 (316)16.0 (61)1.3 (5)90.7 (693)9.3 (71)Controls83.0 (666)16.6 (133)0.4 (3)91.3 (1465)8.7 (139)Acknowledgements:This study was supported by European Union FEDER funds and “Fondo de Investigaciones Sanitarias” (grant PI18/00042) from ‘Instituto de Salud Carlos III’ (ISCIII, Health Ministry, Spain). DP-P is a recipient of a Río Hortega programme fellowship from the ISCIII, co-funded by the European Social Fund (ESF, `Investing in your future´) [grant number CM20/00006]; SR-M is supported by funds of the RETICS Program co-funded by the European Regional Development Fund (ERDF) [grant number RD16/0012/0009]; VP-C is supported by a pre-doctoral grant from IDIVAL [grant number PREVAL 18/01]; BA-M is a recipient of a `López Albo´ Post-Residency Programme funded by Servicio Cántabro de Salud; LL-G is supported by funds of IDIVAL [grant number INNVAL20/06]; RL-M is a recipient of a Miguel Servet type I programme fellowship from the ISCIII, co-funded by the European Social Fund (ESF, `Investing in your future´) [grant number CP16/00033].Disclosure of Interests:Diana Prieto-Peña Speakers bureau: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Consultant of: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Grant/research support from: Abbvie, MSD and Roche, Sara Remuzgo Martinez: None declared, Fernanda Genre: None declared, Verónica Pulito-Cueto: None declared, Belén Atienza-Mateo: None declared, Belén Sevilla: None declared, Javier Llorca: None declared, Norberto Ortego: None declared, Leticia Lera-Gómez: None declared, Maite Leonardo: None declared, Ana Peñalba: None declared, J. Narváez: None declared, Luis Martín-Penagos: None declared, Jose Alberto Miranda-Filloy: None declared, LUIS CAMINAL MONTERO: None declared, PAZ COLLADO: None declared, Javier Sanchez Perez: None declared, Diego de Argila: None declared, Esteban Rubio-Romero: None declared, MANUEL LEON LUQUE: None declared, Juan María Blanco-Madrigal: None declared, E. Galindez: None declared, Javier Martin Ibanez: None declared, Santos Castañeda: None declared, Ricardo Blanco Speakers bureau: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Consultant of: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Grant/research support from: Abbvie, MSD and Roche, Miguel A González-Gay Speakers bureau: Pfizer, Abbvie, MSD, Grant/research support from: Pfizer, Abbvie, MSD, Raquel López-Mejías: None declared

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Bossen, Claudia, Teresa G. Cachero, Aubry Tardivel, Karine Ingold, Laure Willen, Max Dobles, Martin L. Scott et al. "TACI, unlike BAFF-R, is solely activated by oligomeric BAFF and APRIL to support survival of activated B cells and plasmablasts". Blood 111, n. 3 (1 febbraio 2008): 1004–12. http://dx.doi.org/10.1182/blood-2007-09-110874.

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Abstract The cytokine BAFF binds to the receptors TACI, BCMA, and BAFF-R on B cells, whereas APRIL binds to TACI and BCMA only. The signaling properties of soluble trimeric BAFF (BAFF 3-mer) were compared with those of higher-order BAFF oligomers. All forms of BAFF bound BAFF-R and TACI, and elicited BAFF-R–dependent signals in primary B cells. In contrast, signaling through TACI in mature B cells or plasmablasts was only achieved by higher-order BAFF and APRIL oligomers, all of which were also po-tent activators of a multimerization-dependent reporter signaling pathway. These results indicate that, although BAFF-R and TACI can provide B cells with similar signals, only BAFF-R, but not TACI, can respond to soluble BAFF 3-mer, which is the main form of BAFF found in circulation. BAFF 60-mer, an efficient TACI agonist, was also detected in plasma of BAFF transgenic and nontransgenic mice and was more than 100-fold more active than BAFF 3-mer for the activation of multimerization-dependent signals. TACI supported survival of activated B cells and plasmablasts in vitro, providing a rational basis to explain the immunoglobulin deficiency reported in TACI-deficient persons.

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Secreto, Frank J., Michelle K. Manske, Tammy Price-Troska, Steven C. Ziesmer, Stephen M. Ansell, James R. Cerhan e Anne J. Novak. "A Lymphoma-Associated Mutation in BAFF-R Drives Constitutive PI3K Signaling and Increased Expression of Pro-Survival Genes". Blood 118, n. 21 (18 novembre 2011): 2642. http://dx.doi.org/10.1182/blood.v118.21.2642.2642.

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Abstract Abstract 2642 BAFF is essential for B cell maturation, and a lack of either BAFF or its primary receptor, BAFF-R, results in a severe depletion of T2 marginal zone and follicular B cells. Elevated serum BAFF levels have been correlated with an increased risk of developing non-Hodgkin's lymphoma (NHL), along with a more aggressive phenotype. A growing body of genetic evidence points toward an association between the development of human disease and variation in genes encoding BAFF and its receptors. Recently, we characterized a novel lymphoma-associated mutation in TNFRSF13C, the gene encoding BAFF-R. This mutation (BAFF-R H159Y) encodes a His159Tyr substitution in the C-terminus of BAFF-R adjacent to the TRAF3 binding motif. Signaling through BAFF-R H159Y results in increased NF-κB activity, elevated immunoglobulin production and increased association with TRAF2, TRAF3 and TRAF6 compared to wild type (WT) BAFF-R. We have detected this mutation in 6% of total NHL cases (n=129), and in 10% of follicular lymphoma (FL) cases (n=41) evaluated thus far. We previously reported that BAFF-R H159Y expressing mouse B cells exhibited significantly more resistance to Fas ligand (FasL) induced apoptosis compared to their cells expressing BAFF-R WT, and we propose here that BAFF-R H159Y mediated increases in PI3K activity may explain such an enhanced anti-apoptotic response. In this study we now show that BAFF stimulated HEK 293 cells stably expressing BAFF-R H159Y not only display significantly increased Akt phosphorylation when compared to BAFF-R WT expressing cells, but also demonstrate robust Akt phosphorylation in the absence of BAFF. BAFF-R H159Y-dependent Akt activation also led to activation of the downstream Akt targets mTOR and GSK3β and their phosphorylation was inhibited following treatment with the PI3- kinase inhibitor wortmannin. We next examined the impact of the BAFF-R H159Y mutation on expression of BAFF-target genes. Quantitative PCR analyses revealed that BAFF-R H159Y cells exhibited a pattern of gene expression indicative of promoting cell survival, displaying significantly higher levels of BCL2, BCL2L1 and PIN1, while down-regulating expression of the pro-apoptotic gene BIM. We recently reported that TRAF6 associates with BAFF-R, and that such binding is more pronounced in cells expressing BAFF-R H159Y. In order to investigate the role TRAF6 plays in mediating BAFF-R-dependent PI3K activity, we silenced TRAF6 expression in HEK 293 and Karpas 422 lymphoma cells using TRAF6 shRNA. Reduced TRAF6 protein expression resulted in a parallel decrease in BAFF-R WT mediated phosphorylation of mTOR in Karpas 422 cells and phosphorylation of both Akt and GSK3β was markedly reduced in BAFF-R H159Y expressing HEK 293 cells. Interestingly, TRAF6 knock-down did not affect NF-kB2 activation in either Karpas 422 or HEK BAFF-R expressing cells suggesting that Akt does not play a role in BAFF-R mediated activation of non-canonical NF-kB. Finally, preliminary co-precipitation studies indicate that Akt can be recruited to BAFF-R itself, and our initial observations suggest that such an association is significantly reduced in cells expressing BAFF-R H159Y. Taken together, these studies suggest that the BAFF-R H159Y mutation confers enhanced BAFF-R-dependent PI3K signaling and pro-survival gene expression independent of BAFF. Moreover, such enhanced P13K activation is partly dependent upon TRAF6, and decreased recruitment of Akt to BAFF-R H159Y may function to increase the amount of this PI3K target for activation. Thus, BAFF-R H159Y likely contributes to BAFF signaling irregularities in NHL patients harboring this mutation, and may predispose individuals to developing lymphoma regardless of their serum BAFF concentration. Disclosures: No relevant conflicts of interest to declare.

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Hildebrand, Joanne M., Zhenghua Luo, Michelle Manske, Steven Ziesmer, Tammy Price-troska, Wai Lin, Bruce Hostager et al. "A BAFF-R Mutation Associated with Non-Hodgkin Lymphoma Exhibits Altered TRAF Binding and Reveals New Insights Into Proximal BAFF-R Signaling". Blood 116, n. 21 (19 novembre 2010): 468. http://dx.doi.org/10.1182/blood.v116.21.468.468.

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Abstract Abstract 468 The requirement for BAFF and BAFF-R in normal human and murine B cells is well studied, but there is also significant evidence to suggest that BAFF plays an important role in malignant B cell proliferation and survival. Serum BAFF levels are elevated in patients with non-Hodgkin lymphoma (NHL) and high BAFF levels correlate with aggressive disease and a poor response to therapy. There is also increasing genetic evidence suggesting an association between the development of human disease and genetic variation in genes encoding BAFF and its receptors. Mutations in TNFRSF13B (TACI) were identified in patients with familial common variable immunodeficiency (CVID) and IgA deficiency and we have found that single nucleotide polymorphisms (SNP) in TNFSF13B (BAFF) are associated with elevated BAFF levels and risk for developing NHL. To build upon these findings we sequenced BAFF and its receptors; TNFSF13B, TNFRSF13B, TNFRSF17(BCMA), and TNFRSF13C (BAFF-R) in NHL patients to identify novel genetic variants that may be associated with NHL risk. Among 40 individual samples (20 controls and 20 follicular lymphoma (FL) cases) that were bi-directionally sequenced we identified a heterozygous cytosine to thymidine transition in 1 patient specimen at position 475 (C475T) of TNFRSF13C. The C475T transition encodes a missense substitution of tyrosine for histidine in codon 159 (H159Y) in the highly conserved cytoplasmic tail of BAFF-R, adjacent to the TRAF3 binding motif PVPAT. We next expanded our analysis of BAFF-R H159Y and analyzed NHL tumor biopsies for the presence of the mutation. 4/41 (10%) follicular lymphomas (FL), 2/42 (5%) diffuse large B cell lymphomas, 1/22 (5%) lymphoplasmacytic lymphomas (LPL), and 1/24 (4%) mucosal associate lymphoid tissue lymphomas carried the heterozygous mutation. The BAFF-R H159Y mutation was not detected in any of the normal control DNA from healthy donors (n=100). Given its close proximity to the TRAF3 binding site in the cytoplasmic domain of BAFF-R we first wanted to determine if the H159Y mutation altered BAFF induced signaling. We generated cell lines that express HA-tagged wildtype BAFF-R, BAFF-R with the H159Y mutation, or BAFF-R with an ablated TRAF3 binding site as a negative control. Analysis of cells expressing H159Y BAFF-R demonstrates that this mutation results in increased BAFF-R-mediated NFκB1 and NF-κB2 activation. The enhanced signal activated by BAFF-R H159Y is coupled with a several fold increase in TRAF3, TRAF2, and TRAF6 recruitment to BAFF-R and increased IgM production. We further demonstrate that recruitment of TRAF6 to BAFF-R is not unique to the mutant H159Y BAFF-R, but is also an important and necessary feature of BAFF-R signaling in normal B cells. Collectively, our data identify a novel lymphoma-associated mutation in BAFF-R and describe exciting new aspects of BAFF-R signaling that are important for understanding normal B cell homeostasis and function, as well as pathogenic BAFF-R contributions to human disease. Disclosures: No relevant conflicts of interest to declare.

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Tada, S., T. Yasui, T. Okuno, Y. Nakatsuji, H. Mochizuki, S. Sakoda e H. Kikutani. "BAFF controls neural cell survival through BAFF receptor". Journal of the Neurological Sciences 333 (ottobre 2013): e689. http://dx.doi.org/10.1016/j.jns.2013.07.2380.

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Tada, Satoru, Teruhito Yasui, Yuji Nakatsuji, Tatsusada Okuno, Toru Koda, Hideki Mochizuki, Saburo Sakoda e Hitoshi Kikutani. "BAFF Controls Neural Cell Survival through BAFF Receptor". PLoS ONE 8, n. 7 (29 luglio 2013): e70924. http://dx.doi.org/10.1371/journal.pone.0070924.

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Hildebrand, Joanne M., Zhenghua Luo, Michelle K. Manske, Tammy Price-Troska, Steven C. Ziesmer, Wai Lin, Bruce S. Hostager et al. "A BAFF-R mutation associated with non-Hodgkin lymphoma alters TRAF recruitment and reveals new insights into BAFF-R signaling". Journal of Experimental Medicine 207, n. 12 (1 novembre 2010): 2569–79. http://dx.doi.org/10.1084/jem.20100857.

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The cytokine B cell activating factor (BAFF) and its receptor, BAFF receptor (BAFF-R), modulate signaling cascades critical for B cell development and survival. We identified a novel mutation in TNFRSF13C, the gene encoding human BAFF-R, that is present in both tumor and germline tissue from a subset of patients with non-Hodgkin lymphoma. This mutation encodes a His159Tyr substitution in the cytoplasmic tail of BAFF-R adjacent to the TRAF3 binding motif. Signaling through this mutant BAFF-R results in increased NF-κB1 and NF-κB2 activity and increased immunoglobulin production compared with the wild-type (WT) BAFF-R. This correlates with increased TRAF2, TRAF3, and TRAF6 recruitment to His159Tyr BAFF-R. In addition, we document a requirement for TRAF6 in WT BAFF-R signaling. Together, these data identify a novel lymphoma-associated mutation in human BAFF-R that results in NF-κB activation and reveals TRAF6 as a necessary component of normal BAFF-R signaling.

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Feng, Guo-dong, Xiao-chang Xue, Mei-li Gao, Xian-feng Wang, Zhen Shu, Nan Mu, Yuan Gao et al. "Therapeutic Effects of PADRE-BAFF Autovaccine on Rat Adjuvant Arthritis". BioMed Research International 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/854954.

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B cell activating factor (BAFF) is a cytokine of tumor necrosis factor family mainly produced by monocytes and dendritic cells. BAFF can regulate the proliferation, differentiation, and survival of B lymphocytes by binding with BAFF-R on B cell membrane. Accumulating evidences showed that BAFF played crucial roles and was overexpressed in various autoimmune diseases such as systemic lupus erythematous (SLE) and rheumatoid arthritis (RA). This suggests that BAFF may be a therapeutic target for these diseases. In the present study, we developed a BAFF therapeutic vaccine by coupling a T helper cell epitope AKFVAAWTLKAA (PADRE) to the N terminus of BAFF extracellular domains (PADRE-BAFF) and expressed this fusion protein inEscherichia coli. The purified vaccine can induce high titer of neutralizing BAFF antibodies and ameliorate the syndrome of complete Freund’s adjuvant (CFA) induced rheumatoid arthritis in rats. Our data indicated that the BAFF autovaccine may be a useful candidate for the treatment of some autoimmune diseases associated with high level of BAFF.

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Tai, Yu-Tzu, Xian-Feng Li, Rory Coffey, Iris Breitkreutz, Laurence Catley Laurence Catley, Klaus Podar, Teru Hideshima et al. "Role of BAFF in Adhesion and Growth of Human Multiple Myeloma Cells in the Bone Marrow Microenvironment." Blood 106, n. 11 (16 novembre 2005): 627. http://dx.doi.org/10.1182/blood.v106.11.627.627.

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Abstract Recent studies have underscored the role of B-cell activating factor (BAFF), a member of the tumor necrosis factor superfamily, in promoting the survival of malignant B cells, including human MM. Since the tumor bone marrow microenvironment plays a crucial role in MM cell growth and survival, we here characterize the functional significance of BAFF in the interaction between MM and bone marrow stromal cells (BMSCs), and further defined molecular mechanisms regulating these processes. We first confirmed the expression of BAFF and its receptors (BCMA, TACI, BAFF-R) on majority of MM cell lines and CD138-purified patient MM cells. Significantly, gene expression profiling revealed increased BCMA expression on newly diagnosed and relapsed MM versus normal plasma cells (p<0.0001, student T test, Abstract # 552872). Although BAFF and its 3 receptors are expressed on CD138+patient MM cells (n=10) by RT-PCR analysis, the pattern of expression of TACI and BAFF-R receptors was heterogeneous, assessed by flow cytometric analysis. We next examined BAFF expression in BMSC lines (n=4) and BMSCs derived from patient BM (n=5). Baff expression is easily detected in BMSCs, and Baff levels are approximately 3–10-fold higher in supernatants of BMSCs than equivalent numbers of MM cells. Thus BMSCs are the main source of BAFF in MM patients. We then asked whether MM adhesion to BMSCs further upregulates BAFF secretion from BMSCs. Adhesion of 5 MM cell lines to BMSCs augments BAFF secretion by 2–5 fold, using BAFF ELISA. Immunoblotting using anti-BAFF Ab confirmed markedly higher expression of BAFF in BMSCs than MCCAR MM cells, as well as greater BAFF upregulation induced by MM adhesion. Since NF-kappaB (NF-κB) is crucial for MM adhesion-induced cytokine secretion from BMSCs and the BAFF gene promoter contains at least six NF-κB-binding sites, we next transfected KM104 BMSC line with a luciferase reporter vector carrying the BAFF gene promoter (BAFF-LUC) and then allowed MM cells to adhere to BMSCs for 24 hr, followed by measurement of luciferase activity. NF-κB-LUC reporter was used as positive and pGL3 plasmid as a negative control. Adhesion of MCCAR and MM1S MM lines to KM103 BMSC line with BAFF-LUC and NF-κB-LUC, but not control reporters, significantly enhanced luciferase activity, suggesting that NF-κB activation induced by MM adhesion to BMSCs mediates BAFF upregulation. In parallel, we also asked whether BAFF induces MM adhesion to BMSCs. BAFF (0–100 ng/ml) increases adhesion of 5 MM lines to BMSCs in a dose-dependent manner; conversely, TACI-Ig or blocking anti-BCMA Ab inhibited BAFF stimulation, indicating increased adhesion specific triggered by BAFF. Using adenoviruses expressing dominant-negative and constitutively expressed AKT as well as IkappaB kinase (IKK) inhibitor (PS-1145), we further showed that BAFF-induced MM cell adhesion is primarily mediated via activation of AKT and NF-κB signaling. Finally, BAFF significantly increased adhesion of CD138-expressing patient MM cells to BMSCs. These studies suggest a role for BAFF in localization and growth of MM cells in the BM microenvironment and strongly support novel important therapeutics targeting the interaction between BAFF and its receptors in human MM.

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Hu, Shanshan, Rui Wang, Mei Zhang, Kangkang Liu, Juan Tao, Yu Tai, Weijie Zhou, Qingtong Wang e Wei Wei. "BAFF promotes T cell activation through the BAFF-BAFF-R-PI3K-Akt signaling pathway". Biomedicine & Pharmacotherapy 114 (giugno 2019): 108796. http://dx.doi.org/10.1016/j.biopha.2019.108796.

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Sarantopoulos, Stefanie, Kristen E. Stevenson, Haesook T. Kim, Nazmim S. Bhuiya, Corey S. Cutler, Robert J. Soiffer, Joseph H. Antin e Jerome Ritz. "BAFF/Blys Levels Correlate with Disease Activity and Alter Peripheral B Cell Subsets in Patients with Chronic GVHD." Blood 108, n. 11 (16 novembre 2006): 41. http://dx.doi.org/10.1182/blood.v108.11.41.41.

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Abstract Patients with chronic graft versus host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) have been found to have high titers of allo-reactive antibodies, but a role for B cells in the pathology of this disease remains undefined. B Cell Activating Factor, BAFF/Blys (BAFF), promotes differentiation and expansion of antigen-activated B cells and contributes to loss of B cell tolerance in animal models. We hypothesized that the BAFF/BAFF receptor (BAFF-R) pathway may perpetuate potentially allo- or auto-reactive antigen-experienced CD27+ B cells in patients with cGVHD after HSCT. Soluble BAFF was measured in plasma from 104 patients after HSCT. Median BAFF levels were statistically different when groups were compared using a two-sided Wilcoxon-Rank-Sum test (see Table below). Logistic regression analysis revealed that higher BAFF levels were associated with active cGVHD after adjusting for other GVHD prognostic factors (p=0.0007). Patients with ≥10ng/ml BAFF levels had ten-fold increased odds of having cGVHD compared to patients with BAFF levels of <10ng/ml (OR of 10.8, p=<0.0001). High dose prednisone reduced median plasma BAFF levels (3.8ng/ml in patients receiving ≥30mg daily prednisone versus 14ng/ml for those receiving <30mg or no prednisone). Serial BAFF measurements revealed peak BAFF levels at 6 months post-HSCT in patients who later developed limited cGVHD. 81% of patients with BAFF levels >10ng/ml at 6 months subsequently developed cGVHD (median BAFF was 20ng/ml) compared to 39% of patients with BAFF levels <10ng/ml at 6 months (p=0.002). We also found that BAFF-R expression on B cells was down-regulated in vitro in the presence of BAFF. Consistent with this finding flow cytometry revealed very low BAFF-R expression on B cells in patients with active cGVHD. BAFF-R expression on peripheral B cells correlated with BAFF levels (p=0.0001), suggesting that BAFF signals via BAFF-R in cGVHD. We used 5-color FACS to characterize peripheral B cell subsets in 68 post-HSCT patients. Compared to patients without cGVHD, the proportion of antigen-experienced CD27+ B cells was increased in patients with limited cGVHD (n=20, p=0.04). The extensive cGVHD patient group was smaller (n=11) with greater variability in CD27+ B cell frequency resulting in no statistical difference (p=0.27). The proportion of CD27+ post-germinal center B cells was also increased in patients with active cGVHD (p=0.04 and p=0.03 extensive and limited cGVHD, respectively). High BAFF levels correlated with increased total numbers of CD27+ B cells (p=0.05), but not with total or naïve B cell numbers, suggesting that BAFF plays a role in perpetuation of circulating antigen-experienced and memory B cells in cGVHD patients. Our results suggest that high levels of BAFF after HSCT help break peripheral B cell tolerance and contribute to cGVHD pathobiology. Comparison of BAFF Levels Between Extensive/Limited versus Inactive/No cGVHD Groups cGVHD Type N Median BAFF (ng/ml) p-value vs. inactive p-value vs. no Extensive 15 11.5 0.14 0.02 Limited 33 9.0 0.02 0.0004 Inactive 27 5.7 - 0.02 No 29 4.4 0.16 - Normal 26 1.9 0.0002 0.004

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Jia, Wei, Jonathan C. Poe, Hsuan Su, Sarah Anand, Glenn K. Matsushima, Jeffrey C. Rathmell, Ivan Maillard et al. "BAFF promotes heightened BCR responsiveness and manifestations of chronic GVHD after allogeneic stem cell transplantation". Blood 137, n. 18 (6 maggio 2021): 2544–57. http://dx.doi.org/10.1182/blood.2020008040.

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Abstract Patients with chronic graft-versus-host disease (cGVHD) have increased B cell–activating factor (BAFF) levels, but whether BAFF promotes disease after allogeneic bone marrow transplantation (allo-BMT) remains unknown. In a major histocompatibility complex–mismatched model with cGVHD-like manifestations, we first examined B-lymphopenic μMT allo-BMT recipients and found that increased BAFF levels in cGVHD mice were not merely a reflection of B-cell number. Mice that later developed cGVHD had significantly increased numbers of recipient fibroblastic reticular cells with higher BAFF transcript levels. Increased BAFF production by donor cells also likely contributed to cGVHD, because BAFF transcript in CD4+ T cells from diseased mice and patients was increased. cGVHD manifestations in mice were associated with high BAFF/B-cell ratios and persistence of B-cell receptor (BCR)–activated B cells in peripheral blood and lesional tissue. By employing BAFF transgenic (Tg) mice donor cells, we addressed whether high BAFF contributed to BCR activation in cGVHD. BAFF increased NOTCH2 expression on B cells, augmenting BCR responsiveness to surrogate antigen and NOTCH ligand. BAFF Tg B cells had significantly increased protein levels of the proximal BCR signaling molecule SYK, and high SYK protein was maintained by BAFF after in vitro BCR activation or when alloantigen was present in vivo. Using T cell–depleted (BM only) BAFF Tg donors, we found that BAFF promoted cGVHD manifestations, circulating GL7+ B cells, and alloantibody production. We demonstrate that pathologic production of BAFF promotes an altered B-cell compartment and augments BCR responsiveness. Our findings compel studies of therapeutic targeting of BAFF and BCR pathways in patients with cGVHD.

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Tschumper, Renee C., Jaime R. Darce, Xiaosheng Wu, Stephen A. Mihalcik e Diane F. Jelinek. "Comprehensive Analysis of BAFF Binding Receptor Profiles and Receptor Occupancy in B Cell Chronic Lymphocytic Leukemia: Identification of Discrete Phenotypic Subgroups." Blood 110, n. 11 (16 novembre 2007): 1135. http://dx.doi.org/10.1182/blood.v110.11.1135.1135.

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Abstract B cell-activating factor (BAFF) is known to regulate normal B cell development and homeostasis primarily by signaling through the high affinity receptor, BAFF-R, one of three BAFF binding receptors (BBRs). BAFF also binds two other receptors, BCMA and TACI with lesser affinity. We have recently shown that normal peripheral blood (PB) B cells express high levels of prebound soluble BAFF, which is lost upon B cell activation. Because of BAFF’s activity on normal B cells, we have been interested in the roles of BAFF and BBRs in B cell chronic lymphocytic leukemia (B-CLL). We and others have demonstrated that BAFF promotes primary CLL B cell survival and that serum BAFF levels are elevated in some patients. Although CLL B cells are known to express BBRs, a comprehensive and quantitative analysis of BBR levels and CLL B cell capacity to bind BAFF has not yet been done. We began this study by characterizing the level of soluble BAFF bound to freshly isolated CLL B cells, measured by both western blot analysis and flow cytometry. To assess receptor occupancy, cells were incubated with or without exogenous BAFF before assessing anti-BAFF reactivity and changes in median fluorescence intensity (ΔMFI; defined by dividing the MFI of the anti-BAFF antibody by the MFI of the isotype matched control antibody) were calculated. Normal B cells have higher detectable levels of bound BAFF with a ΔMFI ranging from 16 to 35 (mean=22.2). Upon addition of exogenous BAFF, the ΔMFI range increased to 27–96.6 (mean=49.1; n=8). Thus, despite evidence of prebound BAFF, clearly not all BBRs were occupied on normal PB B cells. By contrast, the levels of prebound BAFF on CLL B cells were significantly lower with a ΔMFI ranging from 1 to 13.1 (mean=2.7; n=36). Of note, 10/36 patients did not exhibit increased anti-BAFF reactivity upon incubation with exogenous BAFF (mean fold induction=0.8) whereas 26/36 patients displayed a mean fold induction of anti-BAFF reactivity of 3.5. These observations prompted us to next quantitate CLL B cell BBR expression. All patient CLL B cells expressed BAFF-R but at significantly lower levels than observed in normal B cells (p=0.0009). When CLL patients were categorized into IGHV mutated (M; n=22) and unmutated (UM; n=24), UM patients were observed to express higher levels of BAFF-R (ΔMFI =8.9) than M patients (ΔMFI =5.24). Regarding TACI, we previously demonstrated that normal memory B cells uniformly express TACI (ΔMFI =12.7; n=10) and there is a small population of activated naïve B cells that express TACI at lower levels (ΔMFI =8.3; n=10). In our CLL cohort, 14/22 M patients were TACI+ (ΔMFI =7.0) and 19/24 UM patients were TACI+ (ΔMFI =4.7). Finally, whereas normal PB B cells completely lack BCMA expression, 7/22 M and 4/22 UM patients expressed BCMA. Thus, using the BBR profile and analysis of expression levels relative to normal PB B cells, the following subgroups of B-CLL can be defined: BAFF-R+; BAFF-R/TACI+; BAFF-R/BCMA+; BAFF-R/TACI/BCMA+. It remains to be determined if these BBR profiles correlate with aspects of clinical disease. In addition, given the putative importance of BAFF in this disease, it is interesting to note that in general, CLL B cells display overall lower levels of prebound BAFF. Current studies are focused on determining whether this reflects CLL B cell activation status, increased competition for BAFF, and/or reduced levels of BBR expression.

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Maia, Sara, Sambasiva P. Rao, Stephen E. Sallan, Lee M. Nadler e Angelo A. Cardoso. "Aberrant Expression of BAFF System Molecules on B-Cell Precursor Leukemia Modulates Tumor Cell Survival: Novel Targets for Therapeutic Intervention." Blood 104, n. 11 (16 novembre 2004): 989. http://dx.doi.org/10.1182/blood.v104.11.989.989.

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Abstract Identification of pathways that support the survival and proliferation of acute lymphoblastic leukemia (ALL) cells will provide novel targets for therapeutic intervention. BAFF and APRIL, with their receptors, BAFF-R, BCMA and TACI are members of the TNF family that play a critical role in the survival of mature B cells but not of normal B cell precursors. We sought to determine whether BAFF/APRIL and their receptors might be aberrantly expressed on B-cell precursor ALL. Surprisingly, tumor cells from 28 of 29 ALL patients expressed mRNA for at least one of these receptors. Using flow cytometric analysis, surface expression of BAFF-R, BCMA, and TACI protein was detected on 89%, 78% and 56% of B-lineage ALL, respectively. Binding assays using a BAFF fusion protein demonstrated that ALL cells expressed high-affinity receptors for BAFF. Stimulation of leukemia cells with BAFF fusion protein triggered the activation of the NFκB pathway with phosphorylation of NFκB2 p100 (Ser864), and its processing to p52. However, BAFF binding did not trigger phosphorylation of IKKα, suggesting that BAFF-mediated activation of NFκB on leukemia cells occurs in an IKK-independent manner. These observations demonstrate that B-cell precursor ALL express functional receptors for BAFF/APRIL ligands. To examine the biological significance of the BAFF system in precursor B-cell ALL, we performed survival and proliferation assays using a myc-tagged BAFF. Our results indicate that while BAFF promoted survival of B-ALL cells, it did not induce their proliferation. Moreover, BAFF binding to leukemia cells was accompanied by increased expression of Bcl-2. To determine the source of BAFF in the leukemic BM, expression of membrane-bound BAFF and APRIL was analyzed in both leukemia cells and cells from the BM microenvironment (BM endothelium, BM mesenchymal stem cells and BM stroma). Surprisingly, leukemia cells expressed BAFF in all patients tested, and APRIL was detected in 94% of the cases. BM microenvironmental cells were found to express membrane-bound BAFF but not APRIL. These findings demonstrate that leukemia B-cell precursors express functional receptors for BAFF system ligands. Importantly, we show that BAFF-mediated stimulation of leukemia cells triggers the activation of the NFκB pathway through an IKK-independent mechanism, and promotes the survival of leukemia cells. The differential expression of BAFF and APRIL on B-ALL cells and the BM microenviromental cells suggests that these ligands may act through both autocrine and juxtacrine mechanisms. Our studies indicate that the BAFF/APRIL ligand-receptor axis might provide new opportunities for therapeutic intervention in B-cell ALL.

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Ragheb, Samia, e Robert P. Lisak. "B-Cell-Activating Factor and Autoimmune Myasthenia Gravis". Autoimmune Diseases 2011 (2011): 1–10. http://dx.doi.org/10.4061/2011/939520.

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BAFF is a potent B-cell survival factor, and it plays an essential role in B-cell homeostasis and B-cell function in the periphery. Both normal and autoreactive B cells are BAFF dependent; however, excess BAFF promotes the survival, growth, and maturation of autoreactive B cells. When overexpressed, BAFF protects B cells from apoptosis, thereby contributing to autoimmunity. Three independent studies have shown higher BAFF levels in the circulation of MG patients. BAFF may play an important role in the pathogenesis of MG. BAFF antagonists may well provide new treatment options for MG patients, particularly those patients with thymic lymphoid follicular hyperplasia.

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Patke, Alina, Ingrid Mecklenbräuker, Hediye Erdjument-Bromage, Paul Tempst e Alexander Tarakhovsky. "BAFF controls B cell metabolic fitness through a PKCβ- and Akt-dependent mechanism". Journal of Experimental Medicine 203, n. 11 (23 ottobre 2006): 2551–62. http://dx.doi.org/10.1084/jem.20060990.

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B cell life depends critically on the cytokine B cell–activating factor of the tumor necrosis factor family (BAFF). Lack of BAFF signaling leads to B cell death and immunodeficiency. Excessive BAFF signaling promotes lupus-like autoimmunity. Despite the great importance of BAFF to B cell biology, its signaling mechanism is not well characterized. We show that BAFF initiates signaling and transcriptional programs, which support B cell survival, metabolic fitness, and readiness for antigen-induced proliferation. We further identify a BAFF-specific protein kinase C β–Akt signaling axis, which provides a connection between BAFF and generic growth factor–induced cellular responses.

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Mulazzani, Matthias, Xíaolan Zhou, Wenlong Zhang, Andreas Straube e Louisa von Baumgarten. "TMOD-33. THE ROLE OF BAFF-R SIGNALING IN THE GROWTH OF PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA". Neuro-Oncology 22, Supplement_2 (novembre 2020): ii235. http://dx.doi.org/10.1093/neuonc/noaa215.983.

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Abstract Primary CNS lymphoma (PCNSL) is an aggressive brain tumor. Despite improvements in therapeutic algorithms, long-term survival remains rare, illustrating an urgent need for novel therapeutic targets. BAFF-R is a pro-survival receptor expressed on most malignant B cells, including PCNSL. To date, its role in PCNSL growth remains elusive. Here, we created a BAFF-R knockout lymphoma cell line (BAFF-R-KO) using CRISPR-Cas9. In serum-starved conditions, BAFF-R-KO cells exhibit decreased viability in vitro compared to BAFF-R+ cells. Combining an orthotopic mouse model of PCNSL with chronic cranial windows and intravital microscopy, we demonstrate a significant delay in tumor growth in mice inoculated with BAFF-R-KO cells compared to BAFF-R+ PCNSL. Additionally, median survival of BAFF-R-KO mice was significantly prolonged. Altogether, our results indicate a potential of BAFF-R as a novel treatment target for PCNSL.

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Krumbholz, Markus, Diethilde Theil, Tobias Derfuss, Andreas Rosenwald, Frank Schrader, Camelia-Maria Monoranu, Susan L. Kalled et al. "BAFF is produced by astrocytes and up-regulated in multiple sclerosis lesions and primary central nervous system lymphoma". Journal of Experimental Medicine 201, n. 2 (10 gennaio 2005): 195–200. http://dx.doi.org/10.1084/jem.20041674.

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We report that B cell–activating factor of the tumor necrosis factor (TNF) family (BAFF) is expressed in the normal human brain at ∼10% of that in lymphatic tissues (tonsils and adenoids) and is produced by astrocytes. BAFF was regularly detected by enzyme-linked immunosorbent assay in brain tissue lysates and in normal spinal fluid, and in astrocytes by double fluorescence microscopy. Cultured human astrocytes secreted functionally active BAFF after stimulation with interferon-γ and TNF-α via a furin-like protease-dependent pathway. BAFF secretion per cell was manifold higher in activated astrocytes than in monocytes and macrophages. We studied brain lesions with B cell components, and found that in multiple sclerosis plaques, BAFF expression was strongly up-regulated to levels observed in lymphatic tissues. BAFF was localized in astrocytes close to BAFF-R–expressing immune cells. BAFF receptors were strongly expressed in situ in primary central nervous system (CNS) lymphomas. This paper identifies astrocytes as a nonimmune source of BAFF. CNS-produced BAFF may support B cell survival in inflammatory diseases and primary B cell lymphoma.

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Kern, Catherine, Jean-François Cornuel, Christian Billard, Ruoping Tang, Danielle Rouillard, Virginie Stenou, Thierry Defrance et al. "Involvement of BAFF and APRIL in the resistance to apoptosis of B-CLL through an autocrine pathway". Blood 103, n. 2 (15 gennaio 2004): 679–88. http://dx.doi.org/10.1182/blood-2003-02-0540.

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Abstract (sommario):

Abstract Tumor necrosis factor (TNF) superfamily members BAFF, or B-cell activation factor of the TNF family, and APRIL, a proliferation-inducing ligand, are involved in normal B-cell survival and differentiation. They interact with 3 receptors: BAFF-R, specific to BAFF; and TACI and BCMA, which are shared by BAFF and APRIL. We tested the potential role of these proteins in B-cell chronic lymphocytic leukemia (B-CLL) resistance to apoptosis. TACI and BAFF-R mRNAs were found in leukemic B cells. BAFF and APRIL mRNAs and proteins were detected in B-CLL leukemic cells and normal blood or tonsil-derived B lymphocytes. Yet, in contrast to normal B lymphocytes, BAFF and APRIL were expressed at the membranes of leukemic cells. Adding soluble BAFF or APRIL protected B-CLL cells against spontaneous and drug-induced apoptosis and stimulated NF-κB activation. Conversely, adding soluble BCMA-Fc or anti-BAFF and anti-APRIL antibodies enhanced B-CLL apoptosis. Moreover, a soluble form of BAFF was detected using surface-enhanced laser desorption/ionization–time-of-flight mass spectrometry (SELDI-TOF MS) in the sera of B-CLL patients but not of healthy donors. Taken together, our results indicate that B-CLL cells can be rescued from apoptosis through an autocrine process involving BAFF, APRIL, and their receptors. Inhibiting BAFF and APRIL pathways may be of therapeutic value for B-CLL treatment.

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Ferrer, Gerardo, Kate E. Hodgson, Pau Abrisqueta, Aina Pons, Sonia Jansa, Bernat Gel, Xavier Filella et al. "BAFF and APRIL in Chronic Lymphocytic Leukemia: Clinico-Biological Correlates and Prognostic Significance." Blood 114, n. 22 (20 novembre 2009): 1235. http://dx.doi.org/10.1182/blood.v114.22.1235.1235.

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Abstract Abstract 1235 Poster Board I-257 BAFF (B-cell activating factor) and APRIL (a proliferation-inducing ligand) are TNF family proteins that upregulate anti-apoptotic genes through the NF-kB pathway. Studies in vitro suggest that BAFF and APRIL protect neoplastic B cells from apoptosis in chronic lymphoproliferative disorders (CLPD) including chronic lymphocytic leukemia (CLL). Serum BAFF levels have been previously shown to be lower in CLL than in other CLPD or normal subjects. To contribute to a better understanding of their role in CLL, we analyzed BAFF and APRIL at mRNA and protein serum levels and their receptors [transmembrane activator and CAML interactor (TACI), B-cell maturation antigen (BCMA) and BAFF receptor (BAFF-R)] by flow cytometry, in 82 patients with CLL, 36 with other CLPD and 35 age- and sex-matched controls. mRNA BAFF and APRIL levels were calculated as a the percentage of expression referred to an internal control and the receptor expression as the ratio between the mean fluorescence intensity (MFI) of the receptor antibody and the MFI of the isotype control. Patients with CLL showed significantly lower median BAFF and APRIL levels (0.63 μg/ml and 3.18 μg/ml) than those with other CLPD (1.27 μg/ml and 5.51 μg/ml) (p<0.05). Moreover, BAFF but not APRIL was lower in CLL than in healthy subjects (0.63 μg/ml vs. 0.77 μg/ml; p<0.0001). Serum BAFF levels and blood lymphocyte counts were inversely correlated. Likewise, in follicular lymphoma patients who had circulating neoplastic B cells, median BAFF levels was 0.84 μg/ml vs. 1.46 μg/ml in those without detectable neoplastic cells in blood (p<0.05). We also examined the expression of BAFF and APRIL in purified CD19+ cells from 19 CLL patients and 10 healthy controls. All CLL and normal B cells expressed BAFF and APRIL although heterogeneously. Nevertheless, BAFF and APRIL were lower in CLL than in normal B cells (median: 6.24% and 12.73% in CLL vs. 11.54% and 42.26% in controls). In CLL, mRNA BAFF expression inversely correlated with BAFF serum levels. As far as BAFF and APRIL receptors are concerned, BAFF-R was the one most highly expressed in CLL and normal B cells (MFI ratios of 167.3 and 157.2, respectively). TACI and BCMA were also expressed in all CLL cells and normal B cells (MFI ratios TACI: 1.70 and 2.41; BCMA: 9.51 and 4.72, respectively), but at a significantly lower level than BAFF-R (p<0.001). Furthermore, whereas BCMA MFI ratio was significantly higher in CLL than in normal B cells (p<0.05), no differences were observed in the expression of TACI and BAFF-R. TACI expression was heterogenous in CLL cells. BAFF-R inversely correlated with BAFF and APRIL serum levels. From a clinical standpoint, there is some indication that BAFF and APRIL serum levels as well as their expression in CLL cells may correlate with clinical and biological characteristics of the disease. No significant relationship was observed between BAFF and APRIL and IGVH mutational status, ZAP-70, CD38 or cytogenetics. However, an inverse correlation was observed between BAFF serum levels and blood lymphocyte counts as well as advanced clinical stage (p<0.05). In contrast, APRIL serum levels were only correlated with CD38 expression, the higher the expression of CD38 the higher the APRIL. Although blood lymphocyte counts and BAFF serum levels are correlated, a multivariate analysis showed that these two variables along with poor risk cytogenetics were independent predictors of progression (poor risk cytogenetics RR=11.699, p<0.05; high blood lymphocyte count RR=9.780, p<0.05 and low serum BAFF RR= 6.098, p<0.05). In summary this study confirms that BAFF and APRIL serum levels are lower in CLL than in other CLPD. In patients with CLL, BAFF serum and mRNA levels correlate with blood lymphocyte count and advanced clinical stage but not with other well known prognostic factors. Finally, although BAFF correlates with blood lymphocyte counts, our results suggest that BAFF serum levels have independent prognostic significance. Disclosures No relevant conflicts of interest to declare.

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Chen, Jing, Donghua He, Xing Guo, Qingxiao Chen, Xuanru Lin, Jingsong He, Xi Huang et al. "Interactions Between BAFF and BAFF Receptors Are Involved in Macrophage-Induced Bortezomib Resistance in Myeloma". Blood 128, n. 22 (2 dicembre 2016): 4429. http://dx.doi.org/10.1182/blood.v128.22.4429.4429.

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Abstract (sommario):

Abstract Background:B-cell-activating factor (BAFF) is a member of the TNF family that critical for maintenance of B-cell development and homeostasis. BAFF receptor (BAFF-R), B-cell maturation antigen (BCMA) and transmembrane activator and CAML interactor (TACI) are three BAFF receptors. It has been reported that BAFF is expressed by neutrophils, monocytes, dentritic cells and macrophages and modulates the proliferation, survival and drug resistance of multiple myeloma (MM) cells. Our previous study showed that, macrophages protect MM cells from drug-induced apoptosis by direct interaction with MM cells. We hypothesized that BAFF/BAFF receptors play a role in macrophage-induced bortezomib resistance in myeloma. Methods: First, the expression levels of BAFF and its three receptors in primary MM cells, MM cell lines and peripheral blood monocyte(PBMC)-induced macrophages were detected by semiquantitative real time-polymerase chain reaction (qPCR),Western blot and flow-cytometry. Also the concentration of BAFF in the supernatants of MM patients' bone marrow, MM cell lines and macrophages were determined by ELISA. Second, Primary MM cells and MM cell lines were cocultured with macrophages for the indicated time (usually 4-6h and 24h), for some experiments, we added bortezomib to the coculture system. Cell viability and apoptosis of MM cells were verified by Cell Counting Kit-8(CCK8) after treated with recombinant human (rh) BAFF, BAFF neutralizing antibody and BAFF siRNA. The interactions between BAFF and its receptors are unveiled by flow-cytometry. Then, cell survival signaling activations that may confer MM drug resistance were examined by Western blot. Results: Two receptors of BAFF, TACI and BCMA were highly expressed in various MM cell lines. The expressions of BAFF in PBMC-induced macrophages were heterogeneous. Functional studies showed that rhBAFF promoted RPMI8226 and ARP1 myeloma cells growth (P<0.05) and protected them from bortezomib-induced apoptosis (P<0.05). Then we verified macrophage-mediated MM drug resistance by directly coculturing MM cells (ARP-1, RPMI8226) with PBMC-derived macrophages from healthy donors. The macrophage-induced bortezomib resistance was attenuated by neutralizing antibodies(P<0.05) and siRNA of BAFF(P<0.01) . Next we found that in MM cells cocultured with macrophages, bortezomib-induced PARP and caspase-3 cleavages were highly repressed and phosphorylated Src ,AKT and Erk1/2 were upregulated which indicated that BAFF-mediated MM drug resistance may be through ERK1/2 and Src pathway .In addition, BAFF induced activation of NF-κB2,a pathway critical for the growth and survival of these cells. Conclusions: Our data show that macrophage might induce drug resistance of MM cells by the interaction of BAFF and BAFF receptors, leading to a reduction in caspase proteins and subsequent activation of Src and Erk1/2 kinases and NF-κB2 pathways .These studies reveal a promising unknown role for BAFF/BAFF receptors, suggesting that targeting macrophage-MM interactions may represent a promising therapeutic modality. Disclosures No relevant conflicts of interest to declare.

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Chou, Ho, Lai, Chen, Wu, Shun, Wen e Lai. "B-Cell Activating Factor Enhances Hepatocyte-Driven Angiogenesis via B-Cell CLL/Lymphoma 10/Nuclear Factor-KappaB Signaling during Liver Regeneration". International Journal of Molecular Sciences 20, n. 20 (10 ottobre 2019): 5022. http://dx.doi.org/10.3390/ijms20205022.

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B-cell activating factor (BAFF) is found to be associated with the histological severity of nonalcoholic steatohepatitis (NASH). BAFF was also found to have a protective role in hepatic steatosis via down regulating the expression of steatogenesis genes and enhancing steatosis in hepatocytes through BAFF-R. However, the roles of BAFF during liver regeneration are not well defined. In this study, C57/B6 mice with 70% partial hepatectomy were used as a liver regeneration model. BAFF expression was determined by enzyme immunoassay, and anti-BAFF-neutralizing antibodies were administered to confirm the effects of BAFF on liver regeneration. Western blotting, immunohistochemistry, and florescence staining determined the expression of B-cell CCL/lymphoma 10 (BCL10). The angiogenesis promoting capability was evaluated after the transfection of cells with siRNA targeting BCL10 expression, and the role of NF-κB was assessed. The results revealed that the BAFF and BCL10 levels were upregulated after partial hepatectomy. Treatment with anti-BAFF-neutralizing antibodies caused death in mice that were subjected to 70% partial hepatectomy within 72 h. In vitro, recombinant BAFF protein did not enhance hepatocyte proliferation; however, transfection with BCL10 siRNA arrested hepatocytes at the G2/M phase. Interestingly, conditioned medium from BAFF-treated hepatocytes enhanced angiogenesis and endothelial cell proliferation. Moreover, Matrix metalloproteinase-9 (MMP-9), Fibroblast growth factor 4 (FGF4), and Interleukin-8 (IL-8) proteins were upregulated by BAFF through BCL10/NF-κB signaling. In mice that were treated with anti-BAFF-neutralizing antibodies, the microvessel density (MVD) of the remaining liver tissues and liver regeneration were both reduced. Taken together, our study demonstrated that an increased expression of BAFF and activation of BCL10/NF-κB signaling were involved in hepatocyte-driven angiogenesis and survival during liver regeneration.

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Rihacek, Michal, Julie Bienertova-Vasku, Dalibor Valik, Jaroslav Sterba, Katerina Pilatova e Lenka Zdrazilova-Dubska. "B-Cell Activating Factor as a Cancer Biomarker and Its Implications in Cancer-Related Cachexia". BioMed Research International 2015 (2015): 1–9. http://dx.doi.org/10.1155/2015/792187.

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B-cell activating factor (BAFF) is a cytokine and adipokine of the TNF ligand superfamily. The main biological function of BAFF in maintaining the maturation of B-cells to plasma cells has recently made it a target of the first FDA-approved selective BAFF antibody, belimumab, for the therapy of systemic lupus erythematosus. Concomitantly, the role of BAFF in cancer has been a subject of research since its discovery. Here we review BAFF as a biomarker of malignant disease activity and prognostic factor in B-cell derived malignancies such as multiple myeloma. Moreover, anti-BAFF therapy seems to be a promising approach in treatment of B-cell derived leukemias/lymphomas. In nonhematologic solid tumors, BAFF may contribute to cancer progression by mechanisms both dependent on and independent of BAFF’s proinflammatory role. We also describe ongoing research into the pathophysiological link between BAFF and cancer-related cachexia. BAFF has been shown to contribute to inflammation and insulin resistance which are known to worsen cancer cachexia syndrome. Taking all the above together, BAFF is emerging as a biomarker of several malignancies and a possible hallmark of cancer cachexia.

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Le Pottier, Laëtitia, Boutahar Bendaoud, Yves Renaudineau, Pierre Youinou, Jacques-Olivier Pers e Capucine Daridon. "New ELISA for B Cell–Activating Factor". Clinical Chemistry 55, n. 10 (1 ottobre 2009): 1843–51. http://dx.doi.org/10.1373/clinchem.2009.129940.

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Abstract Background: The B cell–activating factor of the TNF family (BAFF) is upregulated in autoimmune diseases, but a number of conflicting results have cast doubts on the reliability of the ELISA protocols currently used for its quantification. This situation led us to develop a new ELISA for the measurement of BAFF. Methods: BAFF was purified for use alongside nonglycosylated recombinant BAFF. Two monoclonal antibodies (mAbs) and two polyclonal antibodies (pAbs) to BAFF were used. Results: The optimization process showed that the pAb format was preferable to the mAb format as capture antibody, because the pAbs recognized the glycosylated as well as the nonglycosylated forms of BAFF. The most efficient pair of Abs involved using the unconjugated form of a goat pAb to capture BAFF and the same biotinylated goat pAb to detect bound BAFF. This ELISA was not influenced by the presence of rheumatoid factor. Conclusions: This new ELISA helped provide insights into why serum concentrations of BAFF vary between studies for a given population of patients. It is a reliable tool for the management of the diseases in which BAFF is an indication of response to therapy.

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Birnbaum, Tobias, Sigrid Langer, Sigrun Roeber, Louisa Von Baumgarten e Andreas Straube. "Expression of B-cell activating factor, a proliferating inducing ligand and its receptors in primary central nervous system lymphoma". Neurology International 5, n. 1 (21 marzo 2013): 4. http://dx.doi.org/10.4081/ni.2013.e4.

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B-cell activating factor belonging to the tumor necrosis factor family (BAFF) and a proliferating inducing ligand (APRIL) might play an important role in the pathogenesis of systemic B-cell malignancies. However, the BAFF/APRIL system has not been systematically evaluated in primary central nervous system lymphoma (PCNSL) to date. We assessed the expression of BAFF, APRIL and its receptors BAFF-R (BAFF receptor), BCMA (B-cell maturation antigen) and TACI (transmembrane activator and calcium modulator cyclophilin ligand interactor) in five PCNSL specimens by immunohistochemical staining. We found extensive expression of BAFF and weak to moderate expression of APRIL, BAFF-R, BCMA, and TACI in all specimens. CD20 positive cells showed expression of both ligands and receptors at the same time. Our results indicate that autocrine stimulation of the BAFF/APRIL system might be involved in the pathogenesis of PCNSL.

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Castigli, Emanuela, Stephen A. Wilson, Sumi Scott, Fatma Dedeoglu, Shengli Xu, Kong-Peng Lam, Richard J. Bram, Haifa Jabara e Raif S. Geha. "TACI and BAFF-R mediate isotype switching in B cells". Journal of Experimental Medicine 201, n. 1 (3 gennaio 2005): 35–39. http://dx.doi.org/10.1084/jem.20032000.

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The tumor necrosis factor family members BAFF and APRIL induce Ig isotype switching in human B cells. We analyzed the ability of BAFF and APRIL to induce isotype switching in murine B cells to IgG1, IgA, and IgE. APRIL and BAFF each engage two receptors, transmembrane activator and calcium-modulator and cytophilin ligand interactor (TACI) and B cell maturation antigen (BCMA), on B cells. In addition, BAFF engages a third receptor on B cells, BAFF-R. To determine the role of these receptors in isotype switching, we examined B cells from mice deficient in TACI, BCMA, and BAFF-R. The results obtained indicate that both TACI and BAFF-R are able to transduce signals that result in isotype switching.

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Chiu, April, Xugang Qiao, Bing He, Elizabeth Hyjjek, Joong Lee, Ethel Cesarman, Amy Chadburn, Daniel M. Knowles e Andrea Cerutti. "The TNF Family Members BAFF and APRIL Play an Important Role in Hodgkin Lymphoma." Blood 106, n. 11 (16 novembre 2005): 22. http://dx.doi.org/10.1182/blood.v106.11.22.22.

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Abstract Introduction. B cell-activating factor of the TNF family (BAFF) and a proliferation-inducing ligand (APRIL), a BAFF-related molecule, play a key role in the survival and proliferation of mature B cells. In addition, BAFF and APRIL cooperate with IL-4 to induce class switch DNA recombination (CSR) from IgM (or IgG) to IgG, IgA or IgE. This process requires activation-induced-cytidine deaminase (AID), a DNA-editing enzyme involved also in Ig somatic hypermutation and lymphomagenesis. BAFF and APRIL are usually produced by myeloid cells, including dendritic cells, macrophages and granulocytes, and engage three receptors preferentially expressed on B cells, including transmembrane activator and calcium modulator and cyclophylin ligand interactor (TACI), B cell maturation antigen (BCMA), and BAFF receptor (BAFF-R). Our previous studies show that BAFF and APRIL are EBV-inducible molecules implicated in B cell non-Hodgkin’s lymphoma (NHL). The scope of the present studies was to elucidate the expression and function of BAFF, APRIL, TACI, BCMA and BAFF-R in Hodgkin lymphoma (HL). Methods. Tissue sections from 5 primary EBV+ HL cases and 5 primary EBV− HL cases were analyzed for BAFF, APRIL, TACI, BCMA, and BAFF-R expression through immunohistochemistry. RS cells from 6 primary cases were microdissected and analyzed for the expression of AID and CSR byproducts by RT-PCR. The expression of BAFF, APRIL, TACI, BCMA, BAFF-R, AID, and CSR byproducts was also analyzed in 5 HL cell lines cultured in the presence or absence of recombinant BAFF, APRIL and cytokines as previously described1,2,3. Results. We found that the reactive infiltrate of primary HL tumors comprises non-malignant elements, such as macrophages, granulocytes and plasma cells, expressing BAFF and APRIL. Also a variable proportion of malignant CD30+ Reed-Sternberg (RS) cells from both EBV+ and EBV− HL cases express BAFF and APRIL. Unlike NHL B cells, which usually express BAFF-R, primary RS cells and RS cell lines lack BAFF-R, but express TACI and BCMA. In the presence of BAFF or APRIL, RS cell lines are rescued from spontaneous or induced apoptosis. This effect is associated with activation of NF-κB through a classical pathway. Increased RS cell survival is also associated with up-regulation of the pro-survival BCL-2 and BCL-XL proteins, and down-regulation of the pro-apoptotic BAX protein. Finally, in the presence of BAFF or APRIL and IL-4, RS cell lines up-regulate AID expression and increase their spontaneous CSR activity. Of note, AID expression extends to primary RS cells and is associated with ongoing CSR. Conclusions. Our studies indicate that BAFF and APRIL stimulate malignant RS cells through both autocrine and paracrine pathways. Engagement of TACI and BCMA receptors by BAFF and APRIL may enhance the expansion of RS cells by attenuating apoptosis through a mechanism involving NF-κB and BCL family proteins. By up-regulating AID, signals emanating from TACI and BCMA receptors might also introduce genomic instability. Finally, considering that TACI, BCMA and AID are B cell-specific molecules and that CSR is a process confined to B cells, our findings consolidate the notion that RS cells derive from a B cell precursor.

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Hakim, Frances T., Najibah Rehman, John Dickinson, Sivasubramanian Baskar, Christoph M. Rader, Edward W. Cowen, Steven Z. Pavletic e Ronald E. Gress. "Elevated BAFF Is Correlated with Inflammatory Processes in Chronic Graft Versus Host Disease and Supports Increases in Transitional B Cells". Blood 112, n. 11 (16 novembre 2008): 465. http://dx.doi.org/10.1182/blood.v112.11.465.465.

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Abstract B Cell Activating Factor of the TNF Family (BAFF) plays a critical role in the survival, activation and function of B cells. Elevated levels of BAFF in plasma, however, have been reported in systemic autoimmune disorders and in chronic graft versus host disease (CGVHD). We similarly observed elevated plasma BAFF levels in 98 patients in an ongoing NCI CGVHD natural history protocol, with a median of 2653 pg/ml (range 92 to 14907), as compared to 556 pg/ml (range 75 to 1834) in 18 normal donors. Furthermore, in a subset of 40 patients in which severity of cutaneous CGVHD could be assessed by the presence of marked erythema or sclerosis, BAFF levels correlated with total percentage body surface area involvement (p<0.02). We then explored the factors that might contribute to elevated BAFF levels. In recipients recovering from either autologous or allogeneic transplant (without GVHD) we observed the highest BAFF levels at day 0 (median of 10534 and 12240 pg/ml respectively), when B cells were severely depleted. As B cell populations recovered to normal levels post transplant, plasma BAFF concentrations declined (Spearman r = −.80 and r = −.60, respectively), consistent with homeostatic cytokine-consumption dynamics. Despite comparably high levels of BAFF (median of 11342 pg/ml) at transplant day 0 in 16 patients who later developed CGHVD, BAFF levels in the cross-sectional, natural history patient population were only moderately correlated with the degree of post transplant B cell recovery (r = −.46). Since inflammatory triggers can induce elevated BAFF production, we assessed plasma levels of cytokines indicative of an inflammatory process. In 98 patients, the plasma levels of IP-10 and sTNFRII correlated positively with BAFF levels (r = +.579 and r = +.396, respectively), consistent with active inflammatory processes in those CGVHD patients with elevated BAFF levels. In a multi-step regression model, the levels of circulating B cells, plasma IP-10 and sTNFRII combined to strongly predict BAFF levels (R =.704). These findings suggest that both homeostatic recovery of B cell populations consuming BAFF and inflammatory cytokine cascades initiated by donor-anti-host reactivity combine to regulate BAFF levels post transplant. Although a broad range of autoimmune symptoms have been described in CGVHD, the mechanisms by which donor-anti-host reactivity can result in autoimmunity remains poorly understood. In murine models, elevated BAFF levels have been associated with increased survival of the transitional B cell population, altering the normal processes of B cell negative selection, and resulting in failure to eliminate auto-reactive B cells. We therefore assessed whether elevated BAFF levels were associated with increased frequencies of transitional CD21− T1 B cells in CGVHD patients. In 79 CGVHD patients, the median percentage of CD19+CD21− transitional B cells was 6.13% (range 1% to 39.4%) as compared to 2.24% (range 0.66% to 7.44%) in 40 healthy adult donors. Furthermore, the frequency of CD21− transitional B cells was significantly higher in those patients with higher BAFF levels (p<.002). Finally, the expression (mean fluorescent intensity (MFI)) of the BAFF receptor (BAFF-R) was reduced in patients with CGVHD compared with normal donors, consistent with down-regulation upon BAFF consumption; among CGVHD patients, receptor MFI was inversely correlated with BAFF levels (Spearman r = −.44). Elevated BAFF levels in CGVHD therefore may both reflect the inflammatory processes initiated by donor-anti-host reactivity and contribute to the later generation of pathologic autoantibodies by dysregulation of B cell negative selection.

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Jacque, Emilie, Edina Schweighoffer, Victor L. J. Tybulewicz e Steven C. Ley. "BAFF activation of the ERK5 MAP kinase pathway regulates B cell survival". Journal of Experimental Medicine 212, n. 6 (18 maggio 2015): 883–92. http://dx.doi.org/10.1084/jem.20142127.

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B cell activating factor (BAFF) stimulation of the BAFF receptor (BAFF-R) is essential for the homeostatic survival of mature B cells. Earlier in vitro experiments with inhibitors that block MEK 1 and 2 suggested that activation of ERK 1 and 2 MAP kinases is required for BAFF-R to promote B cell survival. However, these inhibitors are now known to also inhibit MEK5, which activates the related MAP kinase ERK5. In the present study, we demonstrated that BAFF-induced B cell survival was actually independent of ERK1/2 activation but required ERK5 activation. Consistent with this, we showed that conditional deletion of ERK5 in B cells led to a pronounced global reduction in mature B2 B cell numbers, which correlated with impaired survival of ERK5-deficient B cells after BAFF stimulation. ERK5 was required for optimal BAFF up-regulation of Mcl1 and Bcl2a1, which are prosurvival members of the Bcl-2 family. However, ERK5 deficiency did not alter BAFF activation of the PI3-kinase–Akt or NF-κB signaling pathways, which are also important for BAFF to promote mature B cell survival. Our study reveals a critical role for the MEK5-ERK5 MAP kinase signaling pathway in BAFF-induced mature B cell survival and homeostatic maintenance of B2 cell numbers.

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Chiu, April, Weifeng Xu, Bing He, Paul Santini, Stacey R. Dillon, Amy Chadburn, Daniel M. Knowles e Andrea Cerutti. "Splenic Sinusoids Stimulate the Survival and Proliferation of Hairy Cell Leukemia B Cells through BAFF, APRIL and Heparan-Sulphate Proteoglycans." Blood 108, n. 11 (16 novembre 2006): 4959. http://dx.doi.org/10.1182/blood.v108.11.4959.4959.

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Abstract Introduction. Hairy cell leukemia (HCL) is a rare chronic B cell lymphoproliferative disorder characterized by massive infiltration of the spleen by cells displaying a unique “hairy” morphology and surface phenotype. The ontogeny of hairy cells (HCs) and the mechanism underlying their accumulation in the spleen remain elusive. Growing evidence indicates that B cell-activating factor of the TNF family (BAFF) and a proliferation-inducing ligand (APRIL) play important roles in malignant B cells. BAFF and APRIL are usually produced by myeloid cells and engage three receptors on B cells known as transmembrane activator and calcium modulator and cyclophylin ligand interactor (TACI), B cell maturation antigen (BCMA), and BAFF receptor (BAFF-R). APRIL binding to TACI and BCMA is reinforced by cell-anchored and matrix-associated heparan-sulphate proteoglycans (HSPGs). In this study we verified the role of BAFF and APRIL in HCL. Methods. Splenic tissue sections and B cells from 5 healthy donors and 5 HCL patients were analyzed for expression of BAFF, APRIL, TACI, BCMA, BAFF-R and other molecules through immunohistochemistry, immunofluorescence, flow cytometry, immunoblotting and quantitative real-time RT-PCR. HCs were also cultured with umbilical vein or splenic endothelial cells in the presence or absence of BAFF and APRIL inhibitors, including soluble TACI-Ig decoy receptor, small interfering RNAs (siRNAs) and HSPG-modifying agents, such as heparinitase. HC proliferation, survival and signaling as induced by recombinant BAFF or APRIL were evaluated through standard assays. Results. We found that splenic sinusoids surrounding HCs were comprised of endothelial cells expressing APRIL and, to a lesser extent, BAFF. Endothelial cells up-regulated BAFF and APRIL upon exposure to HC-derived cytokines, including TNF-α. Unlike naïve, germinal center, memory and plasmacytoid B cells but similar to splenic marginal zone B cells, HCs expressed high levels of TACI, BCMA, BAFF-R and HSPGs together with CD1c, CD11c, CD27, CD83, CD123, endocytic receptors, and carbohydrate receptors. Preliminary data indicated that endothelial cells stimulated HCs through a mechanism involving BAFF, APRIL and HSPGs as pretreatment of endothelial cells with BAFF and APRIL small interfering RNAs or heparinitase attenuated the growth and survival of HCs in co-cultures. TACI-Ig, which binds to and neutralizes BAFF and APRIL, had a similar inhibitory effect. Conversely, BAFF, APRIL as well as TACI, BCMA or BAFF-R cross-linking stimulated HC growth. This stimulation was associated with NF-κB activation as well as up-regulation of various pro-survival and growth-inducing intracellular proteins. Conclusions. The present findings suggest that HCs may derive from a splenic marginal zone B cell precursor. In addition, our studies indicate that splenic sinusoids form a BAFF-APRIL-HSPG-rich niche that promotes HC expansion via TACI, BCMA and BAFF-R. Finally, our data suggest that blocking BAFF and APRIL through TACI-Ig, siRNAs and HSPG-modifying agents could have therapeutic value in HCL.

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Chen, Jing, Donghua He, Xing Guo, Li Yang, Yi Li, Qingxiao Chen, Jingsong He et al. "The Role BAFF and BAFF Receptors in Macrophage Induced Drug Resistance of Multiple Myeloma". Blood 124, n. 21 (6 dicembre 2014): 5701. http://dx.doi.org/10.1182/blood.v124.21.5701.5701.

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Abstract Background: B-cell–activating factor (BAFF) is a member of TNF family that critical for maintenance of B-cell development and homeostasis. BAFF also modulates the proliferation, survival and drug resistance of multiple meyloma (MM) cells. BAFF can be secreted by neutrophils, monocytes,dentritic cells and macrophages. Our previous study showed that, macrophages protect MM cells from drug-induced apoptosis by a cell-to-cell interaction between MM cells and macrophages. We supposed that the interaction of BAFF and BAFF receptors plays a role in macrophages induced MM resistance. Methods: First, we detected the expression levels of BAFF and its three receptors in MM cells were detected by semiquantitative real time-polymerase chain reaction (qPCR) and flow-cytometry. The concentration of BAFF in the culture supernatants of MM cell lines was detected by ELISA. Second, we collect peripheral blood monocytes form healthy donors. Monocytes were induced into macrophages by culturing with M-CSF for 7 days.BAFF expression level in macrophages was detected by qPCR, flow-cytometry and ELISA. Then MM cells were sole-cultured or coculture with macrophages for the indicated time (usually 24 h), after that bortezomib was added to the culture system. Cell viability and apoptosis of MM cells were verified by MTT and flow cytometry.At last,the recombinant human BAFF were added to MM cells, MTT and flow cytometry were used for detection of cell viability and apoptosis of MM cells. Results: Two receptors of BAFF, transmembrane activator and CAML interactor (TACI) and B-cell maturation antigen (BCMA), are highly expressed in various MM cell lines evidenced by real-time PCR and flow cytometry. The expression of BAFF in PBMC-induced macrophages are heterogeneous. We verify macrophage-mediated MM drug resistance by directly coculturing MM cells (ARP-1, 8226 and OPM2) with PBMC-derived macrophages from healthy donors. Functional studies show that recombinant human BAFF rescues RPMI8226 myeloma cells from dexamethasone-induced apoptosis. Conclusions: Our data showed that macrophage might induce drug resistance of MM cells by the interaction of BAFF and BAFF receptors. Further study will focused on the mechanism of interaction between BAFF and BAFF receptors. Disclosures No relevant conflicts of interest to declare.

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Enzler, Thomas, George F. Widhopf, Jason Lee, Weizhou Zhang, Carlo M. Croce, Michael Karin e Thomas J. Kipps. "BAFF Accelerates Development of Chronic Lymphocytic Leukemia in TCL1 Transgenic Mice." Blood 110, n. 11 (16 novembre 2007): 1117. http://dx.doi.org/10.1182/blood.v110.11.1117.1117.

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Abstract The B cell- activating factor of the tumor necrosis factor family (BAFF) is a potent regulator of normal B cells. We recently showed that BAFF supports chronic lymphocytic leukemia (CLL) B cell survival in vitro through activation of the canonical NF-kB pathway. To study the influence of BAFF on CLL development, we crossed BAFF transgenic (Tg) mice with mice that express human TCL1 under a B cell specific promoter/enhancer, and that are known to develop a lymphoproliferative disease resembling human B-CLL. BAFF/TCL1-Tg mice had a shorter mean survival than either TCL1-Tg or BAFF-Tg mice (12 mice each; BAFF/TCL1-Tg mice 9.6±3.4 months; TCL1-Tg 17.2±3.9; BAFF-Tg 17.9±3.6; B6 wildtype (wt) >19.2). To monitor for the development of CLL, mice were bled at 6-week intervals starting at 3 months of age, and blood mononuclear cells (PBMC) were analyzed via flow cytometry using fluorochrome-conjugated antibodies for murine CD5, CD3, CD45R, and human TCL1. Whereas all BAFF/TCL1-Tg mice began to develop a pathological CD5+CD3−CD45Rlo cell population at 3 months of age, such a population was not observed in TCL1-Tg mice before 6 months of age. BAFF-Tg or wt mice did not develop CD5+CD3−CD45Rlo cells over the entire observation period (26 months). CD5+CD3−CD45Rlo B cells expressed the TCL1 transgene. Over time, the CD5+CD3−CD45Rlo population increased in BAFF/TCL1-Tg mice, coming to represent >99% of the total PBMC of 9-month-old animals. To examine the capacity of these cells to propagate, 1x106 CD5+CD3−CD45Rlo B cells were transferred i.v. into either BAFF-Tg or wt mice that previously were irradiated with 600 rad. Ten days after transfer, CD5+TCL1+ cells were detected in BAFF-Tg, but not in wt recipients. Most CLL cells were located in the liver and spleen, as assessed by bioluminescent-based imaging of mice that received luciferase expressing CLL cells. Subsequent examination upon autopsy at 6 months of age, however, revealed that the majority of CLL cells populated the spleens of the recipient mice, which were massively enlarged. At this age, CLL cells also were found in wt recipient mice, although tumor burden was less than 20% of that of BAFF-Tg recipients (n=3 per group). We found that BAFF did not promote CLL cell proliferation in vitro or in vivo using assays to measure BrdU incorporation and flow cytometry to evaluate for enhanced intracellular expression of Ki67. However, BAFF induced CLL cells to express high levels of several anti-apoptotic proteins (e.g. Bcl-XL, Bcl-2, Bim, and A1/Bfl1). Also, while death-associated protein kinase 1 was repressed in CLL cells of TCL1-Tg mice, CLL cells of BAFF/TCL1-Tg mice expressed high-levels. Because of this, we examined whether treatment with BAFF-neutralizing BR3-Fc could influence the survival of CLL cells that were adoptively transferred into BAFF-Tg mice. We found that i.p. injection of 200 ug BR3-Fc into the recipient animals reduced the numbers of circulating CLL cells by nearly 20% (18.2%±5.3%; n=3) within 6 days. These data indicate that BAFF can accelerate the development of CLL cells in TCL1-Tg mice by promoting their survival. Because BAFF can similarly promote survival of human CLL cells, BAFF, and the signaling pathways it activates in neoplastic B cells, could be targeted for the development of novel therapies for this disease.

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Jia, Wei, Jonathan C. Poe, Hsuan Su, Glenn K. Matsushima, Jeffrey Rathmell, Kazuhiro Imai, Nancy J. Reyes et al. "Recipient-Derived BAFF and Alloantigen Synergistically Activate B Cells in Murine Chronic Gvhd". Blood 128, n. 22 (2 dicembre 2016): 498. http://dx.doi.org/10.1182/blood.v128.22.498.498.

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Abstract Increased B cell-activating factor (BAFF) and aberrant B cell survival and activation are associated with chronic graft versus host disease (cGVHD) in patients. Whether excessive BAFF production has a pathologic role in the development of cGVHD after allogeneic hematopoietic stem cell transplantation (allo-HCT) remains unknown. Herein, we address this hypothesis by employing BAFF knockout (KO) and BAFF overexpressing (Tg) donor mice in the major MHC mismatched C57BL/6 (B6)-to-BALB/c cGVHD model (Wu et al J Immunol 2013;191:488), except we increased the T cell depleted bone marrow (TCDBM) dose to 1x107 per recipient to improve engraftment. BALB/c recipients receiving TCDBM plus 1x106 splenocytes (Sp) are the disease group, and those receiving TCDBM only are controls. After verifying cGVHD phenotypic manifestations (including longevity, weight loss, eye and lung findings), we examined whether cGVHD mice had the increased BAFF and B cell findings as occur in human cGVHD (Sarantopoulos et al, Blood 2009; 113: 3865). We observed that cGVHD mice had higher BAFF/B cell ratios compared to controls (Fig. 1A, n=10 each). We fully characterized the peripheral B cell compartment in these mice, and found that the relative composition of B cell subsets was significantly altered in diseased mice. CD93 cell surface expression has been used in mice to define B cells that emigrate from BM and circulate through secondary lymphoid organs. In cGVHD mice, we found a significant increase in the relative proportion of CD93+ B cells and a significant decrease in the proportion of CD93- B cells (Fig1B). Also, a significant increase in the frequency of cells positive for the germinal center and activation marker GL7 was found only within CD93- B cell subset of cGVHD mice (Fig 1C). When stimulated via BCR ex vivo, this GL7+ mature B cell subset had significantly increased Syk and BLNK activation, measured by phosphoflow (n=5, p=0.008). We next aimed to determine whether high BAFF alone or high BAFF and alloantigen together lead to altered B cell homeostasis and to the promotion of GL7+ BCR-activated B cells. C57BL/6 (B6) BAFF Tg TCDBM cells were used as donor to afford excessive and persistent BAFF levels after HCT in either syngeneic or BALB/c recipients. After B6 BAFF Tg TCDBM to BALB/c HCT, body weight decreased significantly. By contrast, B6 BAFF Tg TCDBM to B6 syngeneic HCT recipients remained healthy (Fig.1D, left panel,*p=0.004). Notably, the frequency of the CD93-GL7+ B cell subset was increased in BALB/c mice that received B6 BAFF Tg TCDBM only, compared to recipients of syngeneic BAFF Tg or WT TCDBM only (Fig.1D, right panel, p=0.008). Thus, both BAFF and alloantigen are required for B cell activation after HCT. Together, our data also suggest that GL7+ B cells identify aberrantly BCR-activated B cells in murine cGVHD, arising in the setting of BAFF-driven altered B cell homeostasis. While polymorphisms in either donor or recipient BAFF genes are associated with human GVHD (Clark et al Blood 2011; 118: 1140), the source of excess BAFF after allo-HCT remains unknown. We addressed whether pathologic BAFF was derived from donor or recipient hematopoietic cells using TCDBM from B6 BAFF KO mice vs WT as donor cells for HCT to BALB/c recipients. Consistent with the known requirement of recipient BAFF for recovery of the B cell compartment after syngeneic transplant (Gorelik et al JEM 2003; 198:937), recovery of a donor peripheral B cell pool was not significantly different between groups. Remarkably, plasma BAFF levels were also not different between BALB/c recipients of B6 BAFF KO TCDBM +Sp vs recipients of WT TCDBM +Sp, suggesting that radioresistant recipient cells produced BAFF in cGVHD. Chronic GVHD-associated weight loss was also not different between groups (Fig.1E, representative of 3 separate experiments). We found that BAFF production in the engrafted KO recipient BM was uniformly low. Thus, we have now determined that non-BM, radioresistant recipient cells are the principal source of soluble pathologic BAFF in murine cGVHD. Further characterization of BAFF-producing cells is underway in order to identify therapeutic targets. In summary, we have now demonstrated that recipient-derived BAFF has a mechanistic role in aberrant activation of B cells in cGVHD. Our findings will lead to the development of anti-BAFF and BCR targeting agents for patients. This work was supported the National Institutes of Health (NHLBI R01 HL 129061-01). Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Gorelik, Leonid, Kevin Gilbride, Max Dobles, Susan L. Kalled, Daniel Zandman e Martin L. Scott. "Normal B Cell Homeostasis Requires B Cell Activation Factor Production by Radiation-resistant Cells". Journal of Experimental Medicine 198, n. 6 (15 settembre 2003): 937–45. http://dx.doi.org/10.1084/jem.20030789.

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The cellular source of B cell activation factor (BAFF) required for peripheral B cell survival/maturation is unknown. To determine the nature of BAFF-producing cells we established and analyzed reciprocal bone marrow (BM) chimeras with wild-type (WT) and BAFF-deficient mice. The results revealed that BAFF production by radiation-resistant stromal cells is completely sufficient to provide a necessary signal for B cell survival/maturation, as BAFF−/− BM cells transferred into lethally irradiated WT mice gave rise to normal numbers of follicular (FO) and marginal zone (MZ) B cell subpopulations. On the other hand, transfer of WT BM into BAFF−/− lethally irradiated mice resulted only in minimal reconstitution of mature FO B cells and no restoration of MZ B cells. Thus, in the absence of BAFF+/+ stromal cells, BAFF production by BM-derived cells, presumably by macrophages, dendritic cells, and/or neutrophils, was not at all sufficient to support normal B cell homeostasis. Interestingly, immunization of both types of chimeras stimulated high levels of antigen-specific antibody secretion, indicating that either stromal cell– or hematopoietic cell–derived BAFF is sufficient for B cell antibody responses.

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Sun, Chuan-Yin, Yan Shen, Xiao-Wei Chen, Yu-Cheng Yan, Feng-Xia Wu, Ming Dai, Ting Li e Cheng-De Yang. "The Characteristics and Significance of Locally Infiltrating B Cells in Lupus Nephritis and Their Association with Local BAFF Expression". International Journal of Rheumatology 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/954292.

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Introduction.Dysfunction of the B lymphocyte is considered to be involved in the pathogenesis of lupus nephritis (LN). Intrarenal B cells have been found in several forms of inflammatory kidney disease. B-cell activating factor (BAFF) regulates B lymphocyte proliferation and survival, and contributes to human autoimmune disease. Their role in renal inflammation is not well defined.Methods.Clinical parameters and renal biopsies from 62 LN patients were prospectively analyzed. We performed standard immunohistochemistry on serial paraffin tissue sections using monoclonal antibodies to CD20 and BAFF to investigate the characteristics and significance of locally infiltrating B cells and local BAFF expression in patients with LN.Results.Intrarenal B cells and/or BAFF were mainly distributed in the renal interstitium. Compared to the LN-non-B-cell/BAFF expression group, proteinuria (g/24 hour), blood urea nitrogen, serum creatinine levels, LN renal activity, and chronicity indices, were all significantly greater in the LN-B-cell/BAFF expression groups. The expression of BAFF was strongly associated with the quantity of B-cell infiltrate in the interstitium.Conclusion.As BAFF expression was strongly associated with B-cell infiltration, we hypothesize that altered B-cell differentiation and tolerance induced by excess BAFF may be central to the pathogenesis of LN.

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Kim, Seok Jin, Hwa Jung Sung, Chul Won Choi, In Sun Kim, Byung Soo Kim, Soo-Young Yoon, Jong-Ho Won e Jun Suk Kim. "Serum B-Cell Activating Factor (BAFF) in Diffuse Large B-Cell Lymphoma: Its Prognostic Significance in the Rituximab Era." Blood 110, n. 11 (16 novembre 2007): 1575. http://dx.doi.org/10.1182/blood.v110.11.1575.1575.

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Abstract The introduction of rituximab, a chimeric monoclonal antibody against the CD20 antigen has significantly improved the treatment outcome of diffuse large B-cell lymphoma (DLBCL). However, not all patients with DLBCL respond to rituximab plus CHOP (R-CHOP) chemotherapy. Thus, resistant clones of DLBCL remain a significant clinical problem. Although the underlying mechanisms of this resistance are still not clear, considering that the dysregulation of the balance between cell survival and programmed cell death is a central feature of lymphomagenesis, a factor promoting survival of lymphoma cells may be associated with resistance of DLBCL to rituximab. B-cell activating factor (BAFF), a member of the tumor necrosis factor (TNF) superfamily has shown to be a key mediator in the formation and regulation of normal B-cell response. BAFF is usually expressed by monocytes and macropahges, and is promoting cell survival and preventing apoptosis. Therefore, we performed this study to determine the clinical impact of serum BAFF on the treatment outcome of DLBCL treated with R-CHOP. 48 patients diagnosed as DLBCL were enrolled, and all the patients were treated with R-CHOP every 3 weeks. Before treatment and every two cycles of R-CHOP, their serum was taken and cryopreserved. The level of BAFF was measured by ELSA method (Human BAFF immunoassay, R&D systems, USA). We also analyzed the expression of BAFF receptor in tumor sections by immunohistochemistry (Polyclonal antibody to BAFF receptor, Abcam, UK). Median age of the patients was 56 years old (range 21–79). 20 patients were stage I/II, and 28 were stage III/IV. Rituximab was administered at the dosage of 375mg/m2 on day1, and CHOP chemotherapy was combined with rituximab until 6 – 8 cycles. The mean level of BAFF at the time of diagnosis was 2284.54pg/mL, and the median was 1326.60pg/mL (138.80–13537.92pg/mL). When the patients were dichotomized into high and low BAFF group based on the median value, 21 patients showed complete response in low BAFF group, however, only 3 patients showed complete response in high BAFF group (p=0.011). Among 16 patients showing relapse, 11 patients belonged to high BAFF group. The expression of BAFF receptor was also increased in relapsed patients compared to non-relapse group (p < 0.05). In the analysis of relapse-free survival, low BAFF group did not reach the median value as yet while high BAFF group showed 379 days (p=0.046). Thus, baseline serum BAFF may be associated with response of DLBCL to R-CHOP. When we serially checked the level of serum BAFF, the level of BAFF was increased during treatment (After the 2nd cycle 6448.56pg/mL, and after 4th cycle 7421.28pg/mL). In conclusion, serum B-cell activating factor may be a useful indicator predicting response to R-CHOP and prognosis in patients with DLBCL. Figure Figure

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Raje, Noopur, Shaji Kumar, Teru Hideshima, Kenji Ishitsuka, Hiroshi Yasui, Yu-Tzu Tai, Norihiko Shiraishi et al. "The Role of B Cell-Activating Factor (BAFF) in the Biology of Multiple Myeloma (MM)." Blood 106, n. 11 (16 novembre 2005): 3380. http://dx.doi.org/10.1182/blood.v106.11.3380.3380.

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Abstract BAFF is a member of the tumor necrosis factor (TNF) family and is critical for the maintenance and homeostasis of normal B-cell development. Importantly, BAFF promotes the generation of rapidly dividing immunoglobulin secreting plasmablasts from activated memory B cells by enhancing their survival. Given that MM is a cancer of plasma cells and that the signaling cascades implicated in receptor ligand interactions of BAFF are crucial in MM cell biology, we hypothesized that this cytokine may play a critical role in MM cell development, survival, and proliferation. We performed gene expression profiling (GEP) on CD 138+ plasma cells isolated from 90 MM patients (45 newly diagnosed and 45 relapsed) and 11 healthy controls using the Affymetrix U133A arrays. Our data demonstrates increased expression of transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B-cell maturation antigen (BCMA), 2 receptors used by BAFF to exert its effects. Our data also shows an increased expression of a proliferation-inducing ligand (APRIL), another member of the TNF family with homology to BAFF. Expression levels of BAFF and BAFF-R could not be determined because of lack of these probe sets on the Affymetrix U133A arrays. GEP analysis shows increased BCMA expression (p<0.0001, student T test) on newly diagnosed and relapsed MM versus normal plasma cells. Flow cytometry on MM cell lines demonstrated a differential expression of the three receptors of BAFF, with BCMA present on most cell lines but BAFF-R expressed at low levels only on LR5 cells and DOX40 MM cells. In contrast, flow cytometry performed on MM patient cells demonstrated the presence of all 3 receptors on CD 138+ cells. ELISA assays performed on 30 MM sera demonstrated a mean BAFF level of 618 pg/ml (range: 128–2126pg/ml) versus 235pg/ml (range: 158–326pg/ml) in 7 normal donor sera. Fifty six% (17/30) of MM patients had BAFF levels in excess of the highest value noted in normals. To understand the role BAFF might play in the biology of MM, we studied the effects of recombinant BAFF (rh-BAFF) on MM cells directly and in the context of its bone marrow microenvironment. (abstract # 554746) rh-BAFF conferred a survival advantage to MM cells and protected them against dexamethasone-induced cytotoxicity. Importantly, anti-apoptotic proteins Bcl2 and Mcl-1 were upregulated, as were growth and survival signals belonging to the JAK/STAT and MAPKinase pathways. Conversely, neutralizing antibody to BAFF blocked, at least in part, blocked the upregulation of anti-apoptotic proteins with associated growth and survival, confirming that these effects were due to BAFF. Importantly, all of these signals were downregulated even in the presence of bone marrow stromal cells (BMSCs). These data therefore show a role for BAFF mediating MM cell survival and provide the framework for inhibiting BAFF, either alone or in combination with dexamethasone, to improve patient outcome in MM.

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Nishio, Mitsufumi, Tomoyuki Endo, Nobuhiro Tsukada, Junko Ohata, Shinichi Kitada, John C. Reed, Nathan J. Zvaifler e Thomas J. Kipps. "Nurselike cells express BAFF and APRIL, which can promote survival of chronic lymphocytic leukemia cells via a paracrine pathway distinct from that of SDF-1α". Blood 106, n. 3 (1 agosto 2005): 1012–20. http://dx.doi.org/10.1182/blood-2004-03-0889.

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AbstractWe examined expression of B cell–activating factor of the tumor necrosis factor (TNF) family (BAFF) and a proliferation-inducing ligand (APRIL) on chronic lymphocytic leukemia (CLL) B cells and nurselike cells (NLCs), which differentiate from CD14+ cells when cultured with CLL B cells. NLCs expressed significantly higher levels of APRIL than monocytes and significantly higher levels of BAFF and APRIL than CLL B cells. Also, the viability of CLL B cells cultured with NLCs was significantly reduced when CLL B cells were cultured with decoy receptor of B-cell maturation antigen (BCMA), which can bind both BAFF and APRIL, but not with BAFF receptor:Fc (BAFF-R:Fc), which binds only to BAFF. The effect(s) of BAFF or APRIL on leukemia cell survival appeared additive and distinct from that of stromal cell–derived factor-1α (SDF-1α), which in contrast to BAFF or APRIL induced leukemia cell phosphorylation of p44/42 mitogen-activated protein kinase (extracellular signal-regulated kinase-1/2 [ERK1/2]) and AKT. Conversely, BAFF and APRIL, but not SDF-1α, induced CLL-cell activation of the nuclear factor–κB1 (NF-κB1) and enhanced CLL-cell expression of the antiapoptotic protein Mcl-1. However, BAFF, but not APRIL, also induced CLL-cell activation of NF-κB2. We conclude that BAFF and APRIL from NLCs can function in a paracrine manner to support leukemia cell survival via mechanisms that are distinct from those of SDF-1α, indicating that NLCs use multiple distinct pathways to support CLL-cell survival.

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Rahman, Ziaur SM, Sambasiva P. Rao, Susan L. Kalled e Tim Manser. "Normal Induction but Attenuated Progression of Germinal Center Responses in BAFF and BAFF-R Signaling–Deficient Mice". Journal of Experimental Medicine 198, n. 8 (13 ottobre 2003): 1157–69. http://dx.doi.org/10.1084/jem.20030495.

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The factors regulating germinal center (GC) B cell fate are poorly understood. Recent studies have defined a crucial role for the B cell–activating factor belonging to TNF family (BAFF; also called BLyS) in promoting primary B cell survival and development. A role for this cytokine in antigen-driven B cell responses has been suggested but current data in this regard are limited. A BAFF receptor expressed by B cells (BAFF-R/BR3) is defective in A/WySnJ mice which exhibit a phenotype similar to BAFF-deficient (BAFF−/−) animals. Here, we show that although GC responses can be efficiently induced in both A/WySnJ and BAFF−/− mice, these responses are not sustained. In BAFF−/− mice, this response is rapidly attenuated and accompanied by perturbed follicular dendritic cell development and immune complex trapping. In contrast, analysis of the A/WySnJ GC response revealed a B cell autonomous proliferative defect associated with reduced or undetectable Ki67 nuclear proliferation antigen expression by GC B cells at all stages of the response. These data demonstrate a multifaceted role for the BAFF pathway in regulating GC progression.

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Badr, Gamal, Gwenoline Borhis, Eric A. Lefevre, Nada Chaoul, Frederique Deshayes, Valérie Dessirier, Genevieve Lapree, Andreas Tsapis e Yolande Richard. "BAFF enhances chemotaxis of primary human B cells: a particular synergy between BAFF and CXCL13 on memory B cells". Blood 111, n. 5 (1 marzo 2008): 2744–54. http://dx.doi.org/10.1182/blood-2007-03-081232.

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B-cell–activating factor of the TNF family, (BAFF), and a proliferation-inducing ligand (APRIL) regulate B-lymphocyte survival and activation. We report that BAFF, but not APRIL, increased the chemotactic response of primary human B cells to CCL21, CXCL12, and CXCL13. The BAFF-induced increase in B-cell chemotaxis was totally abolished by blockade of BAFF-R and was strongly dependent on the activation of PI3K/AKT, NF-κB, and p38MAPK pathways. BAFF had similar effects on the chemotaxis of naive and memory B cells in response to CCL21 but increased more strongly that of memory B cells to CXCL13 than that of naive B cells. Our findings indicate a previously unreported role for the BAFF/BAFF-R pair in mature B-cell chemotaxis. The synergy between CXCL13 and BAFF produced by stromal cells and follicular dendritic cells may have important implications for B-cell homeostasis, the development of normal B-cell areas, and for the formation of germinal center–like follicles that may be observed in various autoimmune diseases.

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Chiu, April, Weifeng Xu, Bing He, Stacey R. Dillon, Jane A. Gross, Eric Sievers, Xugang Qiao et al. "Hodgkin lymphoma cells express TACI and BCMA receptors and generate survival and proliferation signals in response to BAFF and APRIL". Blood 109, n. 2 (7 settembre 2006): 729–39. http://dx.doi.org/10.1182/blood-2006-04-015958.

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Abstract Hodgkin lymphoma (HL) originates from the clonal expansion of malignant Hodgkin and Reed-Sternberg (HRS) cells. These B-cell–derived elements constitute less than 10% of the tumoral mass. The remaining tissue is comprised of an inflammatory infiltrate that includes myeloid cells. Myeloid cells activate B cells by producing BAFF and APRIL, which engage TACI, BCMA, and BAFF-R receptors on the B cells. Here, we studied the role of BAFF and APRIL in HL. Inflammatory and HRS cells from HL tumors expressed BAFF and APRIL. Unlike their putative germinal center B-cell precursors, HRS cells lacked BAFF-R, but expressed TACI and BCMA, a phenotype similar to that of plasmacytoid B cells. BAFF and APRIL enhanced HRS cell survival and proliferation by delivering nonredundant signals via TACI and BCMA receptors through both autocrine and paracrine pathways. These signals caused NF-κB activation; Bcl-2, Bcl-xL, and c-Myc up-regulation; and Bax down-regulation, and were amplified by APRIL-binding proteoglycans on HRS cells. Interruption of BAFF and APRIL signaling by TACI-Ig decoy receptor, which binds to and neutralizes BAFF and APRIL, or by small-interfering RNAs targeting BAFF, APRIL, TACI, and BCMA inhibited HRS cell accumulation in vitro and might attenuate HL expansion in vivo.

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Zhu, Xiao-juan, Yan Shi, Jun Peng, Cheng-shan Guo, Ning-ning Shan, Ping Qin, Xue-bin Ji e Ming Hou. "The effects of BAFF and BAFF-R-Fc fusion protein in immune thrombocytopenia". Blood 114, n. 26 (17 dicembre 2009): 5362–67. http://dx.doi.org/10.1182/blood-2009-05-217513.

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Abstract Elevated level of B-cell activating factor (BAFF) has been implicated in the pathogenesis of some autoimmune diseases. Blockade of receptor and ligand binding by decoy receptor has demonstrated a clinical benefit in both oncologic and immunologic diseases. In this report, we have detected plasma BAFF and BAFF mRNA expression in immune thrombocytopenia (ITP) patients by enzyme-linked immunosorbent assay (ELISA) and real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR). The effects of recombinant human BAFF (rhBAFF) and BAFF-R-Fc fusion protein (BR3-Fc) on B cells, T cells, platelets, secretion of interferon γ (IFNγ), and interleukin-4 (IL-4) were measured by flow cytometry and ELISA. Patients with active disease had higher levels of plasma BAFF and BAFF mRNA than patients in remission and controls. In in vitro assays, rhBAFF promoted the survival of CD19+ and CD8+ cells, and increased the apoptosis of platelets and the secretion of IFN-γ. BR3-Fc successfully corrected the effects of rhBAFF on lymphocytes, platelets, and cytokines. These findings suggest that BAFF may play a pathogenic role in ITP by promoting the survival of CD19+ and CD8+ cells, and increasing the apoptosis of platelets and the secretion of IFN-γ. Blockade of BAFF by BR3-Fc might be a promising therapeutic approach for ITP.

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Kim, Bobae, e Chang-Kee Hyun. "B-Cell-Activating Factor Depletion Ameliorates Aging-Dependent Insulin Resistance via Enhancement of Thermogenesis in Adipose Tissues". International Journal of Molecular Sciences 21, n. 14 (20 luglio 2020): 5121. http://dx.doi.org/10.3390/ijms21145121.

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Impaired glucose tolerance is a common feature associated with human aging, which is caused by defects in insulin secretion, insulin action or both. Recent studies have suggested that B-cell-activating factor (BAFF), a cytokine that modulates proliferation and differentiation of B cells, and its receptors are expressed in mature adipocytes and preadipocytes, proposing BAFF as a potential regulator of energy metabolism. In this study, we show that systemic BAFF depletion improves aging-dependent insulin resistance. In aged (10-month-old) BAFF−/− mice, glucose tolerance and insulin sensitivity were significantly improved despite higher adiposity as a result of expansion of adipose tissues compared to wild-type controls. BAFF−/− mice displayed an improved response to acute cold challenge, commensurate with the up-regulated expression of thermogenic genes in both brown and subcutaneous adipose tissues. These changes were found to be mediated by both increased M2-like (alternative) macrophage activation and enhanced leptin and FGF21 production, which may account for the improving effect of BAFF depletion on insulin resistance. In addition, leptin-deficient mice (ob/ob) showed augmented BAFF signaling concomitant with impaired thermogenic activity, identifying BAFF as a suppressive factor to thermogenesis. Our findings suggest that suppression of BAFF could be a therapeutic approach to attenuate aging-dependent insulin resistance.

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Enzler, Thomas, Weizhou Zhang, Arnon P. Kater, George F. Widhopf, Carlo M. Croce, Michael Karin e Thomas J. Kipps. "Constitutive Baff Signalling Plays a Key Role in CLL Development by Promoting Tumor Cell Survival". Blood 112, n. 11 (16 novembre 2008): 28. http://dx.doi.org/10.1182/blood.v112.11.28.28.

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Abstract The B cell-activating factor of the tumor necrosis factor family (BAFF) is a potent B-cell survival factor. We recently found that nurselike cells, which presumably reside in the leukemia-microenvironment, express BAFF, which promotes survival of leukemia cells of patients with chronic lymphocytic leukemia (CLL) cells through activation of the classical NF-kB pathway. To study the influence of BAFF on leukemogenesis, we crossed BAFF transgenic (Tg) mice with either Eμ-TCL-Tg mice, which develop a lymphoproliferative disease resembling human CLL at about 12 months of age, or Ea-MYC-Tg mice, which experience higher rates of apoptosis in their mature B cells, but do not develop overt lymphoproliferative disease per se. We found that BAFF/TCL1-Tg mice had a shorter mean survival than either TCL1-Tg or BAFF-Tg mice due to the early development of a CD5+CD3−CD45Rlo leukemia B-cell population resembling human CLL at the age of about 3–4 months as compared to 7–9 months in TCL1-Tg mice. In contrast none of the BAFF-Tg or wt mice developed lymphoproliferative disease over the 26-month period of observation. The CD5+CD3−CD45Rlo cell population increased in BAFF/TCL1-Tg mice relatively rapidly, coming to represent >99% of the total blood mononuclear cells of 9-month-old double Tg animals. At this age, these mice also developed massive splenomegaly and their spleens were heavily infiltrated with leukemia B cells. Southern blot analyses of splenocytes harvested at various ages detected oligoclonal/monoclonal splenic B cell populations at approximately 4 months of age in the BAFF/TCL1-Tg mice compared to 9–12 months in the TCL1-Tg mice. Similarly, Ea-MYC-Tg mice, generated by inserting a single copy of MYC into the mouse Ig heavy-chain Ca locus, were crossed with the BAFF-Tg mice in order to obtain BAFF/MYC-Tg mice. In contrast to Ea-MYC-Tg mice, the BAFF/MYC-Tg mice developed expansions of CD5+CD3−CD45Rlo CLL-like leukemia B cells in the blood and spleen starting at 4 months of age, resulting in splenomegaly. These cells could be adoptively transferred into syngeneic BAFF-Tg mice, allowing for continued proliferation of such CD5+CD3−CD45Rlo leukemia B-cells and development lymphoproliferative disease. Staining of splenic sections for proliferating-cell nuclear antigen (PCNA) demonstrated similar high-rates of cell-proliferation in Ea-MYC-Tg mice and BAFF/MYC-Tg mice, which were twice greater than those of BAFF-Tg mice or wt mice. In contrast, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) of splenic sections revealed that Ea-MYC-Tg mice had 4 times greater proportions of apoptotic splenocytes than did BAFF/MYC-Tg mice, suggesting that BAFF promoted B cell expansion by inhibiting B cell turnover. Consistent with this, we found that BAFF induced in TCL1-Tg, as well as MYC-Tg mice, high-level B cell expression of anti-apoptotic proteins such as Bcl-XL, Bcl-2, A1/Bfl1, and Pim-2 in leukemia B cells. Also, these leukemia B cells transferred more efficiently into syngeneic BAFF-Tg mice than in mice lacking expression of BAFF. We treated BAFF-Tg mice with intraperitoneal (i.p.) injections of BAFF-neutralizing BR3-Fc or control protein prior to adoptive transfer of leukemia cells of Eμ-TCL1-Tg mice. We found that i.p. injection of 200 mg BR3-Fc into the recipient animals reduced the numbers of circulating CLL cells relative to that found in control-treated mice by nearly 20% (18.2%±5.3%; n=3) within 6 days. These findings indicate that BAFF accelerates development of leukemia in Eμ-TCL1-Tg and Ea-MYC-Tg mice primarily by enhancing leukemia B-cell survival, but not leukemia-cell proliferation, resulting in accelerated rates of tumor development and apparent enhancement of leukemia B cell proliferation in vivo. These findings suggest that targeting BAFF or BAFF-expressing cells within the leukemia microenvironment might be an effective strategy for treatment of CLL and related B-cell malignancies.

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Bienertova-Vasku, Julie, Petr Bienert, Filip Zlamal, Josef Tomandl, Martin Forejt, Marie Tomandlova, Martin Vavrina, Jana Kudelková, Zbynek Splichal e Anna Vasku. "B-cell activating factor (BAFF) — a new factor linking immunity to diet?" Open Medicine 7, n. 3 (1 giugno 2012): 275–83. http://dx.doi.org/10.2478/s11536-011-0153-7.

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AbstractB cell activation factor (BAFF) is a recently discovered member of the TNF ligand superfamily secreted by adipocytes, previously linked to autoimmune and lymphoproliferative disease. The aim of this study was to investigate the relationship between BAFF plasma levels and the non-modified, usual dietary composition as well as obesity-related anthropometric parameters in a cohort of 58 obese and non-obese Central-European Caucasian individuals. We found that BAFF had an independent predictive role for percentage of body fat; moreover, BAFF levels were correlated with waist and hip circumference. BAFF plasma levels were also significantly correlated with investigated dietary composition based on the 7-day food records, as the BAFF levels correlated with the percentage of energy derived from the carbohydrates and with energy derived from the dietary fat. Our results suggest that BAFF may play a role in linking the immune status and metabolic response to diet.

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Schneider, Pascal, Fabienne MacKay, Véronique Steiner, Kay Hofmann, Jean-Luc Bodmer, Nils Holler, Christine Ambrose et al. "BAFF, a Novel Ligand of the Tumor Necrosis Factor Family, Stimulates B Cell Growth". Journal of Experimental Medicine 189, n. 11 (7 giugno 1999): 1747–56. http://dx.doi.org/10.1084/jem.189.11.1747.

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Members of the tumor necrosis factor (TNF) family induce pleiotropic biological responses, including cell growth, differentiation, and even death. Here we describe a novel member of the TNF family, designated BAFF (for B cell activating factor belonging to the TNF family), which is expressed by T cells and dendritic cells. Human BAFF was mapped to chromosome 13q32-34. Membrane-bound BAFF was processed and secreted through the action of a protease whose specificity matches that of the furin family of proprotein convertases. The expression of BAFF receptor appeared to be restricted to B cells. Both membrane-bound and soluble BAFF induced proliferation of anti-immunoglobulin M–stimulated peripheral blood B lymphocytes. Moreover, increased amounts of immunoglobulins were found in supernatants of germinal center–like B cells costimulated with BAFF. These results suggest that BAFF plays an important role as costimulator of B cell proliferation and function.

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