In vitro and in vivo activation induces BAFF and APRIL expression in B cells. J Immunol

Deutsches Rheuma ForschungsZentrum, Berlin, Germany.
The Journal of Immunology (Impact Factor: 4.92). 12/2007; 179(9):5947-57. DOI: 10.4049/jimmunol.179.9.5947
Source: PubMed


B cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) play key roles in peripheral B cell survival, maturation, and differentiation. BAFF and APRIL are produced by a variety of cell types such as macrophages/monocytes and dendritic cells. Our analysis shows that BAFF mRNA is also expressed in all B cell subsets isolated from bone marrow, spleen, and peritoneal cavity of BALB/c mice. APRIL expression is restricted to early stages of B cell development in the bone marrow and the peritoneal B1 subset. Stimulation of B2 and B1 cells with LPS or CpG-oligodeoxynucleotides induced MyD88-dependent plasma cell differentiation and intracellular expression of BAFF and APRIL. Furthermore, activation of B cells up-regulated membrane expression of BAFF. The finding that in vitro activation of B cells is inhibited by the antagonist transmembrane activator and calcium modulator ligand interactor Ig, indicates that BAFF and/or APRIL are released into the culture supernatants. It shows that B cell survival, proliferation, and differentiation are supported by an autocrine pathway. In vivo activation of B cells with a T-dependent Ag- induced BAFF expression in germinal center B cells. In (NZB x NZW)F(1) mice with established autoimmune disease, marginal zone, germinal center B cells, as well as splenic plasma cells expressed high levels of BAFF. In (NZB x NZW)F(1) mice, the continuous activation of B cells and thus overexpression of BAFF and APRIL may contribute to the development of autoimmune disease.

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Available from: Van Trung Chu, Apr 08, 2014
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    • "Here we hypothesized that BAFF and/or the proliferationinducing ligand (APRIL, TNFSF13) could be involved in the physiopathology of pulmonary fibrosis. BAFF and APRIL are produced by innate immune cells [22] such as neutrophils [23], macrophages, monocytes, dendritic cells (DCs) or follicular DCs [24], but also T cells [25], B cells [26] or non-hematopoietic cells such as fibroblastlike synoviocytes from patients with rheumatoid arthritis [27] or salivary gland and conjunctival epithelial cells from patients with Sj€ ogren's syndrome [28] [29]. Receptors for BAFF and APRIL are mainly expressed by B cells but also by T cells, monocytes or DCs, indicating that the role of BAFF and APRIL extends beyond that of B cell biology [22]. "
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    ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a progressive devastating, yet untreatable fibrotic disease of unknown origin. We investigated the contribution of the B-cell activating factor (BAFF), a TNF family member recently implicated in the regulation of pathogenic IL-17-producing cells in autoimmune diseases. The contribution of BAFF was assessed in a murine model of lung fibrosis induced by airway administered bleomycin. We show that murine BAFF levels were strongly increased in the bronchoalveolar space and lungs after bleomycin exposure. We identified Gr1+ neutrophils as an important source of BAFF upon BLM-induced lung inflammation and fibrosis. Genetic ablation of BAFF or BAFF neutralization by a soluble receptor significantly attenuated pulmonary fibrosis and IL-1β levels. We further demonstrate that bleomycin-induced BAFF expression and lung fibrosis were IL-1β and IL-17A dependent. BAFF was required for rIL-17A-induced lung fibrosis and augmented IL-17A production by CD3+ T cells from murine fibrotic lungs ex vivo. Finally we report elevated levels of BAFF in bronchoalveolar lavages from IPF patients. Our data therefore support a role for BAFF in the establishment of pulmonary fibrosis and a crosstalk between IL-1β, BAFF and IL-17A.
    Journal of Autoimmunity 10/2014; 56. DOI:10.1016/j.jaut.2014.08.003 · 8.41 Impact Factor
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    • "Interestingly, we were unable to see binding to resting monocytes in culture or in whole blood from healthy volunteers. Despite a few reports that B-cells express BAFF,32,33 we were not able to observe tabalumab binding to B-cells in whole blood from healthy donors, even at concentrations up to 100 μg/mL (unpublished observation). This is consistent with our data that B-cells do not express BAFF mRNA, even following activation, and that once BAFF is docked into a receptor on a B-cell, tabalumab is unable to recognize BAFF. "
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    ABSTRACT: B-cell activating factor (BAFF) is a B-cell survival factor with a key role in B-cell homeostasis and tolerance. Dysregulated BAFF expression may contribute to autoimmune diseases or B-cell malignancies via effects on abnormal B-lymphocyte activation, proliferation, survival, and immunoglobulin secretion. Monoclonal antibodies were generated against human BAFF, characterized for species specificity and affinity, and screened for the ability to neutralize both membrane-bound and soluble BAFF. In addition, studies were undertaken to determine the relative potency of membrane-bound and soluble BAFF. Tabalumab has a high affinity for human, cynomolgus monkey, and rabbit BAFF. No binding to mouse BAFF was detected. Tabalumab was able to neutralize soluble human, cynomolgus monkey, or rabbit BAFF with equal potency. Our data demonstrate that membrane-bound BAFF can be a more potent stimulus for B-cells than soluble BAFF, and tabalumab also neutralized membrane-bound BAFF. Tabalumab prevented BAFF from binding to BAFF receptors and demonstrated pharmacodynamic effects in human BAFF transgenic mice. Tabalumab is a high-affinity human antibody with neutralizing activity against membrane-bound and soluble BAFF. Given our findings that membrane-bound BAFF can have greater in vitro potency than soluble BAFF, neutralization of both forms of BAFF is likely to be important for optimal therapeutic effect.
    Journal of Inflammation Research 08/2014; 7(1):121-31. DOI:10.2147/JIR.S67751
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    • "BAFF is known to be expressed by monocytes, dendritic cells, T lymphocytes, B lymphocytes, and epithelial cells [6]–[8], [24], [25]; however, its precise expression profile in patients with PDAC has not been previously defined. Recently, Nakajima et al. showed through immunohistochemistry that BAFF-expressing B lymphocytes infiltrate synovial tissues of rheumatoid arthritis [26]. "
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    ABSTRACT: B cell-activating factor (BAFF) is a cytokine belonging to the tumor necrosis factor (TNF) superfamily. It has been reported that BAFF is elevated in patients with autoimmune pancreatitis and contributes to the malignant potential of blood cancers and solid tumors. In this study, clinical evidence of increased BAFF levels in patients with pancreatic ductal adenocarcinoma (PDAC) was obtained, and the roles and mechanisms of BAFF in PDAC were clarified in human tissues of PDAC and from in vitro data of PDAC cell lines. Serum levels of BAFF in patients with PDAC were significantly higher than in healthy subjects (p = 0.0121). Patients with UICC stage IV PDAC (T1-4, N0-1, M1) had significantly higher levels of serum BAFF compared to patients with PDAC (p = 0.0182). BAFF was remarkably expressed in infiltrating B lymphocytes surrounding pancreatic cancer in human pancreatic tissues, suggesting that BAFF may play a role in progression of pancreatic cancer. PDAC cell lines were cultured with human recombinant BAFF, and morphology and gene expression were analyzed; pancreatic cancer cells changed to a fibroblast-like morphology, and showed altered gene expression of E-cadherin, vimentin and Snail. These BAFF-induced changes reflect enhanced cell motility and invasion. BAFF-R-overexpressing cell clones confirmed the association between these BAFF-induced changes and epithelial-mesenchymal transition (EMT)-related genes. BAFF was elevated in patients with metastatic advanced PDAC and induced alterations in PDAC cells via regulation of EMT-related genes. Elucidation of the precise role and mechanism of control of BAFF may lead to new therapeutic approaches with the aim of improving pancreatic cancer survival.
    PLoS ONE 08/2013; 8(8):e71367. DOI:10.1371/journal.pone.0071367 · 3.23 Impact Factor
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