Characterization of a New Member of the TNF Family Expressed on Antigen Presenting Cells

Chiron Corporation, Emeryville, CA 94608-2916, USA.
Biological Chemistry (Impact Factor: 3.27). 01/2000; 380(12):1443-7. DOI: 10.1515/BC.1999.186
Source: PubMed

ABSTRACT The TNF family is involved in the regulation of the immune system, and its members have been implicated in a variety of biological events such as apoptosis, cell proliferation, differentiation and survival. Here we present a new member of the TNF family, tumor necrosis factor superfamily member 20 (TNFSF20) that we have identified from the expressed sequence tag (EST) database and characterized. The human protein is a 285 amino acid long type II transmembrane protein and is 19% homologous to TNF in its extra-cellular domain. TNFSF20 is expressed at the surface of antigen presenting cells such as cells of the macrophagemonocyte lineage and dendritic cells. After treatment with bacterial lipopolysaccharide (LPS), TNFSF20 expression is downregulated at the surface of the expresssing cells, suggesting that the membrane-bound protein gets cleaved, and that a soluble factor is released in the extra-cellular compartment. The soluble form of the recombinant TNFSF20 induces proliferation of resting peripheral blood monocytes (PBMC) and cell death of activated lymphocytes. TNFSF20 might therefore play a critical role in the regulation of cell-mediated immune responses.

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    • "B-cell-activating factor of the TNF family (BAFF) (tumor necrosis factor ligand superfamily, member 13b) is a cytokine which is primarily produced by monocytes and dendritic cells [2-4] in addition to T cells [5,6]. It plays a crucial role in the proliferation, differentiation and survival of B cells [2,4,5,7]. BAFF is a type II membrane-bound protein of 285 amino acid residues. A C-terminal fragment of 152 amino acid residues is released from cells as soluble BAFF (sBAFF) [5]. "
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    ABSTRACT: In this study, we investigated possible aberrations of monocytes from patients with primary Sjögren's syndrome (pSS). We focused on B-cell-activating factor of the TNF family (BAFF) and IL-6 because they are both produced by monocytes and are known to be involved in the pathogenesis of pSS. Peripheral monocytes were prepared from both pSS patients and normal individuals. The cells were stimulated in vitro with IFN-γ, and the amounts of IL-6 and soluble BAFF (sBAFF) produced by the cells were quantitated. The effect of sBAFF itself on the production of IL-6 was also studied. To investigate the response of pSS monocytes to these stimuli, the expression levels of the genes encoding BAFF receptors and IL-6-regulating transcription factors were quantitated. Peripheral pSS monocytes produced significantly higher amounts of sBAFF and IL-6 than normal monocytes did, even in the absence of stimulation. The production of these cytokines was significantly increased upon stimulation with IFN-γ. The elevated production of IL-6 was significantly suppressed by an anti-BAFF antibody. In addition, stimulation of pSS monocytes with sBAFF induced a significant increase in IL-6 production. Moreover, the expression levels of a BAFF receptor and transcription factors regulating IL-6 were significantly elevated in pSS monocytes compared to normal monocytes. The results of the present study suggest that the mechanisms underlying the production of sBAFF and IL-6 are impaired in pSS monocytes. Our research implies that this impairment is due to abnormally overexpressed IL-6-regulating transcription factors and a BAFF receptor. These abnormalities may cause the development of pSS.
    Arthritis research & therapy 10/2011; 13(5):R170. DOI:10.1186/ar3493 · 3.75 Impact Factor
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    • "B lymphocyte stimulator (BLyS, also designated TALL-1, THANK, BAFF, TNFSF13b, and TNFSF20) is a member of the tumor necrosis factor superfamily of ligands [1,2]. BLyS is expressed by activated T cells, activated macrophages, and dendritic cells [1,3,4] and has been implicated in autoimmune disorders characterized by the presence of pathological concentrations of self-antigen-reactive antibodies, such as systemic lupus erythematosus (SLE) [5] and rheumatoid arthritis (RA) [6]. Biological activity of BLyS is mediated via three receptors present on B and T cells designated transmembrane activator and calcium-modulator and cyclophilin ligand [CAML] interactor (TACI), B-Cell Maturation Antigen (BCMA) and BAFF Receptor (BR3 or BAFF-R) [7]. "
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    ABSTRACT: B lymphocyte stimulator (BLyS) is a member of the tumor necrosis factor superfamily of ligands that mediates its action through three known receptors. BLyS has been shown to enhance the production of antibodies against heterologous antigens when present at elevated concentrations, supporting an immunostimulatory role for BLyS in vivo. We constructed a fusion protein consisting of human BLyS and Pneumococcal Surface Adhesin A (PsaA) and used this molecule to immunize mice. The immunostimulatory attributes mediated by BLyS in vivo were evaluated by characterizing immune responses directed against PsaA. The PsaA-BLyS fusion protein was able to act as a co-stimulant for murine spleen cell proliferation induced with F(ab')₂ fragments of anti-IgM in vitro in a fashion similar to recombinant BLyS, and immunization of mice with the PsaA-BLyS fusion protein resulted in dramatically elevated serum antibodies specific for PsaA. Mice immunized with PsaA admixed with recombinant BLyS exhibited only modest elevations in PsaA-specific responses following two immunizations, while mice immunized twice with PsaA alone exhibited undetectable PsaA-specific serum antibody responses. Sera obtained from PsaA-BLyS immunized mice exhibited high titers of IgG1, IgG2a, IgG2b, and IgG3, but no IgA, while mice immunized with PsaA admixed with BLyS exhibited only elevated titers of IgG1 following two immunizations. Splenocytes from PsaA-BLyS immunized mice exhibited elevated levels of secretion of IL-2, IL-4 and IL-5, and a very modest but consistent elevation of IFN-γ following in vitro stimulation with PsaA. In contrast, mice immunized with either PsaA admixed with BLyS or PsaA alone exhibited modestly elevated to absent PsaA-specific recall responses for the same cytokines. Mice deficient for one of the three receptors for BLyS designated Transmembrane activator, calcium modulator, and cyclophilin ligand [CAML] interactor (TACI) exhibited attenuated PsaA-specific serum antibody responses following immunization with PsaA-BLyS relative to wild-type littermates. TACI-deficient mice also exhibited decreased responsiveness to a standard pneumococcal conjugate vaccine. This study identifies covalent attachment of BLyS as a highly effective adjuvant strategy that may yield improved vaccines. In addition, this is the first report demonstrating an unexpected role for TACI in the elicitation of antibodies by the PsaA-BLyS fusion protein. This article was reviewed by Jonathan Yewdell, Rachel Gerstein, and Michael Cancro (nominated by Andy Caton).
    Biology Direct 02/2011; 6(1):9. DOI:10.1186/1745-6150-6-9 · 4.66 Impact Factor
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    • "B-cell-activating factor of the TNF family (BAFF, also known as BLyS, TALL-1, THANK, TNFSF13B and zTNF4) is a newly discovered member of the TNF superfamily expressed by monocytes, dendritic cells and T cells (Moore et al., 1999; Schneider et al., 1999; Shu et al., 1999; Mukhopadhyay et al., 1999; Tribouley et al., 1999). BAFF occurs as both a membrane-bound ligand and a biologically active soluble protein (Schneider et al., 1999; Moore et al., 1999); it is essential for B-cell survival and development (Batten et al., 2000; Do et al., 2000; Thompson et al., 2000). "
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    ABSTRACT: The role of B cells and antibodies in the pathogenesis of multiple sclerosis (MS) is controversial. We investigated the expression of B-cell-activating factor of the tumor necrosis factor family (BAFF), a protein indispensable for B-cell survival, and of its three receptors in MS patients and controls. BAFF mRNA levels in monocytes, and BAFF-receptor mRNA in B and T cells, were higher in patients than in healthy controls; yet, BAFF protein levels in cerebrospinal fluid and plasma were similar in patients and headache controls. In addition, each MS disease course was associated with a unique expression pattern for all four molecules.
    Journal of Neuroimmunology 08/2004; 152(1-2):183-90. DOI:10.1016/j.jneuroim.2004.03.017 · 2.47 Impact Factor
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