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IMMUNOBIOLOGY
From Human Genome Sciences, Inc, Rockville, MD.
B-lymphocyte stimulator (BLyS) is a recently identified novel
member of the tumor necrosis factor ligand superfamily shown to exist
in a membrane-bound and soluble form. BLyS was found to be specifically
expressed on cells of myeloid lineage and to selectively stimulate
B-lymphocyte proliferation and immunoglobulin production. The
expression of a cytokine involved in potentiation of humoral immune
responses, such as BLyS, is expected to be strictly controlled. The
goal of the present study was to examine regulation of BLyS levels in
monocytic cells in response to cytokines and during their
differentiation to macrophages and dendritic cells. The
presence of BLyS on the cell surface and in the culture medium of both
normal blood monocytes and on tumor cells of myelomonocytic origin was
demonstrated. BLyS gene expression and levels of
membrane-associated and soluble BLyS were found to be regulated by
cytokines, in particular interferon (IFN)- The tumor necrosis factor (TNF) family of ligands
encompasses an ever-growing group of proteins, characterized by
homologous cysteine-rich domains, that participates in the regulation
of diverse immune and inflammatory responses.1-4 All the
members, with the exception of lymphotoxin- Recently, we described a novel member of the TNF family of ligands,
B-lymphocyte stimulator (BLyS), which was identified by searching an
expressed sequence tag (EST) database for homology with known TNF-like
molecules.11 The protein has been reported also as TALL-1
(TNF- and ApoL-related leukocyte-expressed ligand 1), BAFF (B-cell
activator factor belonging to the TNF family), or THANK (TNF homologue
that activates apoptosis, NF- Medium and reagents
Cell cultures
Antibodies Polyclonal antibodies (pAbs) were affinity-purified from antisera generated by immunizing rabbits with rhBLyS. We generated mAbs by the fusion of mouse myeloma cells P3 × 63Ag8.653 with splenocytes from BALB/C mice immunized with either histidine-tagged BLyS (mAbs 9B6 and 2E5) or soluble BLyS (mAb 15C10).BLyS ELISA BLyS-specific ELISA was established using 15C10 as capture mAb and rabbit affinity-purified pAb as detector. Culture supernatants were incubated overnight on 15C10-coated microplates at 4°C. Biotinylated pAb (200 ng/mL) and peroxidase streptavidin (Kirkergaard and Perry, Gaithersburg, MD) were added in sequential steps. Conversion of the substrate TMB (Kirkergaard and Perry) was measured at 450 nm. Each value was calculated as the mean ± SD of triplicate samples.Flow cytometry Cells were incubated with 2 µg/106 cells of mouse IgG1 or anti-BLyS mAb for 20 minutes on ice, washed, and then incubated with goat antimouse F(ab')2 for a further 20 minutes on ice. Alternatively, cells were incubated with biotinylated 9B6 and stained with PE-conjugated streptavidin. Cells were washed, resuspended in propidium iodide solution, and analyzed using a flow cytometer and associated Cell Quest software (both from Becton Dickinson, San Jose, CA).Quantitative polymerase chain reaction BLyS messenger RNA (mRNA) levels were assessed in monocytes, macrophages, and dendritic cells using a 7700 Taqman Sequence Detector (Applied Biosystems, Foster City, CA); amplification primers 5'-ACCGCGGGACTGAAAATCT-3' and 5'-CACGCTTATTTCTGCTGTTCTGA-3'; and a probe, 5'-CCACCAGCTCCAGGAGAAGGCAACTC-3', that was designed to span the region from nucleotides 458-533 of the human BLyS sequence (GenBank accession No. AF132600). Total RNA was prepared from cells, and BLyS mRNA was detected by a one-step reverse transcriptase-polymerase chain reaction (RT-PCR) procedure. BLyS mRNA quantitation was conducted with the comparative Delta cycle threshold method using an 18S ribosomal RNA probe as endogenous reference.18 Expression levels in all the cell types tested are shown relative to expression levels in resting monocytes.Generation of cells expressing mutant BLyS Full-length BLyS1-285 was PCR-amplified and cloned as a BamHI/XbaI fragment into the pC4 mammalian expression vector. The mutations around the BLyS cleavage site, lysine132 to alanine (K132A) and arginine133 to alanine (R133A), were introduced by an overlapping 2-step PCR strategy with the subsequent amplicon subcloned as a BamHI/XbaI fragment into pC4. Expression constructs were then transfected (Lipofectamine; Life Technologies, Rockville, MD) into human 293T-embryonic-kidney cells. Supernatants were collected 36 hours after transfection and assayed in the B-cell proliferation assay.B-cell proliferation Human tonsillar B cells were purified by negative selection using the magnetic-activated cell-sorting (MACS) system. Purified cells were greater than 95% B cells as assessed by immunofluorescence staining for CD20 and CD19. We cultured 105 B cells per well in a 96-well plate for 4 days in the presence of 30 µg/mL anti-IgM (DA4-4 hybridoma; American Type Culture Collection, Manassas, VA) or 10 5 dilution SAC (Calbiochem, La Jolla, CA) and
serial dilutions of the test-conditioned media. Proliferation was
quantitated by pulsing the cells during the last 20 hours of culture
with 0.0185 MBq (0.5 µCi) per well of
[3H]thymidine (2.48 × 1011 Bq [6.7
Ci/mM]) (NEN Life Science Products, Boston, MA). The values are
reported as the mean ± SD of triplicate wells.
IgG production Purified B cells were cultured for 10 days at the cell density of 1 × 106 cells per mL in the presence of SAC and serial dilutions of the test-conditioned media. IgG levels in the culture supernatants were determined by ELISA using goat antihuman Ig pAb (Kirkergaard and Perry) as the capture antibody and biotinylated goat antihuman IgG (Southern Biotechnology Associates, Birmingham, AL) as the detector antibody.Western blot analysis Supernatants from 293T-cell cultures and 293T cells were harvested 36-48 hours after transfection. BLyS present in the supernatants was immunoprecipitated using 1 µg mAb 15C10 and protein A-agarose for 2 hours at 4°C. Immunoprecipitations were washed 4 times and boiled in 2 × SDS (sodium dodecyl sulfate) sample buffer, and the proteins were separated on 4%-20% gradient SDS-PAGE (polyacrylamide gel electrophoresis) gels. The 293T cells were washed once in ice-cold PBS and lysed in Brij buffer comprising 10 M Tris (tris[hydroxymethyl] aminomethane) (pH 7.5), 0.875% Brij, 0.125% NP-40, 2.0 mM ethylenediamine tetraacetic acid (EDTA), and 150 mM sodium chloride (NaCl) for 15 minutes on ice. We separated 60 µg of each lysate on 4%-20% gradient SDS-PAGE gels. Immunoblotting was performed using a rabbit pAb to BLyS, and the results were developed by Enhanced Chemiluminescence (Pierce).
Expression and regulation of membrane-bound BLyS on PBMNCs Our group has previously demonstrated that BLyS is preferentially expressed in hematopoietic tissues and is present on monocytes.11 In additional experiments we evaluated BLyS expression on freshly purified human PBMNCs. The cells were double-stained with PE-conjugated mAb 9B6 and with FITC-coupled antibodies specific for T, B, or NK cells or monocytes and then analyzed by flow cytometry. As shown in Figure 1, monocytes are the only cells bound by the BLyS-specific mAb. The restricted expression of BLyS on cells of myeloid origin was further suggested by FACS analysis of a panel of hematopoietic tumor cell lines (Table 1). The cell lines HL-60, THP-1, and U937 displayed membrane-bound BLyS; in contrast, T cell lines (Jurkat and Sup-T1) and B cell lines (Namalwa, Reh, and IM-9) showed negative immunostaining.
The aim of the next series of experiments was to investigate whether
cytokines known to induce B-cell activity modulate BLyS expression on
monocytes. Cells from 9 donors were treated for 3 days with 100 ng/mL
IL-10, 100 ng/mL IL-4, or 5 ng/mL IFN-
The enhancement of membrane-bound BLyS expression by IFN- Membrane-bound BLyS expression on macrophages and dendritic cells Monocytes are present in circulating blood, whereas in tissues and in secondary lymphoid organs, macrophages and dendritic cells represent the majority of the cells of monocytic origin. Peripheral blood monocytes are capable of differentiating in vitro into both macrophages and dendritic cells depending on the signals delivered to the precursor cells. To define BLyS expression on these monocyte-derived subpopulations, monocytes were treated with GM-CSF and IL-4, which allows for differentiation to dendritic cells (CD14 and CD1a+), or with M-CSF, which
induces the differentiation to macrophages (CD68+). FACS
analysis showed that in vitro-derived macrophages expressed membrane-bound BLyS (Figure 2A). Because
cytokines modulated BLyS expression on monocytes, we tested their
effect on the differentiated macrophages. BLyS-specific immunostaining
was enhanced by IFN- treatment and was reduced by IL-4
(Figure 2A).
In contrast, membrane-bound BLyS was not detected by FACS analysis on
monocyte-derived dendritic cells, although expression of cell surface
BLyS was induced by a 3-day treatment with IFN- Regulation of BLyS gene expression To determine whether the changes in cell surface expression of BLyS were regulated at the level of transcription, quantitative PCR was conducted with mRNA from monocytes, macrophages, and dendritic cells stimulated with the cytokines. Cells from 3 different donors were used, and a generally similar pattern of expression was seen in the various cell types. As shown in the representative experiment depicted in Figure 3, a low level of BLyS transcript was observed in unstimulated monocytes. In all donors tested, IFN-
treatment caused over 10-fold increase in BLyS-specific mRNA.
Interestingly, IL-10 treatment did not affect BLyS mRNA level. In
macrophages, IFN- treatment produced a 6-fold increase of the level
of BLyS transcripts, while IL-10 treatment resulted in less than a
4-fold increase. In dendritic cells, BLyS transcripts were increased by
8-fold following IFN- treatment, but they were not increased following IL-10 treatment. Induction of BLyS mRNA levels was also observed after LPS treatment in macrophages and dendritic cells. Kinetic analysis of BLyS mRNA in the various cell types showed a
maximal level of induction after 1 day of IFN- treatment (data not
shown). The level of BLyS mRNA found in B cells was minimal.
Soluble BLyS is released by myeloid cells and has functional activity Because several members of the TNF family, among them TNF- ,
CD40L, and FasL, can be produced as a soluble protein, we have investigated the possibility that soluble forms of BLyS are produced by
monocytic cells. Using a specific 2-site ELISA, conditioned media from
tumor cells of various origins were analyzed for BLyS content (Figure
4A). BLyS was found in the media
conditioned by the myeloid cell lines U937 and HL-60, but not in the
media conditioned by the T and B tumor lines Jurkat, Namalwa, or IM-9
cells. The identity of the protein released in the culture medium of
U937 cells was confirmed by capturing the soluble BLyS on an affinity column. Sequencing of the purified 17-kD protein revealed an
NH2-terminal sequence of AVQGP (alanine valine
glutamine glycine proline) (O. Galperina and D. Parmelee, unpublished
results, January 2000), as it was previously found for the
recombinant BLyS.11
To further characterize the release of the soluble protein, 3-day
culture media from primary cells of different donors (3-4 donors,
depending on the cell type) were tested in the ELISA (Figure 4B).
Monocytes from various donors released BLyS in the range of 0.5-3 ng
for 3 × 106 cells. Incubation of the cells with IFN- Having determined that BLyS is released by myeloid cells, we next
investigated if soluble BLyS present in the conditioned medium is
active in a standard B-cell costimulation assay (Figure 5A). BLyS contained in a U937-conditioned
medium, used at the final concentration of 5.6 ng/mL, induced a 3-fold
increased of B-cell [3H]thymidine uptake compared to the
cells stimulated with only anti-IgM. The proliferation was
BLyS-specific because it was completely abrogated by the neutralizing
mAb 15C10, but not by a control mAb. In addition, BLyS present in the
U937-conditioned medium was able to strongly enhance SAC-induced IgG
synthesis from tonsillar B cells (Figure 5B). Therefore, released BLyS
is active at low concentrations, similarly to the recombinant
protein.11
Soluble BLyS is produced by proteolytic cleavage Recombinant BLyS is readily produced in the supernatants of various transfected cell systems, with an amino terminus sequence beginning with A134.11,13 Because the BLyS sequence does not contain a predicted signal peptide, a possible mechanism for the release of BLyS from the cells is the proteolytic cleavage of the membrane-bound protein. Our next aim was to determine whether a putative protein cleavage site was present in the polybasic sequence of BLyS overlapping amino acids R133 and A134. A double mutation was introduced into full-length BLyS in the 2 basic amino acids that are located immediately upstream of A134: K132 was substituted by A132 and R133 by A133. The mutant cDNA (K132A and R133A) was then transfected into 293T cells, and supernatants from the transfected cells were tested for expression by Western blotting. Supernatants were also collected from 293T cells transfected with either the wild-type BLyS gene or the parental expression vector.As shown in Figure 6A, both the
wild-type and the mutant cDNA were efficiently expressed, as
full-length BLyS was detected in the whole-cell extracts from the
transfected cells (right panel). In contrast, soluble BLyS was found
only in the supernatant of 293T cells transfected with the wild-type
form of BLyS, but soluble BLyS was not in the supernatant of
cells expressing the noncleavable form of BLyS (left panel). The
supernatants were tested for biological activity in a B-cell
proliferation assay in the presence of SAC (Figure 6B). In contrast to
the wild-type BLyS supernatant, which was significantly active down to
approximately a 100-fold dilution, the mutant BLyS supernatant did not
increase B-cell proliferation, indicating that soluble functional
protein was not cleaved and released into the culture medium. It
therefore appears that aa 132 and/or aa 133 play a critical role in
directing cleavage of surface-bound BLyS to a soluble form.
In this report we have extended our earlier observation that
BLyS is produced by monocytes with the finding that the protein is also
synthesized by macrophages and by monocyte-derived dendritic cells. In
addition, we have demonstrated that BLyS belongs to the category of the
functionally active soluble ligands of the TNF superfamily. In the TNF
ligand family, the efficacy of the membrane-bound and the released
proteins varies greatly. Membrane-bound TNF- Having established that released BLyS is a stimulatory factor for B cells, it remains to be fully investigated whether the membrane-bound form participates to BLyS biological activity. It should be pointed out that Schneider et al13 have shown that B cells proliferate when cocultured with paraformaldehyde-fixed 293 cells stable-transfected with BLyS, thus suggesting a role for the cell surface protein. Experiments are currently under way to further define the physiological function of membrane-bound BLyS in regard to B-cell stimulation. The experiments conducted with cells transfected with a mutant BLyS cDNA strongly indicate that soluble BLyS is produced by enzymatic processing of the membrane-bound protein, as suggested previously.13 It appears, however, that there is no correlation between the levels of cell surface-associated BLyS and concentrations of soluble BLyS found in the cultures. The data suggest that there might be additional rate-limiting regulatory steps involved in the release process. It is known that cellular differentiation markedly alters the proteolytic enzymatic profile in monocytic cells,22-24 and therefore higher concentrations of enzyme(s) or more active proteolytic enzyme(s) might be present in dendritic cells and not in monocytes. Expression of membrane-bound and soluble BLyS was investigated
following cytokine treatment. We have used 3 cytokines, IL-10, IL-4,
and IFN- Our experiments indicate that the enhancing effects of IFN- Many lines of evidence support the theory that in vivo-circulating monocytes, upon migration into tissues, undergo phenotypic and functional maturation into macrophages or dendritic cells.32-34 Differentiation of monocytes to macrophages is associated with the acquisition of a strong phagocytic and endocytic capacity and the enhancement of their degradative function.35-37 Dendritic-cell progenitors, once activated by antigens, migrate from the periphery to the secondary lymphoid organs where they become highly efficient antigen-presenting cells.33,38,39 Recent studies have underlined a critical function shared by these accessory cells: that is, the direct activation of B cells.40-42 In this context, Dubois et al43 have suggested a 2-step model of B-cell activation in which the first step, dendritic cell-induced proliferation of naive B cells, is regulated by unknown soluble factor(s). Our data suggest that BLyS may be one of these mediators, thereby contributing to the direct induction of B-cell proliferation. The ability of monocytes, macrophages, and dendritic cells to regulate BLyS expression is consistent with their proposed roles in B-cell activation and Ig secretion. Antigen-primed B lymphocytes enter peripheral tissues in response to pro-inflammatory signals released from local sites of infection or tissue damage. At these sites, macrophages remove damaged tissues and potentiate local immunoresponsiveness by elaborating a variety of cytokines. In this setting, macrophage-derived BLyS may enhance B-cell function by increasing Ig secretion from antigen-reactive B cells. In contrast, naive B cells within secondary lymphoid tissues may use dendritic cell-derived BLyS as a proliferative factor that synergizes with antigen-specific signals and CD40/CD40L interactions. Thus, the ability of BLyS to influence both B-cell activation and effector function requires that BLyS be selectively available during specific stages of an immune response. The experiments presented in this manuscript identify potent regulators of BLyS expression and provide the basis for continued investigation of the mechanisms involved in cytokine-mediated immune regulation.
We thank O. Galperina and D. Parmelee for purification and N-terminal sequencing of the released BLyS; Y. Li and J. Zhang for purification of the recombinant BLyS; and D. Morahan, E. Cochrane, and P. Garcia for assistance with assays.
Submitted March 6, 2000; accepted August 3, 2000.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Bernardetta Nardelli, Human Genome Sciences, Inc, 9410 Key West Ave, Rockville, MD 20850; e-mail: bernardetta_nardelli{at}hgsi.com.
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© 2001 by The American Society of Hematology.
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 H.-A Kim, S.-H. Jeon, G.-Y. Seo, J.-B. Park, and P.-H. Kim TGF-{beta}1 and IFN-{gamma} stimulate mouse macrophages to express BAFF via different signaling pathways J. Leukoc. Biol., June 1, 2008; 83(6): 1431 - 1439. [Abstract] [Full Text] [PDF]
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 M. Krumbholz, H. Faber, F. Steinmeyer, L.-A. Hoffmann, T. Kumpfel, H. Pellkofer, T. Derfuss, C. Ionescu, M. Starck, C. Hafner, et al. Interferon-{beta} increases BAFF levels in multiple sclerosis: implications for B cell autoimmunity Brain, June 1, 2008; 131(6): 1455 - 1463. [Abstract] [Full Text] [PDF]
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S. K. Chang, S. A. Mihalcik, and D. F. Jelinek B Lymphocyte Stimulator Regulates Adaptive Immune Responses by Directly Promoting Dendritic Cell Maturation J. Immunol., June 1, 2008; 180(11): 7394 - 7403. [Abstract] [Full Text] [PDF]
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C. Bossen, T. G. Cachero, A. Tardivel, K. Ingold, L. Willen, M. Dobles, M. L. Scott, A. Maquelin, E. Belnoue, C.-A. Siegrist, et al. TACI, unlike BAFF-R, is solely activated by oligomeric BAFF and APRIL to support survival of activated B cells and plasmablasts Blood, February 1, 2008; 111(3): 1004 - 1012. [Abstract] [Full Text] [PDF]
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R. T. Woodland, C. J. Fox, M. R. Schmidt, P. S. Hammerman, J. T. Opferman, S. J. Korsmeyer, D. M. Hilbert, and C. B. Thompson Multiple signaling pathways promote B lymphocyte stimulator dependent B-cell growth and survival Blood, January 15, 2008; 111(2): 750 - 760. [Abstract] [Full Text] [PDF]
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 J. P. Jayasekera, C. G. Vinuesa, G. Karupiah, and N. J. C. King Enhanced antiviral antibody secretion and attenuated immunopathology during influenza virus infection in nitric oxide synthase-2-deficient mice. J. Gen. Virol., November 1, 2006; 87(Pt 11): 3361 - 3371. [Abstract] [Full Text] [PDF]
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 K. Yoshimoto, Y. Takahashi, M. Ogasawara, Y. Setoyama, K. Suzuki, K. Tsuzaka, T. Abe, and T. Takeuchi Aberrant expression of BAFF in T cells of systemic lupus erythematosus, which is recapitulated by a human T cell line, Loucy Int. Immunol., July 1, 2006; 18(7): 1189 - 1196. [Abstract] [Full Text] [PDF]
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 W. G. Halpern, P. Lappin, T. Zanardi, W. Cai, M. Corcoran, J. Zhong, and K. P. Baker Chronic Administration of Belimumab, a BLyS Antagonist, Decreases Tissue and Peripheral Blood B-Lymphocyte Populations in Cynomolgus Monkeys: Pharmacokinetic, Pharmacodynamic, and Toxicologic Effects Toxicol. Sci., June 1, 2006; 91(2): 586 - 599. [Abstract] [Full Text] [PDF]
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D. Bischof, S. F. Elsawa, G. Mantchev, J. Yoon, G. E. Michels, A. Nilson, S. L. Sutor, J. L. Platt, S. M. Ansell, G. von Bulow, et al. Selective activation of TACI by syndecan-2 Blood, April 15, 2006; 107(8): 3235 - 3242. [Abstract] [Full Text] [PDF]
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B. He, X. Qiao, P. J. Klasse, A. Chiu, A. Chadburn, D. M. Knowles, J. P. Moore, and A. Cerutti HIV-1 Envelope Triggers Polyclonal Ig Class Switch Recombination through a CD40-Independent Mechanism Involving BAFF and C-Type Lectin Receptors J. Immunol., April 1, 2006; 176(7): 3931 - 3941. [Abstract] [Full Text] [PDF]
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S. F. Elsawa, A. J. Novak, D. M. Grote, S. C. Ziesmer, T. E. Witzig, R. A. Kyle, S. R. Dillon, B. Harder, J. A. Gross, and S. M. Ansell B-lymphocyte stimulator (BLyS) stimulates immunoglobulin production and malignant B-cell growth in Waldenstrom macroglobulinemia Blood, April 1, 2006; 107(7): 2882 - 2888. [Abstract] [Full Text] [PDF]
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 A. J. Novak, D. M. Grote, S. C. Ziesmer, M. P. Kline, M. K. Manske, S. Slager, T. E. Witzig, T. Shanafelt, T. G. Call, N. E. Kay, et al. Elevated Serum B-Lymphocyte Stimulator Levels in Patients With Familial Lymphoproliferative Disorders J. Clin. Oncol., February 20, 2006; 24(6): 983 - 987. [Abstract] [Full Text] [PDF]
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Y. Diaz-de-Durana, G. T. Mantchev, R. J. Bram, and A. Franco TACI-BLyS signaling via B-cell-dendritic cell cooperation is required for naive CD8+ T-cell priming in vivo Blood, January 15, 2006; 107(2): 594 - 601. [Abstract] [Full Text] [PDF]
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M. Krumbholz, D. Theil, S. Cepok, B. Hemmer, P. Kivisakk, R. M. Ransohoff, M. Hofbauer, C. Farina, T. Derfuss, C. Hartle, et al. Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment Brain, January 1, 2006; 129(1): 200 - 211. [Abstract] [Full Text] [PDF]
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J. E. Butler, D. H. Francis, J. Freeling, P. Weber, and A. M. Krieg Antibody Repertoire Development in Fetal and Neonatal Piglets. IX. Three Pathogen-Associated Molecular Patterns Act Synergistically to Allow Germfree Piglets to Respond to Type 2 Thymus-Independent and Thymus-Dependent Antigens J. Immunol., November 15, 2005; 175(10): 6772 - 6785. [Abstract] [Full Text] [PDF]
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Y. Zheng, S. Gallucci, J. P. Gaughan, J. A. Gross, and M. Monestier A Role for B Cell-Activating Factor of the TNF Family in Chemically Induced Autoimmunity J. Immunol., November 1, 2005; 175(9): 6163 - 6168. [Abstract] [Full Text] [PDF]
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M. Zhang, K.-H. Ko, Q. L. K. Lam, C. K. C. Lo, G. Srivastava, B. Zheng, Y.-L. Lau, and L. Lu Expression and function of TNF family member B cell-activating factor in the development of autoimmune arthritis Int. Immunol., August 1, 2005; 17(8): 1081 - 1092. [Abstract] [Full Text] [PDF]
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A. L. Gavin, B. Duong, P. Skog, D. Ait-Azzouzene, D. R. Greaves, M. L. Scott, and D. Nemazee {Delta}BAFF, a Splice Isoform of BAFF, Opposes Full-Length BAFF Activity In Vivo in Transgenic Mouse Models J. Immunol., July 1, 2005; 175(1): 319 - 328. [Abstract] [Full Text] [PDF]
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M Schaller, W Stohl, S M Tan, V M Benoit, D M Hilbert, and H J Ditzel Raised levels of anti-glucose-6-phosphate isomerase IgG in serum and synovial fluid from patients with inflammatory arthritis Ann Rheum Dis, May 1, 2005; 64(5): 743 - 749. [Abstract] [Full Text] [PDF]
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C. A. Ogden, J. D. Pound, B. K. Batth, S. Owens, I. Johannessen, K. Wood, and C. D. Gregory Enhanced Apoptotic Cell Clearance Capacity and B Cell Survival Factor Production by IL-10-Activated Macrophages: Implications for Burkitt's Lymphoma J. Immunol., March 1, 2005; 174(5): 3015 - 3023. [Abstract] [Full Text] [PDF]
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 M. Krumbholz, D. Theil, T. Derfuss, A. Rosenwald, F. Schrader, C.-M. Monoranu, S. L. Kalled, D. M. Hess, B. Serafini, F. Aloisi, et al. BAFF is produced by astrocytes and up-regulated in multiple sclerosis lesions and primary central nervous system lymphoma J. Exp. Med., January 18, 2005; 201(2): 195 - 200. [Abstract] [Full Text] [PDF]
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J. Ohata, N. J. Zvaifler, M. Nishio, D. L. Boyle, S. L. Kalled, D. A. Carson, and T. J. Kipps Fibroblast-Like Synoviocytes of Mesenchymal Origin Express Functional B Cell-Activating Factor of the TNF Family in Response to Proinflammatory Cytokines J. Immunol., January 15, 2005; 174(2): 864 - 870. [Abstract] [Full Text] [PDF]
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P. Scapini, A. Carletto, B. Nardelli, F. Calzetti, V. Roschke, F. Merigo, N. Tamassia, S. Pieropan, D. Biasi, A. Sbarbati, et al. Proinflammatory mediators elicit secretion of the intracellular B-lymphocyte stimulator pool (BLyS) that is stored in activated neutrophils: implications for inflammatory diseases Blood, January 15, 2005; 105(2): 830 - 837. [Abstract] [Full Text] [PDF]
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A. J. Novak, D. M. Grote, M. Stenson, S. C. Ziesmer, T. E. Witzig, T. M. Habermann, B. Harder, K. M. Ristow, R. J. Bram, D. F. Jelinek, et al. Expression of BLyS and its receptors in B-cell non-Hodgkin lymphoma: correlation with disease activity and patient outcome Blood, October 15, 2004; 104(8): 2247 - 2253. [Abstract] [Full Text] [PDF]
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B. He, X. Qiao, and A. Cerutti CpG DNA Induces IgG Class Switch DNA Recombination by Activating Human B Cells through an Innate Pathway That Requires TLR9 and Cooperates with IL-10 J. Immunol., October 1, 2004; 173(7): 4479 - 4491. [Abstract] [Full Text] [PDF]
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W Stohl, S Metyas, S-M Tan, G S Cheema, B Oamar, V Roschke, Y Wu, K P Baker, and D M Hilbert Inverse association between circulating APRIL levels and serological and clinical disease activity in patients with systemic lupus erythematosus Ann Rheum Dis, September 1, 2004; 63(9): 1096 - 1103. [Abstract] [Full Text] [PDF]
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M. W. Boule, C. Broughton, F. Mackay, S. Akira, A. Marshak-Rothstein, and I. R. Rifkin Toll-like Receptor 9-Dependent and -Independent Dendritic Cell Activation by Chromatin-Immunoglobulin G Complexes J. Exp. Med., June 21, 2004; 199(12): 1631 - 1640. [Abstract] [Full Text] [PDF]
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 W Stohl A therapeutic role for BLyS antagonists Lupus, May 1, 2004; 13(5): 317 - 322. [Abstract] [PDF]
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 E. Varfolomeev, F. Kischkel, F. Martin, D. Seshasayee, H. Wang, D. Lawrence, C. Olsson, L. Tom, S. Erickson, D. French, et al. APRIL-Deficient Mice Have Normal Immune System Development Mol. Cell. Biol., February 1, 2004; 24(3): 997 - 1006. [Abstract] [Full Text] [PDF]
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A. J. Novak, J. R. Darce, B. K. Arendt, B. Harder, K. Henderson, W. Kindsvogel, J. A. Gross, P. R. Greipp, and D. F. Jelinek Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival Blood, January 15, 2004; 103(2): 689 - 694. [Abstract] [Full Text] [PDF]
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B. P. O'Connor, V. S. Raman, L. D. Erickson, W. J. Cook, L. K. Weaver, C. Ahonen, L.-L. Lin, G. T. Mantchev, R. J. Bram, and R. J. Noelle BCMA Is Essential for the Survival of Long-lived Bone Marrow Plasma Cells J. Exp. Med., January 5, 2004; 199(1): 91 - 98. [Abstract] [Full Text] [PDF]
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K. Schneider, S. Kothlow, P. Schneider, A. Tardivel, T. Gobel, B. Kaspers, and P. Staeheli Chicken BAFF--a highly conserved cytokine that mediates B cell survival Int. Immunol., January 1, 2004; 16(1): 139 - 148. [Abstract] [Full Text] [PDF]
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B. He, N. Raab-Traub, P. Casali, and A. Cerutti EBV-Encoded Latent Membrane Protein 1 Cooperates with BAFF/BLyS and APRIL to Induce T Cell-Independent Ig Heavy Chain Class Switching J. Immunol., November 15, 2003; 171(10): 5215 - 5224. [Abstract] [Full Text] [PDF]
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F Melchers Actions of BAFF in B cell maturation and its effects on the development of autoimmune disease Ann Rheum Dis, November 1, 2003; 62(90002): ii25 - 27. [Abstract] [Full Text] [PDF]
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L. Gorelik, K. Gilbride, M. Dobles, S. L. Kalled, D. Zandman, and M. L. Scott Normal B Cell Homeostasis Requires B Cell Activation Factor Production by Radiation-resistant Cells J. Exp. Med., September 15, 2003; 198(6): 937 - 945. [Abstract] [Full Text] [PDF]
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P. Scapini, B. Nardelli, G. Nadali, F. Calzetti, G. Pizzolo, C. Montecucco, and M. A. Cassatella G-CSF-stimulated Neutrophils Are a Prominent Source of Functional BLyS J. Exp. Med., January 23, 2003; (2003) 20021343. [Abstract] [Full Text] [PDF]
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L.-G. Xu and H.-B. Shu TNFR-Associated Factor-3 Is Associated With BAFF-R and Negatively Regulates BAFF-R-Mediated NF-{kappa}B Activation and IL-10 Production J. Immunol., December 15, 2002; 169(12): 6883 - 6889. [Abstract] [Full Text] [PDF]
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M. K. Park, D. Amichay, P. Love, E. Wick, F. Liao, A. Grinberg, R. L. Rabin, H. H. Zhang, S. Gebeyehu, T. M. Wright, et al. The CXC Chemokine Murine Monokine Induced by IFN-{gamma} (CXC Chemokine Ligand 9) Is Made by APCs, Targets Lymphocytes Including Activated B Cells, and Supports Antibody Responses to a Bacterial Pathogen In Vivo J. Immunol., August 1, 2002; 169(3): 1433 - 1443. [Abstract] [Full Text] [PDF]
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S. Xu and K.-P. Lam B-Cell Maturation Protein, Which Binds the Tumor Necrosis Factor Family Members BAFF and APRIL, Is Dispensable for Humoral Immune Responses Mol. Cell. Biol., June 15, 2001; 21(12): 4067 - 4074. [Abstract] [Full Text]
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Top
Abstract
Introduction
B, and JNK).
20°C.
-glucan receptors are involved in phagocytosis of unopsonized, heat-killed Saccharomyces cerevisiae by murine macrophages.
J Leukoc Biol.
1993;54:564-571