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* CBR Institute for Biomedical Research, Harvard Medical School, Boston, MA 02115; and
Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In contrast, transgenic mice engineered to overexpress BAFF show increased numbers of peripheral B cells and elevated serum Ig levels, including anti-DNA Abs, rheumatoid factor, and circulating immune complexes, and develop autoimmune symptoms resembling human systemic lupus erythematosus and Sjögren’s syndrome as they age. Elevated serum BAFF levels have been detected in patients with rheumatoid arthritis, systemic lupus erythematosus, and Sjögren’s syndrome (1, 2, 3, 4, 5).
BAFF can bind to three receptors of the TNFR family: transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI); B cell maturation Ag (BCMA); and BAFF-R (also known as BLyS receptor 3 or BR3). TACI and BMCA also bind to another TNF family member, a proliferation-inducing ligand (1, 2, 3, 4, 5). A proliferation-inducing ligand, BCMA, and TACI are all dispensable for B cell development (16, 17, 18, 19, 20), indicating that triggering of BAFF-R by BAFF is essential for the generation of mature B cells. A/WySnJ mice contain 10% of the peripheral B cells found in control A/J mice, due to a reduced life span of B2, but not of B1 cells (21, 22, 23, 24). These mice harbor a transposon insertion that replaces the last 8 aa of the C terminus of BAFF-R with 21 aa encoded by the insertion (25, 26). The mutant receptor is expressed on the surface of A/WySnJ B cells and is capable of binding BAFF (27), suggesting that its signaling capacities are impaired. This notion is supported by the fact that BAFF administration increases B cell numbers in A/J, but not in A/WySnJ mice (24). However, significant differences exist between A/WySnJ and Baff–/– mice; A/WySnJ mice, in constrast to Baff–/– mice, contain CD21- and CD23-expressing follicular and CD21highCD23low MZ B cells (12, 26). They exhibit IgM serum levels comparable to A/J mice (28), whereas in Baff–/– mice IgM levels in the blood are strongly reduced (12). A/WySnJ mice mount efficient IgM responses against T-dependent (TD) and T-independent (TI) Ags, but are profoundly deficient in producing primary or secondary IgG responses (28). The Ag-specific Ab production by Baff–/– mice in response to TD and TI Ags, in contrast, is dramatically reduced compared with wild-type mice, suggesting that production of all Ig subclasses is affected (12).
The differences observed in B cell phenotypes and function between A/WySnJ and Baff–/– mice can be explained by the nature of the A/WySnJ mutation, which leaves most of the BAFF-R intact. The mutant receptor could therefore retain some signaling functions. Alternatively, it could heterotrimerize with other TNF-R-like molecules, such as BCMA or TACI, and act as a dominant-negative molecule. Therefore, B cell physiology could be affected more by expression of a mutant BAFF-R, than by lack of the receptor, leading to an overinterpretation of the role of BAFF-R. However, it is also possible that BAFF exerts some of its functions through its other receptors, BCMA and TACI, or in a non-B cell-autonomous fashion through as yet unidentified receptors.
To more precisely define the role of BAFF-R in B cell development, we generated mice that are deficient for this receptor. Baff-r–/– mice demonstrate a block in B cell development at the transitional stage. The mutant mice show a 40-fold reduction in numbers of mature B2 cells and contain very few, if any, MZ B cells. Baff-r–/– B cells produce reduced, but significant Ag-specific Ab titers in response to immunizations with TI and TD Ags, and they develop into GC B cells in mesenteric lymph nodes (mLNs) in response to gut-derived Ags. The main function of BAFF-R appears to provide a survival signal to mature B cells, as overexpression of Bcl-2 rescues mature B cell development in Baff-r–/– mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Construction of a conditional Baff-rFL targeting vector. An EcoRI fragment of the mouse Baff-r genomic locus in pBluescript II was used. The targeting vector was designed to flank exons 3 and 4 of the Baff-r gene with two loxP sites. An frt site-flanked selection cassette, containing a neor gene and the Flpe6 cDNA cloned under control of the ACE promoter (29), was placed into the fourth intron of the Baff-r gene. A 1.9-kb AvrII-MfeI fragment was used as 5' homology region, a 1.3-kb MfeI-AvrII fragment was placed between the two loxP sites, and a 5.0-kb AvrII-BamHI fragment was used as 3' homology region. A thymidine kinase gene was used for negative selection of clones with random integration of the targeting vector.
Bruce-4 embryonic stem (ES) cells (30) derived from C57BL/6 mice were transfected, cultured, and selected, as previously described (31). Of 475 G418 and gancyclovir-resistant colonies, 2 were identified as homologous recombinants with cointegration of the second loxP site by Southern blot analysis of BglII-digested DNA, using a 465-bp fragment as 5' external probe (Fig. 1). Mice were bred and maintained in specific pathogen-free conditions; all mouse protocols were approved by the Harvard University Institutional Animal Care and Use Committee and by the CBR Institute for Biomedical Research. The Eµ-bcl-2-22 (32) transgenic mouse strain was obtained from The Jackson Laboratory (Bar Harbor, ME).
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Total RNA was extracted from splenocytes with TRIzol (Invitrogen Life Technologies, Carlsbad, CA), according to the manufacturer’s protocol. One microgram of total RNA was used for first-strand cDNA synthesis with random hexamer primers and Superscript RT III (Invitrogen Life Technologies). Baff-r and Hprt (hypoxanthine phosphoribosyltransferase) cDNA was amplified by PCR with the following intron-spanning primers: BAFF-R-1, 5'-CCCAGACTCGGAACTGTCCC-3'; BAFF-R-2, 5'-GTAGAGATCCCTGGGTTCCAG-3'; Hprt-1, 5'-ATTAGCGATGATGAACCAGGTTA-3'; Hprt-2, 5'-CCAGTTAAAGTTGAGATCATCTCCAC-3'. PCR conditions were as follows: 94°C for 30 s, 58°C for 30 s, and 72°C for 30 s for 40 cycles with 1 U of KOD HiFi polymerase (Novagen, Madison, WI).
Flow cytometry
Single-cell suspensions prepared from various lymphoid organs and the peritoneum were stained with the following mAbs conjugated to FITC, PE, CyChrome, allophycocyanin, or biotin: anti-CD5 (53-7.3), anti-CD19 (ID3), anti-CD21 (7G6), anti-CD23 (B3B4), anti-CD38 (90), anti-CD1d (1B1), anti-Fas (Jo2), anti-IgD (11-26c.2a) (all from BD Pharmingen, San Diego, CA), and anti-AA4.1 (eBioscience, San Diego, CA). Additional, "homemade" mAbs to IgM (R33-2412) and B220 (RA3-6B2) were used. Rabbit polyclonal Abs to mouse BAFF-R were generated by immunization with a synthesized mouse BAFF-R peptide (aa 1–17). PNA conjugates were PNA-FITC and PNA-biotin (Vector Laboratories, Burlingame, CA). Biotin conjugates were visualized with CyChrome or allophycocyanin (BD Pharmingen). Anti-BAFF-R Ab was visualized with goat anti-rabbit IgG FITC (Zymed Laboratories, San Francisco, CA). All samples were acquired on a FACSCalibur (BD Pharmingen), and results were analyzed with CellQuest software.
Immunohistochemistry
For staining of B cells and macrophages, frozen 6-µm sections were thawed, air dried, fixed in acetone, and stained for 1 h at room temperature in a humidified chamber with biotinylated rat anti-CD19 (BD Pharmingen) and rat anti-MOMA-1 (Cedarlane Laboratories, Hornby, Canada), followed by HRP-conjugated goat anti-rat IgG and alkaline phosphatase-conjugated streptavidin. For staining of B and T cells, sections were stained for 1 h at room temperature in a humidified chamber with biotinylated anti-CD19 and armenian hamster anti-CD3
(eBioscience). Bcl-6 expression was detected with a rabbit anti-Bcl-6 (Santa Cruz Biotechnology, Santa Cruz, CA), followed by incubation with HRP-conjugated goat anti-rabbit IgG (DakoCytomation, Carpinteria, CA).
Immunization and serum analyses
Mice were immunized with 100 µg of TD Ag 4-hydroxy-3-nitrophenylacetyl chicken 
-globulin (NP-CG) in alum i.p. Mice were boosted with 10 µg of NP-CG without adjuvant on day 48. TI immune responses were elicited by i.p. injections of 50 µg of NP-Ficoll. Mice were bled before and after immunization from tail veins. Ig serum concentrations were determined by ELISA, as described previously (33).
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Results |
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To study the physiological role of BAFF-R in vivo, we generated BAFF-R-deficient mice by gene targeting. The targeting vector was designed to place exons 3 and 4, which encode the entire extracellular and transmembrane domains and part of the cytoplasmic domain, between loxP sites (Fig. 1A). Two C57BL/6-derived ES clones (30) with the appropriately targeted allele were obtained (Fig. 1B), injected into BALB/c blastocysts to generate chimeric mice, which transmitted the targeted loxP-flanked Baff-r allele (Baff-rFL) to their progeny (Fig. 1C). All mice were maintained on a pure C57BL/6 genetic background. The frt-flanked neor casette can be removed through intercrossing with Flpe-deleter mice (34). To obtain a Baff-r null allele (Baff-r–), Baff-rFL/+ mice were crossed with the deleter strain (35) (Fig. 1C). The expression of BAFF-R in BAFF-R-deficient mice (Baff-r–/–) was examined both at the RNA and the protein level. No Baff-r mRNA could be detected by RT-PCR analysis in Baff-r–/– mice (Fig. 1D). FACS analysis using a polyclonal anti-BAFF-R Ab revealed absence of BAFF-R expression on the surface of B220+ Baff-r–/– splenic cells (Fig. 1E). Despite the reduction of BAFF-R surface levels on Baff-r+/– B cells (Fig. 1E), we did not detect any statistically significant differences in B cell development in our analyses between Baff-r+/– and wild-type mice, which are therefore collectively referred to as control mice below.
Decreased numbers of mature B cells in Baff-r–/– mice
B cell development in Baff-r–/– mice was examined by flow cytometric analyses. In the BM of Baff-r–/– mice, early B cell development was essentially normal. The only difference between BM B cells of control and Baff-r–/– mice was a strong reduction of mature recirculating B cells in the latter (Fig. 2A). The fraction of IgD-positive B cells was >10-fold reduced in Baff-r–/– BM compared with control mice (data not shown). In the spleen, B cell numbers were strongly reduced (Table I). The reduction occurred mainly in the IgMlowIgD+ mature B cell subset (Fig. 2B). Immunohistological staining of spleen sections revealed small CD19+ B cell clusters, but essentially normal-sized CD3+ T cell areas in Baff-r–/– mice (Fig. 3A). Lymph nodes (LNs) of Baff-r–/– mice also had a >20-fold reduced IgMlowIgD+ mature B cell fraction (Fig. 2C). Accordingly, few and very small B cell clusters were detected in LNs from Baff-r–/– in comparison with control mice (Fig. 3C). In the peritoneal cavity of the mutants, the B220highCD19intemediate B2 cell population was reduced >10-fold, but the CD19highB220low B1 cell population was not affected (Fig. 2D, upper panels). The ratio of B1a (CD5+) to B1b (CD5–) cells was also normal in Baff-r–/– mice (Fig. 2D, lower panels). Analysis of T cell development in Baff-r–/– mice yielded normal numbers of conventional peripheral CD4 and CD8 T cells. The generation of memory-type T cells, regulatory CD4+CD25+ T cells, and NK-like T cells was also not affected by the absence of BAFF-R (data not shown).
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Newly formed or immature B cells emigrate from the BM, reach the spleen as so-called transitional B cells, and subsequently mature into follicular and MZ B cells. Transitional B cells can be subdivided into three distinct subsets (T1–3) according to the surface expression of AA4.1 (CD93, C1qRp), IgM, and CD23 (36). This staining procedure offers the advantage that B1 cells can be separated from the transitional subsets, which is not possible by using the surface markers IgM and IgD or CD21 and CD23 for B cell subpopulation analysis. Only transitional stage B cells express AA4.1, whereas mature B cells do not. In spleens from Baff-r–/– mice, the majority of B220+ cells are AA4.1+ transitional B cells (Fig. 4A and Table I). Further analysis of the transitional stages showed that in Baff-r–/– mice, the sizes of the T2 (IgM+CD23+) and T3 (IgMlowCD23+) populations were reduced, whereas the proportion of T1 B cells (IgM+CD23–) was increased (Fig. 4B and Table I). Absolute T1 B cell numbers were comparable to those of control mice (Table I). Recently, it was reported that the surface expression of CD23 is regulated by BAFF (14). Therefore, the use of CD23 as a B cell maturation marker is problematic in Baff-r–/– mice. However, analysis of IgM expression levels on AA4.1+ Baff-r–/– and control B cells confirmed a developmental block in B cell development from IgM+ cells (T1 + T2) to IgMlow cells (T3) (Fig. 4C). Analysis of CD23 expression on AA4.1– mature B cells revealed two populations, one with low CD23 expression and one with CD23 expression comparable to control B cells (Fig. 4D). This indicates that some B cells can express CD23 in the absence of BAFF-R signaling. MZ B cells are usually defined as CD19+CD21highCD23low populations (37). However, because the expression of both CD21 and CD23 is regulated by BAFF (14), we assessed MZ B cell development in Baff-r–/– mice by using the cell surface markers CD1d and CD38, known to be expressed at higher levels on MZ than on follicular B cells (37, 38). This analysis demonstrated that MZ B cells are essentially absent in Baff-r–/– mice (Fig. 4E and Table I). We confirmed this finding by immunohistological staining of spleen sections with the B cell marker CD19 and the metallophilic macrophage marker MOMA-1. This staining showed little, if any, B cells in the MZ area of spleen sections of Baff-r–/– in contrast to control mice (Fig. 3B).
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Measurement of Ig isotype levels in the blood of unimmunized mice revealed decreased titers of IgM, IgG1, IgG2a, IgG2b, and IgG3 in Baff-r–/– compared with control mice (Fig. 5A). In contrast, the serum concentration of IgA was similar in Baff-r–/– and control mice, most likely reflecting normal numbers of B1 cells in Baff-r–/– mice (39).
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In mLNs, spontaneous GCs occur in response to gut-derived bacterial Ags (40, 41). Because GC formation can be initiated, but not maintained, in Baff–/– and A/WySnJ mice (13, 15), we analyzed GC B formation in mLNs of Baff-r–/– and control mice by flow cytometry. This analysis revealed that B cells in the mLNs of Baff-r–/– mice can continuously differentiate into FashighPNAhigh GC B cells, presumably in response to microbial Ags derived from the gut (Fig. 7A). Histological analysis of mLN confirmed the presence of GC B cells expressing high levels of the transcription factor Bcl-6 in Baff-r–/– mice.
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BAFF is considered to be a B cell survival factor (2). The fact that Baff–/– and Baff-r–/– mice display a similar reduction in B cell numbers (Ref.12 and this study) suggests that BAFF-R is indeed the receptor through which BAFF exerts its antiapoptotic effects. BAFF treatment was shown to increase the levels of the antiapoptotic proteins Bcl-xL, Bcl-2, and A1 in B cells (9, 42, 43, 44, 45). We addressed this issue by attempting to rescue B cell development in BAFF-R-deficient mice by overexpression of the antiapoptotic protein Bcl-2. This was achieved through intercrossing Baff-r–/– mice with Eµ-bcl-2 transgenic mice, which express Bcl-2 in B cells (32). FACS analysis revealed that overexpression of Bcl-2 restored the mature IgD+IgMlow and B220+AA4.1– B cell compartments in the compound mutants to a similar size as in control Baff-r+/–/Eµ-bcl-2 mice (Fig. 8, A and B). However, mature Baff-r–/–/Eµ-bcl-2 B cells expressed lower levels of CD21 than control B cells (Fig. 8C), indicating that the regulation of CD21 by BAFF-R is independent of its prosurvival function.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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50% in offspring of A/WySnJ mice crossed to either A/J (28) or BALB/c mice (24). Therefore, it seems that in a heterozygous situation, the A/WySnJ BAFF-R can act as a dominant-negative molecule. Our analysis of B cell development in Baff-r–/– mice revealed a developmental block at the transitional stages, most likely at the T1 to T2 transition. This corresponds well with the up-regulation of BAFF-R expression from the T1 to the T2 transitional stage (9, 46). It seems possible that BAFF-R engagement at the T1 transitional stage of B cell development promotes further differentiation to the T2 stage (10). Additionally, binding of BAFF to BAFF-R enhances survival of T2, T3, follicular, and MZ B cell subsets. We find <2 million mature B cells in the spleens of Baff-r–/– mice. These cells express reduced levels of CD21 and, to a lesser extent, CD23. Staining with Abs against CD1d and CD38 and immunohistochemistry revealed a near absence of MZ B cells, suggesting that the MZ B cell subset is exquisitely dependent on BAFF-R signals.
Monitoring B cell function in immune responses showed that Baff-r–/– B cells are able to produce class-switched Abs in response to TI-II and TD Ags. The reduction of Ab titers in immunized Baff-r–/– mice can be explained by the overall reduction of B cell numbers in the case of TD and the deficiency in MZ B cells in case of TI-II Ab responses.
The requirements for GC formation in mLNs and Peyer’s patches in response to microbial Ags differ from those for GC formation in the spleen upon antigenic stimulation (47). Therefore, we investigated the role of BAFF-R in this context and show that this receptor is dispensable for chronic GC responses triggered by Ags derived from the gut microflora. The fact that GALT GC reactions occur independently of BAFF-R and the intact B1 B cell population in Baff-r–/– mice most likely both contribute to the normal IgA serum levels observed in these mice.
Taken together, we show in this work that BAFF-R is essential for the survival of peripheral B2 cells from the T2 transitional stage on. In addition, BAFF-R seems to be indispensable for the development of MZ B cells and plays a role in the regulation of CD21 and, to a lesser extent, CD23 surface expression. Ablation of BAFF-R had no effect on the generation of B1 cells. These results suggest that the generation and maintenance of mature B2 and MZ B cells depend on the presence of at least two receptors, the BCR (48) and BAFF-R.
Previous analyses of the role of BAFF signaling in B cell physiology in Baff–/– and A/WySnJ mice expressing a mutant BAFF-R yielded some differences. However, due to the complex nature of the A/WySnJ mutation, it is impossible to distinguish whether these differences are due to BAFF-R-independent signals elicited by BAFF or residual signaling through the mutant receptor in A/WySnJ B cells. By generating BAFF-R-deficient mice, we attempted to clarify these isssues.
Recently, it was suggested that expression of CD21 and CD23 depends on BAFF (14). Residual B cells from A/WySnJ mice, in contrast, have normal surface levels of CD23 and seem to express only slightly decreased levels of CD21 (26). Our results indicate that BAFF regulates CD21 and CD23 expression through BAFF-R-dependent and -independent ways.
In both Baff–/– (14) and A/WySnJ (26) mice, normal proportions of cells with a MZ phenotype were observed among the residual splenic B cells. However, inhibition of BAFF function through transgenic expression of a TACI-Ig fusion protein prevented MZ B cell development altogether (49). In accordance with this finding, our results suggest a very strong reduction of MZ B cells in Baff-r–/– mice. It is therefore possible that the IgMhighIgDlow fraction found in Baff–/– mice (14) is composed entirely of T1 B cells. We propose that BAFF-R signaling is essential for MZ B cell development. A/WySnJ mice, in contrast, appear to contain normal proportions of CD21highCD23low MZ B cells. This suggests that the A/WySnJ mutation impairs BAFF-R-mediated survival signals, but does not completely interfere with MZ B cell differentiation.
MZ B cells are thought to play an important role in TI-II immune responses (50, 51, 52). The stronger reduction in MZ B cell numbers in Baff-r–/– compared with A/WySnJ mice could explain why the latter mice mount normal Ag-specific IgM TI-II responses upon immunizations with TI-II Ags (28), whereas Baff-r–/– mice produce lower levels of Ag-specific IgM than control mice. In response to a TD Ag, Baff-r–/– mice mount a robust, only slightly reduced Ag-specific IgM response, whereas the TD IgG1 primary and secondary immune responses are significantly reduced. Similar results were previously obtained in A/WySnJ mice and correlated to the general B cell deficiency (28). However, despite the prominent role of BAFF-R in B cell survival, BAFF-R could have additional functions in the control of GC responses (13, 15) and class-switch recombination (53) and could contribute in this way to the deficiencies of TD Ab responses in Baff-r–/– mice.
In contrast, Baff–/– mice, which have a similar defect in peripheral B cell numbers as Baff-r–/– and A/WySnJ mice, display a much more pronounced defect in humoral immunity (12). Because Taci–/– mice also show defects in TI-II responses, despite significantly elevated peripheral B cell numbers (20, 54), it seems plausible that BAFF promotes TI-II Ab responses also through TACI. It has been reported that BAFF has costimulatory activity for T cells (55, 56), which could account for a role of BAFF in TD immune responses independent of any of the described receptors. Although the exact mechanisms still need to be uncovered, we show in this study that in the control of humoral immune responses BAFF must operate at least partially independently of BAFF-R.
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Acknowledgments |
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Footnotes |
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1 This work was supported by the National Institutes of Health Grants AI057947 and 1R37AI054636 and the Uehara Memorial Foundation. 
2 Address correspondence and reprint requests to Dr. Yoshiteru Sasaki or Dr. Marc Schmidt-Supprian, CBR Institute for Biomedical Research, 200 Longwood Avenue, Boston, MA 02115. E-mail address: sasaki{at}cbr.med.harvard.edu or supprian{at}cbr.med.harvard.edu
3 Abbreviations used in this paper: BAFF, TNF family member B cell-activating factor; BCMA, B cell maturation Ag; BM, bone marrow; CG, chicken -globulin; ES, embryonic stem; GC, germinal center; HPRT, hypoxanthine phosphoribosyltransferase; LN, lymph node; mLN, mesenteric LN; MZ, marginal zone; NP, 4-hydroxy-3-nitrophenylacetyl; PNA, peanut agglutinin; T1/2/3, transitional type 1/2/3; TACI, transmembrane activator, calcium modulator, and cyclophilin ligand interactor; TD, T dependent; TI, T independent.
Received for publication March 24, 2004. Accepted for publication June 1, 2004.
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B1 p50 is required for BLyS attenuation of apoptosis but dispensable for processing of NF-B2 p100 to p52 in quiescent mature B cells. J. Immunol. 171:761.Related articles in The JI:
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N. P. Shinners, G. Carlesso, I. Castro, K. L. Hoek, R. A. Corn, R. L. Woodland, M. L. Scott, D. Wang, and W. N. Khan Bruton's Tyrosine Kinase Mediates NF-{kappa}B Activation and B Cell Survival by B Cell-Activating Factor Receptor of the TNF-R Family J. Immunol., September 15, 2007; 179(6): 3872 - 3880. [Abstract] [Full Text] [PDF]
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I. Debnath, K. M. Roundy, J. J. Weis, and J. H. Weis Defining In Vivo Transcription Factor Complexes of the Murine CD21 and CD23 Genes J. Immunol., June 1, 2007; 178(11): 7139 - 7150. [Abstract] [Full Text] [PDF]
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A. Waisman, M. Kraus, J. Seagal, S. Ghosh, D. Melamed, J. Song, Y. Sasaki, S. Classen, C. Lutz, F. Brombacher, et al. IgG1 B cell receptor signaling is inhibited by CD22 and promotes the development of B cells whose survival is less dependent on Ig{alpha}/{beta} J. Exp. Med., April 16, 2007; 204(4): 747 - 758. [Abstract] [Full Text] [PDF]
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D. Sakurai, H. Hase, Y. Kanno, H. Kojima, K. Okumura, and T. Kobata TACI regulates IgA production by APRIL in collaboration with HSPG Blood, April 1, 2007; 109(7): 2961 - 2967. [Abstract] [Full Text] [PDF]
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 S. Kothlow, I. Morgenroth, Y. Graef, K. Schneider, I. Riehl, P. Staeheli, P. Schneider, and B. Kaspers Unique and conserved functions of B cell-activating factor of the TNF family (BAFF) in the chicken Int. Immunol., February 1, 2007; 19(2): 203 - 215. [Abstract] [Full Text] [PDF]
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T. Endo, M. Nishio, T. Enzler, H. B. Cottam, T. Fukuda, D. F. James, M. Karin, and T. J. Kipps BAFF and APRIL support chronic lymphocytic leukemia B-cell survival through activation of the canonical NF-{kappa}B pathway Blood, January 15, 2007; 109(2): 703 - 710. [Abstract] [Full Text] [PDF]
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A. Kato, A. Q. Truong-Tran, A. L. Scott, K. Matsumoto, and R. P. Schleimer Airway Epithelial Cells Produce B Cell-Activating Factor of TNF Family by an IFN-beta-Dependent Mechanism J. Immunol., November 15, 2006; 177(10): 7164 - 7172. [Abstract] [Full Text] [PDF]
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A. Patke, I. Mecklenbrauker, H. Erdjument-Bromage, P. Tempst, and A. Tarakhovsky BAFF controls B cell metabolic fitness through a PKC{beta}- and Akt-dependent mechanism J. Exp. Med., October 30, 2006; 203(11): 2551 - 2562. [Abstract] [Full Text] [PDF]
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C. O. Jacob, L. Pricop, C. Putterman, M. N. Koss, Y. Liu, M. Kollaros, S. A. Bixler, C. M. Ambrose, M. L. Scott, and W. Stohl Paucity of Clinical Disease despite Serological Autoimmunity and Kidney Pathology in Lupus-Prone New Zealand Mixed 2328 Mice Deficient in BAFF J. Immunol., August 15, 2006; 177(4): 2671 - 2680. [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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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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L. Heltemes-Harris, X. Liu, and T. Manser An antibody VH gene that promotes marginal zone B cell development and heavy chain allelic inclusion Int. Immunol., November 1, 2005; 17(11): 1447 - 1461. [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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G. P. Sims, R. Ettinger, Y. Shirota, C. H. Yarboro, G. G. Illei, and P. E. Lipsky Identification and characterization of circulating human transitional B cells Blood, June 1, 2005; 105(11): 4390 - 4398. [Abstract] [Full Text] [PDF]
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 M. D. Morrison, W. Reiley, M. Zhang, and S.-C. Sun An Atypical Tumor Necrosis Factor (TNF) Receptor-associated Factor-binding Motif of B Cell-activating Factor Belonging to the TNF Family (BAFF) Receptor Mediates Induction of the Noncanonical NF-{kappa}B Signaling Pathway J. Biol. Chem., March 18, 2005; 280(11): 10018 - 10024. [Abstract] [Full Text] [PDF]
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 J T Merrill BLyS antagonists and peptide tolerance induction Lupus, March 1, 2005; 14(3): 204 - 209. [Abstract] [PDF]
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Z. S. M. Rahman and T. Manser B Cells Expressing Bcl-2 and a Signaling-Impaired BAFF-Specific Receptor Fail to Mature and Are Deficient in the Formation of Lymphoid Follicles and Germinal Centers J. Immunol., November 15, 2004; 173(10): 6179 - 6188. [Abstract] [Full Text] [PDF]
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