Skip Navigation


Rheumatology Advance Access originally published online on May 11, 2007
Rheumatology 2007 46(7):1083-1086; doi:10.1093/rheumatology/kem097
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
46/7/1083    most recent
kem097v2
kem097v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (1)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Morimoto, S.
Right arrow Articles by Takasaki, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Morimoto, S.
Right arrow Articles by Takasaki, Y.
Related Collections
Right arrow Systemic Lupus Erythematosus and Autoimmunity
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Expression of B-cell activating factor of the tumour necrosis factor family (BAFF) in T cells in active systemic lupus erythematosus: the role of BAFF in T cell-dependent B cell pathogenic autoantibody production

S. Morimoto, S. Nakano, T. Watanabe, Y. Tamayama, A. Mitsuo, Y. Nakiri, J. Suzuki, K. Nozawa, H. Amano, Y. Tokano, T. Kobata1 and Y. Takasaki

Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo and 1Department of immunology, Dokkyo Medical University School of Medicine, Tochigi, Japan.

Correspondence to: S. Morimoto, Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan. E-mail: morimoto{at}med.juntendo.ac.jp


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Objectives. To determine whether B cell activating factor of the tumour necrosis factor family (BAFF) is involved in T cell-dependent B cell pathogenic autoantibody production in systemic lupus erythematosus (SLE).

Methods. Peripheral blood mononuclear cells (PBMCs) from 23 SLE patients were analysed by flow cytometry to examine the intracellular expression of BAFF in CD4+ and CD8+ T cells and the surface expression of BAFF-receptor (R) and TACI on CD20+ B cells. Moreover, peripheral blood was used to determine the level of BAFF messenger RNA (mRNA) in CD4+ and CD8+ T cells and the level of BAFF-R mRNA in CD20+ B cells. Blocking of BAFF function with TACI-Ig measured anti-double-stranded DNA (dsDNA) antibodies by enzyme-linked immunosorbent assay (ELISA).

Results. CD4+ and CD8+ T cells from patients with active SLE expressed intracellular BAFF whereas those from normal subjects did not. BAFF-R and TACI were expressed on B cells from both normal controls and patients with active SLE and there was no significant difference. CD4+ and CD8+ T cells from SLE patients expressed BAFF mRNA whereas those from normal controls did not. Expression of BAFF-R mRNA in CD20+ B cells showed no significant difference between SLE patients and normal controls. TACI-Ig suppressed spontaneous in vitro T cell-dependent B cell anti-dsDNA antibodies production on active SLE with kidney involvement.

Conclusions. BAFF may play a pathogenic role in SLE by stimulating T cell-dependent B cell autoantibodies production. Blockade of BAFF is a promising therapeutic approach for SLE especially in patients with kidney involvement.

KEY WORDS: Systemic lupus erythematosus, BAFF, T cell, Autoantibody production


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
B cell activating factor of the tumour necrosis factor (TNF) family (BAFF; also known as BLyS, TALL-1, THANK, TNFSF13B and zTNF4) is a 285-amino-acid member of the TNF ligand superfamily [1–6]. It is expressed as a type II transmembrane protein which is cleaved at the cell surface by a furin protease, resulting in release of a soluble, biologically active 17-kDa molecule [7]. Expression of BAFF is highly restricted to myeloid lineage cells (e.g. monocytes, macrophages, dendritic cells, neutrophils), and levels of BAFF mRNA and protein are up-regulated by interferon (IFN) {gamma}, interleukin (IL)-10 and CD40L. Expression of the three known BAFF receptors (BCMA, TACI and BAFF-R) is also highly restricted. TACI and BCMA bind both BAFF and APRIL, another TNF superfamily member, and their roles are more controversial. The agonist effects of BAFF on B cells are mediated mainly via BAFF-R [8–10].

Systemic lupus erythematosus (SLE) is characterized by loss of B cell tolerance and the presence of polyclonal B cell activation [11–13]. Recent studies have shown that the serum levels of BAFF are elevated in patients with SLE and Sjögren's syndrome and in the synovial fluid of patients with rheumatoid arthritis [14–18]. The association of each these diseases with autoantibody production suggests a potential role of increased BAFF in the disease process. Moreover, cross-sectional studies have demonstrated elevated levels of circulating BAFF in SLE [15, 16]. However, the role of T cell-dependent B cell autoantibody production by the BAFF system in SLE is still unclear.

In the present study, we examined whether BAFF is involved in T cell-dependent B cell pathogenic autoantibody production in SLE.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Acknowledgements
 References
 
Subjects
Twenty-three patients with SLE who had been admitted to Juntendo University Hospital were recruited for this study. The clinical diagnosis in all patients was made in accordance with the American College of Rheumatology 1982 revised criteria for the SLE [17]. In order to be enrolled, each patient had to be suffering from active SLE as assessed subjectively by the patient's physician, and was required to provide informed consent. Disease activity was assessed by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) [18]. Eighteen patients had nephritis [CH50: 19.3 ± 10.2 U/ml, DNA/RIA: 58.3 ± 69.5 IU/ml, SLEDAI: 23.0 ± 6.8, prednisone (median): 21.25 mg/day (range; 0–55)] and five had neuropsychiatric involvement [CH50: 39.2 ± 6.9 U/ml, DNA/RIA: 7.35 ± 4.2 IU/ml, SLEDAI: 19.5 ± 4.9, prednisone (median): 8 mg/day (range; 5–10)]. Twenty-three healthy controls were recruited from personnel at Juntendo University School of Medicine. Ethical approval was not required under the present rules of our university when using and investigating the peripheral blood of patients or healthy donors. All the patients and healthy donors were fully informed and gave their consent to participate in our study. All information and data about patients or healthy donors is kept confidential and the data are fully available to patients or donors upon request.

Antibodies and reagents
Fluorescein isothiocyanate-conjugated anti-CD45RA, anti-CD45RO, anti-CD20, anti-CD27, anti-BAFF, phycoerythrin/Cy5-conjugated anti-CD14, anti-CD20, anti-CD38, anti-BAFF-R, anti-TACI and allophycocyaninn-conjugatted anti-CD4, anti-CD8 and anti-CD20 monoclonal Ab (mAb) were purchased from BD Biosciences (San Jose, CA). Unconjugated antibodies against BAFF (1D6; mouse IgG1) and BAFF-R (8A7; mouse IgG2a) and the matched isotype control were conjugated to biotin, and the specificites of mAbs 1D6 for BAFF and 8A7 for BAFF-R have been documented previously [19, 20]. Recombinant human TACI/Fc chimera (R&D systems, MN) and recombinant human Fas/Fc chimera (Sigma, St Louis, MO) for in vitro blocking of the BAFF systems was used.

Flow cytometric analysis
In order to prepare peripheral lymphocytes, venous blood samples were collected from SLE patients and healthy controls after obtaining informed consent. Peripheral blood mononuclear cells (PBMCs) were isolated from heparinized venous blood by Ficoll density-gradient centrifugation and were triple-stained with fluorescein isothiocyanate-conjugated anti-CD45RA, anti-CD45RO, anti-CD20, anti-CD27, anti-BAFF and phycoerythrin/Cy5-conjugated anti-CD14, anti-CD20, anti-CD38, anti-BAFF-R, anti-TACI and allophycocyanin-conjugated anti-CD4, anti-CD8 and anti-CD20 mAb. For intracellular staining of BAFF, we used Intraprep (Beckman Coulter, Miami, FL) for fixation and membrization according to their manufacturer instruction. Flow cytometric analysis was performed using FACSAria (Becton Dickinson, San Jose, CA), and data were processed using the Cell Quest program (Becton Dickinson).

Determination of BAFF and BAFF-R mRNA levels in peripheral blood
For isolation of peripheral blood CD4+, CD8+ T cells or CD20+ B cells, 5 ml of peripheral blood was labelled with 40 µl of anti-human CD4, CD8 or CD20 antibody coupled to colloidal paramagnetic microbeads (Miltenyi Biotech, Bergisch-Gladbach, Germany) and isolated using AutoMACS (Miltenyi Biotech), respectively. CD4+, CD8+ or CD20+ cells were isolated at a purity of more than 93% and the resulting cell population was <2% CD14+ and <2% CD57+ as assessed by flow cytometric analysis. Total RNA was isolated from 1 x 106 CD4+, CD8+ T cells or CD20+ B cells using an RNeasy Mini kit (QIAGEN, Valencia, CA). Real-time semi-quantitative RT–PCR was performed in a single 50 µl reaction volume containing 25 µl of One-step RT–PCR SYBR Green Master Mix (Applied BioSystems, Foster City, CA) with 1.0 µl of AmpliTaq Gold DNA polymerase (Applied BioSystems), 0.25 µl of 40 x MultiScribe reverse transcriptase (Applied BioSystems), and the following sense and antisense primers at 10 nM: BAFF: 5'-GGAGAAGGCAACTCCAGTCAGAAC-3' and 5'-CAATTCATCCCCAAAGACATGGAC-3', BAFF-R: 5'-CAAGGTCATCATTCTGTCCG-3' and 5'-CGGCTCCCTGCTATTGTTGCTCA-3', APRIL: 5'-ATGCCAGCCTCATCTCCTTTC-3' and 5'-TCACAGTTTCACAAACCCCAGG-3', ß-actin: 5'-GGACTTCGAGCAAGAGATG and 3'-AGCACTGTGTTGGCGTACA. The terminal cycling conditions were 50°C for 2 min and 95°C for 10 min, followed by 40 cycles of complication at 95°C for 15 s and 60°C for 1 min for denaturing and annealing-extension, respectively. Expression of the message level was measured with an ABI PRISM 7500 Sequence Detection System (Applied BioSystems) and normalized to ß-actin mRNA.

BAFF secretion by T cells
PBMCs were isolated from active SLE and healthy controls by Ficoll–Hypaque (Pharmacia, Piscataway, NJ) density-gradient centrifugation. PBMCs were separated by the E rosette-positive and E rosette-negative populations with 5% sheep erythrocytes. The E rosette-positive cells were depleted of monocytes by adherence to the plastic surface of culture dishes and further purified T cells by complement (Cedarlane, Ontario, Canada) lysis with anti-CD57 (HNK-1; mouse IgM), anti-CD14 (63D3; mouse IgG1) plus rat anti-mouse IgG1 mAb (Becton Dickinson). The resultant T cell population was <2% CD19 and CD14, <2% CD57 and >93% CD3. T cells (2 x 105/well) were cultured in 96-well round-bottom plates in 0.2 ml of culture medium for 10 days at 37°C in a humidified atmosphere with 5% CO2. The culture supernatant was harvested and soluble (s) BAFF titres were determined using human BAFF ELISA kit (Bender Medsystems Gmbh, Vienna, Austria). Assays were performed according to the manufacturer's instructions.

Suppression of anti-dsDNA antibodies by TACI-Ig
PBMCs were depleted of monocytes by adhesion to the plastic culture dishes and further purified into lymphocytes by complement (Cedarlane, Ontario, Canada) lysis with HNK-1 and 63D3 plus rat anti-mouse IgG1 mAb (PharMingen). The resulting cell population was <2% CD14+ and <2% CD57+. All cultures were conducted in RPMI 1640 medium supplemented with 10% FCS, 2 mM l-glutamine, penicillin G (200 U/ml) and gentamicine (10 µg/ml). Lymphocytes (2 x 105/well) were cultured in 96-well round-bottom plates in 0.2 ml of culture medium for 10 days at 37°C in a humidified atmosphere with 5% CO2. Nil, TACI-Ig or control-Ig was added at the beginning of the experiment. The culture supernatants were harvested and anti-dsDNA titres were determined using an ELISA kit (Bio-Rad, CA, USA). Assays were performed according to the manufacturer's instructions.

Statistics
Statistical analysis was performed using non-parametric test for comparison of population samples. A value of P < 0.05 was used to reject the null hypothesis.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Acknowledgements
 References
 
Expression of BAFF or BAFF-R on circulating lymphocytes
To determine whether the increased BAFF antigen is produced by circulating T cells in patients with active SLE, we first examined its surface expression by flow cytometric analysis. Monocyte from active SLE was highly expressed BAFF antigen (CD14+; 28.6 ± 3.4) [mean fluorescence intensity (MFI)]. However, we did not detect any cell surface expression of BAFF on T cells from either control subjects or patients with active SLE (data not shown). We then looked for intracellular expression of BAFF in circulating T cells. A striking finding was that CD4+ T cells from patients with active SLE showed the intracellular BAFF expression, whereas those from normal controls did not (Fig. 1A). This CD4+ T cell population comprised almost entirely memory (CD45RO+) T cells (data not shown). Another unexpected finding was that CD8+ T cells from patients with active SLE also expressed the BAFF antigen (Fig. 1B), whereas circulating CD8+ T cells from normal controls did not.


Figure 1
View larger version (45K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		FIG. 1. Expression of BAFF and BAFF receptor in the peripheral blood of representative patients with active SLE and normal controls. (A) CD4+ T cells appear above the vertical line and BAFF appear above the horizontal line. (B) CD8+ T cells are shown above the vertical line and BAFF is shown above the horizontal line. For intracellular staining of BAFF, we used Intraprep for fixation and membrization according to the instructions supplied by the manufacturer. (C) CD20+ cell expression is shown above the vertical line and BAFF-R is shown above the horizontal line. (D) CD20+ cells are shown above the vertical line and TACI is shown above the horizontal line. PBMCs obtained from representative normal controls and representative patients with active SLE were double stained for surface CD20 and surface BAFF-R or TACI. (E) Real-time semi-quantitative RT–PCR for the expression of BAFF mRNA levels on CD4+ and CD8+ T cells in the blood of representative patients with active SLE and normal controls. Peripheral blood CD4+ and CD8+ T cells were isolated by AutoMACS using anti-human CD4 and CD8 antibody coupled to colloidal paramagnetic microbeads, respectively. The sizes of the products for BAFF and ß-actin were 227 and 234 bp, respectively. (F) Real-time semi-quantitative RT–PCR for the expression of BAFF-R mRNA on CD20+ B cells in the blood of representative patients with active SLE and normal controls. Peripheral blood CD20+ B cells were isolated by AutoMACS using anti-human CD20 antibody coupled to colloidal paramagnetic microbeads, respectively. The sizes of the products for BAFF-R and ß-actin were 249 and 234 bp, respectively.

 
In particular, patients with kidney involvement had significantly higher MFI of intracellular BAFF expression on CD4+ T cells (23.4 ± 8.74) and CD8+ T cells (20.1 ± 4.80) in comparison with non-kidney involvement (CD4+: 6.40 ± 0.57, CD8+: 19.7 ± 11.46) and normal controls (CD4+: 4.19 ± 0.74, CD8+: 6.01 ± 1.56), respectively (P < 0.01).

We next examined the expression of BAFF receptors on B cells. BAFF-R and TACI were expressed on B cells from both normal controls and patients with active SLE and the expression levels in the two groups did not differ significantly (Fig. 1C and D). Within the sensitivity limits of flow cytometric analysis, the expression of BAFF receptors on B cells from SLE was similar to that on the same B cell subsets in healthy controls [21].

Expression of BAFF or BAFF receptors mRNA in active SLE
A previous study has demonstrated overexpression of BAFF mRNA in peripheral blood leucocytes from SLE [22], although the subpopulation of lymphocytes expressing the BAFF mRNA was unclear. Therefore, we investigated the expression of mRNA for BAFF in CD4+or CD8+lymphocytes. CD4+ T lymphocytes in SLE expressed the BAFF mRNA, but those from normal controls did not (Fig. 1E and F). Moreover, CD8+ T lymphocytes from SLE was also expressed the BAFF mRNA (Fig. 1E and F). We think that these results neglect the monocyte contamination by flow-cytometric analysis (CD14+ <2%). However, CD4+ and CD8+ T cells did not express APRIL mRNA (data not shown).

We then investigated the expression of mRNA for BAFF-R in CD20+ B cells from SLE and normal controls, and found that both groups expressed the BAFF-R mRNA, with no significant expression level between them (Fig. 1G and H).

BAFF secretion by T cells from active SLE
Then, we examined the BAFF secretion by T cells from active SLE. T cells from active SLE and normal controls produced 7.2 ± 1.1 and 1.3 ± 0.7 (ng/ml), respectively, of sBAFF in vitro without any stimulation (P < 0.05). We found T cells from active SLE produced higher amount of sBAFF than T cells from normal control under basal conditions.

In vitro suppression of anti-dsDNA antibodies production by TACI-Ig
To investigate the direct involvement of BAFF in T cell-dependent B cell autoantibody production, we then examined whether TACI-Ig inhibited spontaneous production of anti-dsDNA antibodies by cultured T and B cells from six patients with active SLE showing kidney involvement. Table 1 shows the characteristics of the individual SLE and the extent of suppression of anti-dsDNA antibody titres by TACI-Ig. The addition of TACI-Ig, but not control-Ig, significantly suppressed in vitro T cell-dependent anti-dsDNA antibodies production by B cells. These results strongly suggest that BAFF plays an important role in T-cell-dependent anti-dsDNA antibodies production in SLE patients through BAFF-R and/or TACI.


View this table:
[in this window]
[in a new window]

  		TABLE 1. Characteristics of individual members of patients in SLE with kidney involvement and suppression of anti-double-stranded DNA (dsDNA) antibodies blockade of BAFF system by TACI-Ig

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Acknowledgements
 References
 
In the present study, we have demonstrated abnormal production of BAFF in T cells from SLE (Fig. 1), especially in patients with kidney involvement. Furthermore, we showed that blocking of BAFF in T cell–B cell interaction reduced the production of autoantibody by TACI-Ig. These results suggest that another mechanism operates in the pathogenesis in SLE, i.e. autoantibody production driven by BAFF produced in part by T cells, supporting a previous study indicating expression of BAFF by T cells [4]. A recent study has also shown that BAFF is expressed in T cells infiltrating salivary glands in patients with Sjögrne's syndrome [14, 23]. Moreover, a very recent report has indicated that SLE T cells produce soluble BAFF upon stimulation and that the BAFF mRNA robustly induced by a human TE cell line, Loucy [24]. Therefore, we tried to stimulate T cells with anti-CD3 to study a possible increase of BAFF expression by intracellular cytometric assay (data not shown). The result was controversial. We speculate this reason why CD3/TCR-mediated response of purified T cells in SLE ranges normal to enhanced [25] and T cells from SLE display a number of signalling abnormalities (e.g. decreased expression of TCR {zeta} chain) [26]. However, previous reports and our present data suggest that the role of T cell-derived BAFF in the production of autoantibodies may provide insight into the pathogenesis and development of SLE, especially that with kidney involvement.

Another unexpected finding in this study was expression of BAFF and increased levels of mRNA in CD8+ T cells from SLE, but not in those from normal controls (Fig. 1B and E). This result leads us to hypothesize that CD8+ T cells synergize with CD4+ T cells to support pathogenic autoantibody production in SLE. A previous report indicating that CD8+ T cells can have positive rather than negative effects on antibody production in SLE has important implications in relation to the mechanism of autoantibody formation in this disease [27]. This report indicated that removal of either CD8+ or CD4+ lymphocytes markedly decreased the spontaneous in vitro production of polyclonal IgG and/or anti-dsDNA antibodies production by PBMC in SLE. Thus, it seems that, in human SLE, there is a requirement for both CD8+ and CD4+ T cells for generation of pathogenic autoantibodies and that regulation of homoeostatic T cells is defective.

Moreover, present study showed that blocking of BAFF in T cell–B cell interaction reduced the production of autoantibody by TACI-Ig which is a soluble decoy receptor for BAFF and APRIL. Patients with SLE have elevated serum levels of BAFF correlated with elevated levels of autoreactive Abs [15]. Therefore, BAFF may be an appropriate target for intervention in autoimmune diseases in which elevated levels of autoantibodies contribute to disease pathology. In NZB/W F1 mice, administration of TACI-Ig and/or BAFF-R-Ig prolongs the life span [28] and prevents the emergence of IgG anti-DNA antibodies [9]. That study has shown that treatment of NZB/W F1 mice with BAFF-R-Ig reduced the circulating levels of anti-dsDNA antibody titres in parallel with clinical improvement [9]. These results and our present data suggest that BAFF derived from T cells may also play a pathogenic role of SLE and blockade of BAFF as a promising therapeutic approach for SLE, especially in patients with kidney involvement.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
References
 
We thank Dr Naoyuki Tsuchiya for helpful discussion and we are grateful to D. Douglas for assistance in preparing the manuscript.

The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 

  1. Gross JA, Johnston J, Mudri S, Enselman R, et al. TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature (2000) 404:995–9.[CrossRef][Medline]
  2. Tribouley C, Wallroth M, Chan V, et al. Characterization of a new member of the TNF family expressed on antigen presenting cells. Biol Chem (1999) 380:1443–7.[CrossRef][ISI][Medline]
  3. Shu HB, Hu WH, Johnson H. TALL-1 is a novel member of the TNF family that is down-regulated by mitogens. J Leukoc Biol (1999) 65:680–3.[Abstract]
  4. Schneider P, MacKay F, Steiner V, et al. BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med (1999) 189:1747–56.[Abstract/Free Full Text]
  5. Mukhopadhyay A, Ni J, Zhai Y, Yu GL, Aggarwal BB. Identification and characterization of a novel cytokine, THANK, a TNF homologue that activates apoptosis, nuclear factor-kappaB, and c-Jun NH2-terminal kinase. J Biol Chem (1999) 274:15978–81.[Abstract/Free Full Text]
  6. Moore PA, Belvedere O, Orr A, et al. BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science (1999) 285:260–3.[Abstract/Free Full Text]
  7. Nardelli B, Belvedere O, Roschke V, et al. Synthesis and release of B-lymphocyte stimulator from myeloid cells. Blood (2001) 97:198–204.
  8. Mackay IR, Groom J, Mackay CR. Levels of BAFF in serum in primary biliary cirrhosis and autoimmune diabetes. Autoimmunity (2002) 35:551–3.[CrossRef][ISI][Medline]
  9. Kayagaki N, Yan M, Seshasayee D, et al. BAFF/BLyS receptor 3 binds the B cell survival factor BAFF ligand through a discrete surface loop and promotes processing of NF-kappaB2. Immunity (2002) 17:515–24.[CrossRef][ISI][Medline]
  10. Claudio E, Brown K, Park S, Wang H, Siebenlist U. BAFF-induced NEMO-independent processing of NF-kappa B2 in maturing B cells. Nat Immunol (2002) 3:958–65.[CrossRef][ISI][Medline]
  11. Livneh A, Or G, Many A, Gazit E, Diamond B. Anti-DNA antibodies secreted by peripheral B cells of lupus patients have both normal and lupus-specific features. Clin Immunol Immunopathol (1993) 68:68–73.[CrossRef][ISI][Medline]
  12. Klinman DM, Shirai A, Ishigatsubo Y, Conover J, Steinberg AD. Quantitation of IgM- and IgG-secreting B cells in the peripheral blood of patients with systemic lupus erythematosus. Arthritis Rheum (1991) 34:1404–10.[ISI][Medline]
  13. Klinman DM, Steinberg AD. Systemic autoimmune disease arises from polyclonal B cell activation. J Exp Med (1987) 165:1755–60.[Abstract/Free Full Text]
  14. Groom J, Kalled SL, Cutler AH, et al. Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjogren's syndrome. J Clin Invest (2002) 109:59–68.[CrossRef][ISI][Medline]
  15. Zhang J, Roschke V, Baker KP, et al. Cutting edge: a role for B lymphocyte stimulator in systemic lupus erythematosus. J Immunol (2001) 166:6–10.[Abstract/Free Full Text]
  16. Cheema GS, Roschke V, Hilbert DM, Stohl W. Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases. Arthritis Rheum (2001) 44:1313–19.[CrossRef][ISI][Medline]
  17. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum (1982) 25:1271–7.[ISI][Medline]
  18. Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum (1992) 35:630–40.[ISI][Medline]
  19. Nakamura N, Hase H, Sakurai D, et al. Expression of BAFF-R (BR 3) in normal and neoplastic lymphoid tissues characterized with a newly developed monoclonal antibody. Virchows Arch (2005) 447:53–60.[CrossRef][ISI][Medline]
  20. Hase H, Kanno Y, Kojima M, et al. BAFF/BLyS can potentiate B-cell selection with the B-cell coreceptor complex. Blood (2004) 103:2257–65.
  21. Carter RH, Zhao H, Liu X, et al. Expression and occupancy of BAFF-R on B cells in systemic lupus erythematosus. Arthritis Rheum (2005) 52:3943–54.[CrossRef][ISI][Medline]
  22. Stohl W, Metyas S, Tan SM, et al. B lymphocyte stimulator overexpression in patients with systemic lupus erythematosus: longitudinal observations. Arthritis Rheum (2003) 48:3475–86.[CrossRef][ISI][Medline]
  23. Lavie F, Miceli-Richard C, Quillard J, Roux S, Leclerc P, Mariette X. Expression of BAFF (BLyS) in T cells infiltrating labial salivary glands from patients with Sjogren's syndrome. J Pathol (2004) 202:496–502.[CrossRef][ISI][Medline]
  24. Yoshimoto K, Takahashi Y, Ogasawara M, et al. Aberrant expression of BAFF in T cells of systemic lupus erythematosus, which is recapitulated by a human T cell line, Loucy. Int Immunol (2006) 18:1189–96.[Abstract/Free Full Text]
  25. Stohl W. Impaired generation of polyclonal T cell-mediated cytolytic activity despite normal polyclonal T cell proliferation in systemic lupus erythematosus. Clin Immunol Immunopathol (1992) 63:163–72.[CrossRef][ISI][Medline]
  26. Nambiar MP, Fisher CU, Warke VG, et al. Reconstitution of deficient T cell receptor zeta chain restores T cell signaling and augments T cell receptor/CD3-induced interleukin-2 production in patients with systemic lupus erythematosus. Arthritis Rheum (2003) 48:1948–55.[CrossRef][ISI][Medline]
  27. Linker-Israeli M, Quismorio FP Jr, Horwitz DA. CD8+ lymphocytes from patients with systemic lupus erythematosus sustain, rather than suppress, spontaneous polyclonal IgG production and synergize with CD4+ cells to support autoantibody synthesis. Arthritis Rheum (1990) 33:1216–25.[ISI][Medline]
  28. Ramanujam M, Wang X, Huang W, et al. Similarities and differences between selective and nonselective BAFF blockade in murine SLE. J Clin Invest (2006) 116:724–34.[CrossRef][ISI][Medline]
Submitted 19 October 2006; revised version accepted 21 March 2007.
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
46/7/1083    most recent
kem097v2
kem097v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (1)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Morimoto, S.
Right arrow Articles by Takasaki, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Morimoto, S.
Right arrow Articles by Takasaki, Y.
Related Collections
Right arrow Systemic Lupus Erythematosus and Autoimmunity
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?