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CUTTING EDGE |
*
Human Genome Sciences, Rockville, MD 20850; and
Division of Clinical Immunology and Rheumatology, University of Alabama, Birmingham, AL 35294
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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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B, NH2-terminal kinase
(THANK), zTNF4), a newly identified member in the TNF gene family, is a
type II membrane protein that exists in both membrane-bound and soluble
forms. BLyS exhibits a strong costimulatory function for B cell
activation in vitro (2, 3, 4, 5). Systemic administration of
soluble BLyS results in B cell expansion and elevated levels of Igs
(2). More importantly, it has been recently demonstrated
that BLyS-transgenic mice develop severe B cell hyperplasia and
autoimmune lupus-like disease characterized by the presence of
autoantibody against nuclear Ags and immune complex deposits in the
kidney. Prolonged survival and hyperactivity of the B cells contributes
to the disease phenotype (6, 7). In two murine models of
human systemic lupus erythematosus (SLE),
MRL/Mp-lpr/lpr and NZB/W F1
mice, there are increased serum levels of BLyS that seem to correlate
with autoimmune kidney damage, and the treatment with the soluble BLyS
receptor significantly improves the survival of lupus mice
(8). These results indicate that increased expression of
BLyS may lead to systemic autoimmune disease in mouse models and imply
a potential role for BLyS in human autoimmune disease. Therefore, in
the present study, we examined serum levels and function of BLyS in the
patients with SLE. Our results demonstrate that BLyS found in the sera
of SLE patients functions as a stimulator for B cell activation and is
markedly elevated compared with normal controls. |
Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Peripheral blood was obtained from 150 SLE patients meeting the American College of Rheumatology (ACR) criteria for the classification of disease (12). Serum from 40 patients was harvested and stored at -30o to -70°C until use, and plasma from a second, independent cohort of 110 SLE patients was collected and also stored at -30o to -70°C until use. Two additional subgroups of patients with positive antinuclear Abs (ANA) titers but who did not meet the ACR criteria were also selected. Disease activity was assessed by direct clinical assessment with the systemic lupus activity measure (13) usually on the same day as the blood specimen and always within 6 days. Cumulative disease damage was assessed with the Systemic Lupus International Cooperating Clinics (14) damage index at the same time. Thirty-eight normal control sera were obtained from the University of Alabama Blood Bank. Forty-four sera and 57 synovial fluids from patients fulfilling the ACR criteria for rheumatoid arthritis (RA) were also collected and stored as above. All studies were reviewed and approved by the Institutional Review Board, and written informed consent was obtained.
ELISA for measurement of BLyS
Monoclonal anti-human BLyS Abs were generated in BALB/c mice
immunized with the recombinant soluble BLyS. 15C10 (IgG2a, ) and 3D4
(IgG1, ) recognize the soluble form of BLyS specifically and are
able to neutralize the activity of BLyS. 9B6 (IgG1, ) recognizes the
membrane-bound form of BLyS and denatured BLyS in Western blot.
Polyclonal anti-BLyS Ab was raised in rabbits immunized with the
recombinant BLyS and affinity-purified by the BLyS-conjugated Sepharose
column. Irrelevant murine IgG isotype controls were purchased from
Southern Biotechnology Associates (Birmingham, AL). The sandwich ELISA
for measurement of soluble form of BLyS was developed in Human Genome
Sciences (Rockville, MD). Briefly, a 96-well plate was coated with
purified monoclonal anti-BLyS Ab (clone: 15C10) at 3 µg/ml in PBS
at 4°C overnight, and blocked with 1% BSA PBS. The purified
recombinant BLyS (2) was used as standard. All sera or
plasmas were preabsorbed with protein A-agarose to deplete Igs, 1:10
diluted in 3% BSA PBS, and incubated in the ELISA plate at 4°C
overnight. After washing, the plate was further incubated with 0.2
µg/ml biotin-conjugated polyclonal anti-BLyS Ab at room
temperature for 2 h. After addition washing, the plate was
incubated with 1:30,000 diluted HRP-conjugated streptavidin (Southern
Biotechnology) for an additional 1 h at room temperature. The
reaction was developed by the tetramethylbenzidine substrate (Sigma,
St. Louis, MO), and read in an E-Max plate reader (Molecular Device,
Sunnyvale, CA). A standard curve using serial dilutions of the
recombinant BLyS (5.57, 1.86, 0.62, 0.21, and 0 ng/ml) was incorporated
into each assay. The absolute value of BLyS for each tested sample was
calculated from the best fit of the standard curve, determined by
nonlinear regression, and multiplied by the dilution factor.
Immunoprecipitation and Western blot analysis of BLyS
Purified monoclonal anti-BLyS Ab (15C10) was conjugated to cyanogen bromide-activated Sepharose beads (Pharmacia, Uppsala, Sweden) according to the manufacturer’s instructions. The recombinant BLyS was serially diluted in 3% BSA PBS as control. One milliliter of each serum was preincubated with 100 µl of the protein A-agarose beads at room temperature for 1 h. The absorbed sera were incubated with 100 µl anti-BLyS-conjugated beads at 4°C overnight. The beads were washed five times with PBS containing 0.1% Tween 20, and denatured in 50 µl of the SDS loading buffer. The samples were separated in 15% SDS-PAGE and blotted onto nylon membranes. After blocking with 5% nonfat dry milk, the blots were probed with 1 µg/ml of a second monoclonal anti-BLyS Ab (clone: 9B6) at 4°C overnight. After washing, the blots were further incubated with HRP-conjugated goat anti-mouse IgG1 at room temperature for 1 h. The blots were developed with chemiluminescense (Kirkegaard & Perry Laboratories, Gaithersburg, MD).
Assay for B cell stimulatory activity
Flat-bottom 96-well culture plates were coated with 10 µg/ml of anti-BLyS Ab or murine IgG1 isotype control at 4°C overnight. After washing and blocking with 3% BSA PBS, various concentrations of the trimerized recombinant BLyS in 100 or 200 µl of serum were added to each of three wells and incubated for 1 h at 37°C. To insure the maximum binding of BLyS to the plates, the incubation with fresh sera was repeated three times. BSA buffer was used as a control. Splenic B cells harvested from BALB/c mice were used as the indicator for B cell proliferation. The B cell fraction was enriched from total spleen cells by depleting Thy1.2-positive cells with anti-Thy1.2 Ab and complement. Cells (5 x 105) from the B cell-enriched fraction were added to each well and incubated with 2 µg/ml of F(ab')2 anti-µ polyclonal Ab (Jackson ImmunoResearch, West Grove, PA). The cultures were conducted for 72 h, and B cell proliferation was determined by [3H]thymidine incorporation assay. The proliferation index is presented as the ratio of cpm in the presence of BLyS captured from the recombinant BLyS solution or from sera in comparison to the buffer control. To determine the ability of an excess of soluble receptor and of blocking Ab to inhibit proliferation, the B cells were incubated with the BLyS captured by 15C10 in the presence of 10 µg/ml of control IgG, 15C10, or transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI)-Fc.
Assay for autoantibodies and total Igs
ELISA kits for anti-dsDNA, anti-Sm, and Sm ribonucleoprotein were purchased from Helix Diagnostics (West Sacramento, CA). Assays were performed according to the manufacturer’s instructions except that HRP-conjugated anti-human IgM and IgA (Southern Biotechnology) were used for Ig classes. Total IgG, IgM, and IgA were measured by ELISA; the paired, purified, and HRP-conjugated anti-human IgG, IgA, and IgM were purchased from Southern Biotechnology, and affinity purified human IgG, IgM, and IgA were used as standards.
Statistics
Statistical analysis was performed using the Student t test or ANOVA test for comparison of population samples. A value of p < 0.05 was used to reject the null hypothesis.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Using a sandwich ELISA, we measured the levels of BLyS in the sera
of 150 patients with SLE, and 38 normal controls. Two independent sets
of SLE sera (SLE1) and plasmas (SLE2) were
collected and assayed. The serum levels of BLyS in both sets of samples
from SLE patients were found to be significantly higher
(p < 0.0001) than normal controls (Fig. 1
). A very similar pattern of BLyS was
found in both patient populations. The serum BLyS levels in majority of
normal controls were below 5 ng/ml, and <10% were higher than 10
ng/ml. None of the normal controls was above 12 ng/ml. In contrast, the
BLyS levels in most SLE patients were higher than 5 ng/ml, and > 30%
were above 10 ng/ml. Approximately 10% of SLE patients exhibited very
high levels (>20 ng/ml) of BLyS. The BLyS levels in a few SLE patients
were as high as nearly 40 ng/ml. Interestingly, the BLyS levels in the
sera of 44 patients with RA and the synovial fluids of 57 RA patients
were also significantly higher than that in normal sera.
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A). Dose-dependent
immunoprecipitation of recombinant BLyS demonstrated a threshold for
detection of about 15 ng/ml. The soluble form of BLyS was detected in
all 16 sera of SLE patients tested, and the size of the
immunoprecipitated BLyS exactly matched the 17 kDa of the recombinant
BLyS (Fig. 2B). However, only one (no. 2) of eight normal
controls was weakly detected (Fig. 2C). Taken together,
these results indicate that serum levels of BLyS are elevated in the
patients with SLE, and the increased BLyS in SLE1 exists in
the soluble form, which is cleaved from cell surface.
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To determine whether the BLyS in the sera of SLE patients is
functional, the B cell costimulation assay was performed using an
anti-BLyS mAb to capture the BLyS in serum onto 96-well plates and
then to costimulate B cells in the presence of anti-µ Abs. First,
we compared the capacity of two monoclonal anti-BLyS Abs and a
murine IgG1 isotype control to capture recombinant BLyS on 96-well
plates. Two anti-BLyS Abs (clone: 15C10 and 3D4) exhibited the
ability to capture of recombinant BLyS while one the isotype control
showed no significant capture activity. With 15C10 as a capture Ab, the
captured BLyS was able to bind a BLyS receptor fusion protein
(TACI-Fc). This binding correlated well with the binding of polyclonal
anti-BLyS (Fig. 3A). In
coculture of anti-µ F(ab')2-stimulated B
cells with the captured and immobilized recombinant BLyS,
dose-dependent B cell-proliferative responses were observed with mAbs
15C10 and 3D4 as capture Ab (Fig. 3B). A significantly
increased B cell proliferation response was seen in the presence of
10 ng/ml of the Ab-captured recombinant BLyS. Taken together, these
results indicate that some anti-BLyS Abs, when immobilized, are
able to capture functional BLyS. Because both 15C10 and 3D4 in solution
are able to block the functional epitope of BLyS (data not shown), we
infer that the recombinant BLyS includes polymeric forms and that all
functional epitopes of polymeric BLyS are not blocked by the
immobilized 15C10 and 3D4 capture Abs. Indeed, this is supported
directly by the availability of TACI-binding epitopes in our ELISA
(Fig. 3A). Furthermore, because BLyS has to be trimerized to
function, this capture method may detect and mimic polymeric forms of
BLyS in the biological samples.
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C). Although normal sera showed
no significant costimulatory activity, most sera from SLE patients
exhibited increased costimulatory activity in anti-µ induced B
cell proliferation. The B cell costimulatory activity captured in
SLE1 is specific for BLyS, because the preabsorption of
SLE1 with anti-BLyS Ab eliminated the activity (data
not shown), and excess mAb 15C10 or TACI-Fc added to the culture media
inhibited the costimulation of BLyS (Fig. 3D). These results
indicate that BLyS is not only increased in SLE patients but also can
function as a B cell stimulator. Correlation of BLyS with increased levels of anti-dsDNA Ab
To determine whether increased levels of BLyS play a role in the
production of autoantibodies, the sera of SLE patients were divided
into two groups according to their BLyS levels:
SLEhigh (BLyS > 15 ng/ml) and
SLElow (BLyS < 5 ng/ml) (Table I). The SLE patients with high levels of
BLyS exhibited significantly higher levels of anti-dsDNA Ab in each
of the IgG, IgM, and IgA classes compared with the SLE patients with
low levels of BLyS and normal controls (p <
0.0001). The percentage of positive anti-dsDNA Ab was also
significantly higher in the patient group with high BLyS. The
SLEhigh patients were 80%, 80%, and 60% IgG,
IgM, and IgA anti-sdDNA Ab positive, compared with 30%, 20%, and
10% in SLElow group, respectively. Total IgA and
IgG levels were slightly but significantly higher in the
SLEhigh group compared with the
SLElow and control groups
(p < 0.005 and p < 0.05,
respectively), while total IgM levels showed no differences. Two major
anti-nuclear protein autoantibodies, anti-Sm and anti-Sm
ribonucleoprotein, were also measured in two SLE and control groups.
Both autoantibody levels were significantly higher in both SLE groups
compared with normal controls but there was no consistent difference
between the BLyShigh and
BLySlow groups (data not shown). These results
indicate that increased levels of BLyS in SLE patients are associated
with increased production of anti-dsDNA Abs, which may participate
in disease pathogenesis, but not with other anti-nuclear
protein Abs.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The clinical manifestations of human SLE are both diverse and variable, and the tools to measure disease activity and disease damage are imperfect. Therefore, it is not surprising that circulating, soluble BLyS levels were not correlated with SLE activity and severity. Nonetheless, it is interesting to note patients with a positive ANA but no other ACR criteria for lupus had marginally elevated BLyS levels while those with a positive ANA and several criteria for lupus had even higher levels. This result suggests that an elevated BLyS precedes the formal fulfillment of criteria for SLE and raises the intriguing possibility that it may be a useful marker for early activation of an autoimmune diathesis. Taken together, our data suggest that BLyS is involved in the loss of B cell tolerance and that additional factors may determine progression of SLE.
BLyS naturally exists in both membrane-bound and soluble forms and may be produced primarily by monocytes (2). Our data indicate that the protein form of circulating BLyS in SLE patients is consistent with the naturally cleaved, soluble form and that it can function as a potent B cell stimulator comparable to recombinant soluble BLyS. However, many interesting questions are apparent. The cell population(s) that produce BLyS in SLE and the role of membrane-bound BLyS in production of autoantibodies through cell-cell interaction may provide insight into the pathogenesis of SLE. Among TNF gene superfamily members, some proteins transduce proliferative signals while others provide apoptosis signals (1). Because deficiencies in apoptosis can lead to the development of lupus-like disease (10), BLyS might well play an anti-apoptotic role in B cell tolerance loss. Indeed, blockade of BLyS function with a soluble form of BLyS receptors can decrease disease severity and prolong the survival in animal lupus models (8). Thus, our results suggest that anti-BLyS might be a potential therapy for human SLE and other autoimmune disease.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Drs. Robert P. Kimberly and Tong Zhou, THT 429, 1530 3rd Avenue South, Birmingham, AL 35294-0006.
3 Abbreviations used in this paper: BLyS, B lymphocyte stimulator; SLE, systemic lupus erythematosus; ANA, antinuclear Abs; SLE1, SLE sera; SLE2, SLE plasmas; RA, rheumatoid arthritis. Sm, Smith Ag; TACI, transmembrane activator and calcium modulator and cyclophilin ligand interior.
Received for publication August 17, 2000. Accepted for publication October 24, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B, and c-Jun NH2-terminal kinase. J. Biol. Chem. 274:15978.This article has been cited by other articles:
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