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Impaired b cell proliferation by Staphylococcus aureus Cowan 1 in patients with systemic lupus erythematosus.

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1008
IMPAIRED B CELL PROLIFERATION BY
STAPHYLOCOCCUS AUREUS COWAN 1 IN PATIENTS
WITH SYSTEMIC LUPUS ERYTHEMATOSUS
SHIGEMASA SAWADA, SATOSHI AMAKI, MASAMI TAKEI,
MIKI KARASAKI, and ICHITA AMAKI
We examined the proliferative response to
Staphylococcus aureus Cowan 1 (SAC) by enriched
peripheral blood B cells from patients with systemic
lupus erythematosus (SLE). Responses of B cells from
patients with active and inactive SLE were significantly
lower than those of B cells from normal individuals.
Hyporesponsivenessto SAC was not observed in healthy
family members of SLE patients. This hyporesponsiveness did not correlate with prednisolone therapy and
could not be attributed to serum factors; it did correlate
with the presence of suppressor monocytes. However,
we could not exclude the possibility of enhanced sensitivity of SLE B lymphocytes to suppressive signals delivered by the monocytes.
Systemic lupus erythematosus (SLE) is an
autoimmune disease characterized by aberrant functioning of immunocompetent cells, high titers of autoantibodies, and hypergammaglobulinemia. Recently, it has been found that unstimulated peripheral
blood lymphocytes (PBL) from patients with SLE
synthesize increased amounts of immunoglobulins and
of antibodies to hapten or DNA in short-term culture
From the First Department of Medicine, Nihon University
School of Medicine, Tokyo, Japan.
Supported in part by a grant from Nihon University School
of Medicine and by an Autoimmune Disease Research grant from
the Ministry of Health and Welfare, Tokyo, Japan.
Shigemasa Sawada, MD: Assistant Professor of Medicine;
Satoshi Amaki, MD: Clinical Fellow; Masami Takei: Postgraduate
Student; Miki Karasaki, MS: Research Assistant; Ichita Amaki,
MD: Professor of Medicine.
Address reprint requests to Shigemasa Sawada, MD, First
Department of Medicine, Nihon University School of Medicine,
Itabashi-ku , Tokyo, Japan.
Submitted for publication July 24, 1984; accepted in revised
form March 4, 1985.
Arthritis and Rheumatism, Vol. 28, No. 9 (September 1985)
(1-5). However, studies of the in vivo response to a
wide variety of antigens in SLE patients have demonstrated hyporesponsiveness, compared with the response found in normal individuals (6-9). Furthermore, in vitro production of immunoglobulins by SLE
PBL stimulated with pokeweed mitogen (PWM) is
lower than that in normal subjects (10-12). These
contradictory results may reflect differences in T cell
regulation of these different respanses by B cells.
To further study these mechanisms, it was
necessary to examine the function of B cells independent of T cell regulation. Killed Staphylococcus aureus Cowan 1 (SAC) is a T cell-independent B cell
mitogen (13). Falkoff et a1 (14) found that the proliferative response of B cells to SAC was completely
independent of T cells, although T cells are required
for B cells to mature into immunoglobulin-secreting
cells. Because the proliferative response to SAC is
independent of T cells, we used this mitogen to study
B cell function in patients with SLE.
PATIENTS AND METHODS
Patients. Twenty-seven patients with inactive SLE, 7
patients with active SLE, and 5 patients with other diseases
were studied. All SLE patients fulfilled either the American
Rheumatism Association (ARA) 1971 preliminary criteria for
the diagnosis of SLE (15) or the ARA 1982 revised criteria
for the classification of SLE (16). The normal control group
consisted of 22 healthy, age- and sex-matched individuals.
All patients with inactive SLE were taking low doses of
prednisolone (2.5-10 mg/day). None of the normal individuals or the patients with active SLE was taking any medication. Active SLE was defined by the criteria of Budman et a1
(3) as the presence of clinically identifiable active disease
(convulsions, serositis, nephritis, arthritis) in at least 1 organ
B CELL PROLIFERATION IN SLE
system, not including the skin. All patients were graded as
having active or inactive SLE by their attending physician.
Mitogens. SAC was the gift of Dr. Tsuchiya of the
Department of Clinical Pathology, Nihon University School
of Medicine, Tokyo. It was used at a final dilution of 0.01%/
well. Phytohemagglutinin-P (PHA; Difco, Detroit, MI) was
used at a final concentration of 10 pg/ml.
Cell culture. Various mononuclear cell preparations
were cultured in RPMI 1640 supplemented with penicillin (50
unitdml), streptomycin (25 pg/ml), and 10% fetal calf serum
(FCS; Cimera Biomedics, Arlington, TX). Cells were cultured in triplicate in microtiter plates, with 2 x lo5 cells in
200 pl per flat well. Since 2 x 10’ cells per flat well was the
lowest cell density in the plateau region of maximum response, this density was used in the standard assay procedure for SAC response. Dose-response curves to the mitogens were obtained, and all further experiments were done at
optimal concentrations of the mitogen. The cultures were
pulsed with tritiated thymidine (0.1 pCi per well; New
England Nuclear, Boston, MA) at 56 hours, and the cells
were harvested onto glass-wool filters with a cell harvester
(Labo Science Co., Tokyo, Japan) at 72 hours. The filters
were counted in a liquid scintillation counter. Cell viability
was checked (by ability to exclude trypan blue) after 72
hours of SAC culture.
Preparation of lymphocytes. Peripheral venous blood
was collected in heparin or acid citrate dextrose solution.
Mononuclear cells were isolated by centrifugation over
Ficoll-Hypaque (Litton Bionetics, Kensington, MD).
Isolation of enriched B lymphocytes, enriched T lymphocytes, and monocytes. A fraction enriched with T lymphocytes was separated on a nylon-wool column by a modification of the method of Julius et a1 (17). A fraction enriched
with B lymphocytes was recovered from the column by
mechanical agitation. In brief, 0.5 gm of nylon-wool (Wako
Pure Chemical Industries, Osaka, Japan) was packed into a
20-ml plastic syringe and equilibrated with RPMI 1640 with
10% FCS. Four milliliters of cell suspension (1-5 x lo7 cells)
was incubated on the column in 5% COz at 37°C for 1 hour,
and then washed with approximately 60 ml of RPMI 1640
with 10% FCS. Passed cells were collected; this was the T
cell-enriched fraction. The nylon-wool was then removed
from the syringe and compressed vigorously in RPMI with
10% FCS. Cells in the eluate were collected; this was the B
cell-enriched fraction.
Monocytes from B cell-enriched fractions were obtained by collecting the cells that adhered firmly to a petri
dish kept at 37°C for 2 hours. More than 90% of these
adherent cells were monocytes, as identified by nonspecific
esterase staining. More than 70% of the cells in the B cellenriched fractions from both patients and controls were B
cells, as determined by staining with fluorescein isothiocyanate (FITC-onjugated
goat F(ab’)* anti-human immunoglobulin (Tago, Inc., Burlingame, CA) using a FACS analyzer (Becton-Dickinson, Sunnyvale, CA). This fraction also
contained monocytes (18 5 0.8% in SLE patients and 19 ?
4% in controls, mean k SD) as determined by nonspecific
esterase staining. In B cell-enriched fractions, <6% of the
cells were T cells, as determined by the sheep red blood cell
(SRBC) rosette method or by using the FACS analyzer with
FITC-conjugated monoclonal anti-Leu-4 antibody (BectonDickinson). T cell preparations from 2 passages over nylon-
1009
wool columns contained >85% T cells, as determined by
staining with anti-Leu-4.
T cell depletion from the B cell-enriched fraction. T
cells remaining in the B cell-enriched fraction were removed
by SRBC rosetting followed by separation of rosette-forming
cells on a Ficoll-Hypaque gradient, or by cytotoxic treatment with anti-Leu-1 plus rabbit complement, according to
the method of Falkoff et a1 (14).
Pronase treatment of lymphocytes. To remove serum
factors from the surface of B cells, B cell-enriched fractions
were treated with pronase (18). Briefly, 20 pg of pronase
(Sigma, St. Louis, MO) was added to 1 ml containing 2 x lo7
enriched B cells and 100 pg of DNase (Sigma). The cells
were incubated in a 37°C water bath for 1 hour with frequent
agitation. The digestive activity of pronase was stopped by
the addition of cold RPMI with 10% FCS.
Partial depletion of monocytes by silica suspension.
Enriched B cell fractions were mixed with a 10% volume of a
silica suspension (Nihon Kotai Kenkyuzyo, Takasaki, Japan) and incubated at 37°C for 1 hour with gentle agitation.
The cell suspension was then layered over Ficoll-Hypaque
and centrifuged at 400g for 30 minutes at room temperature.
Less than 2% of the collected lymphocytes were monocytes,
as determined by nonspecific esterase staining.
Prostaglandin inhibitor. Indomethacin (Sigma), an
inhibitor of prostaglandin synthesis, was dissolved in 95%
ethyl alcohol at 10 mgiml and diluted with phosphate buffered saline, resulting in final concentrations of 0.001-0.2%
alcohol in the cultures. Indomethacin was added at final
concentrations of 0.2 pg/ml and 0.5 pg/ml at the start of cell
culture. The ethyl alcohol concentrations used had no effect
on the mitogenic response of B cell-enriched fractions from
SLE patients or normal individuals.
RESULTS
Confirmation of the independence of B cell proliferation from T cells. The proliferative response of B
cells to SAC was not diminished by extensive T cell
depletion. Depletion of T cells from the B cell-enriched fraction was confirmed by the absence of
proliferative response to PHA, despite the intact proliferative response of T cells to PHA. These results
were consistent with those of Falkoff et a1 (14).
Mitogen responses of B cell-enriched fractions
from SLE patients and normal individuals. The kinetics
of the response to SAC by cells from patients with
SLE and from normal subjects were compared. Cells
from SLE patients were hyporesponsive at the optimal
concentration of SAC (O.Ol%/well) during 9 days of
culture. The response to SAC by the B cell-enriched
fractions both from normal individuals and patients
with inactive SLE was maximal on the third day of
culture (Figures 1 and 2).
The responses to SAC of B cell-enriched fractions from the 22 normal individuals were compared
with those of all 34 SLE patients at the SAC level that
SAWADA ET AL
1010
0.1
0.01
0.001 0.OOOl
SAC concentration (%)
gave maximum response, on the third day of culture.
The mean responses by the B cell-enriched fractions
from patients with both active and inactive SLE were
significantly lower than that from normal individuals
( P < 0.01, active SLE versus controls; P < 0.0001,
inactive SLE versus controls, Student's t-test) (Figure
3). The responses to SAC by the 7 patients with active
SLE (mean A 10,366 disintegrations per minute) and
those by the 27 patients with inactive SLE (mean A
8,119 dpm) were not significantly different (P < 0.1).
In patients with active SLE, the mean percentage of
immunoglobulin-positive cells in the B cell-enriched
fractions was 78%; it was 74% in patients with inactive
SLE, and 72% in control subjects.
Effect of in vivo prednisolone on in vitro SAC
response. Because there was no apparent difference in
the response to SAC by patients taking prednisolone
versus those not taking the drug, it seemed unlikely
that prednisolone contributed to the low response by
cells from SLE patients. To further examine this, the
responses to SAC of B cell-enriched fractions from 6
non-SLE patients who had been taking prednisolone
(2.5-10 mg/day) were compared with responses by
Figure 1. Dose-response to Sraphylococcus aureus Cowan 1 (SAC)
of B cell-enriched fractions from 3 patients with inactive systemic
lupus erythematosus (hatched bars) and 3 normal individuals (open
bars). Data shown are from day 3 of 9 days of culture, at which time
response was highest in both patients and controls. Brackets represent SE. 3H-TdR = tritiated thymidine.
30
n
m
I
0
7
W
2c
E
Q
U
a
10
Active Inactive
(n=7) (n=27)
SLE
Figure 2. Kinetics of Sruphylococcus aureus Cowan 1 (SAC) responses of B cell-enriched fractions from 4 patients with inactive
systemic lupus erythematosus (broken line) and 4 normal individuals
(solid line), at the optimal concentration of SAC (O.Ol%/well).
Brackets represent SE. 'H TdR = tritiated thymidine.
1
Normal
(n=22)
Figure 3. Sraphylococcus aureus Cowan 1 response of B cellenriched fractions from patients with active or inactive systemic
lupus erythematosus (SLE) and from normal individuals. Values
shown are mean
SE. The response was significantly lower in
patients with active (P < 0.01) and inactive ( P < 0.0001) SLE
compared with normal individuals.
*
B CELL PROLIFERATION IN SLE
1011
Table 1. Effect of incubation with serum from patients with active systemic lupus erythematosus
(SLE), on Staphylococcus aureus Cowan 1 (SAC) response of B cell-enriched fractions from normal
individuals
SAC response (A dpm) with and without serum exposure
Treated with serum (dilution)*
Experiment
1
2
3
4
Source of serum
Normal
SLE
Normal
SLE
Normal
SLE
Normal
SLE
Not treated with serum
x2
x4
13,993
25,610
21,712
24,001
21,449
23,015
26,448
28,198
ND
ND
18,099
18,260
21,940
22,057
25,640
22,741
ND
ND
21,734
17,053
20,788
17,893
27,778
19,896
34,681
33,930
34,369
32,576
33,746
35,110
ND
ND
17,619
19,676
17,270
37,278
* Cells (5 x lo5) were incubated with dilute serum for 60 minutes at 4°C and for 120 minutes at 15°C.
After incubation, cells were washed twice by medium containing 10% fetal calf serum. ND = not done.
normal individuals. There was no significant difference
in the responses of the 2 groups (mean A 25,445 dpm
versus mean A 26,027 dpm, P > 0.9).
Effect of exposure to pronase on the response to
SAC by SLE sera. To examine the possibility that
hyporesponsiveness to SAC in SLE patients was due
to serum factors, B cell-enriched fractions from SLE
patients were exposed to pronase before addition of
SAC. Pronase treatment did not alter responses to
SAC of B cell-enriched fractions from SLE patients or
from normal individuals, although the percentage of
lymphocytes that had detectable surface immunoglobulins was reduced from 70-75% to 1-2%. Furthermore, B cell-enriched fractions from normal individuals were incubated for 1 hour at 4°C with sera from
patients with active SLE whose B cell-enriched fractions had exhibited a low response to SAC. The
exposure to SLE sera of B cell-enriched fractions
from normal individuals did not decrease the response
to SAC (Table 1).
Family studies. To look for a possible genetic
contribution to the hyporesponsiveness to SAC in
SLE patients, 3 family members of SLE patients were
tested for responsiveness to SAC. Their responses
were normal.
Effect of monocytes or adherent cells on the
response to SAC. To study the role of monocytes in the
hyporesponsiveness to SAC in SLE, monocytes in the
B cell-enriched fraction from patients with inactive
SLE were partially depleted by incubation with silica
suspension, followed by centrifugation through FicollHypaque. Responses to SAC by the remaining cells
were markedly increased (Figure 4). These results
suggest that hyporesponsiveness to SAC in SLE patients might be due to suppressor monocytes. The
percentage of immunoglobulin-positive cells in B cellenriched fractions increased slightly (about 4%) after
monocyte depletion, both in SLE patients and in
controls, but the increase was not significant.
S L E
p
<0.0003
s
p <0.5
30
20
10
lica (--)
Normal
(+)
Figure 4. Staphylococcus aureus Cowan 1 response of B cellenriched fractions with and fractions without silica suspension, from
patients with inactive systemic lupus erythematosus (SLE) and from
normal individuals. Responses of SLE patients were significantly
greater when the fractions were in silica suspension. There was no
significant difference between the responses of silica-treated and
nontreated fractions from normal individuals.
SAWADA ET AL
1012
To assess the role of suppressor monocytes in
SLE, adherent cells were added back to nonadherent
B cell-enriched cells, and the SAC response was
examined. The responses to SAC of B cell-enriched
fractions from SLE patients were increased by removal of adherent cells on petri dishes, and replacement of
autologous adherent cells suppressed responses to
SAC. However, responses to SAC by B cell-enriched
fractions from normal individuals did not change following removal of adherent cells (Table 2), indicating
that the presence of suppressor monocytes was unique
to SLE.
Next we used a crossover protocol: normal
adherent cells were added to B cells from patients with
inactive SLE, and SLE adherent cells were added to
normal B cells. The SAC response of SLE B cells was
not decreased by addition of normal adherent cells,
and that of normal B cells was not decreased by
addition of SLE adherent cells (Figure 5). These
results indicate that suppressor monocytes are unique
to patients with inactive SLE and that SLE B cells are
more sensitive to the suppressor signals delivered by
the SLE monocytes than are normal B cells.
Effect of indomethacin on SAC responses of B
cell-enriched fractions from SLE patients. When indomethacin was added to the culture, the responses to
SAC of B cell-enriched fractions from patients with
inactive SLE were significantly increased, whereas
only a negligible change in the responses of fractions
from normal individuals was observed (Figure 6).
Table 2. Effect of adherent cells on Staphylococcus aureus Cowan
I (SAC) responses by B cell-enriched fractions from systemic lupus
erythematosus (SLE) patients and normal controls
SAC response (A dpm)
Experiment 1
Experiment 2
Treatment
SLE
Control
SLE
Control
No treatment
Depletion of adherent
cells*
Depletion of adherent
cells and subsequent
addition to cultures
6,424
13,517t
28,821
28,094$
3,549
12,603t
28,666
28,558$
8,792
24,049
7,476
26,986
* Adherent cells from B cell-enriched fractions were depleted and
the number of lymphocytes was adjusted.
t P < 0.001 versus no treatment; P < 0.02 versus depletion of
adherent cells and subsequent addition to culture.
t No significant difference versus no treatment or versus depletion
of adherent cells and subsequent addition to culture.
§ Adherent cells (4 x lo4) from B cell-enriched fractions were
returned to culture (final % of added adherent cells: 28%).
Exp. B cells
Adherent cells
normal
normal
SLE
SLE
SLE
normal
1-
normal
SLE
normal
normal
SLE
SLE
SLE
normal
normal
SLE
normal
SLE
normal
SLE
SLE
normal
normal
SLE
1I
I
1
1
I
1
2
I
1-1
b
3
b
,
10
20
30
40
50
( X lO-’a dpm.)
SAC response
Figure 5 . Staphylococcus aureus Cowan 1 (SAC) response by 2 X
lo5 normal B cells or B cells from patients with inactive systemic
lupus erythematosus (SLE), cocultured with 4 x lo4 allogeneic
normal or SLE adherent cells. Monocytes in B cell-enriched
fractions were depleted by silica suspension. B cells from SLE
patients and from normal individuals were <2% monocytes. In
patients with inactive SLE, 80% of the cells were immunoglobulinpositive; this figure was 76% in normal individuals. More than 90%
of the adherent cells were monocytes both in SLE patients and
normal individuals.
DISCUSSION
In this study we found that the response to SAC
by B cells from patients with systemic lupus erythematosus was significantly lower than that of normal
individuals. The decreased response to SAC was not
due to prednisolone therapy or to serum factors. Such
responses were observed only in SLE patients, not in
healthy family members of the patients. Responsiveness to SAC by B cell-enriched fractions from SLE
patients reached normal levels after monocyte depletion, and replacement of monocytes in the cultures
decreased the response.
Previous investigations of the mitogenic activity of SAC on human B lymphocytes showed that the
response is independent of T cells and that the stimulatory component is protein A on the bacterial wall
B CELL PROLIFERATION IN SLE
300r
I
T
’
0
I
0.2
I
0.5 W m l )
Amount of indomethacin
Figure 6. Effect of indomethacin on Staphylococcus aureus Cowan
1 response of B cell-enriched fractions from systemic lupus erythematosus (SLE) patients (0)and normal controls (0).
Fractions were
cultured for 3 days in medium containing the indicated concentrations of indomethacin. Each point is the mean of values from 8 SLE
patients and 8 normal controls. Brackets represent SE. * P < 0.05,
SLE patients versus normal controls; ** P < 0.01, SLE patients
versus normal controls.
(13,14). Responses to SAC of B cell-enriched fractions
from non-SLE patients taking prednisolone (2.5-10
mg/day) were equivalent to those in normal individuals; thus, the mitogenic effect of SAC is not altered
by prednisolone at these dosages. Other researchers
have found that normal individuals taking low doses of
prednisolone have decreased numbers of T cells in
their peripheral blood and have a defect in suppressor
T cell function (19-21). Fauci and coworkers (22)
found that in vitro hydrocortisone in physiologically
and pharmacologically attainable concentrations
caused marked enhancement of PWM-induced response of plaque-forming cells of normal human
peripheral blood B lymphocytes. The response of B
cells to PWM is regulated by T cells. Under our study
conditions, the response to SAC was not dependent on
T cells, which may explain why prednisolone did not
affect the response.
Some patients with SLE have impaired delayed
hypersensitivity; this is seen more frequently in untreated patients (23,24). Patients with active SLE have
decreased reactivity in their lymphocyte mitogenic
response (25-28). The hyporesponsiveness to PHA
seen in some SLE patients is moderated by adherent
cells, which may be functioning as suppressor cells
(29). Patients with Hodgkin’s disease have glass-wooladherent suppressor cells, largely responsible for in
1013
vitro PHA hyporesponsiveness (30). These suppressor
adherent cells have also been found in patients with
sarcoidosis and with melanoma (3 1,321.
Stobo (33) provided evidence that immunosuppression of T cells by monocytes is due to an indirect
interaction in which macrophages may generate, or
potentiate, active suppressor T cells. Similarly, Yoshinaga et a1 (34) suggested that interactions between
macrophages and regulatory T cells may be involved
in the suppression of the B cell proliferative response
to lipopolysaccharides, because macrophages fail to
suppress such response by T-depleted spleen cells. It
has been suggested that suppressive T cells may exert
their effect through macrophages (35). From our results, it seems unlikely that cellular interactions between macrophages and regulatory T cells are involved in the hyporeponsiveness to SAC of patients
with SLE, because T cells were depleted from the
responding B cells.
Some subpopulations of human peripheral
blood monocytes produce prostaglandin (36). Goodwin et al (37) reported that the addition of indomethacin to cultured cells increased the response to PHA in
patients with Hodgkin’s disease. Moreover, adherent
cells from these patients produced more prostaglandin
E2 than did adherent cells from normal individuals. We
recently found that B ceil-enriched fractions from
SLE patients produced large amounts of prostaglandin
El, compared with those from normal individuals (38).
Decreased in vitro immunoglobulin production by
peripheral blood mononuclear cells of SLE patients or
decreased in vivo production of antibodies to a variety
of antigens in these patients might be related to
activation of suppressor monocytes in a prostaglandinmediated event.
Hasler et al(39) found that T cells from patients
with rheumatoid arthritis are strikingly more sensitive
to prostaglandin E than are normal T cells. Our results
did not exclude the possibility of enhanced sensitivity
of SLE B lymphocytes to the suppressive signals
delivered by monocytes, since the SAC response of
normal B cells was not decreased by addition of SLE
adherent cells, whereas the SAC response of SLE B
cells was. We are presently studying the sensitivity to
prostaglandin E of B lymphocytes from SLE patients
and from normal individuals.
Polyclonal activation of B cells has been seen in
short-term culture of cells from patients with SLE.
Under these circumstances, either suppressor monocytes are not stimulated or they do not suppress
preactivated B cells. It is possible that SAC activates
suppressor monocytes either directly or indirectly.
SAWADA ET AL
1014
However, this w a s evidently not t h e case with monocytes from normal controls. T h e mechanism of monocyte suppression and its effect on immune responses
requires further study, a n d we are now examining this
relationship.
ACKNOWLEDGMENTS
We wish to express our appreciation to Drs. William
Seaman, Joseph Michalski, and Candy McCombs for their
many helpful suggestions and for their critical comments.
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