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Dysregulation of interleukin-10 production in relatives of patients with systemic lupus erythematosus.

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ARTHRITIS & RHEUMATISM
Vol. 40, No, 8, August 1997, pp 1429-1435
0 1997, American College of Rheumatology
1429
DYSREGULATION OF INTERLEUKIN-10 PRODUCTION IN
RELATIVES OF PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS
LUIS LLORENTE, YVONNE RICHAUD-PATIN, JACQUES COUDERC, DONATO ALARCON-SEGOVIA,
RODRIGO RUIZ-SOTO, NATASHA ALCOCER-CASTILLEJOS, JORGE ALCOCER-VARELA,
JULIO GRANADOS, SUSANA BAHENA, PIERRE GALANAUD, and DOMINIQUE EMILIE
Objective. To evaluate interleukin-10 (IL-10) production in relatives of patients with systemic lupus
erythematosus (SLE).
Methods. Production of IL-10 was evaluated in 13
families in which several members had SLE. The constitutive IL-10 production in SLE patients (n = 16) was
compared with that in healthy members of these multiplex families (n = 70), in 30 SLE patients who had no
relatives with SLE, and in 46 healthy unrelated controls.
Results. The level of IL-10 production did not
differ between SLE patients who were members and
those who were not members of multiplex families
(mean f SEM 4,384 f 908 pglml and 4,709 f 560
pglml, respectively), but was higher in both groups than
in healthy unrelated controls (515 & 88 pglml). The
healthy members of the multiplex families constitutively
produced large amounts of IL-10 (3,080 -C 311 pglml; P
< 0.001 compared with healthy unrelated controls).
This high IL-10 production was independent of age and
sex, and was similar in first- and second-degree relatives of SLE patients. The IL-10 was produced both by
monocytes and by a subpopulation of B lymphocytes in
SLE patients and in their relatives.
Conclusion. The dysregulation of IL-10 producSupported in part by grants from the Consejo Nacional de
Ciencia y Tecnologia (CONACYT) (0005PM), Mexico, the INSERMCONACYT Joint Research Program, the Association de Recherche
sur la Polyarthrite, the Association Claude Bernard, and the Universite
Paris-Sud, France.
Luis Llorente, MD, Yvonne Richaud-Patin, BS, Donato
Alarcon-Segovia, MD, Rodrigo Ruiz-Soto, MD, Natasha AlcocerCastillejos, MD, Jorge Alcocer-Varela, MD, Julio Granados, MD,
Susana Bahena, BS: Instituto Nacional de la Nutricion Salvador
Zubiran, Mexico City, Mexico; Jacques Couderc, PhD, Pierre Galanaud, MD, Dominique Emilie, MD, PhD: Institut-Paris-Sud sur les
Cytokines, Clamart, France.
Address reprint requests to Luis Llorente, MD, Department
of Immunology and Rheumatology, Instituto Nacional de la Nutricion
Salvador Zubiran, Vasco de Quiroga 15, 14000 Mexico, DF, Mexico.
Submitted for publication January 16, 1997; accepted in
revised form March 17, 1997.
tion previously identified in SLE patients is also present
in healthy members of families with several cases of
SLE, and it may contribute to the immunologic abnormalities affecting relatives of SLE patients.
The immune dysregulation that leads to overt
systemic lupus erythematosus (SLE) is complex, but has
2 main characteristics. One is B lymphocyte hyperactivity and immunoglobulin repertoire changes causing both
increased spontaneous production of immunoglobulins
and autoantibody production (1). The other is impaired
cell-mediated immunity (2). This includes decreased T
cell proliferative responses in autologous mixed lymphocyte reactions or following stimulation with mitogens,
interleukin-1 (IL-1), or IL-2, as well as decreased production of these 2 cytokines (3-5). The impaired cellmediated immunity results from both T lymphocyte and
antigen-presenting cell dysfunctions (6,7).
IL-10 is a potent stimulator of B lymphocytes (8),
and it stimulates the production of anti-DNA autoantibodies by peripheral blood mononuclear cells (PBMC)
from SLE patients (9). It is also a potent inhibitor of
both antigen-presenting cell and T lymphocyte functions
(10-12). Increased production of IL-10 could thus explain the 2 main characteristics of the immune dysregulation of SLE. Consistent with this, several recent studies
have demonstrated increased production of IL-10 in
SLE patients (13-17).
Immune dysregulation partially mimicking that of
SLE has been described in healthy relatives of SLE
patients. Some of these relatives display autoreactive B
lymphocyte hyperactivity, although the autoantibodies
produced are of low affinity and are not pathogenic (18).
A larger proportion of the relatives display impaired
cell-mediated immunity, decreased IL-2 production, and
polyclonal B lymphocyte hyperactivity (19,20). Therefore, relatives of SLE patients may display a dysregula-
LLORENTE ET AL
1430
tion of IL-10 production similar to that found in patients. This hypothesis was tested in the present work.
PATIENTS AND METHODS
Patients and normal subjects. The study included 16
SLE patients who were members of 13 multiplex families, each
of which had at least 2 members with SLE, 70 healthy members
of these 13 families, 30 unrelated SLE patients with n o other
cases of SLE in their families, and 46 healthy unrelated
controls. The 4 groups were tested in parallel in all experiments. All SLE patients fulfilled the American College of
Rheumatology revised criteria for SLE (21). Nine SLE patients
from the multiplex families and 26 of the unrelated SLE
patients were treated with corticosteroids, with or without
other immunosuppressive agents. Under the experimental
conditions used, these treatments had no detectable effect on
the constitutive production of IL-10. In the multiplex families,
first-degree and second-degree relatives of SLE patients were
studied in addition to SLE patients. All subjects included in
this study were born in Mexico of Mexican parents and had the
characteristics of Mexican Mestizos.
Purification and culture of PBMC. PBMC were isolated on Histopaque (Sigma, St. Louis, MO) by gradient
centrifugation. In some experiments, PBMC populations were
fractionated as follows. PBMC were cultured for 2 hours at
37°C on plastic Petri dishes. Then nonadherent cells were
removed, and adherent cells were cultured for 1 hour at 4°C in
phosphate buffered saline (PBS)/EDTA. They were then recovered using a rubber policeman. B cells were isolated from
the nonadherent cell population by incubating them with
anti-CD19-coated magnetic beads (Dynal, Oslo, Norway). The
remaining cells (T lymphocytes) were rosetted twice with
AET-treated sheep red blood cells. Pellets of PBMC or of their
subpopulations were stored at -70°C for analysis of RNA.
Cell cultures. One million unfractionated PBMC or
cell subpopulations were cultured for 24 hours in 1 ml RPMI
1640 containing 10% gamma globulin-free fetal calf serum
(Gibco BRL, Gaithersburg, MD). The concentration of IL-10
in the supernatant was measured by enzyme-linked immunosorbent assay (Diaclone, Besanson, France).
Flow cytometric detection of intracellular IL-10. A
FACScan (Becton Dickinson, Mountain View, CA) was used
for 2-color flow cytometric analysis. PBMC were washed twice
in PBS containing 1% fetal calf serum and stained for 20
minutes at 4°C with an anti-CD3, an anti-CD19, or an antiCD14 phycoerythrin (PE)-conjugated monoclonal antibody
(MAb) (Immunotech, Marseille, France). Washed cells were
fixed in 1 ml 4% paraformaldehyde for 15 minutes at room
temperature and were permeabilized for 1 hour in 1 ml 0.1%
saponin in Hanks’ balanced salt solution containing 0.01M
HEPES. After 2 washes, cells were incubated with an antiIL-10 fluorescein isothiocyanate (F1TC)-conjugated MAb
(Diaclone) for 20 minutes at 4°C. After 6 washes, cells were
analyzed. As controls, y l and y2a MAb conjugated with either
PE or FITC (Becton Dickinson) were used to set the threshold
and gates in the cytometer. An electronic gate was set for
CD3+ cells, CD19-t cells, or CD14+ cells, and l-parameter
histograms were analyzed for specific quantitation of intracellular IL-10 in each subpopulation studied.
Detection of IL-10 messenger RNA by semiquantitative reverse transcriptase polymerase chain reaction (RTPCR). Evaluation of IL-10 production was performed as
previously described (14). RNA was isolated from frozen B
lymphocytes, T lymphocytes, and monocytes using the Trizol
technique according to the recommendations of the manufacturer (Gibco BRL). The RNA was treated at 37°C for 30
minutes with 10 units of RNase-free DNase (Gibco BRL), then
extracted with phenol and chloroform/isoamyl alcohol (24/1,
volume/volume) and precipitated with ethanol. RT-PCR was
performed using 1 pg of RNA that had been treated for 1hour
at 42°C with 50 units of Moloney murine leukemia virus RT
(Gibco BRL) in the presence of 2.5 p M oligo-dT(,,.,,, (Gibco
BRL) and 0.5 mill of each of the 4 dNTPs.
For each sample, half of the RT product was then
processed for IL-10 PCR. To the reaction mixture were added
30 pmoles of sense primer (5’-ATCAAGGCGCATGTGA
ACTC-3’), 30 prnoles of antisense primer (5’-AGAGCGC
CAGATCCGATTTT-3‘), and 2 units of Tuq polymerase
(Gibco BRL). The expected size of the amplified product was
295 basepairs. Each cycle of amplification was at 94°C for 1
minute, 55°C for 1 minute, and 72°C for 1 minute. After 28
cycles, the products were subjected to electrophoresis on
agarose gels and stained with ethidium bromide. The other
half of the RT product was tested for p-actin messenger RNA
(mRNA) using the same procedure with the oligonucleotides
5’-GGGTCAGAAGGATTCCTATG-3’
and 5‘-GGTCTC
AAACATGATCTGGG-3’ as sense and antisense primers,
respectively. The size of the amplified p-actin product was 268
bp. Negative controls included samples from which RT was
omitted during the processing, and samples to which no
complementary DNA was added during the PCR reaction.
Polaroid negatives were used for densitometric analysis. The intensity of IL-10 bands and that of p-actin bands were
each determined, and for each sample, results are expressed as
the ratio between IL-10 and p-actin band intensities. The band
intensities for the p-actin mRNA-amplified product from
undiluted RNA sample and from graded dilutions of the same
sample were measured in 3 SLE patients with high levels of
IL-10 mRNA as described previously (14). This experiment
showed that the IL-1O:D-actin ratio is directly related to IL-10
mRNA concentration for ratios <1S.
RESULTS
Increased IL-10 production in relatives of patients with SLE. We studied IL-10 production in members of 13 multiplex families, each containing several
SLE patients. T h e families comprised 70 healthy individuals and 16 SLE patients. We similarly studied 76
unrelated individuals: 30 SLE patients and 46 healthy
controls. IL-10 production was similar in SLE patients
from the multiplex families and in SLE patients who had
no relative with the disease. Consistent with previous
findings (13,14), production of IL-10 in both groups of
SLE patients was higher than that in healthy unrelated
controls (mean 2 SEM 4,384 ? 908 pg/ml and 4,709 +560 pg/ml in patients who were a n d those who were not
IL-10 DYSREGULATION IN RELATIVES OF SLE PATIENTS
1431
Table 1. Prevalence of abnormally high interleukin-10 production
among systemic lupus erythematosus (SLE) patients who were and
SLE patients who were not members of multiplex families, healthy
members of the multiplex families, and healthy controls not related to
any SLE patients*
Healthy individuals
SLE patients
Controls
0
1000
2000
3000
4000
5000
6000
IL-10 (pglml)
Figure I. Production of interleukin-10 (IL-10) by systemic lupus
erythematosus (SLE) patients and their relatives. The constitutive
production of IL-10 by cultured peripheral blood mononuclear cells
was determined for SLE patients unrelated to the multiplex families
(n = 30), for SLE patients from multiplex families ( M x . SLE; n = 16),
for the healthy relatives of the patients from multiplex families (n =
70), and for 46 healthy unrelated controls. Values are the mean and
SEM.
members of multiplex families, respectively). Healthy
members of the multiplex families produced much more
IL-10 than did healthy unrelated controls (3,080 % 311
pg/ml versus 515 % 88 pg/ml; P < 0.001 by Student’s
t-test). In the multiplex families, IL-10 production by
healthy members was only slightly lower than that by
SLE patients (P < 0.05) (Figure 1).
In each group, we determined the proportion of
individuals with abnormally high IL-10 production. The
cutoff value for normal IL-10 production was defined as
2 standard deviations above the mean in healthy unrelated controls; this cutoff value was 1,042 pg/ml. The
prevalence of increased IL-10 production was high in the
group of healthy members of multiplex families, and did
not differ significantly from that in the SLE patients
(Table 1).
IL-10 dysregulation in relatives of SLE patients,
and associations with sex, age, and relatedness to SLE
patients. We next investigated whether, among healthy
members of the multiplex families, the prevalence of
high IL-10 production and its level differed according to
sex, age, or relatedness to SLE patients. Neither the
prevalence of high IL-10 production nor the mean level
of production differed between males and females (P >
0.1) (Table 2). The mean level of IL-10 production was
higher in healthy first-degree than in healthy seconddegree relatives of SLE patients, but the difference was
not significant (P > 0.1) (Table 2). IL-10 production in
Unrelated individuals,
no. (5%)
Members of the
multiplex families,
no. (%)
2/46 (4.3)
25/30 (83.3)
42/70 (60.0)t
12/16 (75.0)
* Abnormally high interleukin-10 production was defined as constitutive production >1,042 pg/ml.
t P < 0.001, by chi-square test, versus healthy individuals not related to
any SLE patients.
healthy members of the multiplex families was not
significantly related to their age. The tendency toward
lower IL-10 production in young individuals was not
significant (P = 0.064, regression analysis).
Production of IL-10 by monocytes and B lymphocytes in relatives of SLE patients. The cellular origin of
IL-10 production in relatives of SLE patients was then
studied. PBMC were fractionated and cultured for 24
hours without deliberate stimulation. The IL-10 concentration in the supernatant was then measured. Both
monocytes and B lymphocytes from healthy members of
the multiplex families constitutively released IL-10,
whereas those from healthy controls did not. T lymphocytes from healthy members of the multiplex families did
not produce significant amounts of IL-10 (Figure 2).
We then investigated for IL-10 mRNA in the
various cell populations. We purified monocytes, B
lymphocytes, and T lymphocytes from healthy members
of the multiplex families and from healthy unrelated
controls, and we determined their IL-10 mRNA content
using a semiquantitative RT-PCR. Only a small amount
Table 2. Interleukin-10 (IL-10) production in relation to sex and
degree of relatedness in healthy members of the multiplex families*
First-degree
relatives
Second-degree
relatives
Total
Males
Females
Total
3,375 2 621
(13/20)
2,098 -t 547
(315)
3,119 t 535
(16/25)
3,435 i- 560
(18/26)
2,543 5 564
(14119)
3,059 i- 390
(32/45)
3,409 -t 403
(31146)
2,451 t 483
(17124)
* The constitutive production of IL-10 by peripheral blood mononuclear cells from healthy members of the multiplex families was
determined according to sex and to the degree of relatedness to
systemic lypus erythematosus patients. Values are the mean i- SEM
IL-10 production in pg/ml (no. of subjects with abnormally high IL-10
production [>1,042 pgiml]). There were no statistically significant
differences among the variables studied.
LLORENTE ET AL
1432
4000
T
~
H
-E
.
-
w
SLE relatives
controls
SLE relatives
controls
T
3000
D)
a
C
.-
2000
a
U
en
z
i
1000
0
L
B lymphocytes
B lymphocytes
monocytes
T lymphocytes
Figure 2. Production of IL-10 by B lymphocytes and monocytes from
relatives of SLE patients. The constitutive production of IL-10 was
measured as the spontaneous release of IL-10 in short-term cultures.
IL-10 production by purified B lymphocytes, T lymphocytes, and
monocytes from healthy members of the multiplex families (n = 6) and
from healthy unrelated controls (n = 6) is shown. Values are the mean
and SEM. See Figure 1 for definitions.
of IL-10 mRNA was detected in cells from healthy
controls, whether of B lymphocyte, T lymphocyte, or
monocyte origin. In contrast, IL-10 gene expression was
detected in both B lymphocytes and monocytes from
healthy members of the multiplex families. T lymphocytes from members of this latter group contained only
low amounts of IL-10 mRNA (Figure 3).
IL-10 production by a fraction of B lymphocytes
from SLE patients and their relatives. To determine
whether high IL-10 production by B lymphocytes and by
monocytes resulted from the recruitment of an IL-10producing cell subpopulation, we analyzed the IL-10
production of single cells. Intracellular IL-10 was detected by flow cytometric analysis of freshly isolated and
unstimulated PBMC. Results of a typical experiment are
shown in Figure 4, and the complete results are shown in
Table 3. Few, if any, T lymphocytes from healthy controls, SLE patients, or healthy relatives of SLE patients
contained IL-10. IL-10-containing monocytes were observed in these 3 groups of subjects, and the fraction of
positive cells did not dramatically differ between them.
Since the level of IL-10 in individual cells is not accurately measured by flow cytometry, it is unclear whether
IL-10 production by monocytes is increased in SLE
patients and in their relatives because the entire monocyte population is activated and produces more IL-10, or
because a fraction of monocytes is abnormally activated.
B lymphocytes from healthy controls did not
monocytes
T lymphocytes
Figure 3. Expression of IL-10 gene by monocytes and B lymphocytes
from relatives of SLE patients. IL-10 messenger RNA (mRNA) was
detected by semiquantitative reverse transcriptase polymerase chain
reaction in B lymphocytes, T lymphocytes, and monocytes from
healthy members of the multiplex families (n = 6) and from healthy
unrelated controls (n = 6). Values are the mean and SEM ratio of
IL-10 mRNA/P-actin mRNA in each cell population. See Figure 1 for
other definitions.
contain IL-10. In contrast, a significant fraction of B
lymphocytes from SLE patients and their healthy relatives contained IL-10. These IL-10-positive cells represented only a minority of all B lymphocytes (Table 3).
This shows that IL-10 production by B lymphocytes in
RNTI-IL-I0
IFITCl
Mononuclear cells
-
RNT I I L I 0
< F IT C 1
B lymphocytes (CD19+)
5 00
-
R N T I I L l 0 (F I T C 1
T lymphocytes (CD3+)
RNT I
- I L-10
< F I TC 1
Monocytes (CD14+)
Figure 4. Detection of intracytoplasmic IL-10 in relatives of SLE
patients. The presence of intracytoplasmic IL-10 in total peripheral
blood mononuclear cells and in the various cell populations from
relatives of SLE patients was analyzed using flow cytometry. Results
shown are from 1 typical experiment (of 42). FITC = fluorescein
isothiocyanate. See Figure 1 for other definitions.
IL-10 DYSREGULATION IN RELATIVES OF SLE PATIENTS
Table 3. Intracellular detection of interleukin-10 (IL-10)'
B lymphocytes Monocytes T lymphocytes
SLE patients
(n = 32)
Healthy members of the
multiplex families
(n = 42)
Healthy controls
(n = 16)
5.3 2 1.3t
82.5 2 4.8$
1.5 2 0.3
6.0 t 1.23t
66 2 5.4
1.8 2 0.3
<1
59.1 t 9.0
<1
* The presence of intracellular IL-10 was tested by flow cytometry. The
phenotype of IL-10-containing cells was determined by doublelabeling experiments using anti-IL-10 monoclonal antibody (MAb)
with an anti-CD19, an anti-CD14, or an anti-CD3 MAb. Values are the
mean rt SEM fraction of cells that stained with the anti-IL-10 MAb.
t P < 0.01 versus healthy controls.
$ P < 0.05 versus healthy members of the multiplex families; P < 0.025
versus healthy controls.
SLE families results from the emergence or the activation of a minor subpopulation of producer B lymphocytes not present or not activated in healthy unrelated
controls.
DISCUSSION
In previous studies, we have shown that PBMC
from SLE patients constitutively produce high levels of
IL-10, and that both B lymphocytes and monocytes are
responsible for this increased production (13,14). The
present results demonstrate that in multiplex SLE families, healthy individuals also exhibit dysregulation of
IL-10 production. The level of constitutive IL-10 production in healthy members of multiplex families was
higher than that in healthy controls who were not related
to any SLE patient, and was only slightly lower than that
in the SLE patients in the same families. Moreover, as in
SLE patients, both B lymphocytes and monocytes contributed to this abnormally high IL-10 production in the
healthy members of multiplex families. The prevalence
of this abnormality in the multiplex families was high,
with 60-75% of individuals affected, regardless of
whether they had SLE. Among healthy members of the
multiplex families, the prevalence was independent of
age and of sex, and was not significantly different
between first- and second-degree relatives of SLE patients. Whether our present findings in Mexican multiplex families also apply to single-case Mexican families
and to families of other ethnic origins remains to be
determined.
Interestingly, IL-10-producing B lymphocytes,
which were found in SLE patients and in their relatives
but not in controls, represented only a minor fraction of
1433
the total B lymphocyte population. This indicates that
there may be an abnormal, activated B lymphocyte
subpopulation in SLE families. In mice, IL-10 production by B lymphocytes has been specifically attributed to
a subpopulation of cells bearing the Ly-1 marker, which
displays a propensity to produce autoantibodies (22). It
would be interesting to investigate whether an equivalent subpopulation of B lymphocytes is present and
activated in SLE patients and in their relatives.
Increased IL-10 production contributes to the
spontaneous hyperactivity of the B lymphocyte compartment and to the production of autoantibodies in SLE
patients (9,17), as well as in patients with rheumatoid
arthritis (23). In view of the ability of IL-10 to inhibit
antigen-presenting cell and T lymphocyte functions, it is
likely that this high IL-10 production also contributes to
the impaired cell-mediated immunity of SLE patients,
although this has not been demonstrated. Our present
results suggest that dysregulation of IL-10 production
may also be involved in the immunologic abnormalities
previously described in relatives of SLE patients. Impaired cell-mediated immunity, associated with decreased lymphocyte proliferation and decreased IL-2
production, is a frequent abnormality in relatives of SLE
patients, occurring in -50% of such individuals. Polyclonal B lymphocyte hyperactivity is even more frequent,
affecting -75% of relatives (19,20). Such high prevalences are in the range of that of IL-10 dysregulation
reported here, which is consistent with the notion that
IL-10 plays a role in immunologic imbalances in relatives
of SLE patients.
We compared IL-10 production and the presence
of antinuclear antibodies in a limited number of healthy
relatives of SLE patients, and found no correlation
between the 2 (data not shown). Moreover, several
relatives had both antinuclear antibodies and high IL-10
production, indicating that even the concurrence of
these 2 conditions is not sufficient to generate the
disease. Therefore, increased IL-10 production alone
does not account for the biased antibody repertoire in
relatives, in whom nonpathogenic autoantibodies are
mainly of IgM type and of low affinity. This biased
repertoire relies on genetic and/or environmental factors
not directly related to IL-10 dysregulation.
In SLE patients, for undetermined genetic or
environmental reasons, there is a shift of the autoreactive repertoire toward production of high-affinity, IgGtype pathogenic autoantibodies. It is only under this
condition that IL-10 contributes to increased autoantibody production (9). This suggests that IL-10 is acting on
a step of the autoreactive B lymphocyte maturation
LLORENTE ET AL,
1434
process not reached in healthy relatives of SLE patients
with antinuclear antibodies. Alternatively, IL-10 may
play the same role in patients and their healthy relatives,
but in the latter, mechanisms of deletion of high-affinity
autoantibody-producing clones may persist and prevent
the disease.
Emergence of SLE requires a concurrence of
genetic and environmental factors (24,25), and those
responsible for the dysregulation of IL-10 production
have not been identified. Additional epidemiologic and
genetic studies are therefore needed. Among genetic
factors, an abnormally high incidence of various
HLA-DR alleles and of C4-null alleles has been reported in SLE patients and in their healthy relatives
(26,27). An association between SLE and other alleles,
encoding immunoglobulin heavy chain constant domains
(28) and T cell receptor chains (29), has also been
shown. However, the prevalence of these genetic markers in SLE families is much lower than that of IL-10
dysregulation, providing evidence against a direct relationship between them and the abnormality we describe.
Recent studies have indicated extensive polymorphism of the IL-10 gene regulatory sequences (30), and
some of these alleles may be overrepresented among
patients with SLE (31). Whether such alleles are associated with higher constitutive production of IL-10 is
unknown. In the (New Zealand black X New Zealand
white)F, hybrid mouse model of SLE, up to 8 loci have
been found to predispose to the disease (32). Interestingly, 1 of them is closely linked to the IL-10 gene (32).
Increased IL-10 production has not been reported in this
murine model, but administration of an anti-IL-10 MAb
to these mice prevents emergence of the autoimmune
disease (33). Along the same lines, IL-10 has been shown
to stimulate the autoreactive Lyl+ B lymphocyte population in normal (34) or transgenic (35) mice.
Our findings show that dysregulation of IL-10
production is one of the most frequent abnormalities
observed as yet in relatives of SLE patients, and that, as
in SLE patients, it originates from monocytes and from
a subpopulation of B lymphocytes. Further studies are
needed to characterize the phenotype and the functional
properties of this B lymphocyte subpopulation, in order
to demonstrate whether the dysregulated IL-10 production contributes to the immunologic imbalance in relatives of SLE patients, and whether it is of genetic or
environmental origin.
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