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*
Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Florida, Gainesville, FL 32610; and
Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, NC 27599
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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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Mutations of the Fas (lpr) or Fas ligand (gld) genes impair activation-induced cell death (5, 6, 7), resulting in abnormal peripheral deletion of autoreactive T and B cells and the development of a lupus-like syndrome characterized by anti-ssDNA and anti-chromatin autoantibodies and lymphoproliferation (8). On autoimmune backgrounds such as MRL (5) or BXSB (9), the lpr mutation greatly accelerates lupus. In view of the abnormal peripheral deletion of autoreactive T and B cells resulting from these mutations and the autoantibodies produced spontaneously by B6/lpr and B6/gld mice, lpr or gld would be expected to exacerbate autoantibody production in pristane-treated B6 mice. The present studies show that, contrary to expectations, defective Fas-Fas ligand interaction antagonizes the autoimmune syndrome induced by pristane.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Four-week-old female B6, B6 lpr/lpr, and B6 gld/gld mice were purchased from The Jackson Laboratory (Bar Harbor, ME), and housed in a virus-free conventional animal facility with barrier cages. The lpr and gld double mutant mouse, B6/lpr-gld, was described previously (8). At 3 mo of age, 7–16 mice per group received 0.5 ml i.p. of pristane (Sigma, St. Louis, MO) or sterile PBS (3). Sera were collected from the tail vein before injection, at 2 and 4 wk, and monthly thereafter. Sera from untreated B6/lpr, B6/gld, and B6/lpr-gld double mutant mice also were studied.
Ig levels
Total levels of IgG1, IgG2a, IgG2b, IgG3, IgA, and IgM were measured by sandwich ELISA, as described (10).
Radiolabeling and immunoprecipitation
Autoantibodies to cellular proteins in murine and human sera were analyzed by immunoprecipitation of 35S-radiolabeled K562 cell extract using 3 µl murine serum, as described. Specificity of autoantibodies was confirmed using human reference sera for anti-nRNP/Sm, anti-Su, and anti-ribosomal P.
ELISAs for autoantibodies to nRNP/Sm, ssDNA, and chromatin
A standard ELISA for anti-nRNP/Sm was used (11). Sera were tested at a 1/500 dilution, and OD405 was converted to units using a standard curve based on Y2 anti-Sm mAb, as described (11). The anti-ssDNA Ab ELISA was performed, as described, using heat-denatured calf thymus DNA (Sigma) as Ag (4). IgM anti-ssDNA levels between groups were compared as a group because of the occasional presence of this specificity in sera from normal mice. The ratio of increase in IgM anti-ssDNA Abs was calculated as follows: OD405 of sera 2 wk after pristane treatment ÷ OD405 of sera before treatment. IgG anti-ssDNA Ab levels were considered positive when OD405 of the sample was higher than the mean + 3 SD of sera from PBS-treated mice.
Anti-chromatin Abs were measured as described (12), with minor modifications. Wells of microtiter plates (Nunc, Maxisorp, Naperville, IL) were coated with 100 µl of 1 µg/ml of chicken chromatin in borate-buffered saline (200 mM boric acid, 75 mM NaCl, pH 8.4) at 4°C for 16 h. Wells were washed with NET/Nonidet P-40 (0.15 M NaCl, 2 mM EDTA, 50 mM Tris-HCl, pH 7.5, 0.5% Nonidet P-40) and blocked with 0.5% BSA in NET/Nonidet P-40 for 1 h at 22°C. Wells were then incubated with 100 µl of 1/500 mouse sera in same buffer for 1 h at 22°C, washed three times with NET/Nonidet P-40, and incubated with 100 µl alkaline phosphatase-labeled goat anti-mouse IgG (1/1000) in blocking buffer for 1.5 h at 22°C. After washing, the plates were developed with p-nitrophenyl phosphate substrate (Sigma). OD405 was converted to units based on a standard curve produced by serial dilutions of pooled sera from MRL/lpr mice: 1/500 dilution = 1,000 U; 1/5,000 = 100 U; 1/50,000 = 10 U; 1/500,000 = 1 U. Usually, the standard is clearly positive at a 1/500,000 dilution. Because anti-chromatin Abs are produced sporadically in some nonautoimmune strains of mice, the mean + 3 SD of 10 blank wells was used as cutoff for positive and negative.
Tissues and peritoneal lavage
Mice were euthanized with CO2, and the peritoneal cavity was lavaged with 5 ml of high-glucose DMEM + 10% FCS and 1 U/ml heparin using a 5-ml plastic syringe and 18-gauge needle. Samples were kept on ice before centrifuging at 1200 rpm for 10 min. Aliquots of the supernatant were frozen at -80°C. After peritoneal lavage, the liver, spleen, kidney, lymph nodes (cervical, axillary, inguinal, and paraaortic), and thymus/mediastinal lymph nodes were harvested and weighed.
Cytokine ELISA
ELISAs for IL-6, IL-10, IL-12, and TNF-
were performed using
rat mAb pairs for various mouse cytokines (PharMingen, San Diego, CA).
After incubation with biotinylated cytokine-specific Abs, 100 µl/well
of 1/1000 streptavidin-alkaline phosphatase (Southern Biotechnology
Associates, Birmingham, AL) was added for 30 min at 22°C, and the
reaction was developed.
Statistical analysis
Frequencies of autoantibodies were compared by Fisher’s exact test. The Kruskal-Wallis test and Mann-Whitney tests were used to compare levels of Abs or cytokines (ELISA), and organ weights.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Pristane has little effect on IgG anti-DNA/chromatin Ab production by B6/lpr mice
IgG Abs to ssDNA were present in all PBS-treated B6/lpr
and B6/gld mice at 8 mo (5 mo after PBS treatment; Fig. 1
A, see below). These Abs were
detectable as early as 6 mo of age (3 mo after PBS treatment; not
shown). Pristane had little effect on this spontaneous anti-ssDNA
autoantibody production, although the levels in pristane-treated
B6/lpr mice were somewhat higher than those in PBS-treated
group. One of 7 PBS-treated mice vs 7 of 12 pristane-treated mice had
IgG anti-ssDNA >1 U, but differences in the levels or frequencies
were not significant (Mann-Whitney and Fisher’s exact test,
respectively). In contrast, IgG anti-ssDNA Abs were not found in
PBS-treated B6 controls. Nor were they increased substantially by
pristane treatment (Fig. 1A, Table I).
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B). All PBS-treated B6/lpr and
B6/gld mice spontaneously produced high levels of IgG
anti-chromatin Abs, as expected (5). However, the
levels of IgG anti-chromatin Abs were similar in PBS vs
pristane-treated B6/lpr and B6/gld mice. In
addition, 2 of 8 PBS-treated and 3 of 10 pristane-treated B6 mice had
low levels of IgG anti-chromatin Abs (Fig. 1B). These
results suggest that pristane treatment had little effect on the
pathogenesis of anti-DNA/chromatin Abs in B6/lpr or
B6/gld mice. Autoantibodies induced in B6 mice by pristane vs lpr or gld
Immunoprecipitation was used to examine other (non-DNA/chromatin)
autoantibody responses induced in B6 mice by pristane vs those induced
by lpr or gld. Pristane-treated B6 mice produced
autoantibodies to the nRNP/Sm (35%), Su (24%), and ribosomal P (12%)
Ags (Fig. 2A, Table I) at
frequencies comparable with those in MRL/lpr mice or human
SLE patients. Two mice also produced autoantibodies to the
dsRNA-binding factor NF90/NF45 (13). In striking contrast,
none of the B6/lpr, B6/gld, or
B6/lpr-gld double mutant mice spontaneously (PBS treated or
untreated) produced any of these specificities. Immunoprecipitation of
a group of proteins likely to include core histones was common in
control B6/lpr (Fig. 2B), B6/gld (Fig. 2C), and B6/lpr-gld double mutant mice (not
shown). MRL/lpr mice also produce these autoantibodies
(14), but this pattern was not seen in pristane-treated B6
mice, despite the induction of a variety of other lupus autoantibodies
(Table I). mAbs specific for histones and dsDNA, but not ssDNA, also
immunoprecipitate these proteins, arguing that this pattern may reflect
the presence of a subset of anti-DNA/chromatin Abs
(15). These data strongly suggest that pristane
enhances/accelerates autoantibody production in a manner different from
lpr or gld. This interpretation was supported by
studies of the effects of these mutations on the phenotype of
pristane-induced lupus.
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Only one mouse each in the pristane-treated B6/lpr and
B6/gld groups produced very low levels of anti-nRNP/Sm
Abs by immunoprecipitation, whereas anti-Su, ribosomal P, and
NF45/90 were not induced at all (Table II). In contrast, pristane induced
anti-nRNP/Sm, Su, or ribosomal P in 35%, 24%, and 12% of B6
mice, respectively (Table I). Production of at least one of these
specificities occurred more frequently in B6 mice than in
B6/lpr (8/17 vs 1/12, p = 0.0432 by
Fisher’s exact test). Combining the B6/lpr and
B6/gld groups, the increased frequency of autoantibody
induction by pristane in B6 was even more obvious (8/17 in B6 vs 2/21
in B6/lpr + B6/gld, p = 0.0232).
Taken together with the lack of enhancement of spontaneous
anti-dsDNA or chromatin Ab production by pristane treatment, these
data suggest that Fas and Fas ligand mutations make B6 mice refractory
to the induction of autoantibodies by pristane.
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To see whether lpr reduces the levels of autoantibodies
induced by pristane as well as their frequency, IgG anti-nRNP/Sm
Abs were quantified by ELISA in B6 and B6/lpr mice 6 mo
after PBS or pristane treatment (Fig. 3).
Consistent with the very weak signal by immunoprecipitation, levels of
anti-nRNP/Sm Abs were much lower in pristane-treated
B6/lpr mice than in pristane-treated B6 mice. One
B6/gld mouse developed anti-nRNP/Sm Abs at very low
levels 2 mo after pristane injection, but died before 3 mo (not
shown).
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Pristane rapidly (2 wk after injection) induces the production of
IgM anti-ssDNA Abs. Unlike late (1–6 mo after pristane injection)
autoantibody production, the early phase probably corresponds to the
production of natural autoantibodies (16). To examine the
effect of lpr and gld on the early phase, the
increase in IgM anti-ssDNA Abs was determined in sera of individual
mice 2 wk after treatment. Ratios of (OD405 2 wk
after treatment) ÷ (OD405 before treatment)
for PBS vs pristane-treated B6 and B6/lpr mice are shown in
Fig. 4. B6 mice treated with pristane
averaged a 3-fold increase in IgM anti-ssDNA Abs, whereas little
increase was seen in PBS-treated mice (p =
0.019, Mann-Whitney test). In striking contrast, serum IgM
anti-ssDNA Abs in pristane-treated B6/lpr and
B6/gld mice did not increase after pristane treatment,
suggesting that Fas or Fas ligand mutant mice lack the early
pristane-induced autoantibody response.
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IgM and IgG3 levels increase within 2 wk of pristane injection in
BALB/cByJ mice in conjunction with the production of IgM anti-ssDNA
Abs (4). Similarly, in comparison with PBS-treated
controls, total IgM levels increased 2.5-fold
(p = 0.0028) and IgG3 levels 2-fold
(p = 0.057) within 2 wk after treating B6 mice
with pristane (Fig. 5). In contrast, IgM
and IgG3 levels were comparable in PBS and pristane-treated
B6/lpr mice. There were modest, but not statistically
significant, increases in IgM and IgG3 in pristane-treated
B6/gld mice. Taken together, these data suggest that early
Ig production is deficient in pristane-treated Fas or Fas ligand
mutant mice.
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2-fold higher in
pristane-treated B6 mice than in PBS-treated controls (Fig. 5). With
the exception of IgG1 in B6/gld mice
(p = 0.22, not significant), there was little
difference in the total IgG1, IgG2a, or IgG2b levels in
B6/lpr and B6/gld mice between the PBS- and
pristane-treated groups. Thus, although B6/lpr and
B6/gld mice had higher baseline IgG1, IgG2a, and IgG2b
levels than B6 mice, pristane had little effect in these strains,
whereas levels of the same isotypes were increased significantly by
pristane treatment in B6 controls. Effects of pristane on survival and proteinuria
Pristane did not promote the development of renal disease in
B6/lpr or B6/gld mice. Proteinuria
3+ was not seen in any of the mice (Table III), and only a single PBS-treated
B6/lpr mouse developed 2+ proteinuria.
Early death following pristane injection seldom occurs in BALB/c mice.
However, 10–50% of mice with a B6 background die within 1 mo of
pristane injection due to pulmonary hemorrhage of unknown cause
(H. B. Richards, et al., unpublished data). In the present study,
two B6 and three B6/gld mice died within 1 mo following
pristane injection.
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Effect of pristane on organ weights
Hepatosplenomegaly is characteristic of lpr and
gld mice as well as pristane-treated mice. Livers of
pristane-treated B6 mice weighed more than those of PBS-treated
controls (p = 0.04, Mann-Whitney, Table IV). In contrast, in pristane-treated
B6/lpr mice, the weights of liver (p
= 0.028), spleen (p = 0.04), and possibly lymph
nodes (p = 0.075) all were less than that of
PBS-treated controls, suggesting that pristane did not enhance
lymphoproliferation in B6/lpr mice, but rather, suppressed
it. This trend was not apparent in B6/gld mice, although the
weight of the thymus (plus mediastinal lymph nodes) of pristane-treated
mice was greater than that of PBS-treated mice. The latter did not
reach statistical significance, however.
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In view of the evidence that cytokines play a role in the
pathogenesis of autoantibodies in pristane-induced lupus
(12) (H. B. Richards, manuscript in preparation), the
levels of IL-6, IL-10, IL-12, and TNF- in peritoneal lavage were
examined (Fig. 6). Spontaneous production
of all four cytokines was minimal in B6 mice (PBS treated). In
contrast, B6/lpr mice spontaneously produced high levels of
IL-12, and some also produced TNF- (Fig. 6, C and
D). Pristane treatment induced the production of IL-12 and
smaller amounts of TNF-, but not IL-6 in B6 mice. It also induced
the production of IL-6 (p = 0.0193) and TNF-
in B6/lpr mice. In contrast to B6 controls, IL-12 production
was unchanged in B6/lpr mice by pristane treatment.
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was detectable in significant amounts in the
peritoneal lavage fluid from PBS- or pristane-treated B6 wild type,
lpr, gld, or lpr/gld mice
(data not shown). As a surrogate marker of Th1 vs Th2 cytokine balance,
the ratio of total IgG2a to IgG1 was evaluated 5 mo after treatment. As
shown in Fig. 7, PBS- as well as
pristane-treated B6 (+/+) mice had a significantly higher ratio than
B6/lpr or B6/gld (for pristane-treated mice,
p = 0.003 vs B6/lpr and p =
0.0027 vs B6/gld by Mann-Whitney). These data suggest that
Fas or Fas ligand deficiencies increase serum levels of IgG1 (IL-4
dependent) out of proportion to IgG2a (IFN- dependent), despite
increased spontaneous production of IL-12 in the peritoneal cavity
(Fig. 6). However, this may be unique to the B6 background, in view of
the marked IgG2a hypergammaglobulinemia in MRL/lpr
mice.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B6/lpr and B6/gld mice are resistant to autoantibody induction by pristane
In contrast to the severe lupus in MRL/lpr mice or pristane-treated normal mice (2, 4, 5, 12), B6/lpr mice have an attenuated lupus-like syndrome characterized by the development of anti-chromatin/DNA Abs, but not anti-nRNP/Sm, anti-Su, or anti-ribosomal P Abs, nephritis, or arthritis (5). The restricted spectrum of autoantibodies in B6/lpr mice has been attributed to the absence of critical susceptibility genes. However, the production of anti-nRNP/Sm, anti-Su, and anti-ribosomal P autoantibodies by pristane-treated mice demonstrates conclusively that B6 mice are capable of responding to these Ags. The lpr defect apparently cannot turn on these autoantibodies in B6 mice despite accelerating their spontaneous production on the MRL background. Remarkably, the effect of pristane on autoantibody production was diametrically opposed to that of lpr or gld. Whereas B6 mice treated with pristane produced IgG anti-nRNP/Sm, anti-Su, and anti-ribosomal P, they did not produce anti-ssDNA or anti-chromatin Abs. Conversely, all B6/lpr and B6/gld mice spontaneously developed high levels of IgG anti-DNA/chromatin, but not anti-nRNP/Sm, anti-Su, or anti-ribosomal P. This reciprocal relationship is consistent with the existence of multiple pathways of autoantibody formation.
It is not simple to differentiate whether the effects of pristane and the lpr or gld defects are antagonistic vs the alternative possibility that 3-mo-old B6/lpr and B6/gld mice were preprogrammed to develop a particular autoantibody response and pristane merely failed to modify its course. However, we recently have obtained evidence that this resistance to pristane-induced lupus is a unique characteristic of lpr and gld mice. When pristane was given to NZB/W F1 and BXSB mice with preexisting signs of lupus-like autoimmunity, disease and autoantibody production were enhanced and accelerated.4 More importantly, the same thing was seen in MRL+/+ mice, but not in MRL/lpr mice (M. Satoh et al., manuscript in preparation). Thus, while we cannot completely exclude the possibility that the lpr and gld mice were preprogrammed at 3 mo, the possibility that the lpr or gld defects and pristane are mutually antagonistic may be more likely.
Fas-mediated apoptosis is thought to protect against autoimmunity by facilitating peripheral deletion of autoreactive T (17, 18, 19) and B (20, 21, 22) lymphocytes. Also, apoptotic cell death may avoid potentially harmful inflammatory effects following the release of necrotic cell constituents (7, 23, 24). However, the present observations are difficult to reconcile with this hypothesis, although we cannot exclude an abnormality in the deletion of autoreactive cells responsible for the spontaneous production of anti-DNA/chromatin in B6/lpr mice. Our data are more consistent with the possibility that Fas-mediated apoptosis enhances the processing and presentation in an immunogenic form of a subset of self Ags. This model receives support from the clustering and specific cleavage of multiple lupus autoantigens in surface blebs in apoptotic cells (25).
An alternative, but not mutually exclusive, hypothesis is that the
nonspecific inflammatory response caused by pristane is a critical
determinant of whether the uptake of nRNP/Sm, Su, or ribosomal P by
APCs promotes immunity or tolerance (26, 27). Thus,
defective Fas signaling could interfere with the establishment of a
Th1-dominant inflammatory state promoting the development of
anti-nRNP/Sm and other autoantibodies. Although pristane causes a
nonspecific inflammatory response in the peritoneal cavity, it
exacerbates lupus-like disease by a mechanism distinct from that of
other nonspecific inflammatory mediators such as LPS. In contrast to
LPS (28, 29), pristane did not induce glomerulonephritis
in B6/lpr mice (Table III), nor did it enhance
lymphoproliferation. Indeed, pristane treatment decreased spleen,
liver, and lymph node weights of B6/lpr mice (Table IV).
Pristane and LPS also had different effects on natural autoantibody
production. LPS induces polyclonal B cell activation and anti-ssDNA
Ab production in both normal (30) and B6/lpr
mice (28). These were absent in pristane-treated
B6/lpr and B6/gld mice (Fig. 4), but could be
induced in Fas/Fas ligand-intact animals (4). We conclude
that the effects of pristane in lpr or gld mice
differ fundamentally from those of LPS.
Anti-DNA/chromatin response in B6 mice
Pristane-treated BALB/cAn mice produce IgG
anti-DNA/chromatin autoantibodies at high levels in an IL-6-
and IFN--dependent manner (12) (H. B. Richards, et
al., in preparation). The inability of pristane to induce these
autoantibodies in B6 mice (Fig. 1) does not reflect unresponsiveness to
chromatin because they are produced spontaneously at high levels in
B6/lpr and B6/gld mice. Intraperitoneal injection
of pristane led to local production of IL-12, but not IL-6, in the
peritoneal cavity of B6 mice (Fig. 6, A and C).
In contrast, pristane-treated BALB/c mice produce large amounts of IL-6
and IL-12 (V. Shaheen, et al., unpublished data), raising the
possibility that both cytokines are needed to generate an
anti-DNA/chromatin response in Fas/Fas ligand-intact mice. B6 mice
may fail to generate an anti-DNA/chromatin following pristane
treatment due to a defect in IL-6 production.
The cytokine requirements for anti-DNA/chromatin Abs may be
different in mice with defective Fas signaling. The levels of IL-6 in
peritoneal lavage from B6/lpr mice increased markedly
following pristane treatment (Fig. 6A) even though
autoantibody levels were not augmented (Fig. 1). It is unlikely,
therefore, that IL-6 plays a major role in the production of
anti-DNA/chromatin autoantibodies in B6/lpr mice,
despite its importance in pristane-treated BALB/cAn mice
(12).
The role of IL-12 in anti-DNA/chromatin autoantibody production by
Fas-defective mice is less certain. IL-12 (31) and IFN-
(32, 33, 34) are important for the production of anti-DNA
Abs in MRL/lpr mice. However, we found no correlation
between the level of IL-12 in the peritoneal lavage and the level of
serum anti-DNA/chromatin (data not shown). The low IgG2a/IgG1 ratio
in B6/lpr and B6/gld mice compared with B6 (Fig. 7) suggests that anti-DNA/chromatin Abs are produced in
Fas-defective mice via an IL-4-dependent pathway (35).
Paradoxically, however, B6/lpr mice spontaneously produced
IL-12.
Spontaneous IL-12 production in B6/lpr mice
The spontaneous IL-12 production by B6/lpr mice has not
been reported previously. However, in comparison with
MRL+/+, peritoneal macrophages from
MRL/lpr mice exhibit greatly increased IL-12 production in
response to LPS plus IFN- (31). This could reflect
acceleration of the autoimmune disease or could be a direct consequence
of the lpr mutation. The latter possibility is supported by
the enhanced spontaneous production of IL-12 in lpr mice
(Fig. 6). The normal microbial flora of the intestine stimulates B and
T lymphocytes as well as APCs in the peritoneal cavity
(36, 37, 38). The elevated IL-12 levels in B6/lpr
mice may reflect an inability to delete activated peritoneal APCs,
because normal macrophages activated by IFN- or TNF- up-regulate
Fas expression and are eliminated by apoptosis (39, 40).
Consistent with that notion, the macrophage compartment expands in
MRL/lpr mice (41). Interestingly, the increased
IL-12 production in B6/lpr mice does not lead to an
increased ratio of IgG2a/IgG1, a surrogate marker for Th1/Th2 cytokine
balance. Moreover, for unclear reasons, pristane appears to have only a
small effect on the IgG2a/IgG1 ratio in B6 background mice at 5 mo.
This strain is genetically skewed toward Th1 responses
(42). In contrast, the IgG2a/IgG1 ratio increases
dramatically in BALB/c (genetically skewed toward Th2 responses) and
most other strains (M. Satoh, unpublished data). However, despite these
differences, both BALB/c and B6 mice are susceptible to the induction
of anti-nRNP/Sm and Su autoantibodies.
In summary, the lpr and gld mutations can either accelerate or retard the development of autoimmunity, possibly reflecting the existence of different pathways of autoantibody formation. Further defining these pathways may pave the way to a better understanding of the variable phenotype of human SLE.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Westley H. Reeves, Division of Rheumatology and Clinical Immunology, University of Florida, P.O. Box 100221, Gainesville, FL 32610-0221.
3 Abbreviations used in this paper: SLE, systemic lupus erythematosus; nRNP, nuclear ribonucleoprotein.
4 H. Yoshida, M. Satoh, C-G. Lee, H. B. Richards, V. M. Shaheen, and W. H. Reeves. Submitted for publication.
Received for publication December 28, 1999. Accepted for publication April 27, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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is essential for the development of autoimmune glomerulonephritis in MRL/lpr mice. J. Immunol. 158:5484.[Abstract]
is required for lupus-like disease and lymphoaccumulation in MRL-lpr mice. J. Clin. Invest. 101:364.[Medline]
receptor signaling is essential for the initiation, acceleration, and destruction of autoimmune kidney disease in MRL-Faslpr mice. J. Immunol. 161:494./
T cells for production of IFN- is mediated by bacteria via macrophage-derived cytokines IL-1 and IL-12. J. Immunol. 154:5832.[Abstract]
. J. Exp. Med. 181:127.This article has been cited by other articles:
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  V. R. Chowdhary, J. P. Grande, H. S. Luthra, and C. S. David Characterization of haemorrhagic pulmonary capillaritis: another manifestation of Pristane-induced lupus Rheumatology, September 1, 2007; 46(9): 1405 - 1410. [Abstract] [Full Text] [PDF]
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 N. Calvani, R. Caricchio, M. Tucci, E. S. Sobel, F. Silvestris, P. Tartaglia, and H. B. Richards Induction of Apoptosis by the Hydrocarbon Oil Pristane: Implications for Pristane-Induced Lupus J. Immunol., October 1, 2005; 175(7): 4777 - 4782. [Abstract] [Full Text] [PDF]
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 J. Akaogi, H. Yamada, Y. Kuroda, D. C. Nacionales, W. H. Reeves, and M. Satoh Prostaglandin E2 receptors EP2 and EP4 are up-regulated in peritoneal macrophages and joints of pristane-treated mice and modulate TNF-{alpha} and IL-6 production J. Leukoc. Biol., July 1, 2004; 76(1): 227 - 236. [Abstract] [Full Text] [PDF]
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 Y. Kuroda, J. Akaogi, D. C. Nacionales, S. C. Wasdo, N. J. Szabo, W. H. Reeves, and M. Satoh Distinctive Patterns of Autoimmune Response Induced by Different Types of Mineral Oil Toxicol. Sci., April 1, 2004; 78(2): 222 - 228. [Abstract] [Full Text] [PDF]
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 J. Drappa, L. A. Kamen, E. Chan, M. Georgiev, D. Ashany, F. Marti, and P. D. King Impaired T Cell Death and Lupus-like Autoimmunity in T Cell-specific Adapter Protein-deficient Mice J. Exp. Med., September 2, 2003; 198(5): 809 - 821. [Abstract] [Full Text] [PDF]
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 M. Satoh, A. Mizutani, K. M. Behney, Y. Kuroda, J. Akaogi, H. Yoshida, D. C. Nacionales, M. Hirakata, N. Ono, and W. H. Reeves X-linked immunodeficient mice spontaneously produce lupus-related anti-RNA helicase A autoantibodies, but are resistant to pristane-induced lupus Int. Immunol., September 1, 2003; 15(9): 1117 - 1124. [Abstract] [Full Text] [PDF]
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C. O. Jacob, S. Zang, L. Li, V. Ciobanu, F. Quismorio, A. Mizutani, M. Satoh, and M. Koss Pivotal Role of Stat4 and Stat6 in the Pathogenesis of the Lupus-Like Disease in the New Zealand Mixed 2328 Mice J. Immunol., August 1, 2003; 171(3): 1564 - 1571. [Abstract] [Full Text] [PDF]
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S. Bolland, Y.-S. Yim, K. Tus, E. K. Wakeland, and J. V. Ravetch Genetic Modifiers of Systemic Lupus Erythematosus in Fc{gamma}RIIB-/- Mice J. Exp. Med., May 6, 2002; 195(9): 1167 - 1174. [Abstract] [Full Text] [PDF]
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, immunoprecipitation negative
samples.
,
PBS-treated B6/lpr; 
, pristane-treated
B6/lpr; 
, PBS-treated B6/gld; 
,
pristane-treated B6/gld.
