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Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA 19140
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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production and is necessary for
differentiation of naive T cells into the Th1 subset. To gain an
understanding of T cell control in this syndrome and, in particular,
Th1/Th2 regulation, we assessed the effect of IL-12 administration in
mercury-induced autoimmunity. Groups of A.SW mice (H-2s)
received HgCl2 plus IL-12, HgCl2 alone, or
IL-12 alone. IL-12 treatment resulted in a dramatic reduction of the
anti-nucleolar Ab titers. IL-12 also inhibited the
HgCl2-induced serum IgG1 increase, but, in contrast, did
not significantly affect IgE induction in this model. This observation
may be related to our unexpected finding that IL-12 further potentiated
the HgCl2-triggered IL-4 induction in this model. The
levels of renal Ig deposits were similar in mice receiving
HgCl2 alone or HgCl2 plus IL-12. Our results
indicate that IL-12 can down-regulate the autoimmune component of this
experimental syndrome and that the various manifestations of
mercury-induced autoimmunity are independently regulated. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, while Th2 cells secrete IL-4, IL-5, and IL-10. The
development of Th1 and Th2 subsets from naive precursor cells depends
upon cytokines present during the initiation of the immune response.
IL-12 is critical for the development of the Th1 phenotype and thereby
for initiating an inflammatory immune response (3). As a corollary to
the Th1-promoting role of IL-12, Th2-mediated diseases can be prevented
by the administration of IL-12. In a murine model of leishmania,
susceptible BALB/c mice are protected from Th2-mediated disease by
IL-12 administration at the time of parasite challenge (4, 5).
Conversely, the presence of IL-12 is a contributor to certain
Th1-mediated autoimmune diseases, and Abs to the p40 component of the
IL-12 molecule can abrogate disease (6). A targeted deletion of the
gene coding for the IL-12 p40 subunit results in a defect in generating
a Th1 response and prevents diabetes development in NOD mice (7). Thus,
IL-12 serves as a potentially important immunoregulator in determining
disease outcome. Mouse or rat strains expressing certain MHC Ags are exquisitely susceptible to the heavy metal induction of a complex autoimmune syndrome (8, 9, 10, 11). In susceptible H-2s mice, subtoxic doses of mercuric chloride (HgCl2) induce an autoimmune dysfunction characterized by the production of anti-nucleolar autoantibodies (ANoA),3 lymphoproliferation, hyperglobulinemia (especially pronounced for IgG1 and IgE), and mild glomerulonephritis with renal Ig deposits. These manifestations peak 2 to 3 wk after the beginning of the Hg injections, and the ANoA can persist for as long as 1 yr after the induction phase. Most of the other manifestations, however, spontaneously resolve in about 4 to 5 wk, even if HgCl2 injections are continued. The increase in serum IgG1 and IgE in Hg-treated mice suggests that Th2 cells play an important role in the pathogenesis of this syndrome (10, 12). HgCl2 can directly induce IL-4 secretion in susceptible strains (13, 14, 15), and some of the manifestations can be prevented by anti-IL-4 treatment (16). The role of Th1 cells in this syndrome is less well defined, although it has been suggested that this subset might be involved in the regulation phase of the disease. In the rat, depletion of the Th1-like subset (OX22high) leads to an exacerbation of tissue injury, presumably due to a loss of Th1 regulation (17). In mice, treatment with anti-CD2 Abs, which is believed to down-regulate the Th1 pathway, exacerbates the manifestations of mercury-induced autoimmunity (18).
We reasoned that administration of IL-12, a potent Th1 inducer, may be able to bypass the Th2 phase of the disease and result in early induction of the regulatory Th1 cells. In the present study we examined the effect of IL-12 administration on the development of Hg-induced autoimmunity in A.SW (H-2s) mice. Our results indicate that IL-12 can dramatically decrease the autoantibody component of the syndrome, but that it has differing effects on the other manifestations of the syndrome.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female A.SW/SnJ (H-2s) mice were obtained from The Jackson Laboratory (Bar Harbor, ME) and were maintained in our animal facilities.
HgCl2 and IL-12 treatment
Groups of at least 2-mo-old mice were injected with HgCl2 alone, IL-12 alone, or both HgCl2 and IL-12 as follows. Mice treated with HgCl2 were injected three times a week s.c. with 30 µg of HgCl2 (Sigma Chemical Co., St. Louis, MO) in 100 µl of sterile PBS throughout the duration of the experiment (16). Mice treated with rIL-12 (gift from Genetics Institute, Inc., Cambridge MA) received a standard regimen of four injections of 0.2 µg of IL-12/day i.p. for 4 consecutive days (19). In mice that received both treatments, the IL-12 injection regimen was started 1 day before the first HgCl2 administration. Blood was obtained weekly by retro-orbital bleeding.
ANoA immunofluorescence
ANoA levels in serially diluted mouse serum were determined by indirect immunofluorescence as previously described (20). Sera diluted in PBS containing 1% BSA and 0.02% sodium azide were incubated with HEp-2 slides (Chemicon, Temecula, CA) for 30 min, and ANoA were detected with FITC-conjugated goat anti-mouse IgG1, IgG2a, or IgG2b Abs (Southern Biotechnology Associates, Birmingham, AL). The initial serum dilution was 1/100. The inverse of the highest serum dilution at which nucleolar fluorescence could be detected was defined as the ANoA titer.
B cell flow cytometry
On day 7 of treatment, spleens were removed from mice receiving HgCl2 alone, IL-12 alone, or both HgCl2 and IL-12 and were used to generate individual single cell suspensions. Cells were then treated with 0.165 M NH4Cl to eliminate erythrocytes and washed three times in ice-cold staining medium (deficient RPMI 1640 medium (Irvine Scientific, Santa Ana, CA) containing 10 mM HEPES, 3% FBS, and 0.1% NaN3). Cells were resuspended in 0.1 ml of staining medium containing either 0.2 µg of FITC-RA3–6B2 anti-B220 mAb (PharMingen, San Diego, CA) or FITC-rat IgG2a isotype control mAb (PharMingen) and incubated for 15 min at 4°C. Cells were then washed three times in staining medium and analyzed by flow cytometry using an Coulter EPICS Elite apparatus (Coulter Electronics, Hialeah, FL).
ELISA for mouse serum IgG1, IgG2a, and IgG2b
Total serum IgG1, IgG2a, and IgG2b were determined using a
sandwich ELISA adapted from a previously described method (16). For
quantitation of IgG1, IgG2a, and IgG2b serum levels, plates were coated
overnight at 4°C with goat anti-mouse Ig 
(Southern
Biotechnology Associates, Birmingham, AL) diluted 2 µg/ml in
carbonate buffer. Following three washes with PT buffer (PBS and 0.05%
Tween), wells were blocked with PBTN (PBS containing 1% BSA, 0.05%
Tween-20, and 0.02% sodium azide) for 30 min. Sera diluted 1/250,000
in PBTN were then added to wells and incubated at room temperature for
2 h. Samples were washed six times with PT, and alkaline
phosphatase (AP)-conjugated goat anti-mouse IgG1, IgG2a, or IgG2b
secondary Ab (Southern Biotechnology Associates), diluted 1/4,000 in
PBTN, was added for 1.5 h. Secondary Ab was washed out with two
washes each of PT and AP substrate buffer (10 mM diethanolamine and 0.5
mM MgCl2 in dH2O). The
p-nitrophenylphosphate substrate (1 mg/ml in AP buffer) was
then added and allowed to develop for 20 min. Absorbances were read at
450 nm. A standard curve was generated using varying concentrations of
ASWU1 (IgG1), PA3 (IgG2a), or FB3 (IgG2b) mAbs (20, 21, 22), ranging in
concentration from 0.8 to 100 ng/ml.
ELISA for mouse IgE
Total serum IgE levels were determined using a sandwich ELISA. Briefly, plates were coated overnight at 4°C with a rat anti-mouse IgE capture mAb (clone R35-72, PharMingen) diluted 2 µg/ml in carbonate buffer. The capture Ab was washed out five times with PT, and the plate was blocked with PBTN for 30 min. Sera diluted 1/100 in PBS with 1% BSA and 0.02% sodium azide were then added to wells and incubated at room temperature for 2 h. Serum samples were washed six times with PT, and the secondary Ab, biotinylated rat anti-mouse IgE (clone R35–92, PharMingen), diluted 2 µg/ml in PBTN, was added to wells and incubated at room temperature for 45 min. Secondary Ab was then washed out with six washes of PT, and streptavidin-AP (Southern Biotechnology Associates), diluted 1/2000 in PBTN, was added to each well and allowed to stand at room temperature for 45 min. Plates were washed several times with PT, and p-nitrophenylphosphate substrate (1 mg/ml in AP buffer) was added to each well. Absorbance values were measured at 405 nm after 2 h. A standard curve was generated using varying concentrations (3–800 ng/ml) of purified mouse IgE (clone IgE-3, PharMingen).
In vitro splenocyte stimulation
Spleens from day 7 treated mice were used to prepare single cell suspensions as described above. Cells were then washed several times in DMEM and resuspended in murine growth medium (DMEM containing 2 mM L-glutamine, 50 IU/ml penicillin, 50 µg/ml streptomycin, 1 mM sodium pyruvate, 10 mM HEPES buffer, 5.5 x 10-5 M 2-ME, nonessential amino acids, and 10% FBS) at a concentration of 2 x 106 cells/ml. Cells were then stimulated with 50 ng/ml PMA (Sigma) and 1 µM ionomycin (Sigma) for 19 h at 37°C. Cell supernatants were collected and assayed for IL-4 using the following ELISA.
IL-4 ELISA
IL-4 levels in supernatants were quantified using a sandwich ELISA. Plates were coated overnight at 4°C with a rat anti-mouse IL-4 capture mAb (clone 11B11, PharMingen) diluted at 2 µg/ml in carbonate buffer. The capture Ab was washed out five times with PT, and the plate was blocked with PBTN for 30 min. Supernatants, either undiluted or diluted 1/5 in growth medium containing 0.02% sodium azide, were then added to wells and incubated at room temperature for 2 h. Samples were then washed six times with PT, and the detection Ab, biotinylated rat anti-mouse IL-4 (clone BVD6–24G2, PharMingen), diluted 1 µg/ml in PBTN, was added to wells and incubated at room temperature for 1 h. After six PT washes, streptavidin-AP (Southern Biotechnology Associates), diluted 1/2,000 in PBTN, was added to each well and allowed to stand at room temperature for 30 min. Plates were then washed several times with PT, and p-nitrophenylphosphate substrate (1 mg/ml in AP buffer) was added to each well. Absorbance values were measured at 405 nm after 16 h. A standard curve was generated using varying concentrations (15–8000 pg/ml) of purified rIL-4 (National Cancer Institute Biologic Resources, Frederick, MD).
Renal Ig deposits
After 3 wk of treatment, kidneys were removed from mice that received HgCl2, IL-12, or both. Bisected halves were snap-frozen in 1 to 2 ml of optimal cutting temperature (O.C.T.) compound (Miles, Inc., Elkhart, IN). Six-micron cryostat sections were prepared on a microtome (IEC, Needham Heights, MA) and fixed in acetone for 20 min. Sections were then soaked in PBS for 20 min and blocked with PBS containing 10% goat serum in a moist chamber. Following blocking, sections were incubated with dilutions of FITC-conjugated detection Abs specific for IgG1, IgG2a, or IgG2b. The primary dilution used was 1/50, and twofold dilutions were used until specific glomerular fluorescence was no longer detected. The inverse of the highest conjugate dilution at which fluorescence could be detected was defined as the glomerular Ig deposit titer (23).
Statistical analyses
These analyses were conducted with nonparametric tests using the GraphPad Prism software (version 2.01 (GraphPad Software, Inc., San Diego, CA)).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Groups of A.SW mice (H-2s) were injected with
HgCl2 alone, IL-12 alone, or HgCl2 and IL-12 as
described in Materials and Methods. The production of highly
specific autoantibodies against nucleolar Ags is the hallmark of
Hg-induced autoimmunity, and we tested the sera from the various
experimental groups for the presence of ANoA by immunofluorescence on
HEp-2 cells. ANoA were not detectable at any time point in the group of
mice that received IL-12 only. Although IgG class ANoA became
detectable in the sera of both groups of mice receiving
HgCl2 injections (Fig. 1
),
the fluorescence staining intensity was, however, much lower in the
group of animals that also received IL-12 (not shown). Since IL-12 can
have different effects on various Ig isotypes, we determined the serum
titers of the three major ANoA isotypes, i.e., IgG1, IgG2a, and IgG2b
(Fig. 2). IgG1 ANoA were present after 2
wk in sera of mice receiving HgCl2 at titers exceeding
10,000 and peaked at week 3. In contrast, sera from mice receiving both
HgCl2 and IL-12 showed no detectable IgG1 ANoA until week
3. ANoA levels in this group then slowly increased, but their mean
titer was never >1,500 (Fig. 2). Likewise, both IgG2a and IgG2b ANoA
titers steadily increased until week 4 and decreased thereafter in mice
treated with HgCl2 only, whereas the levels of these
autoantibodies remained very low throughout in animals that received
both HgCl2 and IL-12 (Fig. 2).
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After 1 wk, HgCl2 treatment resulted in a
significant increase (p < 0.05) in splenic B
cell numbers compared with untreated animals (Fig. 3). Animals treated with both
HgCl2 and IL-12 or with IL-12 alone also displayed a
moderate augmentation in splenic B cell numbers, although this increase
was not significantly different from that in the control group (Fig. 3). To further characterize the effects of HgCl2 and/or
IL-12 on Ig production by B cells in A.SW mice, dilutions of sera were
tested for IgG1, IgG2a, and IgG2b subclass Abs using a sandwich ELISA.
While no overall changes in IgG1 were seen in sera of mice receiving
four injections of IL-12, mice receiving HgCl2 treatment
showed an approximately 10-fold increase in IgG1 levels after 2 wk
compared with preinjection levels (Fig. 4). Serum IgG1 levels in these mice
peaked at week 3, declining rapidly thereafter. A.SW mice receiving
both HgCl2 and IL-12 had reduced levels of serum IgG1 after
2 wk compared with those in A.SW mice receiving HgCl2 alone
(Fig. 4).
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) compared with preinjection levels, confirming
previous findings (16). Injection with IL-12 alone also resulted in an
increase in serum IgG2a after 3 wk. Mice receiving both
HgCl2 and IL-12 had greater levels of serum IgG2a than
either of the other two groups by week 3 (Fig. 4). Serum levels of
IgG2b remained relatively unchanged for all three groups of mice
throughout the course of the experiment (Fig. 4). It is worth emphasizing that in mice receiving HgCl2 only, ANoA production did not closely follow the time course of IgG subclass production in the serum of A.SW mice. IgG1 and IgG2a ANoA developed slightly later than the total serum increases in the corresponding isotypes, and IgG2b ANoA were readily detectable even though there was no significant increase in total serum IgG2b. These and previous observations support the view that ANoA are not merely the product of nonspecific polyclonal activation, but result from a specific Ag-driven response (20).
IL-12 does not inhibit the Hg-induced increase in serum IgE
To determine the effect of IL-12 on the Hg-induced increase in
serum IgE, A.SW mice were treated as described above, and total serum
IgE was measured by ELISA at various time points after the beginning of
the injections. IL-12 alone did not affect the overall levels of serum
IgE (Fig. 5). In contrast, by week 2,
mice receiving HgCl2 displayed a 38-fold increase in
serum IgE over week 0 levels. Mice receiving HgCl2 and
IL-12 also showed increased levels of IgE that were not significantly
different (p > 0.05) from those in mice that
received HgCl2 only. The serum IgE peak, however, was
delayed in the HgCl2 plus IL-12 group (week 3) compared
with that in the HgCl2 only group (week 2).
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Several studies have shown that in susceptible animal strains,
HgCl2 can elicit IL-4 production both in vivo and in
vitro (13, 14, 18). We therefore investigated whether IL-12 treatment
affected the HgCl2 induction of IL-4 secretion in A.SW
mice. After 1 wk of treatment with HgCl2 and/or IL-12, A.SW
splenocytes were restimulated in vitro with PMA plus ionomycin, and
IL-4 production in the supernatant was measured by ELISA. The results
presented in Figure 6 show that in vivo
treatment with HgCl2 induced IL-4 production by A.SW
splenocytes and that this induction was increased in animals receiving
both HgCl2 and IL-12 (p < 0.05).
In contrast, splenocytes from animals receiving IL-12 only without
HgCl2 produced IL-4 levels comparable to those in untreated
controls.
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Renal Ig deposits were detected by immunofluorescence
performed on kidney cryostat sections prepared from A.SW mice injected
with HgCl2 alone, IL-12 alone, or HgCl2
and IL-12. IgG1, IgG2a, and IgG2b deposits were detected 3 wk after the
start of the injections using isotype-specific fluorescent conjugates.
Since even normal mice showed a significant level of Ig background
staining, kidney cryostat sections from untreated A.SW mice were also
used as controls. Compared with normal mice, these background levels of
renal deposits were not significantly increased in mice treated with
IL-12 only (and were most pronounced for the IgG2a subclass; Fig. 7). IgG1 renal deposits were
significantly higher in both groups of mice that received
HgCl2 compared with those in mice that received IL-12 alone
(Fig. 5). However, there was no significant difference in the levels of
IgG1 deposits between the groups receiving HgCl2 alone or
HgCl2 plus IL-12. The IgG2a and IgG2b deposits were not
significantly different among the three experimental groups (Fig. 7).
These results indicate that IL-12 treatment did not alter Ig deposition
in mice injected with HgCl2.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Hyperglobulinemia is a major feature of the Hg-induced immune syndrome
in H-2s mice. Because the increase in serum Ig is
especially pronounced for IgG1 and IgE, several authors have suggested
that Hg-induced activation of the Th2 subset is the critical event
underlying the syndrome (12). In susceptible Brown-Norway rats, Hg can
indeed directly stimulate IL-4 secretion in lymphocytes and mast cells
(13, 14), and IL-4 is produced in vivo after Hg injections (15). Recent
results suggest that Hg-treated Brown-Norway rats are deficient in the
expression of IL-12, the main Th1 regulatory cytokine, compared with
the resistant Lewis strain (30). We therefore investigated whether the
administration of IL-12, a cytokine critical in favoring the
establishment of a Th1 over a Th2 response, would affect the
development of Hg-induced autoimmunity. Our results indicate that
administration of rIL-12 at the onset of the syndrome inhibits the
Hg-induced increase in serum IgG1 and potentiates the IgG2a induction,
but does not significantly affect the IgE increase. This result was
partly unexpected, since the induction of IFN- by IL-12 can
down-regulate class-switching to both IgG1 and IgE (31). Nevertheless,
under certain circumstances, IL-12 can enhance IgE synthesis. In CBA/J
mice, administration of high doses of IL-12 suppresses IgE responses
after phospholipase A2 immunization, whereas low doses of
IL-12 lead to elevated levels of IgE Abs against the same immunogen
(31). When keyhole limpet hemocyanin is used as an immunogen in the
same CBA/J strain, both high and low doses of IL-12 suppress IgE
responses. In contrast, in BALB/c mice, both high and low doses of
IL-12 enhance the synthesis of IgE directed against keyhole limpet
hemocyanin (31). Thus, the ability of IL-12 to influence Th2
cytokine-dependent IgE production varies according to the immunologic
setting. These apparently paradoxical results can be partly explained
by recent developments in our understanding of Th cell differentiation.
IL-12 and IL-4 control the development of Th1 and Th2 cell types,
respectively. Nevertheless, in the presence of both cytokines, IL-4
effects are dominant, and IL-12 even enhances the development of Th2
cytokine-producing cells (32). Likewise, we observed an increase in
Hg-induced IL-4 production in mice treated with IL-12. In susceptible
strains, HgCl2 strongly induces IL-4 synthesis by T cells
and mast cells, both in vivo and in vitro (13, 14, 15). Thus, treatment of
mice with both HgCl2 and IL-12 may favor the development of
Th cells with a mixed Th0 phenotype. The balance of Th1 and Th2
cytokines induced by these treatments may determine the differential
effects of IL-12 on IgG1 and IgE levels, since switching to these two
isotypes is differentially controlled (33).
Our results are in contrast with those of Ochel et al., who found that
anti-IL-4 treatment did not prevent the development of ANoA, but
shifted the response from the IgG1 to the IgG2a and IgG2b isotypes
(16). In contrast, anti-IL-4 treatment prevented both IgG1 and IgE
hyperglobulinemia (16). A recent study from the same group showed that
IFN- treatment can partly prevent the HgCl2-induced
increase in serum IgE, but does not affect the formation of ANoA (34).
Therefore, three "Th1-promoting" treatments (anti-IL-4,
IFN-, and IL-12) differed in their effects on the various
manifestations of Hg-induced autoimmunity. In view of the current
interest in manipulating immune responses by affecting the Th1-Th2
balance, these combined observations suggest that apparently analogous
biologic agents can have largely different results on Th-dependent
manifestations of autoimmune disease.
In susceptible strains, Ig deposits form in the kidneys of Hg-treated animals, resulting in a transient proteinuria. The exact mechanisms of kidney damage are not understood, and there is even controversy as to whether these animals develop true glomerulonephritis (9). In our study, IL-12 treatment did not significantly affect the kidney deposit levels of the various IgG isotypes. These results indicate that ANoA do not contribute significantly to the nephritis, since their titers were dramatically decreased in IL-12-treated mice. Our findings are in agreement with those of several studies that concluded that ANoA are not required for the presence of Ig deposits in Hg-induced autoimmunity. For instance, backcross studies between susceptible SJL and resistant C57Bl/6 mice have shown that mercury-treated mice can develop renal IgG deposits without concomitant serum ANoA (35). Conversely, the presence of ANoA does not necessarily result in the development of immune complex deposits. Susceptible mice treated orally with HgCl2 (36) or injected with silver nitrate produce ANoA without renal IgG deposits (37). Therefore, ANoA production does not correlate with renal immune complex deposition (38).
Murine chronic graft-vs-host disease (GVHD) shares several features with heavy metal-induced autoimmunity, suggesting that common mechanisms underlie both syndromes. Thus, the injection of parental splenocytes into (C57Bl/6 x DBA/2) F1 mice results in hyperglobulinemia, increased secretion of Th2 cytokines, and autoantibody production. Pretreatment of these mice with IL-12 abolishes most of the manifestations of chronic GVHD, but actually results in a more lethal and acute form of GVHD (39, 40). Furthermore, the effect of IL-12 on the manifestations of chronic GVHD differs somewhat from its effect on Hg-induced autoimmunity. For instance, IL-12 decreases autoantibody production in both models, but whereas it prevents the induction of all serum Ig isotypes in chronic GVHD (40), it prevents only the IgG1 increase in the Hg-induced syndrome. These results indicate that the cytokine interactions that control metal-induced autoimmunity and chronic GVHD are only partly similar. Furthermore, our observations support the view that the various manifestations of Hg-induced autoimmunity are independently regulated.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Marc Monestier or Dr. Padmini Salgame, Department of Microbiology and Immunology, Temple University School of Medicine, 3400 North Broad St., Philadelphia, PA 19140. E-mail address:
3 Abbreviations used in this paper: ANoA, anti-nucleolar Abs; PT, PBS and 0.05% Tween; AP, alkaline phosphatase; PBTN, PBS containing 1% BSA, 0.05% Tween-20, and 0.02% sodium azide; HBe, hepatitis B e Ag; GVHD, graft-vs-host disease.
Received for publication June 9, 1997. Accepted for publication October 24, 1997.
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