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Departments of Medicine and Microbiology-Immunology and Multipurpose Arthritis Center, Northwestern University Medical School, Chicago, IL 60611
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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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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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NZB and SWR mice were purchased from Jackson Laboratory (Bar Harbor, ME). SNF1 hybrids were bred at our animal facility. Female mice were used.
Abs
The following mAbs were used: anti-I-Ad (HB3), anti-I-Ab,d,q (TIB120), anti-HSA (TIB183), anti-Thy1.2 (TIB99), anti-CD8 (TIB211), and anti-CD3 (145-2C11), all obtained from American Type Culture Collection (Manassas, VA).
Synthesis of peptides
All peptides were synthesized by F-moc chemistry (Chiron Mimotopes, San Diego, CA). The purity of the peptides was checked by amino acid analysis by the manufacturer. The nucleosomal histone peptides were H416–39, H471–94, and H2B10–33 (3). We also used an I-Ad binding, 17-mer OVA (OVA323–339) peptide that does not accelerate disease in SNF1 mice upon immunization with CFA (3, 21). The peptides were purified by HPLC using a gradient of water and acetonitrile and were analyzed by mass spectrometry for purity.
Tolerance induction with histone-derived peptides in vivo
In long-term follow-up experiments, autoimmune but prenephritic
SNF1 females that were 12-wk-old (nine mice per group),
were injected i.v. with either H2B10–33, H416–39, H471–94, or OVA323–339 peptide
(300 µg/mouse) in saline. The control group received only saline. The
animals received three more injections at 2-wk intervals (300 µg
peptide/mouse each time). The mice were monitored weekly for
proteinuria using albustix (VWR Scientific, Chicago, IL) and killed
when they developed persistent proteinuria (two consecutive weekly
readings of 300 mg/dl or greater). Sera were collected for the
determination of IgG anti-nuclear autoantibodies. Blood urea
nitrogen was measured by azostix (Miles, Ekhart, IN). Kidney sections
were stained with hematoxylin and eosin and anti-mouse Ig for the
detection of immune complex deposition, and grading of
glomerulonephritis by blinded observer was done as described (1, 14, 22, 23, 24, 25). In short-term follow-up experiments to test the immunological
consequences of the tolerance therapy early on, another batch of
12-wk-old SNF1 mice (nine per group) were treated as
mentioned above, but they received the peptide injections every week
for 4 wk. Two weeks after the last injection, these mice were killed
for analysis of autoimmune T and B cells and grading of renal lesions.
For chronic therapy of established glomerulonephritis, 18-mo-old
SNF1 mice with 300 mg/dl of persistent proteinuria were
injected i.p. once a month with 300 µg peptide/mouse (six mice/group)
until they were moribund and succumbed to renal disease.
Autoantibody quantitation
IgG-class autoantibodies to ssDNA, dsDNA, histones, and nucleosomes (histone/DNA complex), in culture supernatants or serum, were estimated by ELISA. Anti-DNA mAbs 564 and 205 were used to generate standard curves (1, 3, 14, 23). Sera were diluted 1:400 and heat-inactivated before use. Serum from normal SWR mice were used as negative control. Total polyclonal IgG levels were also measured by ELISA (1, 14, 23).
Isolation of CD4+ T cells and B cells
Splenic CD4+ T cells were isolated as reported earlier (1, 14). Briefly, splenic T cells were purified from 3- to 4-mo-old SNF1 mice by nylon wool column followed by the lysis of CD8+ T cells and contaminating B cells using anti-CD8 (TIB211), anti-Ia (TIB120), anti-HSA (TIB183), mAbs, and a mixture of rabbit and guinea pig complement (1:10) (Pel Freeze Biologicals, Rogers, AR). B cells were prepared from SNF1 mice by treating splenocytes that had been passed through nylon wool with anti-Thy1.2 (TIB99) and complement twice.
Cytokine assays
Fresh splenic CD4+ T cells (1 x
105/microwell) from tolerized or control mice were
cocultured in triplicate with irradiated (3000 rad) anti-Thy-1.2
and complement-treated splenocytes (5 x 105/well) as
APC (B cells plus macrophage preparation; Refs. 1 and 3) and different
concentrations of "control" or "test" peptide in 200 µl final
volume in HL-1 serum-free medium (BioWhittaker, Walkersville, MD) for
24–36 h in flat-bottom 96-well plates (Costar, Cambridge, MA). The
culture supernatants were removed from wells after 24–36 h for
cytokine assays (3). Anti-IL-2, anti-IFN-
, and anti-IL-4
capture and biotinylated-revealing Ab pairs and the respective
standards (rIL-2, rIL-4, rIFN-) were purchased from PharMingen (San
Diego, CA). Streptavidin-HRP and the substrate tetramethylbenzidine
were purchased from Sigma (St. Louis, MO). The cytokines were
quantitated according to the manufacturer.
Helper assays for IgG autoantibody production
T cells (2.5 x 106/well) from the short-term follow-up batch of treated mice or T cells from unmanipulated SNF1 mice were cocultured, respectively, with unmanipulated or tolerized SNF1 splenic B cells (2.5 x 106/well) in 24-well plates for 7 days, as previously described (26, 27). Respective B cell preparations were cultured alone to measure baseline autoantibody production. Culture supernatants were collected, freeze-thawed, and assayed by ELISA for Abs against ssDNA, dsDNA, histones, and nucleosomes (histone/DNA complex). For studies involving stimulation of B cells by soluble CD40 ligand (CD40L), CD40L-CD8 fusion protein (28) was added at 1:4 dilution for the entire 7-day culture period. To further determine the fate of B cells in tolerized mice, B cells (2.5 x 106/well) were stimulated with 10 µg/ml of LPS or 10 µg/ml of anti-mouse Ig F(ab')2 with and without rIL-4 (50 U/ml) in cultures.
Assay for regulatory T cells
To determine whether the tolerance therapy had induced any regulatory T cells, SNF1 T cells (2.5 x 106/well) or purified CD4+ or CD8+ T cells (1 x 106/well) from the short-term follow-up batch of tolerized or saline-treated control mice were cocultured with a mixture of splenic B cells (2.5 x 106/well) and T cells (2.5 x 106/well) from unmanipulated SNF1 mice in 24-well plates for 7 days. Culture supernatants were then collected, freeze-thawed, and assayed by ELISA for IgG Abs against ssDNA, dsDNA, histones, and nucleosomes.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Twelve-week-old prenephritic SNF1 females that did not
have proteinuria (nine mice per group) were injected i.v. with either
H2B10–33, H416–39, H471–94, or
OVA323–339 peptide (300 µg/mouse) in saline, and the
control group of mice received only saline. Each group of animals
received three additional injections at 2-wk intervals. The mice were
monitored weekly for proteinuria and sacrificed when they developed
severe nephritis. By 22 wk, the control mice that received only saline
started developing severe nephritis as documented by persistent
proteinuria of 300 mg/dl or greater, and a 4+ grading of renal
pathology (Fig. 1
). At 28 wk of age,
55.5% of the saline control group, 33.3% (p =
0.637, Fisher’s exact test) of the H471–94
peptide-injected group, and 11.1% (p = 0.131)
of the OVA323–339 peptide-injected group of mice developed
severe nephritis, whereas the H2B10–33 or
H416–39 peptide-injected mice did not develop disease at
this time (p = 0.029). The largest difference
in incidence of severe nephritis between the peptide-injected groups
and the saline control was from 36–38 wk of age. In the control group,
88.8% of the mice had developed severe disease, whereas the
OVA323–339, H2B10–33, or H471–94
group had an incidence of only 33.3% (p =
0.05) and in the H4 16–39 group only 11.1%
(p = 0.003) of the animals had developed severe
nephritis (Fig. 1). Mice in all groups, except the H416–39
peptide-injected mice, developed severe nephritis by 54 wk of age. The
H416–39 peptide-injected group had a 55.5% incidence of
severe nephritis even at this advanced age, but the differences were
not that significant (p = 0.08 compared with
saline group; p = 0.294 compared with
OVA323–339 group).
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In unmanipulated SNF1 mice, T cells are spontaneously
primed to the nucleosomal peptides early in life and respond to them in
vitro (3). Therefore, T cells isolated at the time of sacrifice from
peptide-treated or control mice in the long-term follow-up experiments
(Fig. 1
) were cocultured with APC in the presence of the peptides or
nucleosomes, and their responses were measured by incorporation of
[3H]thymidine for proliferation and cytokine (IL-2,
IFN-, and IL-4) production by ELISA. As these mice had already
developed a 4+ grade of severe nephritis at the time of testing, the
background levels of proliferation were high (data not shown). There
was no deviation in cytokine production when the saline-treated group
was compared with the peptide-treated groups (data not shown).
To test the immunologic consequences of the peptide therapy early on,
before it is obscured by full-blown disease, another set of
12-wk-old SNF1 mice was injected with the various
peptides or saline once a week for 4 wk and were killed 2 wk after the
last injection. The animals were 22- to 23-wk-old at this time. We
refer to this batch of mice as the "short-term" follow-up batch. At
this earlier time point of sacrifice, the incidence and grading of
renal pathology in this batch of mice are shown in Table I. Also in this batch of mice, we did not
detect any consistent differences in cytokine production levels or
cytokine profiles in T cells from the saline control vs the
peptide-treated groups of mice in response to any of the peptides or to
nucleosomes (data no shown).
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The helper assay for autoantibody-inducing ability is a much more
rigorous test for autoimmune Th function. Therefore, in additional
experiments we used the helper assay to determine the function of T and
B cells in tolerized animals from the short-term follow-up batch. To
test the ability of T cells to functionally help B cells,
CD4+ T cells were isolated from the peptide-treated mice
and cocultured with B cells isolated from unmanipulated 16- to
20-wk-old SNF1 mice in a helper assay. The coculture
supernatants were assayed for the presence of IgG Abs against ss-DNA,
ds-DNA, nucleosomes, and histones. The results shown are the mean
values ± SEM of five experiments (Fig. 2). Anti-dsDNA Ab production was reduced
by 50% in the cultures containing T cells from
OVA323–339, H471–94, and H416–39
peptide-injected groups in comparison to the saline-injected group
(p = 0.03). The H2B10–33
peptide-treated group showed a 5-fold decrease. Induction of
anti-ssDNA Ab was also reduced by 55% in the
H2B10–33 and H416–39 groups in comparison to
the saline-injected group (p = 0.005–0.001),
but reductions in the OVA323–339 and H471–94
peptide-treated groups were not significant. Anti-nucleosomal Ab
production showed a similar pattern. The cocultures with T cells from
H2B10–33, H416–39, and H471–94
peptide-injected groups produced 2.5- to 4-fold less
anti-nucleosome autoantibody compared with that of the
saline-treated control group (p = 0.03–0.05),
but in the case of OVA323–339 group the reduction was not
significant (p = 0.061). The effect on
anti-histone Ab induction, overall, was not as dramatic
(p = 0.1).
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To determine whether the diminished help by the CD4+ T
cells from peptide-treated mice were due to anergy or deletion, rIL-2
ranging from 12.5 to 100 U/ml was added to the helper assay cocultures
(T cells from treated mice plus B cells from unmanipulated
SNF1 mice) at the beginning of the 7-day period. The
saline-treated control mice produced 102 ± 15.5 U of
anti-dsDNA Ab, and the addition of rIL-2 increased this
concentration very little (Fig. 3).
CD4+ T cells from the OVA323–339,
H471–94, and H2B10–33 peptide-treated mice
did not show any improvement in their helping ability after the
addition of rIL-2 (Fig. 3). The exception was the H416–39
peptide-treated group, where there was a modest recovery of help with
an increase by 35% in anti-dsDNA autoantibody production after the
addition of rIL-2 (p = 0.05), but the 30%
increase in anti-ssDNA and 20% increase in anti-nucleosome Abs
were not significant (Fig. 3).
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The effect of peptide therapy on immune function of the B cells
was determined by coculturing the B cells from the peptide-treated mice
with CD4+ T cells from unmanipulated SNF1 mice
(3- to 4-mo-old) in the helper assay. When such T cell help was
provided, the B cells from the peptide- and saline-treated groups did
not show any difference in augmenting their ability to produce IgG
autoantibodies, with the exception of the H416–39
peptide-injected animals, whose B cells still produced diminished
levels of all autoantibodies in these cocultures. The level of
anti-dsDNA Abs produced by B cells from H416–39
peptide-treated mice (45 ± 10.1 U/dl) was significantly reduced
in comparison to saline-treated mice (160 ± 18.5 U/dl)
(p = 0.03; Fig. 4). The production of anti-ssDNA Abs
also showed a similar pattern: B cells from the saline-treated group
produced 170 ± 10.9 U vs B cells from the H416–39
peptide-treated group, which produced 60 ± 7.9 U
(p = 0.005). Production of anti-nucleosome
Abs was reduced by 3-fold compared with controls (145 ± 20.8 vs
45 ± 5.9 U) in the H416–39 peptide-treated group,
and anti-histone Ab production was reduced by 4-fold
(p = 0.003) in H416–39
peptide-injected animals as compared with the saline group. In the case
of H471–94 peptide-injected animals, the production of
anti-nucleosome (p = 0.01) and
anti-histone (p = 0.003) autoantibodies,
but not anti-dsDNA or anti-ssDNA autoantibodies, remained
significantly low as compared with the saline group, even with the T
cell help. The baseline autoantibody production by B cells cultured by
themselves ranged from 1.3 to 2.5 U/ml in these experiments (Fig. 4).
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B cells from H416–39 peptide-treated animals were
less responsive to help from T cells of unmanipulated SNF1
mice (Fig. 4). To assess whether this was due to deletion of autoimmune
B cells or due to anergy, purified (T cell-depleted) B cells from the
treated mice were stimulated with anti-Ig F(ab')2 in
the presence or absence of rIL-4, and the production of IgG
anti-dsDNA, ssDNA, nucleosome, and histones were measured.
Saline-treated or OVA323–339 peptide-treated mice produced
high levels of autoantibodies, whereas B cells from the
H416–39 peptide-treated group did not respond even when
stimulated with anti-Ig F(ab')2 in the presence of high
levels of rIL-4, suggesting a possible deletion of autoimmune B cells
(Fig. 5). In contrast, B cells from
H471–94 peptide-treated mice could be stimulated to
produce autoantibodies to levels similar to the saline-injected mice
(data not shown). The basal level of autoantibody production by B cells
cultured alone ranged from 1.9 to 2.1 U (Fig. 5).
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Soluble CD40L-CD8 fusion protein was added to the B cell cultures
at a 1:4 final concentration with or without rIL-4. Purified (T
cell-depleted) B cells from the saline-treated or
OVA323–339 peptide-treated mice produced anti-nuclear
autoantibodies upon stimulation with CD40L (Fig. 6). The addition of rIL-4 to these
cultures enhanced the production of Abs by B cells from the
saline-treated mice further: anti-dsDNA increased from 22 ±
3.2 to 60 ± 4.1 U, anti-ssDNA from 25 ± 3.5 to 54
± 2.2 U, anti-nucleosome from 7 ± 1.8 to 75 ± 5.6 U,
and anti-histone from 19 ± 2.7 to 70 ± 3.3 U. However,
the levels of augmentation with soluble CD40L and IL-4 were much lower
than that induced by intact Th cells from the autoimmune mice (Fig. 4
vs Fig. 6), indicating that additional molecules/mechanisms might be
involved. B cells from the H416–39 peptide-treated group
did not produce significant amounts of autoantibodies even with CD40L
and rIL-4. (Fig. 6).
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Purified B cells (T cell-depleted) were isolated from the
peptide-treated mice and stimulated with the potent mitogen LPS. B
cells from all the groups responded by augmenting autoantibody
production to levels comparable to that of the saline-treated group
(p = 0.07–0.1; Fig. 7).
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Sera were collected from the mice at the start of treatment, at 36
wk of age (a time point of greatest difference in incidence of severe
nephritis between peptide-treated vs control-saline group; Fig. 1), and
at the peak of the disease. IgG Ab levels were measured for
anti-dsDNA, ssDNA, nucleosome, and histone at a 1:400 dilution of
sera. The anti-dsDNA Ab level in the saline-treated group
(mean ± SEM) was 5.5 ± 0.3 U, and in the
OVA323–339, H2B10–33, H416–39,
and H471–94 groups these levels were 8.0 ± 1.0,
7.7 ± 0.9, 9.0 ± 2.1, and 5.4 ± 1.1 U, respectively,
at the start of treatment. At 36 wk of age in the saline-injected
group, anti-dsDNA levels went up to 26 ± 3.2 U, but were
15.6 ± 4.2, 14.0 ± 3.2, 13.0 ± 4.0, and 17.1 ±
2.7 U in the OVA323–339, H2B10–33,
H416–39, and H471–94 groups, respectively
(compared with the saline-injected group, the p values
ranged from 0.03 to 0.05) (Fig. 8).
Similar time point comparisons of anti-ssDNA and
anti-nucleosome Ab levels also showed a reduction in the
peptide-treated mice that was comparable to the reduction in their
anti-dsDNA autoantibody levels (p =
0.04–0.05). The levels of anti-histone Abs varied in different
groups (p = 0.3–0.01; Fig. 8). At the time of
sacrifice, when the mice had developed severe nephritis (Fig. 1), the
serum levels of autoantibodies were similar among the peptide- and
saline-treated groups (data not shown). Total polyclonal IgG levels
were not significantly different in the peptide-treated group from the
saline-control group, varying from 8–11 mg/ml.
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To find if any regulatory T cells might have been generated by peptide therapy, the ability of the T cells from treated mice to inhibit the autoantibody production in cocultures of T and B cells from unmanipulated SNF1 mice was determined. T cells or purified CD4+ or CD8+ subsets of T cells from the short-term follow-up batch of tolerized or control mice were cocultured with splenic B and T cell mixtures from unmanipulated SNF1 mice in 24-well plates for 7 days. IgG Abs against ssDNA, dsDNA, histones, and nucleosomes were estimated. No significant reduction in autoantibody production by the addition of T cells from the peptide-treated mice was observed (data not shown).
Treatment of established glomerulonephritis with nucleosomal peptides
Among unmanipulated SNF1 mice, a small fraction of
animals develop severe renal disease relatively later than others. We
followed >1000 animals and found 30 18-mo-old SNF1 mice
that had established glomerulonephritis with persistent proteinuria of
300 mg/dl. These old mice (six/group) were chronically treated every
month with the nucleosomal histone peptides H416–39,
H471–94, or H2B10–33 or the
OVA323–339 peptide (300 µg/mouse). The mice were
monitored by measuring proteinuria until they died. The saline-injected
mice showed rapid progression of disease and died within 2 mo after the
start of the treatment. At this time point, 66.6% of the
H471–94 and H2B 10–33 peptide-injected group
of animals were alive (p = 0.061), whereas none
of the animals treated with OVA323–339, or
H416–39 had died (p = 0.002), even
at 22 mo of age (Fig. 9). All of the
peptide-treated groups maintained their starting levels of proteinuria
during the course of the therapy, with the exception of the
H416–39 peptide-injected group, where 66.6% of the
animals actually showed a reduction in proteinuria levels from 300-1000
mg/dl to <100 mg/dl. By 26 mo of age, all H416–39
peptide-treated mice remained alive; in contrast, all
H471–94 peptide-treated mice were dead
(p = 0.002), and only one animal in the
OVA323–339 and H2B10–33 peptide-treated
groups survived (p = 0.015 vs
H416–39 group; Fig. 9).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The mechanism of the "tolerogenic" effect of the nucleosomal
peptides on the diminishing autoantibody-inducing ability of the Th
cells of lupus is unknown. Anergy of the autoimmune Th cells in the
conventional sense is unlikely, because their helper activity in
autoantibody production could not be revived by supplements of IL-2
(Fig. 3) or stimulation with nucleosomal peptides plus IL-2 (data not
shown). Moreover, we did not detect any immune deviation in cytokine
profiles of T cells from the treated mice. The administration of high
doses of soluble protein or peptide Ags is known to cause tolerance by
apoptosis or anergy of cognate T cells or by generation of regulatory T
cells (reviewed in 8). Some deletion of autoimmune Th cells in the
treated mice here remains a possibility, but it is probably minor,
because cytokine responses to the peptides were not different between T
cells from the saline control and the peptide-treated groups. Perhaps
the autoantigen-primed memory T cells of lupus are more resistant to
deletion or anergy by these criteria. Moreover, no evidence of
down-regulatory T cells were detected in the treated mice. Therefore,
the peptide therapy might have impaired some unknown signals or
mechanisms involved in the interactions between autoimmune T and B
cells that are required for the specialized function of pathogenic
autoantibody production. Indeed, this special functional ability to
induce pathogenic autoantibodies may require some maturational
event(s), because it is detectable in T cells of older, 3- to 4-mo-old
SNF1 mice, whereas the T cells of younger mice are
incapable of providing such help (26), although they respond to
nucleosomes spontaneously and hyperexpress CD40L (1, 14). The superior
autoantibody-inducing ability of intact T cells, as compared with
soluble CD40L and IL-4 (Fig. 4 vs Fig. 6), also suggests the
involvement of additional mechanisms. Furthermore, what is striking
here is that any one of the nucleosoamal peptide autoepitopes we
identified could diminish pathogenic autoantibody production across the
board (tolerance spreading) and markedly delay the development of
nephritis.
Large doses of soluble peptides could competitively block immunogenic presentation of autoepitopes by displacing them from class II molecules of APC and also by being predominently displayed on class II molecules of resting APC (41, 42, 43, 44). In fact, the former may be the reason for the beneficial effect of the OVA peptide, which binds strongly to I-Ad (21, 41, 42). Alternatively, the OVA peptide, which also bears charged residues, could have acted as an antagonist or an altered peptide ligand for the promiscuous T cells of lupus (4, 21, 41, 42). But, unlike the nucleosomal peptides, immunization with the OVA peptide in CFA does not induce lupus nephritis or stimulate the pathogenic Th cells of lupus (3). Tolerization with peptides corresponding to complementarity-determining regions 1 and 2 of the VH region of an anti-DNA autoantibody that is recurrently expressed in SNF1 mice (1), or with the complementarity-determining region peptide of a nonspecific control, anti-malaria Ab (1), does not have any significant effect on the incidence of nephritis in the SNF1 mice (S. Adams, P. LeBlanc, and S.K. Datta, unpublished observations). However, in the (NZB x NZW)F1 mice, tolerization with autoantibody-derived peptides does have a therapeutic effect (45), and interestingly such peptides have charged residues like the nucleosomal peptides. In the future, studies to define the TCR and MHC contact residues in the nucleosomal peptide autoepitopes may reveal the mechanism of the beneficial effect of the OVA peptide.
The second reason for "tolerance spreading" could be because individual TCRs of the pathogenic autoantibody-inducing Th cells of lupus recognize more than one nucleosomal peptide epitope in a promiscuous or degenerate fashion and in the context of diverse class II molecules (3, 4). High-affinity interactions between the lupus TCRs and MHC-nucleosomal peptide complex due to reciprocally charged residues probably overcomes the requirement for MHC restriction. Therefore, a single nucleosomal epitope with charged residues could possibly tolerize a spectrum of lupus Th cells that could recognize, in different registers, one or two shared residues in apparently different peptide autoepitopes. This plasticity of TCRs is being increasingly appreciated by structural and functional analysis (4, 46, 47, 48, 49, 50, 51).
The third possibility for "tolerance spreading" is the multipotent
and promiscuous helper activity of the pathogenic Th cells of lupus.
Remarkably, a single lupus Th clone can help either a dsDNA-specific,
ssDNA-specific, histone-specific, high-mobility group chromosomal
protein-specific, or nucleosome-specific B cell, because each of these
B cells by binding to its respective epitope on the whole chromatin can
take it up and process and then present the relevant peptide epitope in
the chromatin to the Th clone (Fig. 10,
and Refs. 1, 2, and 52), resulting in intermolecular help. Therefore,
the multipotent (promiscuous helper) Th cells of lupus cause immediate
epitope diversification, rather than the sequential epitope spreading
that comes with inflammatory damage and the progression of autoimmune
disease (24, 53, 54). Tolerization of such Th cells would obviously
deprive multiple autoimmune B cells of T cell help.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Syamal K. Datta, Arthritis Division, Ward 3-315, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611-3008. E-mail address:
3 Abbreviations used in this paper: SLE, systemic lupus erythematosus; SNF1, (SWR x NZB)F1; CD40L, CD40 ligand.
Received for publication October 13, 1998. Accepted for publication February 23, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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chain. J. Exp. Med. 187:367.This article has been cited by other articles:
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M. A. Michaels, H.-K. Kang, A. Kaliyaperumal, E. Satyaraj, Y. Shi, and S. K. Datta A Defect in Deletion of Nucleosome-Specific Autoimmune T Cells in Lupus-Prone Thymus: Role of Thymic Dendritic Cells J. Immunol., November 1, 2005; 175(9): 5857 - 5865. [Abstract] [Full Text] [PDF]
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M. Blank and Y. Shoenfeld Experimental models of systemic lupus erythematosus: anti-dsDNA in murine lupus Rheumatology, September 1, 2005; 44(9): 1086 - 1089. [Full Text] [PDF]
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G. Riemekasten and B. H. Hahn Key autoantigens in SLE Rheumatology, August 1, 2005; 44(8): 975 - 982. [Full Text] [PDF]
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H.-K. Kang, M. A. Michaels, B. R. Berner, and S. K. Datta Very Low-Dose Tolerance with Nucleosomal Peptides Controls Lupus and Induces Potent Regulatory T Cell Subsets J. Immunol., March 15, 2005; 174(6): 3247 - 3255. [Abstract] [Full Text] [PDF]
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C G Katsiari and G C Tsokos Re-establishment of tolerance: the prospect of developing specific treatment for human lupus Lupus, July 1, 2004; 13(7): 485 - 488. [PDF]
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S. Fournel, S. Neichel, H. Dali, S. Farci, B. Maillere, J.-P. Briand, and S. Muller CD4+ T Cells from (New Zealand Black x New Zealand White)F1 Lupus Mice and Normal Mice Immunized Against Apoptotic Nucleosomes Recognize Similar Th Cell Epitopes in the C Terminus of Histone H3 J. Immunol., July 15, 2003; 171(2): 636 - 644. [Abstract] [Full Text] [PDF]
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H. Zinger, E. Eilat, A. Meshorer, and E. Mozes Peptides based on the complementarity-determining regions of a pathogenic autoantibody mitigate lupus manifestations of (NZB x NZW)F1 mice via active suppression Int. Immunol., February 1, 2003; 15(2): 205 - 214. [Abstract] [Full Text] [PDF]
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K. Yasutomo Pathological lymphocyte activation by defective clearance of self-ligands in systemic lupus erythematosus Rheumatology, February 1, 2003; 42(2): 214 - 222. [Abstract] [Full Text] [PDF]
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J W. Dieker, J van der Vlag, and J H. Berden Triggers for anti-chromatin autoantibody production in SLE Lupus, December 1, 2002; 11(12): 856 - 864. [Abstract] [PDF]
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L E Schiffer, N Hussain, X Wang, W Huang, J Sinha, M Ramanujam, and A Davidson Lowering anti-dsDNA antibodies--what's new? Lupus, December 1, 2002; 11(12): 885 - 894. [Abstract] [PDF]
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 G.-C. Fan and R. R. Singh Vaccination with Minigenes Encoding VH-derived Major Histocompatibility Complex Class I-binding Epitopes Activates Cytotoxic T Cells that Ablate Autoantibody-producing B Cells and Inhibit Lupus J. Exp. Med., September 16, 2002; 196(6): 731 - 741. [Abstract] [Full Text] [PDF]
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H. Y. Wu, F. J. Ward, and N. A. Staines Histone Peptide-Induced Nasal Tolerance: Suppression of Murine Lupus J. Immunol., July 15, 2002; 169(2): 1126 - 1134. [Abstract] [Full Text] [PDF]
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A. Kaliyaperumal, M. A. Michaels, and S. K. Datta Naturally Processed Chromatin Peptides Reveal a Major Autoepitope That Primes Pathogenic T and B Cells of Lupus J. Immunol., March 1, 2002; 168(5): 2530 - 2537. [Abstract] [Full Text] [PDF]
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B H Hahn Lessons in lupus: the mighty mouse Lupus, September 1, 2001; 10(9): 589 - 593. [PDF]
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M R Salaman, D P. Mawer, M B Hogarth, M H Seifert, and D A Isenberg Counter-proliferative effects of nucleosomal antigens in cultures from lupus patients Lupus, May 1, 2001; 10(5): 332 - 339. [Abstract] [PDF]
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 L. M. Godsel, K. Wang, B. A. Schodin, J. S. Leon, S. D. Miller, and D. M. Engman Prevention of Autoimmune Myocarditis Through the Induction of Antigen-Specific Peripheral Immune Tolerance Circulation, March 27, 2001; 103(12): 1709 - 1714. [Abstract] [Full Text] [PDF]
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 E. Eilat, M. Dayan, H. Zinger, and E. Mozes The mechanism by which a peptide based on complementarity-determining region-1 of a pathogenic anti-DNA auto-Ab ameliorates experimental systemic lupus erythematosus PNAS, January 30, 2001; 98(3): 1148 - 1153. [Abstract] [Full Text] [PDF]
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Y. Yi, M. McNerney, and S. K. Datta Regulatory Defects in Cbl and Mitogen-Activated Protein Kinase (Extracellular Signal-Related Kinase) Pathways Cause Persistent Hyperexpression of CD40 Ligand in Human Lupus T Cells J. Immunol., December 1, 2000; 165(11): 6627 - 6634. [Abstract] [Full Text] [PDF]
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P. Decker, A. Le Moal, J.-P. Briand, and S. Muller Identification of a Minimal T Cell Epitope Recognized by Antinucleosome Th Cells in the C-Terminal Region of Histone H4 J. Immunol., July 15, 2000; 165(2): 654 - 662. [Abstract] [Full Text] [PDF]
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J. H. Freed, A. Marrs, J. VanderWall, P. L. Cohen, and R. A. Eisenberg MHC Class II-Bound Self Peptides from Autoimmune MRL/lpr Mice Reveal Potential T Cell Epitopes for Autoantibody Production in Murine Systemic Lupus Erythematosus J. Immunol., May 1, 2000; 164(9): 4697 - 4705. [Abstract] [Full Text] [PDF]
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M. L. Stoll and J. Gavalchin Systemic lupus erythematosus--messages from experimental models Rheumatology, January 1, 2000; 39(1): 18 - 27. [Full Text] [PDF]
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