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Receptor
Departments of
*
Orthopaedic Surgery, and
Microbiology and Immunology, Hamamatsu University School of Medicine, Hamamatsu, Japan; and
Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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in the development of CIA. Therefore, we employed IFN-R-deficient
mice to study the role of IFN-. To introduce the CIA susceptibility
gene (H-2q), IFN-R-deficient
(H-2b/b/IFN-R-/-) mice were mated with
DBA/1 (H-2q/q/IFN-R+/+) mice; next, the
F1 mice were interbred to yield F2 offspring
bearing different combinations of H-2 (H-2q/q,
H-2q/b, and H-2b/b) and IFN-R
(IFN-R+/+, IFN-R+/-, and
IFN-R-/-) genes. Although the H-2q allele
appeared to confer susceptibility to CIA, mice that were homozygous for
the IFN-R mutation showed a substantially decreased incidence and
severity of CIA. The CII-specific IgG levels of serum samples, which
are known to be involved in the development of CIA, were remarkably
reduced in IFN-R-/- mice. Furthermore, the
anti-CII IgG2a levels controlled by IFN-R were significantly
reduced in IFN-R-/- F2 mice compared with
those seen in IFN-R+/+ and IFN-R+/-
mice, although the levels of all IgG subclass Abs examined were lower
in IFN-R-/- mice than in IFN-R+/+ mice.
No clear evidence of the imbalance of Th1/Th2 cytokines was observed in
CII-immunized, IFN-R-deficient mice. Taken together, these results
suggest that IFN- exacerbates CIA by affecting, at least, levels of
CII-specific IgG Ab rather than the imbalance of Th1/Th2
cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It is well known that CD4+ T cells are divided into two
functionally distinct subsets, Th1 and Th2, according to their cytokine
profiles. Th1 cells primarily secrete IFN- and IL-2, while Th2 cells
predominantly produce IL-4, IL-5, IL-10, and IL-13 (10, 11, 12). The
imbalance of cytokines produced by Th1/Th2 subsets is believed to play
a pivotal role in the development of autoimmune diseases (5, 13). It is
generally accepted that Th1 cells have a pathogenic role in the
development of autoimmune diseases including CIA (14), whereas Th2
cells can control and reverse disease evolution (15, 16, 17). The presence
of Mycobacterium tuberculosis in CFA in the induction of CIA
leads to a predominant Th1 response, thereby inducing the activation of
CII-specific cellular immunity and the production of CII-specific IgG2a
and IgG2b (6, 18, 19). Both immune mechanisms have been shown to be
required for the induction of full-blown disease (6, 18, 20). However,
the role of the IFN- secreted by Th1 cells in the arthritogenic
response in CIA is a subject of controversy. Several investigators have
reported that an injection of IFN- increased the incidence and
accelerated the onset of CIA in mice (21, 22, 23, 24), whereas another group
demonstrated that the systemic administration of IFN- reduced the
severity of the disease (22). On the other hand, the therapeutic
efficacy of IFN- was demonstrated in the experimental disease and in
clinical trials for the treatment of rheumatoid arthritis (25, 26).
Furthermore, a blockade of IFN- using mAb demonstrated paradoxical
effects on CIA, with early prevention of the disease followed by
late-stage disease exacerbation (23).
Our work was undertaken to determine directly the role of IFN- in
the onset of CIA; IFN-R-deficient mice (IFN-R-/-)
with the CIA-susceptible H-2q allele were employed for this
purpose. Here, we report a significant reduction in both the incidence
and severity of CIA in IFN-R-/- mice compared with
IFN-R+/+ and IFN-R+/- mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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DBA/1 mice were purchased from Japan SLC (Hamamatsu, Japan) and
used at 8 to 10 wk of age. 129/Sv/Ev mice with a disrupted IFN-R
gene (IFN-R-/-) and their wild-type
(IFN-R+/+) littermates were kindly provided by Dr. M.
Aguet (Genentech, San Francisco, CA) (27). To introduce the
CIA-susceptible H-2q gene, 129/Sv/Ev mice
(H-2b/b/IFN-R-/-) were crossed with DBA/1
mice to yield F1 and F2 mice. Mice were
screened for H-2 and IFN-R genotypes by PCR using DNA prepared from
a piece of ear, as described previously (28). The following two sets of
primers were used to distinguish between H-2q and
H-2b genes. Two primer sets (5'-CATTTCGTGGCCCAGTTGAA-3' and
5'-CGCTGTCGAAGCGCACCC-3'; and 5'-CATTTCGTGTACCAGTTCAT-3' and
5'-CGCTGTCGTAGCGCACGT-3') were used to detect the 108-bp product of
the H-2q gene (29, 30) and the 108-bp product of the
H-2b gene (31), respectively. In addition, the following
two sets of primers were used to distinguish between homozygous and
heterozygous IFN-R knockout and wild-type mice. The first set of
primers (5'-TGTCATTGGCGAATTGFAAC-3' and 5'-CACGCGTCACCTTAATATGC-3') was
used to amplify the herpes simplex virus thymidine kinase promoter to
detect the mutant IFN-R gene (IFN-R-/-) with a PCR
product of 80 bp (27, 32, 33, 34). The second set of primers
(5'-TTCTGGCAAGTTAGAACAGA-3' and 5'-TCCTTTCTGTCATCATGGAA-3') was
used to amplify the wild-type IFN-R gene with a 70-bp product (17).
Induction and assessment of CIA
Bovine CII (MCK, Tokyo, Japan) was dissolved in 0.05 M acetic acid and emulsified with an equal volume of CFA (Life Technologies, Tokyo, Japan). Mice were injected intradermally at the base of the tail with 0.1 ml of emulsion containing 100 µg of CII; at 21 days after the primary immunization, mice were boosted with 0.1 ml of emulsion containing 100 µg of CII and IFA (Life Technologies) as described previously (35). Thereafter, mice were monitored for signs of arthritis, and the date of disease onset was recorded. The severity of arthritis was assessed from day 21 to day 70 after primary immunization using a visual according method that had been described by Holmdahl et al. (36). Briefly, the four paws were individually graded from 0 to 3, yielding a maximum possible score of 12 per animal, as follows: grade 0, no swelling; grade 1, paws with detectable swelling in one joint; grade 2, paws with swelling in more than one joint; and grade 3, severe swelling of entire paw and/or ankylosis.
Histology
Relevant paws that were obtained from animals at end of the study were fixed in 10% formaldehyde and subjected to acid decalcification (37). Decalcified paws were embedded in paraffin and stained with hematoxylin and eosin.
Measurement of serum anti-CII Ab levels
The levels of serum Abs to CII were measured by ELISA as described previously (38). The serum samples were collected at 26, 35, and 70 days after primary immunization for the determination of anti-CII IgG Ab levels. Native bovine CII was dissolved in 0.1 M acetic acid at 1 mg/ml and diluted with 0.1 M sodium bicarbonate at 10 µg/ml (pH 9.6). The microtiter plate (96-well; Corning Costar, Cambridge, MA) was coated with 100 µl of CII Ag solution and incubated overnight at 4°C. After washing three times with PBS (10 mM phosphate, 150 mM NaCl, pH 7.6) containing 0.05% Tween-20, nonspecific binding was blocked with 170 µl of PBS containing 10% BSA for 2 h at room temperature. After washing three times, 100 µl/well of serum samples that had been serially diluted in PBS/Tween-20/10% BSA and control serum in a serial dilution from 1:1,000 to 1:64,000 to provide standard titration curves were added and incubated for 1 h at 37°C. After washing, peroxidase-conjugated goat anti-mouse IgG (at 1.4 µg/ml, 100 µl/well) (Organon Teknika, Durham, NC) was added and incubated for 1 h at 37°C. In addition, 100 µl of peroxidase-conjugated rabbit anti-mouse IgG1, IgG2a, or IgG2b (Zymed, San Francisco, CA) at a 1:1000 dilution with PBS/Tween-20/10% BSA was added to detect anti-CII subclass Abs. A total of 100 µl of o-phenylenediamine (0.5 mg/ml) dissolved in 0.1 M citrate buffer (pH 5.0) containing 0.012% H2O2 was added, and finally, the reaction was stopped using 8 N H2SO4 (20 µl/well). OD was measured at 500 nm with a microplate reader. A standard serum sample from a DBA/1 mouse with exhibitory arthritis was measured in serial dilutions, and standard curves were generated. Ab titers of serum samples were calculated from this standard curve and indicated as an arbitrary unit compared with the former standard control serum sample.
Cytokine induction and assays
H-2q/b/IFN-R+/- and
H-2q/b/IFN-R-/- mice were immunized with a
primary and booster injection of CII, as described above. Spleens and
draining lymph nodes were removed on days 20, 23, and 31 after primary
immunization. Single-cell suspensions were prepared and were cultured
in 48-well plates in Cosmedium (CosmoBio, Tokyo, Japan) at 1 x
106 cells/ml/well in the presence or absence of 50 µg/ml
of CII for 48 h at 37°C in 5% CO2. Next,
supernatants were collected and assayed for cytokines, IFN-, IL-4,
IL-2, and IL-10. IFN- and IL-4 were measured by sandwich ELISA.
Briefly, 96-well microtiter plates were coated with capture Abs (at a
1:1000 dilution, 100 µl/well) and incubated overnight at 4°C. The
plates were washed and blocked with 5% BSA in PBS for 2 h at
37°C. After washing three times, 100 µl of samples and serially
diluted standard IFN- (at a twofold dilution, from
104-36 pg/ml) (Genzyme, Cambridge, MA) or IL-4 (at a
twofold dilution, from 5 x 103-17 pg/ml) (PeproTech,
Rocky Hill, NJ) were added and incubated for 3 h at room
temperature. After washing, biotinylated detecting Abs (0.5 µg/ml,
100 µl/well) were added and incubated for 1 h. Streptavidin
conjugated with alkaline phosphatase (at a 1:1000 dilution, 100
µl/well) (Zymed) was also added and incubated for 1 h. Finally,
phosphatase substrate (at 250 µg/ml, 100 µl/well) (Sigma, St.
Louis, MO) in diluted water was incubated for 1 h after washing,
and the reaction was stopped by adding 30 µl of 0.1 M EDTA. The
absorbance was read at 405 nm with a microplate reader. The pairs of
capture and detecting anti-mouse Abs were listed by R4–6A2
mAb/XMG1.2 mAb (PharMingen, San Diego, CA) for IFN- and by 11B.11
mAb/BVD6-24G2 mAb (PharMingen) for IL-4. In addition, IL-2 and IL-10
were also measured using ELISA kits (Endogen, Boston, MA).
Statistical analysis
Data were analyzed using the Macintosh StatView software program
(Tokyo, Japan). Group comparisons were performed using the
2 test or the Mann-Whitney U test for
independent samples of nonparametric data.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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R-deficient mice
DBA/1, 129/Sv/Ev (IFN-R-/-), 129/Sv/Ev
(IFN-R+/+), and (129/Sv/Ev x DBA/1)F2
mice were immunized with CII and monitored for the development of
arthritis for 70 days after primary immunization. As shown in Table I
, the incidence of arthritis was 75% in
DBA/1 mice, 0% in 129/Sv/Ev (IFN-R-/-) mice, and
7.1% in 129/Sv/Ev (IFN-R+/+) mice. No statistical
difference was found between latter two groups. Among F2
mice that were homozygous for H-2q and homozygous and
heterozygous for the IFN-R mutation, only 9% of
H-2q/q/IFN-R-/- mice developed arthritis
compared with 53% of H-2q/q/IFN-R+/+ mice
(p < 0.02) and 50% of
H-2q/q/IFN-R+/- mice
(p < 0.03). The same is true of
H-2q/b mice. The incidence of arthritis in
IFN-R-/- mice (15%, 3 of 20 mice) was significantly
decreased compared with IFN-R+/+ mice (47%, 8 of 17
mice; p < 0.05) and IFN-R+/- mice
(49%, 17 of 35 mice; p < 0.02). In contrast,
F2 mice bearing H-2b/b mice showed
significantly reduced disease incidence as expected
(IFN-R+/+, 17%; IFN-R+/-, 16%;
IFN-R-/-, 14%), and no significant differences were
observed among these mice. These data imply that susceptibility to CIA
is primarily controlled by the H-2q gene in F2
mice and that the incidence of CIA is significantly decreased in
IFN-R-/- mice.
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R mutation
The mean clinical scores of F2 mice are shown in
Figure 1. In F2 mice
homozygous for H-2q (Fig. 1A), the disease
severity in IFN-R-/- mice was significantly reduced
compared with IFN-R+/+ and IFN-R+/-
mice. Likewise, IFN-R-/- mice showed significantly
reduced arthritic scores compared with IFN-R+/+ and
IFN-R+/- mice among H-2q/b mice (Fig. 1B). In contrast, mice that were homozygous for
H-2b showed only mild arthritis regardless of IFN-R
mutation (Fig. 1C).
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R+/- and
IFN-R-/- mice
A histologic examination of the metatarsophalangeal joints of
H-2q/b/IFN-R+/- mice showed typical
arthritis, which is characterized by extensive infiltration of
inflammatory cells, synovial hyperplasia, and bone erosion (Fig. 2A). In contrast, most joints
of IFN-R-/- mice showed either mild cellular
infiltration or no sign of inflammation (Fig. 2B). Thus,
histologic evaluations confirmed the characteristic arthritic lesions
and showed an excellent correlation with clinical grading.
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R-/- mice
To examine the time course of the generation of the
anti-CII-specific IgG Ab, serum samples were collected on days 26,
35, and 70 after primary immunization. The production of anti-CII
IgG Ab in both DBA/1 and H-2q/b/IFN-R+/-
F2 mice peaked by day 36 and remained constant thereafter
(Fig. 3). However,
H-2q/b/IFN-R-/- F2
mice showed detectable levels of the Ab for the duration of the study.
This observation prompted us to measure the serum levels of the Ab in
all groups of mice examined in this study when sacrificed (day 70). As
shown in Figure 4, all groups of mice
expressing functional IFN-R (IFN-R+/+ and
IFN-R+/-) showed IgG Ab levels that were comparable
with those seen in DBA/1 mice. It is of particular interest that IgG Ab
levels in H-2b/b mice expressing functional IFN-R
(IFN-+/+ and IFN-R+/-) were lower but
were not significantly different from those in H-2q/q and
H-2q/b mice expressing functional IFN-R and in DBA/1
mice; this observation indicates that the Ab level does not directly
correlate with the development of CIA. Nevertheless, mice that were
homozygous for the IFN-R mutation produced significantly lower Ab
levels compared with mice expressing IFN-R.
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induces class-switching to IgG2a (39) and
CII-specific IgG2a and IgG2b have been implicated in the pathogenesis
of CIA (18, 40), serum levels of CII-specific IgG1, IgG2a, and IgG2b
subclasses were measured in H-2q/b F2 mice
bearing IFN-R+/+, IFN-R+/-, or
IFN-R-/-. Figure 5 shows
the effect of the IFN-R mutation on the levels of the IgG
subclasses. Essentially similar results were observed in all of the
subclasses examined. Both on day 35 and on day 70 after primary
immunization, IFN-R-/- mice produced the lowest level
among three groups of mice. Levels of the subclass Abs produced in
IFN-R+/- mice were between IFN-R+/+ and
IFN-R-/- mice, with the exception of IgG1 on
day70, reflecting the gene-dose effect of the IFN-R mutation.
However, it is especially noteworthy that, among the IgG subclasses
analyzed, IgG2a levels were remarkably reduced in mice that were
homozygous and heterozygous for the IFN-R mutation.
|
R+/- and IFN-R-/- mice
To investigate Th1/Th2 cytokine patterns,
H-2q/b/IFN-R+/- and
H-2q/b/IFN-R-/- mice were sacrificed at
three time points after CII immunization, single-cell suspensions from
spleens were cultured in the presence or absence of CII, and
supernatants were measured for IFN-, IL-2, IL-4, and IL-10 (Fig. 6). On day 20 (before booster
immunization) and on day 23 (at 2 days after booster immunization)
after primary immunization, IFN-, IL-2, IL-4, and IL-10 levels in
CII-stimulated samples were not significantly different between
IFN-R+/- and IFN-R-/- mice. On day 31,
the level of IFN- in CII-stimulated samples from
IFN-R+/- mice was significantly higher than the level
seen in samples from IFN-R-/- mice, whereas no
significant differences in IL-2, IL-4, and IL-10 levels were observed
between both mice. The same cytokine patterns were obtained in draining
lymph nodes (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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during the induction of murine CIA. Although the
H-2q allele appeared to confer susceptibility to CIA on
(129/Sv/Ev x DBA/1)F2 mice, incidence and severity
were significantly decreased in IFN-R-/- mice.
A body of conflicting reports have been accumulated regarding the role
of IFN- in the development of CIA. Neutralizing IFN- by
administrating anti-IFN- mAb in mice before primary immunization
exerted a reduction of the incidence of CIA, while treatment with
IFN- increased the incidence and shortened the time of onset of CIA,
suggesting an aggravating effect of IFN- (21, 23). Conversely, it
has been reported that therapeutic as well as prophylactic treatment
with high doses of IFN- inhibited the development of murine CIA
(22). The heterogeneous effects of IFN- and anti-IFN- mAb
seem to be dependent upon the timing and routes of administration. This
possibility was suggested by the following reports. The administration
of anti-IFN- mAb demonstrated paradoxical effects on CIA, with
early suppression of the disease followed by late-stage disease
exacerbation (23). Furthermore, IFN- injected into paws led to the
exacerbation of CIA, whereas dorsal s.c. injection of IFN- was
capable of inhibiting CIA (21, 22). Employing IFN-R-deficient mice,
we confirmed the aggravating effect of IFN- during the induction of
CIA.
IFN- may exacerbate CIA through a variety of mechanisms, such as the
production of proinflammatory cytokines, nitric oxide, and Abs against
CII. IL-1, which is known to be produced in vivo and in vitro by
macrophages stimulated with IFN- (41, 42, 43), has been considered
relevant to the destruction of joint cartilage in arthritis (44, 45, 46, 47).
In addition, IFN- has been shown to induce the expression of MHC
class II Ag on synoviocytes (21) and to increase the expression of
ICAM-1 on monocytes (41, 48, 49, 50), which are known to be involved in the
development of CIA in mice (51). It has also been suggested that the
nitric oxide produced by IFN--stimulated macrophages plays a pivotal
role in the development of arthritis (52).
Anti-CII Abs, in addition to the cellular immune response, have been
shown to be required for the expression of full-blown arthritis (6, 18). The adoptive transfer of CIA in T cell-depleted DBA/1 mice or SCID
mice reportedly requires both T cells and anti-CII Abs (6, 7, 53, 54). In the present study, F2 mice that were homozygous for
the IFN-R mutation produced substantially reduced anti-CII IgG
Ab after immunization compared with F2 mice expressing
functional IFN-R (IFN-R+/+ or
IFN-R+/-), indicating that the production of
anti-CII IgG could be influenced by IFN-. However, even
CIA-resistant H-2b/b mice, if expressing functional
IFN-R, were able to produce a substantial amount of anti-CII IgG
that was comparable to that produced by DBA/1 mice, supporting previous
studies suggesting that both cellular and humoral immune responses are
required for the development of arthritis (6, 18, 19, 47). Since Th1
and Th2 cells are involved in class switching to IgG2a and IgG1 (55, 56), respectively, we examined anti-CII IgG subclass Ab in the
mice. However, essentially all of the subclass Abs examined (IgG1,
IgG2a, and IgG2b) were reduced in IFN-R-/- mice. Our
findings are in line with previous study showing that both IgG1 and
IgG2a CII-specific Ab levels were reduced in IL-12-deficient mice that
had been immunized with CII (57). In addition, the findings that
IFN- is involved in B cell differentiation and Ab production (58, 59) could also support our data. Nevertheless, it is worthy of note
that the reduction of IgG2a levels was most prominent in
IFN-R-/- mice, reflecting a critical role of IFN-R
in class-switching to IgG2a. IFN-R+/- mice showed
essentially the same trend, but the reduction of Ab was moderate
compared with IFN-R-/- mice, suggesting the gene-dose
effect of IFN-R mutation.
Since the early decision toward Th1 and Th2 cells in the immune
response is dependent upon a balance between IL-12 or IFN- (23),
which favors a Th1 response, and IL-4 or IL-10 (16), which favors a Th2
response, it is possible that the reduced incidence and severity of the
disease in the IFN-R-deficient mice is due to the imbalance of the
immune response in favor of Th2 cells. Therefore, we evaluated Th1/Th2
cytokine patterns by the in vitro cytokine production of CII-stimulated
spleen cells. Supernatants from the CII-stimulated spleen cells of
H-2q/b/IFN-R+/- mice displayed a
significantly higher level of IFN- production on day 31 compared
with H-2q/b/IFN-R-/- mice. The time course
of promoting IFN- production in an in vitro cytokine assay appeared
to be in accordance with the severity of CIA. Since IFN- production
is up-regulated directly by IFN- itself (60) or through the
production of IL-12 (61), spleen cells from IFN-R-deficient mice
seem to fail to display accelerated production of IFN-. However, it
should be emphasized that there was no significant difference in IL-2,
IL-4, and IL-10 levels in both IFN-R+/- and
IFN-R-/- mice. The data did not demonstrate the
apparent predominance of the Th2-type immune response in
IFN-R-deficient mice.
Taken together, the results obtained from our study employing
F2 mice indicate the crucial aggravating effect of
endogenous IFN- during the induction of murine CIA. This observation
is consistent with the idea that Th1 cells have a pathogenic role of in
the development of CIA (15, 16, 17, 62). Therefore, antagonists of IFN-
may provide a suppressive effect in the development of autoimmune
arthritis.
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Footnotes |
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2 Abbreviations used in this paper: CIA, collagen-induced arthritis; CII, type II collagen.
Received for publication June 16, 1997. Accepted for publication March 30, 1998.
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G.-X. Zhang, B.-G. Xiao, X.-F. Bai, P. H. van der Meide, A. Orn, and H. Link Mice with IFN-{gamma} Receptor Deficiency Are Less Susceptible to Experimental Autoimmune Myasthenia Gravis J. Immunol., April 1, 1999; 162(7): 3775 - 3781. [Abstract] [Full Text] [PDF]
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), IFN-
), and
IFN-
) with H-2q/q
(A), H-2q/b (B), and
H-2b/b haplotypes (C), respectively, were
immunized on day 0 with CII that had been emulsified with CFA and
boosted on day 21 with CII that had been emulsified with IFA. Mice were
monitored for visual signs of CIA for 70 days.
) or medium (