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* Department of Immunology and
Division of Rheumatology, Mayo Clinic, Rochester, MN 55905;
Department of Radiation Oncology, University of Chicago, Chicago, IL 60637; and
Research Services, Veterans Administration Medical Center and Department of Medicine, University of Utah, Salt Lake City, UT 84148
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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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Collagen-induced arthritis (CIA) is an experimental model of autoimmune inflammatory polyarthritis sharing clinical and pathological features with RA (23). Susceptibility to CIA is associated with MHC class II polymorphism (H2Aq and H2Ar), suggesting an important role of MHC-restricted T cell in development of disease (24). CII-specific CD4+ T cells have been reported to be fundamental in initiation and perpetuation of the disease (25, 26) and are essential for transferring arthritis into SCID mice (27). Further evidence is provided by the observations that treatment of CIA mice with either anti-TCR Ab (28) or anti-CD4 Ab (29) abrogates disease. In contrast, CII-reactive CD4+ T cells have been reported in some circumstances to protect against CIA (30). DBA/1·mCD4-deficient mice in a model of CIA were susceptible to CIA, suggesting that, in the absence of CD4+ T cells, CD8 and double-negative (DN) T cells could play a role in initiation of disease (31). While CD8+ T cells have been shown to be crucial in the onset of several experimental autoimmune disease models (32, 33, 34), the contribution of CD8+ T cells in CIA has yet to be defined.
In this study, we investigated the role of CD4+
and CD8+ T cells in initiation of CIA
in transgenic mice expressing a RA-associated HLA class II
molecule, DQ8 (DQA1*0301, DQB1*0302). Previous
studies from our laboratory (35) have shown that
A
o·DQ8 mice elicit a vigorous CD4-mediated, DQ8-restricted
cellular response following immunization using CII which progresses to
a severe form of CIA. To investigate whether CD8+
T cells or any other cell can initiate CIA in Ao·DQ8 mice in the
absence of CD4 expression, we generated Ao·DQ8 mice deficient in
mCD4 (DQ8·CD4-/-). To delineate the role of
CD8 T cells we also generated Ao·DQ8 mice deficient in mCD8
molecules (DQ8·CD8-/-). While
DQ8·mCD4-/- mice were completely resistant to
CIA, DQ8·CD8-/- mice developed a severe form
of CIA with earlier onset than DQ8 mice, suggesting that
CD8+ T cells may have a protective or regulatory
role in arthritogenic processes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Ao·DQ8·CD4-/- and
Ao·DQ8·CD8-/- mice were generated by
mating Ao·DQ8 mice in B6/129 background with mCD4-deficient and
mCD8-deficient mice (generously provided by Dr. T. Mak, University of
Toronto, Toronto, Ontario, Canada), also in B6/129 background,
respectively. The F1 mice were intercrossed two
to four generations to generate
Ao·DQ8·CD4-/- and
Ao·DQ8·CD8-/- mice. Thus, all the mice
used in this study had a similar B6/129 background. For all the groups,
parental mice and negative littermates were included as controls. All
mice were typed for phenotypic expression of DQ8, CD4, and CD8
molecules.
Mice of both sexes (8–12 wk of age) used in this study were bred and
maintained in the pathogen-free Immunogenetics Mouse Colony at the Mayo
Clinic (Rochester, MN). All mice used in this study lack endogenous
class II molecules (Ao).
Flow cytometry
Expression of HLA-DQ, H2A, CD3, CD4, CD8, pan-B, and TCR V
chain molecules on PBLs was analyzed by flow cytometry using FACS IV
(BD Biosciences, Mountain View, CA) as described earlier
(36). Abs used for staining are IVD12 (anti-DQB1),
HB163 (anti-Ab), GK1.5 (anti-CD4), 53.6.8
(anti-CD8), MR9-4 (anti-V5.1), MR9-8 (anti-V5.1.2),
44-22-1 (anti-V6), F23.1 (anti-V8.1.2.3), KJ-16
(anti-V8.1.2), F23.2 (anti-V8.2), and KT11
(anti-V11).
Induction and evaluation of CIA
Pure native chick CII was obtained by multiple step purification described previously (37). To induce CIA, 8- to 12-wk-old transgenic mice and negative littermates were immunized with 100 µg of CII emulsified 1:1 with CFA H37Ra (100 µl; Difco, Detroit, MI) intradermally at the base of the tail. Animals received a booster of 100 µg of CII emulsified in IFA (100 µl) 28 days later. Mice were monitored for the onset and progression of CIA from 3 to 12 wk postimmunization. The arthritic severity of mice was evaluated as described previously with a grading system for each paw from 0 to 3 (24). The mean arthritic score was determined using arthritic animals only.
Histopathology
Mice were sacrificed after 10–12 wk of immunization and kidneys were extracted and snap-frozen in OCT tissue-embedding medium (Sakura Finetek, Torrance, CA). Cryostat sections were prepared, fixed, and stained with H&E. Paws from these mice were also fixed and sections were stained with H&E.
Anti-collagen Abs
Mice were bled on day 35 postimmunization, and the level of anti-mouse CII and anti-chick CII Abs in sera were determined using a standard ELISA technique as described previously (38). Briefly, microtiter plates were coated overnight with chick or mouse CII (6 µg/well in KPO4, pH 7.6) at 4°C, washed, and blocked with 1% BSA in PBS/0.05% Tween 20. Sera were added in 4-fold dilutions (1/100–1/65,000) and incubated overnight at 4°C. The plates were washed and peroxidase-conjugated goat anti-mouse IgG (Organon Teknika, West Chester, PA) was added for another overnight incubation at 4°C. After washing, O-phenylenediamine was added and the colorimetric change was measured at 410 nm. All assays were performed in duplicate and were quantified against a standard curve obtained with a known positive sera, arbitrarily determined to equal 100 Ab units per milliliter.
Rheumatoid factor
Rheumatoid factor (RF) was measured by ELISA as previously described (39). Briefly, ELISA plates were coated with rabbit IgG overnight at 4°C. After washing, sera (1/40 dilution) were added and incubated for 45 min at room temperature and washed five times with PBS containing 0.05% Tween 20. Subsequently, wells were incubated with HRP-conjugated rabbit anti-mouse IgG (Fc specific; Pierce, Rockford, IL) or rabbit anti-mouse IgM (µ-chain specific; Pierce) for 1 h and washed. 3,3',5,5'-Tetramethylbenzidine substrate (Sigma-Aldrich, St. Louis, MO) was added, and the absorbance spectrum was determined with automated spectrophotometer (Bio-Rad, Hercules, CA). Sera from MRL/lpr (39) and B6 mice were used as positive and negative controls, respectively. Sera from the following groups of mice were also tested concurrently: DQ8 naive mice, littermates negative for transgene, B10.Q mice immunized with CII, and DQ8·CD8-/- mice immunized with only CFA.
Antinuclear Abs
Hep-2 cell line slides (Bio-Rad) were used as substrates for antinuclear Ab (ANA) detection. Sera diluted (1/100) in PBS containing 1% BSA were added, incubated for 1 h at room temperature, and washed three times in PBS for 15 min. Bound Abs were detected with FITC-coupled goat anti-mouse IgG (Accurate Chemical & Scientific, Westbury, NY). Stained slides were washed three times in PBS for 15 min and examined by fluorescence microscopy. Autoantibodies to ssDNA, dsDNA, and histone were determined by ELISA as previously described (40).
In vitro T cell proliferation
Mice were immunized with 200 µg of CII emulsified 1:1 in CFA
(Difco) intradermally at the base of the tail and one hind footpad. Ten
days postimmunization, draining popliteal, caudal, and lumbar lymph
nodes were removed and prepared for in vitro culture. A total of 1
x 106 lymph node cells (LNCs) were
challenged by adding 100 µl of medium (negative control), Con A (20
µg/ml, positive control), and native collagen (50 µg/ml). For
inhibition experiments, culture supernatant containing mAb (25 µg/ml
Ab) GK1.5 (anti-CD4), IVD12 (anti-HLA-DQ), or Lyt2
(anti-CD8) was added to the cells challenged in vitro with CII at
50 µg/ml. The cells were incubated for 48 h at 37°C. During
the last 18 h the cells were pulsed with
[3H]thymidine and the tritium incorporation was
determined by liquid scintillation counting. Results are calculated as
cpm (mean cpm of triplicate cultures containing Ag - mean cpm
of medium).
Measurement of cytokines
Capture ELISA was done for measuring cytokines IFN-
and
IL-4 (from Genzyme, Cambridge, MA), and TNF-
, IL-10, and IL-6 (from
BD PharMingen, San Diego, CA) in culture supernatants using
commercial kits.
Cell division and cytokine production by CD3+CD4-CD8- cells
Mice were sacrificed on days 7, 14, and 21 after immunization with CII. For every experiment, pooled LNCs from two to three mice were collected and stained with conjugated Abs CD3-FITC, CD4-PE, CD8-PE, and NK1.1-PE mAbs (BD PharMingen) according to the manufacturer’s instructions and then sorted by FACS IV (BD Biosciences) for FITC+PE- cells. CD3+ DN cells were collected from both naive and immunized mice and cultured for further analysis. For cell division, an equal number of CD3+ DN cells were stained with cell division tracking dye, CFSE (41), and cultured in vitro for 72–96 h with or without CII. Culture supernatants were collected and assessed for cytokines.
AICD
To study the sensitivity of the proliferating cells to CII-induced activation-induced cell death (AICD), CD3+ cells were stained with annexin V conjugated with FITC after in vitro stimulation with CII and analyzed by FACS.
Statistical analysis
Difference in incidence of arthritis between groups was analyzed
using the 
2 test with Yates’ correction. Ab
levels and means scores for arthritic mice were compared using
Student’s t test. Differences in T cell types
(CD3+ DN, NK1.1) between groups was analyzed
using the 2 test.
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Results |
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Transgenic HLA-DQ8 and DQ8·CD4-/- mice
were immunized with CII and followed for onset and progression of
arthritis for 12 wk. The DQ8 mCD4-/- mice did
not show any evidence of arthritis either phenotypically or
histologically, although 70% of DQ8 mice exhibited severe arthritis.
There was no evidence of disease or infiltration of
mononuclear cells in the synovia of
DQ8·CD4-/- mice (Fig. 1
). In addition, while all the immunized
DQ8 mice produced anti-CII Abs, none of the
DQ8·CD4-/- mice produced anti-CII Abs,
although the B cell numbers in CD4-deficient and DQ8 mice are
comparable (50 and 56%, respectively; mean values from 10 mice in each
strain).
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Both DQ8 and DQ8·CD8-/- mice were
immunized with CII and followed for development of arthritis. Both
strains developed severe arthritis, although a higher incidence (70 vs
95%, respectively; p < 0.05) and an earlier onset
(mean ± SD onset: 41 ± 12 vs 35 ± 10 days,
respectively) of arthritis was detected in the latter group (Fig. 2A). A more severe disease was
observed in CD8-deficient mice compared with DQ8 mice
(p < 0.05) (Fig. 2B). To determine
the Ab responses to CII, sera were collected and Abs to CII and mouse
CII (MsII) were assayed by ELISA. All mice produced anti-CII and
anti-MsII Abs, although the levels were significantly higher in the
DQ8·CD8-/- mice (p <
0.0008) (Fig. 2C). Mice immunized with adjuvant alone
produced no detectable anti-collagen Abs (data not shown).
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To further determine the clinical relevance of this animal model
and the fact that these mice carry human gene, sera from these mice
were tested for the presence of RF. The result showed that both DQ8-
and DQ8·CD8-/--immunized mice produced IgM
and IgG RF. The incidence and level of IgM-RF were not significantly
different between DQ8·CD8-/- (74%, 25 of 34)
and DQ8 (67%, 10 of 15) mice. However, more
DQ8·CD8-/- mice were positive for IgG-RF (28
of 34) than DQ8 (6 of 15, p < 0.004) mice. Moreover,
the levels of IgG-RF were significantly higher in
DQ8·CD8-/- compared with DQ8 mice
(p < 0.005) (Fig. 3). In contrast, none of the naive DQ8,
DQ8·CD4-/-, transgene negative littermates,
Ao, and DQ8·CD8-/--transgenic mice
immunized with adjuvant alone produced a detectable level of RF.
CIA-susceptible B10.Q mice also failed to develop RF following
immunization with CII (data not shown).
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Sera obtained at day 35 postimmunization with CII or adjuvant were
used to study ANAs. All DQ8·CD8-/- sera (35
of 35) tested positive for ANAs with homogenous pattern while none of
the DQ8 and DQ8·CD4-/- sera elicited ANA
staining (Fig. 4). In addition, while DQ8
and DQ8·CD4-/- mice did not produce
detectable levels of ssDNA, dsDNA, or anti-histone Abs, 66% of
DQ8·CD8-/- mice produced anti-histone Abs
and 43% of DQ8·CD8-/- mice produced
anti-dsDNA Abs (Fig. 4). However, none of the mice positive for
ANAs developed proteinuria and glomerulonephritis (data not shown).
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LNCs were harvested from mice primed with CII and cultured in
vitro in the presence or absence of collagen. DQ8 and
DQ8·CD8-/- mice gave a robust response to
immunizing collagen (Fig. 5A).
Inhibition assays using specific Abs demonstrated that the response to
CII in these mice was mediated by CD4+ T cells
and restricted by DQ8 molecules (Fig. 5B).
DQ8·CD4-/- mice mounted minimal response to
CII in vitro, thus indicating that CD4 T cells are required to initiate
response against CII.
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To determine whether there was any alteration in T cell
populations in our CD4 and CD8 knockout mice, we analyzed the number of
different CD3+ T cell populations. Total numbers
of CD3+ cells were decreased in
DQ8·CD4-/- and CD8-/-
mice by 
15 and 5%, respectively, when compared with DQ8 mice (Fig. 6). Of the CD3+
cells, 80% were positive for CD4 in
DQ8·CD8-/- mice and 90% were positive for
CD8 in DQ8·CD4-/- mice, 20 and 10% being
CD3+ DN, respectively. Expression of DQ8 was
similar in all the transgenics as observed by FACS
analysis, although the number of spleen cells positive for DQ molecule
was lower in CD4-deficient mice than in the other two strains (Fig. 7). The number of cells positive for CD5
and CD40 were lower in DQ8·CD4-/- mice
compared with DQ8 and DQ8·CD8-/- mice,
although differences reached statistical significance only for CD5 (DQ8
vs DQ8·CD4-/-, p < 0.01;
DQ8·CD4-/- vs
DQ8·CD8-/-, p < 0.05).
Interestingly, activation marker CD69 was seen with similar frequency
in primed mice of all three strains.
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usage by T cells selected by the
transgenics. All the strains represented most of the V, although the
DQ8·CD4-/- had a decreased frequency of all
the V that reflects the lower number of total CD3 T cells (data not
shown). Role of CD3+ DN T cells in arthritis
A significant role of CD3+ DN T cells has
been suggested for initiation of CIA (29). To determine
the role of these cells in initiation/progression of arthritis, we
studied CD3+ DN cells in all mice included in the
study. Cells were sorted for
CD3+CD4-CD8-
T cells by FACS. Characterization of CD3+ T cells
showed an increased number of CD4 and DN cells in
DQ8·CD8-/- mice compared with the DQ8 mice.
DQ8·CD4-/- mice had more
CD8+ T cells and CD3+ DN
cells than did DQ8 mice. However, CD3+ DN cells
in DQ8·CD4-/- mice were significantly lower
in number than those in DQ8·CD8-/- mice.
Similar results were observed for naive and immunized mice (Table I). Moreover, the single-positive
cells decreased in LNCs, while a concomitant increase in
CD3+ DN T cells up to 14 days postimmunization
with CII was seen. After 21 days of immunization,
CD3+ DN T cells decreased in all mice except
DQ8·CD8-/-, in which they were persistently
elevated and comprised 35–45% of CD3+
cells.
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Susceptible mice have a defect in AICD
To study the kinetics of cell division, splenic
CD3+ and CD3+ DN T (sorted
from LNCs) cells were isolated from primed mice at days 7, 14, and 21,
and challenged in vitro with CII after staining them with CFSE. Higher
numbers of dividing CD3+ T cells at day 14 were
observed in DQ8 and DQ8·CD8-/- mice as
compared with DQ8·CD4-/- mice after 48 h
in response to CII (Fig. 8A).
A similar phenomenon was seen in 7- and 21-day primed mice (data not
shown). CD3+ DN T cells isolated from mice after
14 days of immunization also showed a higher number of cells undergoing
multiple divisions in DQ8·CD8-/- and DQ8 mice
(80 and 60%, respectively), whereas only 45% cells underwent division
in CD4-deficient mice (Fig. 8B). Characterization of the
CD3+ DN cells showed a high number of cells being
positive for B220. In DQ8·CD8-/- mice, the
CD3+B220+ DN cells
proliferated actively after immunization. In contrast, there was no
significant increase in proliferation of
CD3+B220+ DN cells after
immunization in the other two strains (Fig. 8C).
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A). To confirm the above
results, we analyzed the levels of Bcl2 and caspase-3 in primed mice.
Both DQ8 and DQ8·CD8-/- mice had higher Bcl2,
with lower caspase-3 levels compared with DQ8·CD4-deficient mice
(Fig. 9B).
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TNF- and IFN- (Th1) cytokines, IL-4 and IL-10 (Th2)
cytokines, and IL-6 (regulatory) cytokines were studied in all
the test and control mice included in this study. High levels of
IFN- and TNF- were produced by DQ8 and
DQ8·CD8-/- mice (Fig. 10A). No detectable levels
of IFN- were observed in DQ8·CD4-/- mice,
although some IL-4 were produced. Both
DQ8·CD4-/- and
DQ8·CD8-/- mice produced IL-6, although there
was a consistent trend toward increased levels of IL-6 production in
DQ8·CD8-/- compared with
DQ8·CD4-/- and DQ8 mice. However, differences
did not reach statistical significance (Fig. 10B). There was
a late production of IL-10 in DQ8·CD4-/- mice
after 21 days of immunization and 96 h in vitro culture only,
while in DQ8 and CD8·DQ8-/- mice IL-10 was
detected after 7 days of immunization. CD3+ DN
cells did not produce IFN- in all mouse strains, although a large
amount of TNF- was produced in response to CII in
DQ8·CD4-/- mice. In DQ8 and
DQ8·CD8-/- mice, CD3+
DN cells produced large amounts of IL-10 (Fig. 10C).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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TCRs and develop severe CIA
(35), indicating that DQ8 molecule can interact
efficiently with mCD4. DQ8 is a promiscuous molecule that can bind many
antigenic peptides with low affinity. Thus, one plausible explanation
for autoimmune responses in DQ8-transgenic mice could be thymic
selection of potential autoreactive T cells by DQ8 molecules which have
escaped central tolerance.
Our observations indicate an important role of CD4 T cells in
initiation of CIA and CD8 T cells in regulation of disease. The
scenario in the development of arthritis in transgenic mice can be
compared with that of RA in human. Both require presentation of
arthritogenic epitope by HLA class II molecules to CD4 T cells, leading
to proliferation of autoreactive T cells and production of RF by B
cells subsequently leading to joint pathology. Using CD8 knockout mice
we have associated CD8 T cells with an immunoregulatory role in CIA, as
absence of CD8 leads to production of ANAs and more severe disease. A
similar phenomenon can be envisaged in RA, where production of
autoantibodies like RF and ANAs could be related to the functional
status of CD8 T cells. However, susceptibility conferred by class II
alleles might be modulated by MHC class I polymorphism. Indeed, it has
been shown that CII can be recognized by class I-restricted T cells
(31, 42). In the CIA model, contrasting observations have
been reported on the role of CD8 T cells (42, 43).
Depletion of CD8 T cells has been shown to suppress or lower incidence
of arthritis in the CIA model (31, 44), while other
studies have reported no role of CD8 T cells (42) or
immunomodulation of arthritis by CD8 T cells (43). In some
autoimmune diseases, CD8+ T cells have been shown
to transfer disease from affected to naive mice, but they require the
help of CD4 T cells (34). In our study,
DQ8·CD8-/- mice get severe arthritis with
earlier onset and produce high amounts of proinflammatory cytokines
(IFN- and TNF-) as well as immunoregulatory cytokines (IL-6 and
IL-10) in response to CII. The present data provide evidence that CD8 T
cells modulate disease, in part, by down-regulation of potentially
pathogenic Ag-specific Th1 cells in vivo. This could lead to skewing of
the cytokine profile and decreased production of autoantibodies. In
vivo depletion of CD8 T cells in DQ8-transgenic mice can provide
further evidence of immunomodulatory role of CD8+
T cells.
Most of the studies in RA and animal models of arthritis have
implicated CD4+ T cells to be primarily
responsible for disease activity. However, class II-restricted response
to T cell-dependent Ag and production of cytokines by
CD3+ DN T cells upon activation in mouse models
and humans indicate an immunoregulatory role of these cells in vivo
(45, 46, 47). In the CIA model,
CD3+ DN T cells have been shown to play an
important role in disease pathogenesis (31). Our results
showed an increased number of CD3+ DN T cells in
DQ8·CD8-/- mice compared with
DQ8·CD4-/- mice. Also,
CD3+ DN cells proliferated in response to CII,
indicating a role in pathogenesis of arthritis, although they may not
be involved in initiation of the disease. Higher proliferation of
CD3+ DN T cells in
DQ8·CD8-/- mice compared with other two
strains could be another factor responsible for increased severity in
DQ8·CD8-/- mice. An increased number of
CD3+B220+ DN T cells in
DQ8·CD8-/- mice corroborates recent data
showing that CD4-CD8- T
cells survive chronic stimulation and further suggests that these cells
might persist as Ag-specific DN B220+ T cells
(48). Our results also showed that
CD3+ DN cells produced TNF- in vitro in
response to CII; however, in the DQ8·CD4-/-
mice, other cell types were not able to mount optimum specific response
and produce the right cytokine milieu needed to initiate development of
arthritis.
Our data are consistent with a significant role for CD4 T cells in
initiation of CIA pathogenesis (25, 26, 27). We observed an
important role of CD4+ T cells in initiation of
arthritis in DQ8-transgenic mice because CD8+ T
cells as well as CD3+ DN cells were not able to
initiate CIA in DQ8·CD4-/- mice. In addition,
DQ8·CD4-/- mice do not present CII as
efficiently as the other two strains. However, our results are in
contrast with a study in DBA/1 mice suggesting no role of
CD4+ T cells (31). Unlike CIA in
most of the susceptible strains of mice, DBA/1 mice can spontaneously
develop arthritis that phenotypically resembles autoimmune arthritis
but is T cell independent (49) and is therefore not CD4
dependent and MHC class II restricted. Thus, CIA in DBA/1 mice might
involve both classical and nonclassical pathways for disease
development. DQ8·CD4-/- mice do not produce
Abs to CII and IFN- in vitro, indicating that CIA in transgenic mice
is much more complex and requires CII-specific CD4 T cell interaction
with B cells for disease initiation. Low T cell proliferation with no
IFN- production and lack of autoantibodies are responsible for
resistance to developing arthritis in
DQ8·CD4-/- mice. Even though
DQ8·CD4-/- mice did produce IL-6, there was
no Ig production by B lymphocytes, indicating either that there was a
defect in B cell function in these mice or that IL-6 did not play a
direct role in initiation/pathogenesis but might be involved in
progression of disease. Ohshima et al. (50) demonstrated
that IL-6 knockout mice develop a more modest form of CIA, which
supports the notion that IL-6 may not be involved directly in disease
pathogenesis.
Oligoclonal CD4+ T cells from arthritic patients have been shown to have defects in apoptotic pathways (51). CD3+ T cells from CIA-resistant DQ8·CD4-/- mice showed enhanced apoptosis compared with susceptible DQ8 and DQ8·CD8-/- mice. Decreased apoptosis in susceptible mice was confirmed by poor cleavage of caspase-3, a hallmark of apoptosis. Increased expression of antiapoptotic protein, Bcl2, in CIA-susceptible mice correlates with decreased apoptosis in RA patients. This indicates a possible defect in AICD in mice developing arthritis. Activation of CD3+ T cells with subsequent resistance to apoptosis may contribute to CIA pathology.
Our data bring forth the following points: 1) transgenic mice expressing the RA-associated HLA-DQ8 gene develop CIA mediated by CD4 T cells and also produce RF similar to RA, 2) CD3+ DN T cells can undergo chronic stimulation and may persist as Ag-specific T cells, 3) expansion following exposure to Ag as well as a defect in AICD might lead to pathology seen in RA and CIA, and 4) CD8 T cells play a regulatory role, as their absence leads to production of higher levels of autoantibodies.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Veena Taneja, Department of Immunology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905. E-mail address: taneja.veena{at}mayo.edu
3 Abbreviations used in this paper: RA, rheumatoid arthritis; CIA, collagen-induced arthritis; CII, type II collagen; MsII, mouse CII; RF, rheumatoid factor; ANA, antinuclear Ab; AICD, activation-induced cell death; DN, double negative; LNC, lymph node cell.
Received for publication January 22, 2002. Accepted for publication March 25, 2002.
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References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-chain polymorphism in HLA-DR4 haplotypes associated with rheumatoid arthritis. Lancet 2:1118.[Medline]
3.1 allele is a determinant of susceptibility to DR4-associated rheumatoid arthritis. Hum. Immunol. 26:59.[Medline]
/ T cells by a monoclonal Ab against the / T cell receptor suppresses established adjuvant arthritis, but not established collagen-induced arthritis in rats. J. Exp. Med. 175:907.-TCR+CD4-CD8- T cells produce IL-4. J. Immunol. 149:1211.[Abstract]
/ TCR+, CD4- and CD8- double-negative (DN) T cells. Microbiol. Immunol. 43:153.[Medline]
/ T cells: implications for autoimmunity. J. Exp. Med. 193:1113.This article has been cited by other articles:
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  V. Taneja, M. Behrens, E. Basal, J. Sparks, M. M. Griffiths, H. Luthra, and C. S. David Delineating the Role of the HLA-DR4 "Shared Epitope" in Susceptibility versus Resistance to Develop Arthritis J. Immunol., August 15, 2008; 181(4): 2869 - 2877. [Abstract] [Full Text] [PDF]
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 P. Jha, B. Matta, V. Lyzogubov, R. Tytarenko, P. S. Bora, and N. S. Bora Crucial Role of Apoptosis in the Resolution of Experimental Autoimmune Anterior Uveitis Invest. Ophthalmol. Vis. Sci., November 1, 2007; 48(11): 5091 - 5100. [Abstract] [Full Text] [PDF]
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X. Yu, K. Bauer, P. Wernhoff, D. Koczan, S. Moller, H.-J. Thiesen, and S. M. Ibrahim Fine Mapping of Collagen-Induced Arthritis Quantitative Trait Loci in an Advanced Intercross Line J. Immunol., November 15, 2006; 177(10): 7042 - 7049. [Abstract] [Full Text] [PDF]
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S. L. Hayward, N. Bautista-Lopez, K. Suzuki, A. Atrazhev, P. Dickie, and J. F. Elliott CD4 T Cells Play Major Effector Role and CD8 T Cells Initiating Role in Spontaneous Autoimmune Myocarditis of HLA-DQ8 Transgenic IAb Knockout Nonobese Diabetic Mice. J. Immunol., June 15, 2006; 176(12): 7715 - 7725. [Abstract] [Full Text] [PDF]
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V. Taneja, N. Taneja, M. Behrens, M. M. Griffiths, H. S. Luthra, and C. S. David Requirement for CD28 May Not Be Absolute for Collagen-Induced Arthritis: Study with HLA-DQ8 Transgenic Mice J. Immunol., January 15, 2005; 174(2): 1118 - 1125. [Abstract] [Full Text] [PDF]
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 P. M. Stuart, B. Summers, J. E. Morris, L. A. Morrison, and D. A. Leib CD8+ T cells control corneal disease following ocular infection with herpes simplex virus type 1 J. Gen. Virol., July 1, 2004; 85(7): 2055 - 2063. [Abstract] [Full Text] [PDF]
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V. Taneja, N. Taneja, M. Behrens, S. Pan, T. Trejo, M. Griffiths, H. Luthra, and C. S. David HLA-DRB1*0402 (DW10) Transgene Protects Collagen- Induced Arthritis-Susceptible H2Aq and DRB1*0401 (DW4) Transgenic Mice from Arthritis J. Immunol., October 15, 2003; 171(8): 4431 - 4438. [Abstract] [Full Text] [PDF]
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 M. D. Bodman-Smith, V. M. Corrigall, D. M. Kemeny, and G. S. Panayi BiP, a putative autoantigen in rheumatoid arthritis, stimulates IL-10-producing CD8-positive T cells from normal individuals Rheumatology, May 1, 2003; 42(5): 637 - 644. [Abstract] [Full Text] [PDF]
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