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Spontaneous rheumatoid-like arthritis in a line of mice sensitive to collagen-induced arthritis.

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1716
SPONTANEOUS RHEUMATOID-LIKE ARTHRITIS
IN A LINE OF MICE SENSITIVE TO
COLLAGEN-INDUCED ARTHRITIS
JEAN-PIERRE BOUVET, JACQUES COUDERC, YOLANDE BOUTHILLIER, BRIGITTE FRANC,
ANNIE DUCAILAR, and DENISE MOUTON
Twenty-eight percent of 13-month-old male mice
of the high antibody responder line of Biozzi’s selection
I (H,) spontaneously developed a long-lasting inflammatory arthritis. This disease was clinically and histologically similar to human rheumatoid arthritis. The synovium of joints and some tendons was hypertrophied,
with thickening of the synovial cell layer and infiltration
by polymorphonuclear and mononuclear leukocytes. In
some cases, synovial pannus formation led to destructive
damage of articular cartilage and bone. Rheumatoid
factor and antinuclear, anti-DNA, and anti-type I1
collagen (CII) antibodies were often found in the sera of
both arthritic mice and clinically normal littermates.
The presence of CII autoantibodies in this line of mice
suggests that a potentially harmful anti-CII T cell
autoimmunity can also develop spontaneously and lead
to joint damage. Moreover, HI mice are also susceptible
to collagen-induced arthritis, while a closely related
mouse line (H,) is resistant to both diseases. These data
support the hypothesis that collagen-induced arthritis is
pathogenetically related both to this spontaneous arthritis and to rheumatoid arthritis.
From the Unite d’Immunologie Microbienne, Institut Pasteur,
the Unit6 d’Immunog6netiqueCNRS PR A0305, Institut Curie, and the
Laboratory of Pathology and Laboratory of Hematology and Immunology, HGpital Ambroise Park, Universite Paris V, Paris, France.
Jean-Pierre Bouvet, MD, PhD: Rheumatologist, Charge de
Recherche INSERM, Unit6 d’Immunologie Microbienne; Jacques
Couderc, PhD: Charge de Recherche CNRS; Yolande Bouthillier:
Ingtnieur de Recherche INSERM; Brigitte Franc, MD: Pathologist,
Hdpitai Ambroise Pare; Annie Ducailar: Hematologist, HGpital
Ambroise Pare; Denise Mouton, PhD: Directeur de Recherche
INSERM, Unite d’ImmunogCn6tique.
Address reprint requests to Jean-Pierre Bouvet, MD, PhD,
Unite d’trnmunologie Microbienne, Institut Pasteur, F75724, Paris
15, France.
Submitted for publication March 20, 1990; accepted in
revised form May 28, 1990.
Arthritis and Rheumatism, Vol. 33, No. 11 (November 1990)
Spontaneous arthritis mimicking rheumatoid arthritis (RA) occurs rarely in animals. RA-like diseases
have been occasionally reported in dogs (1,2) and in a
line of rabbits (3), but have been studied less extensively than the spontaneous inflammatory arthritides
of mice. In this species, animals homozygous for the
ank gene develop an ankylosing spondylitis-like arthritis (4,5), which is unrelated to human RA. In
contrast, the MRL-lpr mouse strain exhibits an RAlike arthritis at 6 months of age, before developing a
lupus-like disease after the age of 10 months (6).
Although these mice produce type I1 collagen (CII)
autoantibodies during their joint disease, they do not
seem to be susceptible to collagen-induced arthritis
(7), an experimental RA-like disease with similar clinical and pathologic findings (8). Nevertheless, a relationship between the respective susceptibilities to a
spontaneous arthritis and to collagen-induced arthritis
would be of considerable interest. Indeed, it is likely
that CII autoimmunity can occur spontaneously, since
collagen-induced arthritis can be induced with autologous CII (9), and this autoimmunity might occur in
humans since collagen-induced arthritis has been reported in several species of primates (10-12).
In a recent study (13), we reported the induction of collagen-induced arthritis in several lines of
Biozzi mice. These lines, which were obtained from
selective breedings of Swiss mice for either high or low
antibody responses to heterologous erythrocytes, also
show high or low antibody responses to a wide variety
of unrelated antigens (for review, see ref. 14). In this
study, we report the spontaneous occurrence of an
RA-like disease in older male mice of the high antibody responder line of Biozzi’s selection I (HI), a line
SPONTANEOUS ARTHRITIS IN BIOZZI HI MICE
1717
Table 1. Frequency of spontaneous arthritis in 13-month-old
Biozzi H, mice
Arthritis grade
No./
sex of mice
No. affectedl
0
1
2
3
total (%)
m
14
14
1
3/M
I1
1
6
0
4
0
0
4/F
19
1
0
0
7/21 (33)
2/16 (12.5)
6/17 (35)
1/20 (5)
1IM
2
I
of mice that is highly sensitive to collagen-induced
arthritis.
MATERIALS AND METHODS
Mice. Biozzi H, mice were bred in our animal unit at
the Institut Curie. Their major histocompatibility complex
(MHC) haplotype is Kq,Aq, E absent, Dq(15). They were
carefully examined for the occurrence of joint swelling until
Figure 2. Radiograph of the forepaw of a male Biozzi H, mouse:
with spontaneous arthritis, showing destruction of the proximal
interphalangeal joint of the fourth digit (arrow), with periarticular
bony formations.
Figure 1. Symmetric polyarthritis (grade 3) in the distal forepaws
(top) and hindpaws (bottom) of a 15-month-old male Biozzi HI
mouse. See Materials and Methods for definition of the grading
scales.
the age of 19 months. The following scale was used for
semiquantitation of joint swelling: grade 1 = swelling limited
to an interphalangeal joint, grade 2 = swelling of 1 large
joint, and grade 3 = more severe involvement.
Type I1 collagen autoantibodies. Mouse CII was purified from the xiphoid process of the sternum according to
the method of Trentham et a1 (16), and the purity of the
preparation was controlled as described (13). An enzyme
linked immunosorbent assay (ELISA) was performed in
duplicate, using 10 &ml of this preparation as the coating
antigen. Dilutions (150) of mouse sera were used as the first
antibody, and a peroxidase-labeled anti-mouse Ig was used
as the second antibody. Results are expressed as units of
optical absorbance at 492 nm after subtraction of the background value of a pool of sera from young HI mice.
Assays for rheumatoid factor and antinuclear antibodies. The presence of rheumatoid factor was investigated in
duplicate samples by ELISA, using purified rabbit IgG as
antigen, a 1:50 dilution of serum as the first antibody, and the
peroxidase-labeled anti-mouse Ig as the second antibody.
Results are expressed as for the CII autoantibodies. Antinuclear antibodies were detected by an indirect immunofluorescence using rat liver slices as the antigen and fluoresceinlabeled goat anti-mouse Ig serum as the second antibody.
1718
BOUVET ET AL
Anti-DNA antibodies were measured by an immunofluorescence assay using Crithidia luciliae as the substrate.
Anatomic and histologic preparations. After the mice
were killed, radiographs were taken of skinned paws, which
were fixed in 10% buffered formalin. The specimens were
decalcified, embedded in paraffin, and sectioned for microscopic examination. Sections (4p) were stained with hematoxylin, eosin, and safran.
RESULTS
Clinical features. At 13 months of age, 15 of 54
male HI mice (28%) developed a clinical arthritis,
while only 1 of 20 females was affected (Table I).
Disease onset occurred at 12 months of age, with a
discrete swelling of 1 or more digits. In the following
months, the severity of the symptoms progressively
increased; 13 males were scored as having grade 3
involvement at the fifteenth month, while the percentage of the affected animals remained unchanged. Similar to human RA, the joint involvement was distal and
symmetric (Figure 1). However, the mobility of these
mice, even when they were severely affected, was
apparently not significantly impaired compared with
their unaffected littermates, a finding that has also
been observed in collagen-induced arthritis.
A
Radiographic findings. Most clinically affected
joints did not exhibit any radiographic changes, while
a few had bone erosions and joint space narrowing
(Figure 2). In some cases, a periarticular bony formation occurred outside the joint, as is often observed in
collagen-induced arthritis and in other experimental
RA-like diseases in rodents (13,17,18).
Pathologic findings. The synovium in mice with
spontaneous arthritis was hypertrophied, and there
was thickening of the synovial lining cell layer and
infiltration by polymorphonuclear leukocytes and lymphocytes (Figure 3A). These changes were found both
in joints and in tendon sheaths (Figure 3B). In some
joints, profuse formation of pannus-like tissue led to
erosive lesions (Figure 4). Bony formations were of
the osseous type and were clearly different from the
amorphous calcium deposits observed in other diseases. In 2 cases, an inguinal, tumor-like hyperplastic
lymph node was infiltrated by normal lymphoid cells.
Autoantibodies. A prospective analysis of 19 H,
male mice, 2 of which died during the thirteenth month
and 1 during the fourteenth month (experiment 3,
Table l), demonstrated the presence of serum autoantibodies, irrespective of the presence or severity of
arthritis (Figure 5). The levels of anti-CII antibodies
B
Figure 3. Photomicrographs of changes in the synovium of a Biozzi H, mouse with spontaneous arthritis. A, Joint synovium with proliferation
of the synovial lining cells (SL), and infiltrates of both polymorphonuclear leukocytes (PMN)and lymphocytes (Ly).B, Identical synovitis of
a tendon sheath (T).(Hematoxylin, eosin, and safran stained, original magnification x 250.)
SPONTANEOUS ARTHRITIS IN BIOZZI HI MICE
1719
were low compared with those found in the same line
of mice with collagen-induced arthritis (13). The median level did not vary between 12 and 14 months of
age. Rheumatoid factor was also present at low levels
during this period. In contrast, high titers of antinuclear antibodies were found in several mice. Investigation of the specificity of these antibodies revealed
that the sera of 4 animals were positive for DNA
antibodies at a dilution of 1:lOO.
DISCUSSION
This is, to our knowledge, the first report of
spontaneous RA-like arthritis in a line of mice that is
highly sensitive to the experimental RA-like disease
induced by CII. This newly recognized disease in mice
exhibits some similarities to the human disease, while
other characteristics seem to be related to the autoimmune disorders of MRL-lpr mice. A similarity between the spontaneous arthritis in mice and human RA
emerges from the clinical, radiologic, and pathologic
findings. The location of the articular lesions, which
involve the distal joints symmetrically (Figure I), the
erosion of articular cartilage and bone (Figure 4), and
Figure 4. Photomicrograph of joint destruction in a Biozzi H,
mouse with spontaneous arthritis, showing cartilage loss, with
erosion of subchondral bone (B)by a synovial fibrous pannus (P)and
infiltration by polymorphonuclear cells, mononuclear cells, lymphocytes, histiocytes, and plasmacytes (hematoxylin, eosin, and safran
stained, original magnification x 500).
anti-CII
-8-’
RF
anti-N
0
o
o
o
~
0
0
-6-
8
0
8
0
0
U
a
0
0
0
0
8 -4-
0
0
ooo
0-
0
0
0
0
00
0
0
-2-
0
??0
0-
i
*
0
00
0
Qp
12
14
0
00
12
mo
14
mo
mo
mo
0
0
%uwsI3
12
mo
14
mo
Figure 5. Serum levels of type I1 collagen autoantibodies (anti-CII), rheumatoid factor (RF), and antinuclear
antibodies (anti-N) in male Biozzi H, mice at 12 months (n = 19) and 14 months (n = 16) of age. Two
nonarthritic mice in this group died during the thirteenth month, and 1 died during the fourteenth month. RF
was not tested in I 12-month-old nonarthritic mouse. 0 = grade 0 joint swelling; 0 = grade I joint swelling;
= grade 2 joint swelling; * = grade 3 joint swelling; OD,,
= optical density at 492 nm. Bars show the
median values.
1720
the histologic appearance of the synovium (Figures 3
and 4) are similar in these 2 diseases. Moreover, the
involvement of tendon sheaths (Figure 3B), which is
usually present in RA, has not been reported in other
RA-like arthritides of rodents. The presence of periarticular bony formation and the absence of significant
mobility impairment do not lessen this similarity, since
these findings seem to be common features of arthritis
in rodents and have been observed in mice with
collagen-inducedarthritis (13), but have been absent in
affected monkeys (19). The sex ratio also differs between mice with the spontaneous arthritis and humans
with RA, but this difference might be species related,
since the same discrepancy was also observed between mouse and monkey susceptibilities to collageninduced arthritis (19). In addition, rheumatoid factor
and CII autoantibodies are observed both in RA in
humans and in the disease in HI mice.
The frequency of antinuclear antibodies at
fairly high titers (Figure 5), including antibodies to
native DNA, warrants discussion of the relationship
between this spontaneous arthritis and the lupus-like
syndromes observed in some strains of mice. Among
these strains, MRL-lpr mice develop a spontaneous
arthritis with histologic features that are very similar
to those of RA (20); the development of the arthritis
does not show a correlation with the laboratory or
clinical features of the lupus syndrome in these mice.
In the HI mice, arthritis seems to be also unrelated to
the presence of antinuclear or anti-DNA antibodies,
which were found both in arthritic and nonarthritic
mice (Figure 5). Hence, the diseases of these 2 strains
differ essentially in chronology and severity, with
arthritis occurring later in HI mice, and the other
autoimmune disorders having greater severity in
MRL-lpr mice.
Demonstration of a relationship between the
spontaneous and the collagen-induced arthritis in HI
mice could lead to interesting developments in the
study of the pathogenesis of human RA. The possibility that they are actually the same disease was easily
ruled out, since collagen-induced arthritis occurred in
much younger animals, and no arthritis occurred in an
age-matched control group of mice injected with adjuvant alone. The possibility remains, however, that
collagen autoimmunity participates in the joint damage
of spontaneous arthritis, and/or that premature onset
of this disease is induced by the injection of heterologous CII in Freund’s complete adjuvant. Very high
amounts of CII antibodies can passively transfer a
transient arthritis (21), but T cell immunity is neces-
BOUVET ET AL
sary for the perpetuation of collagen-induced arthritis
(22). In our previous study with Biozzi mice, the H line
of selection I1 (HIl) was shown to respond to CII
immunization by developing autoantibodies at titers
similar to those found in H, and DBN1 mice, but this
line failed to develop arthritis. Similarly, SWR mice, in
which 50% of the V, genes of the T cell receptor are
deleted, are not susceptible to collagen-induced arthritis, even though they produce high levels of CII
antibodies (23).
Therefore, CII antibodies do not seem to be
sufficient for the induction of joint damage, and their
low levels both in mice with spontaneous arthritis and
in normal littermates do not support a direct pathogenic role. However, the presence of these antibodies
may suggest that a potentially harmful anti-CII cellular
immunity can develop spontaneously in this line of
mice.
In older HI mice, the presence of CII autoantibodies cannot be a secondary phenomenon induced by
the release of CII from damaged cartilage since, similar to the case of collagen-induced arthritis, these
antibodies occur at the onset of arthritis, and in
contrast to findings in MRL-lpr mice (24), their levels
do not increase during the disease (Figure 5).
One hypothesis concerning the relationship between the spontaneous and the induced arthritis is that
injection of CII into young mice may trigger a premature onset of the arthritis seen in H, mice. Alternatively, the development of both autoimmune joint
diseases might be partially regulated by a common
genetic control mechanism. Search for a correlation
between age and the degree of susceptibility to collagen-induced arthritis in H, mice is currently under way
in order to investigate the first hypothesis. The second
hypothesis is supported by the finding that MHC genes
play a role in susceptibility to collagen-induced arthritis, with the most frequently involved gene located in
the I region of H-2q (25,26). However, this gene alone
is not sufficient for development of collagen-induced
arthritis, since SWR and HI, mice, both of which are
H-2q positive, are resistant to the disease (15,24).
Moreover, the MHC linkage ;s not absolute, since
collagen-induced arthritis was induced in L,, mice that
showed heterogeneity at the H-2 locus, as well as in
outbred monkeys (10-12,19). Thus, non-MHC genes
are involved in the susceptibility to collagen-induced
arthritis in mice, a finding that has also been hypothetized in the rat model of this disease (27).
A comparison between the HI and HIIlines will
allow further investigation of these genes. The HI, line
SPONTANEOUS ARTHRITIS IN BIOZZI HI MICE
has been independently obtained from another mouse
population using the same selection schedule as t h e H,
line, but it is resistant to both collagen-induced arthritis (13) and spontaneous arthritis (28). A correlation
between these lines a n d either susceptibility or resistance to both diseases will strengthen t h e hypothesis
of a relationship between these 2 arthritides, a n d will
increase the usefulness of collagen-induced arthritis in
investigation of t h e pathogenesis of human RA.
ACKNOWLEDGMENT
We thank Dr. S. Iscaki for helpful discussions and
constant support.
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1721
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1722
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BOUVET ET AL
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