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Impaired salivary gland function in NOD miceAssociation with changes in cytokine profile but not with histopathologic changes in the salivary gland.

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ARTHRITIS & RHEUMATISM
Vol. 54, No. 7, July 2006, pp 2300–2305
DOI 10.1002/art.21945
© 2006, American College of Rheumatology
Impaired Salivary Gland Function in NOD Mice
Association With Changes in Cytokine Profile but Not With
Histopathologic Changes in the Salivary Gland
Malin V. Jonsson, Nicolas Delaleu, Karl A. Brokstad, Ellen Berggreen,
and Kathrine Skarstein
Objective. To characterize the chronologic disease
course and possible interrelationships between salivary
gland inflammation, hyposalivation, and cytokine levels
in NOD mice, a model for Sjögren’s syndrome (SS).
Methods. NOD mice of different ages were used to
mimic different disease stages of SS. Histopathologic
findings and rates of salivary secretion were compared
between 8-week-old, 17-week-old, and 24-week-old female mice. In addition, 10 cytokines were analyzed in
serum and saliva obtained from NOD and BALB/c mice.
Results. In NOD mice, the salivary flow rate did
not change between 8 weeks and 17 weeks of age, while
a significant decrease in the salivary flow rate occurred
between 17 weeks and 24 weeks of age (P < 0.001). In
contrast, significant histopathologic changes in the salivary glands occurred before 17 weeks of age. Chronic
inflammatory cell infiltrates were characterized by T
and B cell infiltration. Interestingly, in one-third of the
mice, proliferating cells were observed in the focal
infiltrates. Significant changes in the levels of
interleukin-2 (IL-2), IL-5, and granulocyte–macrophage
colony-stimulating factor in serum, and in the levels of
IL-4 and tumor necrosis factor ␣ (TNF␣) in saliva
occurred contemporarily with the decrease in salivary
flow. Correlation analyses revealed a negative association between salivary secretion and the levels of IL-4,
interferon-␥, and TNF␣ in saliva obtained from NOD
mice, while the correlation with inflammatory changes
in the glands was consistently weak.
Conclusion. Consistent with previous findings,
our results indicate at least 2 phases of SS-like disease
in NOD mice. Hyposalivation was preceded by inflammatory changes in the salivary glands, whereas abrupt
changes in secretion occurred without significant progression of inflammation. Changes in cytokine levels are
an indication of the mechanisms involved in the adaptive immune response in the transition from early to
overt disease.
Sjögren’s syndrome (SS) is an autoimmune disease characterized by oral and ocular dryness. Histopathologically, the disease is manifested by focal lymphocytic infiltrates within the target organ, but a direct
association between the degree of lymphoid infiltration
and exocrine dysfunction is not always obvious. Inhibition of acinar cell enervation by autoantibodies to the
muscarinic M3 receptor (M3R) may inhibit secretion of
saliva (1).
The NOD mouse is a recognized animal model
for the study of SS. The first signs of SS-like disease—
mononuclear cell infiltration in the salivary glands—
occur at 8 weeks of age and are accompanied by a loss of
salivary secretion later in life (2–4).
Genetically modified NOD mice such as
interleukin-4 knockout (IL-4⫺/⫺) (5), interferon-␥
knockout (IFN␥⫺/⫺), and IFN␥ receptor knockout
(IFN␥R⫺/⫺ (6) mice have been characterized in relation
to SS-like disease. Despite having glandular infiltration
similar to that in NOD/LtJ or NOD.B10-H2b mice,
Supported by the Faculty of Odontology, University of Bergen, Bergen, Norway, the L. Meltzer Foundation, the Research
Council of Norway, the Norsk Dental Depot Fund for Dental Research, the Broegelmann Foundation, Helse Vest, and the Strategic
Research Program at Helse Bergen.
Malin V. Jonsson, DMD, Nicolas Delaleu, BSc, Karl A.
Brokstad, PhD, Ellen Berggreen, DMD, PhD, Kathrine Skarstein,
DMD, PhD: University of Bergen, Bergen, Norway.
Address correspondence and reprint requests to Malin V.
Jonsson, DMD, Department of Oral Sciences, Oral Pathology and
Forensic Odontology, Haukeland University Hospital, N-5021 Bergen,
Norway. E-mail: malin.jonsson@odont.uib.no.
Submitted for publication December 22, 2005; accepted in
revised form March 24, 2006.
2300
CYTOKINE PROFILE AND SS-LIKE DISEASE PROGRESSION
NOD.B10-H2b.IL-4⫺/⫺ and NOD IL-4⫺/⫺ mice had
salivary secretion comparable with that in 4-week-old
mice of the same strain (5). NOD IFN␥⫺/⫺ and NOD
IFN␥R⫺/⫺ mice did not display SS-like disease features
in the salivary glands and retained a normal rate of
salivary secretion (6).
Various cytokines have been studied in plasma
(7), saliva, and salivary gland tissue obtained from
patients with SS (8). The aim of this study was to
investigate the relationship between lymphoid infiltration and exocrine dysfunction in NOD mice. Ten cytokines were analyzed in saliva and serum to further
characterize local and systemic immune reactions.
MATERIALS AND METHODS
Animals. Female NOD and BALB/c mice were purchased from Taconic (Bomholtgård, Denmark). The animals
were maintained under standard animal-housing conditions.
Serum glucose levels were measured using the Reflotron Plus
glucose test kit (Roche Diagnostics, Laval, Quebec, Canada)
and did not differ significantly between or within age groups in
NOD or BALB/c mice. The weight of NOD mice did not
decrease between 17 weeks and 24 weeks of age. The experimental protocol was approved by the Committee for Research
on Animals/Forsøksdyrutvalget (79-04/BBB).
Measurement of stimulated salivary flow rate. Prior to
stimulation, mice were fasted for a minimum of 5 hours (with
water ad libitum) and anesthetized using 0.10 ml of ketamine
per 10 grams of body weight. After stimulation of secretion by
pilocarpine (Sigma, St. Louis, MO) in saline (0.5 ␮g/gm body
weight) via the femoral artery to ensure reliable uptake, saliva
was collected with capillary tubes for 10 minutes, and the
volume was determined. The samples were stored at ⫺80°C
until analyzed.
Measurement of cytokines in serum and saliva. Serum
and saliva samples obtained from the mice were analyzed using
a mouse cytokine Ten-Plex assay kit (catalog no. LMC0001;
BioSource, Nivelles, Belgium), as recommended by the manufacturer, measured on a Luminex 100 system (Luminex,
Austin, TX), and analyzed using StarStation software (Applied
Cytometry Systems, Dinnington, Sheffield, UK). Mean cytokine levels were compared within and between the different
age groups.
Evaluation of salivary gland inflammation. Submandibular and sublingual salivary glands were surgically removed,
snap-frozen in isopentane by liquid nitrogen, and stored at
⫺80°C. Five-␮m–thick sections were obtained using a cryostat
(Leica Instruments, Nussloch, Germany) and placed onto
SuperFrost Plus glass slides (Menzel, Braunschweig, Germany).
Hematoxylin and eosin (H&E) staining was performed
to determine the degree of inflammation. Salivary gland tissue
samples were evaluated and morphometrically analyzed using
a Leica DMLB light microscope connected to a ColorView III
camera and AnalySIS software (Soft Imaging System, Munster,
Germany), to determine the focus score (i.e., the number of
foci comprising ⱖ50 mononuclear cells/mm2 of glandular
2301
tissue) (9) and the ratio index (i.e., the ratio of the area of
inflammation to the total area of glandular tissue) (10). At
least 2 tissue sections from both glands were examined, first by
H&E staining and then consecutively by immunohistochemical
analysis. In the majority of cases, histomorphologic features
and the degree of inflammation were similar. In case of
inconsistencies, the tissue block was cut down further, and new
H&E-stained sections were evaluated.
Immunohistochemical analysis. Immunostaining was
performed by the avidin–biotin complex method, as described
previously (10), using the following antibodies: for T cells
(CD4), rat IgG2B,␬, clone GK1.5 (R&D Systems, Abingdon,
UK); for B cells (B220), rat IgG2B, clone RA3-6B2 (R&D
Systems); for proliferating cells (Ki-67), rat IgG2a, clone
TEC-3 (Dako, Glostrup, Denmark); and for follicular dendritic cells (FDCs), rat IgG2c, clone FDC-M1 (BD Biosciences, San Jose, CA). Briefly, following fixation in cold
acetone, endogenous peroxidase (Blocking Kit) and biotin
were blocked (Avidin/Biotin Blocking Solution; Vector Laboratories, Burlingame, CA). Nonspecific binding was inhibited
by normal rabbit serum. Diaminobenzidine was used as chromogen. Sections were counterstained with hematoxylin. Unless
specified otherwise, all reagents were purchased from Dako
(Glostrup, Denmark).
Statistical analysis. Data were analyzed using one-way
analysis of variance followed by the Bonferroni posttest for
selected groups (modified unpaired Student’s 2-tailed t-test for
multiple group comparisons). To normalize skewed distributions and improve the homogeneity of variance, cytokine data
were log-transformed prior to all statistical analyses. To determine the linear relationship between 2 variables, values were
compared using Pearson’s correlation test (2-tailed). Correlation analyses were restricted to NOD mice and data sets in
which a scientific reason for a causal connection was given. P
values less than 0.05 were considered significant. Statistical
analyses were performed using GraphPad Prism 4.0 software
(San Diego, CA).
RESULTS
Impaired salivary secretion and histopathologic
changes in the salivary glands. The mean salivary flow
rate in 24-week-old NOD mice was reduced by ⬃70%
compared with that in the 8-week-old NOD mice (P ⬍
0.001), the 17-week-old NOD mice (P ⬍ 0.001), and the
age-matched BALB/c mice (P ⬍ 0.001) (Figure 1).
Significant changes were not detected in any of the other
groups.
Periductal inflammatory cell foci were observed
in the submandibular glands in 2 of 6 8-week-old NOD
mice and in all of the 17-week-old and 24-week-old
NOD mice (Figures 2A–C). Inflammation was assessed
by the focus score and the ratio index, and the mean
focus scores were 0.1 in the 8-week-old NOD mice, 0.5 in
the 17-week-old NOD mice, and 0.7 in the 24-week-old
NOD mice (Figure 1). The mean ratio indexes were
0.003 in the 8-week-old NOD mice, 0.019 in the 17-
2302
week-old NOD mice, and 0.039 in the 24-week-old NOD
mice (data not shown). An association was observed
between the results obtained with both methods (r ⫽
0.9497, P ⬍ 0.001). Foci comprising ⬍50 mononuclear
cells/mm2 of glandular tissue were observed in 3 of the
remaining 8-week-old NOD mice. Scattered, nonfocal
infiltration was observed in samples obtained from the
BALB/c mice and was considered to represent a normal
morphologic appearance (Figure 2D).
In contrast to the decrease in the rate of salivary
secretion that occurred between 17 and 24 weeks of age
(P ⬍ 0.001), a significant increase in inflammation was
detected when comparing 8-week-old and 17-week-old
NOD mice (P ⬍ 0.05) (Figures 1 and 2A and B). A
reduction in the salivary flow rate showed only a weak
association with inflammation (r ⫽ ⫺0.4688, P ⫽ 0.0497
and r ⫽ ⫺0.5710, P ⫽ 0.0133 for focus score and ratio
index, respectively). The most pronounced change in
inflammation (focus score and ratio index) was observed
between 8-week-old and 24-week-old NOD mice (P ⬍
0.01), but neither the focus score nor the ratio index
increased significantly when comparing 17-week-old and
24-week-old NOD mice (P ⬎ 0.05) (Figure 1).
Cellular composition and lymphoid organization. Infiltration by T cells and B cells was observed in
focal periductal and perivascular infiltrates. Scattered
clusters of T cells and B cells were also observed in close
relationship to (and sometimes infiltrating into) ductal
and acinar epithelium. Interestingly, in 2 of 6 17-weekold NOD mice and in 2 of 6 24-week-old NOD mice,
inflammatory cell infiltrates contained distinct areas of T
cells and B cells (Figures 2E and F, respectively), prolifer-
Figure 1. Salivary secretion in NOD mice ages 8 weeks, 17 weeks, and
24 weeks, and age-matched BALB/c mice. The salivary flow rate is
expressed as microliters of saliva secreted per minute per gram of body
weight. The focus score (in NOD mice) represents the number of foci
comprising ⱖ50 mononuclear cells/mm2 of glandular tissue. Bars show
the mean and SEM for each group. ⴱ ⫽ P ⬍ 0.05; ⴱⴱ ⫽ P ⬍ 0.01; ⴱⴱⴱ
⫽ P ⬍ 0.001.
JONSSON ET AL
Figure 2. A–D, Hematoxylin and eosin–stained frozen sections of
submandibular salivary gland tissue, showing focal inflammation in the
3 groups of NOD mice and lack of focal inflammation in age-matched
BALB/c mice. A, Representative section from 2 of 6 8-week-old NOD
mice that presented with focal mononuclear cell infiltrates in the
submandibular salivary glands. B, Representative section from 17week-old NOD mice, all of which presented with moderate to large
chronic inflammatory cell foci within the submandibular salivary
glands. C, Representative section from 24-week-old NOD mice, all of
which showed infiltration similar to that in 17-week-old NOD mice. D,
Focal mononuclear cell infiltration was not observed in frozen submandibular salivary gland tissue sections obtained from BALB/c mice,
as represented here by a specimen from a 24-week-old BALB/c mouse.
E–H, Immunohistochemistry showing T cell/CD4 cell infiltration (E),
B cell/B220 cell infiltration (F), Ki-67⫹ proliferating cells (G), and
follicular dendritic cells (H) in tissue from a 17-week-old NOD mouse.
Incubations with antibody diluent were performed as negative controls. Salivary gland tissue from the age-matched BALB/c mice served
as negative tissue controls, and associated cervical lymph nodes served
as positive tissue controls. Controls are not shown. Bars ⫽ 0.1 mm.
CYTOKINE PROFILE AND SS-LIKE DISEASE PROGRESSION
ating cells (Figure 2G), and FDCs (Figure 2H). The focus
score was significantly higher in these mice compared with
that in mice that did not present with proliferating cells and
FDCs in the salivary glands (P ⬍ 0.05).
Changes in cytokine levels in serum and saliva.
Mean IL-2 levels were significantly increased in the
serum of 24-week-old BALB/c mice compared with
24-week-old NOD mice (P ⬍ 0.05) (Figure 3A). IL-4
was detected in all serum and saliva samples investigated. In serum, the level of IL-4 was similar within age
groups and strains of mice. In contrast, a significant
increase in the level of IL-4 was detected in saliva from
the 24-week-old NOD mice compared with 8-week-old
NOD mice (P ⬍ 0.05) (Figure 3B). Correlation analyses
showed a negative association between the salivary flow
rate and the level of IL-4 in saliva (r ⫽ ⫺0.6899, P ⫽
0.0015) (Figure 3C), but not with salivary gland inflammation (r ⫽ 0.5957, P ⫽ 0.0091 and r ⫽ 0.5526, P ⫽
0.0174 for focus score and ratio index, respectively).
IL-5 was also detected in all serum and saliva
samples investigated. In the NOD mice, serum levels of
IL-5 were similar at 8 weeks and 17 weeks of age but
decreased significantly between 17 and 24 weeks of age
(P ⬍ 0.001) (Figure 3A). A reduction in the level of IL-5
in serum was also observed in 24-week-old BALB/c
mice, but the level remained significantly higher than
that in 24-week-old NOD mice (P ⬍ 0.001).
The levels of granulocyte–macrophage colonystimulating factor (GM-CSF) were significantly increased in 24-week-old NOD mice (P ⬍ 0.001) and in
24-week-old BALB/c mice compared with the levels in
8-week-old mice of the respective strains (P ⬍ 0.05)
(Figure 3A). Low levels of IFN␥ were detected in serum
and saliva from both NOD and BALB/c mice at 8 and 17
weeks of age. Despite the fact that at 24 weeks of age,
IFN␥ was no longer detectable in half of the samples
from NOD and BALB/c mice, serum and saliva levels
did not differ significantly. The salivary flow rate correlated with IFN␥ levels in saliva (r ⫽ ⫺0.7604, P ⫽
0.0002) (Figure 3C), whereas an insignificant negative
association was observed with increased inflammation
(r ⫽ 0.4616, P ⫽ 0.0538 and r ⫽ 0.4662, P ⫽ 0.0511 for
focus score and ratio index, respectively).
Tumor necrosis factor ␣ (TNF␣) was present in
all serum samples. The level of TNF␣ was significantly
increased in saliva from 24-week-old NOD mice compared with 8-week-old NOD mice (P ⬍ 0.05) (Figure
3B) and was negatively correlated with the salivary flow
rate (r ⫽ ⫺0.7471, P ⫽ 0.0004) (Figure 3C) but with
neither the focus score (r ⫽ 0.5563, P ⫽ 0.0165) nor the
ratio index (r ⫽ 0.5432, P ⫽ 0.0198). Finally, IL-6, IL-10,
2303
Figure 3. Cytokine levels in serum and saliva samples obtained from
NOD and BALB/c mice. A and B, Levels of interleukin-2 (IL-2), IL-5,
and granulocyte–macrophage colony-stimulating factor (GM-CSF) in
serum (A), and levels of IL-4 and tumor necrosis factor ␣ (TNF␣) in
saliva (B). Values are the mean and SEM. C, A decreased salivary flow
rate (microliters of saliva secreted per minute per gram of body
weight) in NOD mice was associated with increased levels of IL-4,
TNF␣, and interferon-␥ (IFN␥) in saliva. Data were analyzed using
one-way analysis of variance followed by Bonferroni posttest for
comparison of selected groups accounting for multiple group comparisons. N24 ⫽ NOD mice at 24 weeks; B24 ⫽ BALB/c mice at 24 weeks;
N08 ⫽ NOD mice at 8 weeks; N17 ⫽ NOD mice at 17 weeks; B08 ⫽
BALB/c mice at 8 weeks; B17 ⫽ BALB/c mice at 17 weeks. ⴱ ⫽ P ⬍
0.05; ⴱⴱ ⫽ P ⬍ 0.01; ⴱⴱⴱ ⫽ P ⬍ 0.001.
and IL-12 were detected in serum and saliva, but the
levels of these cytokines did not differ significantly
between age groups or strains, and IL-1␤ was detected
2304
JONSSON ET AL
only in serum from one 17-week-old and one 24-weekold NOD mouse (data not shown).
DISCUSSION
Clinical symptoms of primary SS develop late in
the disease course; thus, in most patients primary SS is
most likely diagnosed at an advanced stage of disease
(1). Consistent with results reported by other investigators (2), our results suggest that hyposalivation in NOD
mice does not follow the occurrence of focal lymphoid
infiltration and thus cannot be explained solely by the
destruction or replacement of glandular tissue by inflamed cells (1,4). An alternative murine model for SS,
the MRL/lpr mouse, has a normal salivary flow rate
despite more pronounced inflammation and several
other features of human SS (3,9,10). Results of adoptive
transfer experiments indicated that SS is a T cell–
mediated autoimmune disease (10), although B cells
may contribute to hyposalivation (1,11).
In our study, significant changes in the levels of
IL-2, IL-5, and GM-CSF in serum and in the levels of
IL-4 and TNF␣ in saliva occurred contemporarily with
the decrease in the salivary flow rate. However, the
NOD mouse strain must be considered a model of
general as well as specific immune dysregulation, and
the observed changes may, to some extent, represent
immune processes unrelated to the SS-like disease (2–
4). In addition, environmental factors as well as other
interactions may influence the incidence and extent of
autoimmune manifestations of disease. Therefore, caution must be exerted when comparing NOD mice that
are acquired from different suppliers and hosted in
different environments.
IL-2 plays a crucial role in the maintenance of
natural immunologic self-tolerance by promoting growth
and suppressor functions of regulatory T cells, and
neutralization of circulating IL-2 led to the aggravation
of diverse autoimmune manifestations (12). Although
recent studies have indicated that the absence of IL-5
can induce a shift toward adaptive immune responses,
the decrease in the level of IL-5 is difficult to interpret,
because little is known about the role of IL-5 in SS.
Increased levels of IL-4 in saliva further imply a function
of the adaptive immune system. Assuming a connection
between salivary glands and saliva, our findings of IL-4
and TNF␣ in saliva from both NOD and BALB/c mice
are in accordance with results of previous studies (2). The
negative association between IL-4 and salivary secretion
is in conformity with findings in NOD.B10-H2b.IL-4⫺/⫺
mice, which experience focal salivary gland inflammation
but no loss of salivary secretion, possibly related to the lack
of M3R antibodies of an IgG1 isotype (5).
GM-CSF is a major regulator of granulocytes and
macrophages, and a recent report indicated a role of
GM-CSF in inflammation and autoimmunity (13). Unfortunately, little is known about the role of GM-CSF in
SS. TNF␣ is one of the cytokines capable of inducing
GM-CSF production, and, interestingly, in our study the
overt stage of disease in NOD mice was associated with
increased levels of TNF␣ in saliva. TNF␣ is considered
to be a key cytokine in the pathogenesis of rheumatic
disease. Anti-TNF␣ therapies were successfully introduced in the treatment of rheumatoid arthritis, and
initial results in patients with SS were encouraging (14).
However, subsequent clinical trials failed to confirm
these findings (15).
In conclusion, our findings indicate at least 2
phases of the SS-like disease manifested in NOD mice.
Although major inflammatory cell infiltration is present
in the gland, salivary secretion remains unchanged,
whereas hyposalivation takes place without significant
changes in histopathologic features. The observation of
Ki-67⫹ cells in the inflammatory cell infiltrates indicates
a role for local proliferation in addition to recruitment
of inflamed cells in propagation of the disease. From this
point of view, we hypothesize that qualitative changes in
immunologic processes such as cytokine expression and
lymphoid organization rather than quantitative inflammatory changes modify salivary secretion, and reactions
within the chronic inflammatory cell infiltrates deserve
special attention.
ACKNOWLEDGMENTS
We gratefully acknowledge excellent technical assistance by Gunnvor Øijordsbakken, Gudveig Fjell, and Åse
Eriksen, and Joanna G. Stormark and the staff at the animal
facilities for taking good care of the mice.
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