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Receptor Deletion Prevents Autoantibody Production and Glomerulonephritis in Lupus-Prone (NZB x NZW)F1 Mice1
*
Institute of Anatomy of the University of Zürich, Zurich, Switzerland, and
Institute of Pathology of the University of Basel, Switzerland
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Abs and accelerated by IFN-
injections. To define the role of IFN- in the pathogenesis of
glomerulonephritis, we established a population of BW mice deficient in
IFN-R (BWR-/-) by repeated crossing; these mice were compared
with BWR+/+ and +/- littermates. Of the BWR+/+ and +/- mice,
50% showed immune complex glomerulonephritis with heavy proteinuria at
8 mo of age, while only 10% of the BWR-/- mice were affected at
14 mo. The serum concentration of anti-dsDNA and anti-histone
Abs was dramatically reduced in BWR-/- mice. The role of IFN-
in promoting class switch to IgG2a and IgG3 could not fully account for
the impaired production of anti-dsDNA in BWR-/- animals since,
IgM and IgG1 levels were also reduced. There was a high incidence of B
cell lymphoma in the BWR-/- mice, which might be related to the
suppression of autoAb production. Thus, the absence of
glomerulonephritis in BWR-/- mice is likely due to a dramatic yet
unexplained effect of the inactivation of IFN- signaling on autoAb
production. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Th2-type cytokines have been implicated in murine lupus. IL-4 mRNA
expression increased with aging in BW females, while IL-2 mRNA
expression decreased (4). Cytokine profiles of mitogen-stimulated T
cells in BW mice showed high Th2 cell-related cytokine production
(IL-4, IL-5, IL-10), while Th1 cell products (IL-2, IFN-) were low
(5). The administration of anti-IL-10 or anti-IL-6 Abs in BW
mice delayed the onset of disease, while injection of IL-6 accelerated
onset (6, 7, 8). Surprisingly, BW mice were protected from autoimmune
disease by inhibition of Th1-type responses as well. This protection
was achieved by either transgenic expression of IL-4 (9) or inhibition
of IFN- signaling. Neutralization of IFN- by Abs or soluble
IFN-R prevented glomerulonephritis (10, 11), while administration of
exogenous IFN- accelerated autoAb production and renal disease
(10, 11, 12).
How IFN- contributes to autoimmune disease in BW mice remains a
matter of speculation. In an attempt to elucidate that point, we
established a BW population that was deficient in IFN-R. Such an
approach has advantages over neutralization protocols. The signaling
pathway is completely disrupted, no prolonged treatment is required,
and reproducibility is presumably better. BW mice deficient in IFN-R
(BWR-/-) were obtained by a crossing protocol. Essentially, a
comparison of the BWR-/- mice with BWR+/+ and BWR+/-
littermates confirmed previous data obtained by neutralization of
IFN- (10, 11). However, the protection from glomerulonephritis and
the inhibition of autoAb production was more striking in the present
study. Unexpectedly, the effect of the IFN-R-/- mutation on autoAb
production was not limited to class switch, since it inhibited not only
the IFN--dependent isotypes IgG2a and IgG3 but also IgM and IgG1.
The dramatic inhibition of autoAb production may be sufficient to
explain the absence of glomerulonephritis in BWR-/- mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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NZB and NZW mice were provided by Bomholtguard Breeding and
Research Center (Ry, Denmark). The IFN-R null mutation (13) was
backcrossed separately in the NZB and NZW background. The carrier of
the mutation had the background 129/Sv. Mice were screened for the
disrupted gene by PCR analysis of tail DNA lysate according to standard
protocols using the following primers:
5'-CCCATTTAGATCCTACATACGAAACATACGG-3' (sense) and
5'-TTTCTGTCATCATGGAAAGGAGGGATACAG-3' (antisense). The
F1 backcross generation was produced by mating a
129/Sv IFN-R-/- female with a NZB or a NZW male. For further
generations, IFN-R+/- offspring were mated with their fathers.
Heterozygous NZB as well as NZW mice of the F5 backcross
generation were intercrossed to achieve the following three genotypes
of littermates: mice homozygous for the disrupted IFN-R gene
(BWR-/-), homozygous wild-type mice (BWR+/+), and heterozygous
mice (BWR+/-). NZW mice that were 4 mo old were used as controls.
The experimental groups were constituted as follows: 25 BWR+/+ mice,
26 BWR+/- mice, 20 BWR-/- mice, and 11 NZW mice. They were
housed under standard conditions. Mice were killed when urinary protein
levels reached 3 mg/ml or if they showed signs of severe disease, such
as 
15% weight loss or prostration. The remaining mice were killed at
the age of 14 mo. One kidney was fixed in 4% buffered
paraformaldehyde, and the other kidney was shock-frozen. Additional
organs were fixed in paraformaldehyde if they showed macroscopic signs
of disease.
Clinical scoring
Body weights and urinary protein levels were measured weekly.
Proteinuria was assessed semiquantitatively using dip sticks (Albustix,
Bayer Diagnostics, Basingstoke, U.K.). Starting at 2 mo of age, blood
was taken every month from the retroorbital plexus in 12 BWR+/+, 14
BWR+/-, 13 BWR-/-, and 10 NZW mice.
Serum IgG (sIg)G levels
sIgG levels were quantified by ELISA. All reagents were obtained from Sigma (St. Louis, MO). Microtiter plates were coated with goat anti-mouse IgG at 5 mg/ml in PBS. Plates were then blocked with 2% BSA-PBS. The mouse sera to be tested were incubated overnight at a 10-6 dilution. A goat anti-mouse IgG coupled to alkaline phosphatase was used as second Ab, and the disodium salt of p-nitrophenyl phosphate was used as the substrate. The absorbance at 405 nm was measured. The total IgG concentration was calculated with reference to an internal standard of pure mouse IgG.
Serum titers of IgG anti-dsDNA autoAbs
sIgG anti-dsDNA levels were quantified by ELISA essentially as described above for sIgG alone. Microtiter plates were coated with dsDNA from salmon testes at 10 µg/ml in PBS. The mouse sera to be tested were incubated overnight at a dilution of 500x. A standard curve was constructed using serial dilutions of a pool of sera from MRL/lpr mice showing glomerulonephritis. The titer of a given sample was the reciprocal value of the standard dilution yielding the same OD as the tested serum multiplied by 1 x 107.
Serum titers of IgM, IgG1, IgG2a, IgG3 anti-dsDNA, and IgG anti-histone
Serum levels of IgG anti-dsDNA subclasses and IgG anti-histone were determined by ELISA when the mice were 7 mo old. Serum levels of IgM anti-dsDNA were measured in 3- and 7-mo-old mice. The alkaline phosphatase-labeled mouse IgG subclass-specific Abs were obtained from Southern Biotechnology Associates (Birmingham, AL), and the alkaline phosphatase-labeled mouse IgG- and IgM-specific Abs were supplied by Sigma. The assays were performed basically as described above for total IgG. The microtiter plates were coated with dsDNA from salmon testes at 10 µg/ml in PBS or with total histone from calf thymus at 2.5 µg/ml in PBS (both from Sigma). Mouse sera were diluted from 30 to 105. The titer was calculated as the dilution giving an OD of 0.2 over background as estimated by a linear regression analysis of plots of the OD against the reciprocal value of the dilution.
Cytokine production by splenocytes in vivo
Spleens from three BW+/+ and three BW-/- 5-mo-old female mice
were squeezed through an 80-mesh sieve (Bellco, Vineland, NJ) and
cleared of erythrocytes by osmotic lysis. Splenocytes were resuspended
at a concentration of 5 x 106 cells/ml in RPMI
1640 including 25 mM HEPES (supplemented with 10% FCS, 1%
penicillin/streptomycin mix, 1% L-glutamine (200 mM), and
0.1% 2-ME (50 mM)). They were cultured in 1 ml aliquots in 24-well
tissue culture plates either in medium alone or with 5 mg/ml Con A
(Sigma). The supernatants were collected after 24 h and stored at
-20°C. Two ELISA kits were used for the detection of IFN-
(Genzyme, Cambridge, MA) and IL-4 (ImmunoKontact, Bioggio,
Switzerland). Cytokine concentrations were calculated with reference to
standard curves using recombinant cytokines.
Histology
The kidneys of all animals along with six livers showing macroscopic abnormalities were analyzed histologically. Organ slices were fixed in 4% buffered paraformaldehyde and processed for paraffin sectioning. Sections of 3-µm thickness were stained with the periodic acid Schiff reagent followed by hematoxylin.
Immunofluorescence
The left kidneys of four BWR+/+ and four BWR+/- mice that
were killed after showing proteinuria and the left kidneys of six
BWR-/- mice that reached 14 mo of age, as well as the livers of
four BWR-/- mice in which lymphomas were suspected, were
shock-frozen. Sections of 6-µm thickness were cut on a cryostat and
air-dried for storage at -80°C. Fixation in acetone (10 min at
0°C) was performed just before immunolabeling. After a rinse in PBS,
the sections were incubated for 16 h at 4°C with the primary Abs
diluted in PBS. The sections were then washed in PBS and incubated for
1 h at room temperature with cyanine (Cy3)-labeled goat
anti-rat or rabbit anti-goat Ig Ab diluted 1:200. After rinsing
in PBS, the sections were mounted in Immu-mount (Shandon, Pittsburgh,
PA). Goat anti-mouse C3 was purchased from Bethyl laboratories
(Montgomery, TX), and both goat anti-mouse Ig(G+M) (Cy3-conjugated
F(ab)2 fragment) as well as Cy3-conjugated rabbit
anti-goat IgG were purchased from Jackson ImmunoResearch
Laboratories (West Grove, PA). The following clones of rat
anti-mouse Abs were used: OKT3 (anti-CD3), RA3–6B2
(anti-B220), 114.15.2 (anti-MHC class II), and F4/80
(anti-macrophage).
Statistics
A variance analysis was performed using ANOVA software, and the significance was tested with the Bonferroni/Dunn test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Most BWR+/+ (23 of 25) and BWR+/- (23 of 26) mice were
killed because they showed protein uria. Of the 20 BWR-/- mice, 2
were killed at the ages of 10 and 12 mo because of proteinuria, while 4
others became moribund at the ages of 11 and 13 mo and were killed
while showing normal urinary protein levels (
0.3 mg/ml). Of the
latter, three had lymphomas, which were readily visible
macroscopically, appearing as pale spots on the liver surface. The
remaining mice were killed at the age of 14 mo.
Since we killed the mice as soon as they showed heavy proteinuria or
other symptoms of severe pathology, the time-course of mortality (Fig. 1
) does not reveal the actual longevity
of the experimental groups. However, since proteinuria (3 mg/ml) in
BWR+/+ and +/- mice (Fig. 2)
developed over a time-course similar to that seen with BW mice in other
studies (1, 6, 10), it is likely that in those two experimental groups,
the longevity is close to that seen in the wild-type BW, in which a
50% mortality rate occurs over a range of 
7 mo to 9 mo in various
studies (1, 6, 10, 11, 12, 14). Disruption of IFN- signaling had a
profound effect on mortality, since 70% of the BWR-/- mice
reached 14 mo of age.
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About 90% of the BWR+/+ and +/- but only 10% of the
BWR-/- mice developed proteinuria during the experimental period
(Fig. 2
). Histology revealed glomerulonephritis in all mice that showed
proteinuria, and exclusively in those mice (Fig. 3).
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R-/- mice that survived 14 mo, they were as low as in the
non-lupus-prone NZW mice (Fig. 4). Thus,
90% of the BWR-/- mice did not show any functional or histologic
signs of glomerulonephritis.
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Evaluation of IgG anti-dsDNA Abs by ELISA showed a continuous
and massive increase in BWR+/+ and +/- mice with age, whereas the
titers remained low in the BWR-/- mice for up to 9 mo (Fig. 5). At 7 mo, IgG1, IgG2a, and IgG3
anti-dsDNA Abs were elevated in the BWR+/+ and +/- mice, while
BWR-/- mice displayed levels similar to those seen in NZW mice
(Fig. 6). The effect of IFN-R
deficiency on autoAb production at 7 mo was not restricted to
anti-dsDNA, since IgG anti-histone Abs were also low in
BWR-/- mice (Fig. 7). At 3 mo, IgM
anti-dsDNA Abs were elevated in BWR+/+, +/-, and -/- mice but
at 7 mo, the levels of BWR-/- mice were as low as the levels in
NZW mice (Fig. 8). Thus anti-dsDNA Ab
production was initiated normally in BWR-/- mice but was then
repressed. In contrast to IgG autoAbs, there was no statistically
significant difference in total sIgG levels between the populations of
BW mice at 7 mo (5.5 ± 1 mg/ml in R+/+, 5.8 ± 2.7 mg/ml
in R+/-, and 4.2 ± 0.8 mg/ml in R-/-; mean ± SD,
n = 6).
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by Con A-stimulated splenocytes in
vitro
Splenic T cells from BWR-/- mice produced significantly more
IL-4 (477 ± 39 pg/5 x 106 cells) than
those from BWR+/+ mice (302 ± 66 pg/5 x 106
cells). There was no difference in the production of IFN- between
BWR-/- (5838 ± 118 pg/5 x 106 cells) and
BWR+/+ mice (5599 ± 553 pg/5 x 106 cells).
These data indicate that the production of Th1 and Th2 cytokines is not
impaired in BWR-/- mice.
Lymphomas
Of the six BWR-/- mice that showed signs of disease and were
killed before the end of the experimental period, three showed pale
foci at the liver surface. Histology of those livers revealed
accumulations of large lymphocytes with cleaved nuclei and prominent
nucleoli (Fig. 9). Similar foci were
found in the kidneys of the same mice but, with the exception of one
mouse, they were much less conspicuous than those in the liver and were
restricted to the periarterial connective tissue (data not shown). Of
the remaining 14 BWR-/- mice that were killed at the end of the
experimental period (after 14 mo), 3 more showed macroscopically
abnormal livers and accumulations of large lymphocytes in the liver and
kidney. The spleens of the latter three mice were also fixed and
processed for histology. Periarterial lymphatic sheaths (PALS),
germinal centers, and the marginal zone were not visible. The cellular
composition of the white pulp appeared monotonous, consisting mainly of
large lymphocytes with the same morphology as those infiltrating the
liver and kidney (Fig. 9). In the four livers that were processed for
immunofluorescence, the lymphocytic foci expressed MHC class II, B220,
and IgM and could thus be identified as B cells (Fig. 10). CD3+ T cells were
intermingled among B cells in all foci, but they clearly represented a
minority of the lymphocyte population (data not shown). Macrophages,
identified by the F4/80 Ab, were rare (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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influences
glomerulonephritis in a murine model of systemic lupus erythematosus
(10, 11), we generated BW mice that were deficient in IFN-R by
backcrossing. The development of glomerulonephritis and the production
of autoAbs were assessed in BWR-/-, +/+, and +/- littermates. The
data confirm previous studies showing the importance of IFN- in the
pathogenesis of glomerulonephritis in this animal model (10, 11, 12). The
protection observed in BWR-/- mice was actually better than that
obtained by neutralization of IFN- in previous studies. Indeed, at
11 mo, 40% of mice treated with IFN--neutralizing Abs showed
proteinuria (10) compared with 5% in BWR-/- mice. Furthermore,
although neutralizing treatments did delay the production of IgG
anti-DNA, the levels were clearly increased at 6 mo (10, 11).
Incomplete neutralization of IFN- in previous studies might explain
the lesser degree of protection from autoimmunity compared with the
present study in which IFN- signaling was completely abolished.
Also, in earlier studies, neutralizing treatment was conducted for a
limited period of time, namely from 4 to 7 or 8 mo of age (10, 11).
The very low levels of IgG anti-dsDNA and IgG anti-histone in
BWR-/- mice might reflect a defective Th cell function. In this
respect, it is interesting that the impairment of the Th1 response to
parasites provoked by deletion of the IFN-R in mice did not result
in the expected shift to a Th2 response (15, 16). However, since
splenocytes of BWR-/- mice and BWR+/+ mice produced similar
amounts of IL-4 and IFN- in vitro, Th2 cell help for Ig isotype
switch is presumably available in the mutants. The similarity of total
sIgG levels among the BWR-/- mice and their R+/- and R+/+
counterparts supports this possibility.
There is no previous report of defective autoAb production in
mice with deficient IFN- signaling. Production of IgG anti-dsDNA
Abs after LPS-treatment was not inhibited in IFN-R-/- mice with
the 129/Sv background (17). In the lupus-prone strain
MRL/lpr, IFN--/- mutants (18) and IFN-R-/- mutants
(19) produced high amounts of IgG autoAbs, even though the
IFN--promoted IgG2a and IgG3 isotypes remained at low levels as
expected. The defective IgG autoAb production in R-/- mice in the
present study might therefore reflect some peculiarity of the BW
background. In that context, one relevant characteristic of NZB-derived
strains is the high incidence of CD5+ B cell malignancy
(20, 21, 22, 23, 24). In the present study, foci of neoplastic B cells were
observed in the livers and kidneys of 6 of 20 BWR-/- mice. Since
we focused on glomerulonephritis and observed lymphoma by chance at the
end of the experimental period, the true incidence of B cell neoplasy
may have been underestimated. During passaging in vivo, some
CD5+ B cell clones derived from NZB mice with chronic
lymphatic leukemia acquired the capacity to infiltrate various organs
and produce large-cell lymphomas that are strikingly similar to those
observed in the present study in BWR-/- mice. Indeed, the B cell
clones colonize preferentially the liver and consist of large
lymphocytes with cleaved nuclei as well as prominent nucleoli (21, 25).
Importantly, spontaneous development of that type of lymphoma has not
been described before in either NZB or BW mice. Likewise, lymphomas
were not observed in BWR+/+ mice in the present study. Thus, it
appears that the IFN-R-/- mutation might accelerate or modify a
pathway of neoplastic development of B cells that is typical for
NZB-derived strains. An accelerated development of malignant B cells in
BWR-/- mice is plausible, since proliferation of those cells might
be under the control of specific NK1+ T cells via
IFN- (26).
There is convincing evidence in the literature for a link between B
cell neoplasy and the inhibition of Ab production. Malignant
CD5+ B cells seem to be responsible for the inhibition of B
cell function in multiple myeloma patients (27). The decrease of IgM
anti-dsDNA between the ages of 3 mo and 7 mo in BWR-/- mice is
reminiscent of the decrease of total sIgM and IgM autoAb in recipients
of NZB malignant B cells (28, 29). Clearly, a detailed comparison of
the development of B cells between BWR-/- mice and BWR+/+ mice
will be necessary to substantiate the hypothesis that neoplastic B
cells suppress autoAb production in BWR-/- mice.
IFN- may contribute to glomerulonephritis by up-regulating the
expression of MHC gene products and adhesion molecules as well as by
activating macrophages. However, the IFN-R-/- mutation did not
protect mice from mild glomerular inflammation induced by LPS (17) or
from anti-glomerular basement membrane glomerulonephritis (30). In
BW mice, it is not necessary to invoke the proinflammatory properties
of IFN- to explain the profound protective effect of blocking
IFN- signaling. The low titers of circulating autoAbs and
intraglomerular immune complexes constitute the most likely
explanation.
The crucial importance of IFN- for the production of autoAbs in BW
mice was unexpected, and it remains to be explained. The BWR-/-
mice might represent a useful tool in the study of the regulation of
autoAb production in murine lupus.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Michel Le Hir, Institute of Anatomy, University of Zürich-Irchel, CH-8057 Zürich, Switzerland.
3 Abbreviations used in this paper: autoAb, autoantibody; sIg, serum Ig.
Received for publication May 16, 1997. Accepted for publication December 15, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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receptor inhibits the onset of glomerulonephritis. Eur. J. Immunol. 25:6.[Medline]
receptor are susceptible to infection with Leishmania major but mount a polarized T helper cell 1-type CD4+ T cell response. J. Exp. Med. 181:961. signaling. Exp. Nephrol. 4:222.[Medline]
and interleukin-4 in murine lupus. J. Clin. Invest. 99:1936.[Medline]
is essential for the development of autoimmune glomerulonephritis in MRL/lpr mice. J. Immunol. 158:5484.[Abstract]
ß T cells in the peritoneal cavity: specific T cell receptor-mediated cytotoxicity and selective IFN- production against B cell leukemia and myeloma cells. J. Immunol. 157:3925.[Abstract]
receptor-deficient mice. J. Inflamm. 47:206.[Medline]
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E. Esfandiari, I. B. McInnes, G. Lindop, F.-P. Huang, M. Field, M. Komai-Koma, X.-q. Wei, and F. Y. Liew A Proinflammatory Role of IL-18 in the Development of Spontaneous Autoimmune Disease J. Immunol., November 1, 2001; 167(9): 5338 - 5347. [Abstract] [Full Text] [PDF]
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A M Walker Unmodified and phosphorylated prolactin and gamma delta T cell development and function Lupus, October 1, |
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