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*
Rheumatology Section and
Department of Histopathology, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom
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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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The influence of background genes on disease expression in other murine autoimmune models has been described, especially with respect to the lpr and Yaa disease susceptibility genes. In MRL/Mp mice, the presence of the lpr gene accelerates the development of high level and broad spectrum autoantibody production and lethal GN in addition to marked lymphoproliferative disease. In contrast, homozygosity of the lpr gene in other strains such as C57BL/6, AKR, LG/J, and C3H leads only to autoantibody production and lymphoproliferation; GN is largely absent (6). The Y-chromosome-linked Yaa gene in BXSB and MRL/Mp+/+ males enhances the rapid development of autoantibodies and GN (7, 8). However, in the C57BL/6 background, the Yaa gene does not lead to an autoimmune phenotype (7). Extensive mapping analyses of (New Zealand Black x New Zealand White)-derived cohorts of mice have provided insights into the genetic aspects of disease inheritance in murine models of SLE. Significant conclusions drawn from these studies indicate that murine SLE exists as a complex trait disorder in which specific combinations of susceptibility alleles are required for expression of the full phenotype (9, 10).
To investigate further the role of C1q deficiency in the spontaneous
development of autoimmune disease and to provide a clearer perspective
on the effects of background genes, the disrupted C1qa gene
was backcrossed for seven generations onto C57BL/6 and
MRL/Mp+/+ strains. These were intercrossed with
C57BL/6.lpr/lpr and MRL/Mp-lpr/lpr strains to
generate C1q-deficient substrains. The C57BL/6.lpr/lpr and
MRL/Mp-lpr/lpr strains spontaneously develop autoantibodies
and lymphoproliferative disease associated with the lpr
mutation that gives rise to Fas deficiency, although severe
GN and early mortality are only seen in MRL/Mp-lpr/lpr mice
(6). The MRL/Mp+/+ strain shares 
99% of
its background genome with the MRL/Mp-lpr/lpr strain
(11), except that Fas expression is normal.
MRL/Mp+/+ mice do not develop the massive
lymphoproliferative disorder seen in their lpr/lpr
counterparts, although late-onset ANA production and mild GN are found,
typically after 12 mo.
We report in this work the results of studies of the effects of homozygous C1q deficiency on the autoimmune phenotype in C57BL/6 and MRL/Mp+/+ mice in the presence and the absence of the lpr gene.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The disrupted murine C1qa gene was backcrossed for seven generations onto the C57BL/6 strain (Harlan Olac, Bichester, U.K.). The C57BL/6.C1qa-/-(N7) animals were intercrossed with commercially obtained C57BL/6.lpr/lpr mice (The Jackson Laboratory, Bar Harbor, ME) to generate a novel C57BL/6.lpr/lpr.C1qa-/- strain. Cohorts of MRL/Mp-lpr/lpr.C1qa-/-(N7) and MRL/Mp+/+.C1qa-/-(N7) mice were generated in a similar fashion. Throughout the backcrossing procedure, the targeted C1qa and lpr genes were monitored via PCR assays. All the mice involved in this experiment were maintained in the same specific pathogen-free, but not germ-free, environment. All animal care and procedures were conducted according to institutional guidelines.
Autoantibody assays
Assays were conducted using serum obtained from the various cohorts of mice at designated time points determined by the anticipated and observed stages of disease. Serum was stored at -70°C before analysis. Levels of IgG ANA were sought by indirect immunofluorescence using Hep-2 cells. Anti-dsDNA Abs were detected by indirect immunofluorescence on Crithidia luciliae (12). Serum samples were screened at a 1/80 (ANA) or a 1/20 (anti-dsDNA) dilution, and the positive samples were titrated to end point. Abs to ssDNA were measured by ELISA as described previously (13). Samples were screened at a 1/50 dilution, and the results were expressed in arbitrary ELISA units (AEU) relative to a standard positive sample (derived from an MRL/Mp-lpr/lpr mouse) that was assigned a value of 100. Serum samples were considered positive if they were above the mean ± SD of the negative serum. The intra-assay coefficients of variation were between 3.5 and 9.5%, and the interassay coefficients were between 3.6 and 18.9% for the samples measured.
A flow cytometric test was used to detect anti-mouse RBC Abs in the
serum. Diluted serum was incubated with 20 µl of 1% RBC suspension,
prepared from BALB/c mice, in 1% BSA/PBS for 30 min at 4°C. After
washing three times with 1% BSA/PBS, the RBC were incubated with
biotinylated rat anti-mouse 
-chain mAb (H139.52.1; Southern
Biotechnology Associates, Birmingham, AL), followed by PE-conjugated
streptavidin R (BD PharMingen, Oxford, U.K.) and analyzed with a
FACScan (BD Biosciences, San Jose, CA). Results were expressed as the
fluorescence intensity. New Zealand Black female serum was used as a
positive control, and BALB/c serum was used as a negative control.
Serum samples were considered positive if they were above the mean
± SD of the negative serum. Rheumatoid factor activity was measured by
ELISA as previously described (14). Briefly, microtiter
plates were coated with 5 µg/ml
(4-hydroxy-3-iodo-5-nitrophenyl)acetyl-conjugated BSA, followed by a
mouse IgG2a 
anti-(4-hydroxy-3-iodo-5-nitrophenyl)acetyl Ab
(NIP-23) (15). The plates were then incubated with
appropriately diluted sera, and the assay was developed with alkaline
phosphatase-labeled rat anti-mouse -chain mAb (H139.52.1;
Southern Biotechnology Associates). The results were expressed in AEU,
referring to a standard curve derived from a serum pool of
MRL/Mp-lpr/lpr mice.
Histology
Kidney portions were fixed in Bouin’s solution for 2 h, transferred into 70% ethanol, and processed into paraffin. The sections were stained with periodic acid-Schiff reagent and scored for GN as previously described (16). Glomerular hypercellularity was graded on a scale of 0–IV, in which grade 0 represents no involvement and grade IV represents severe proliferative GN in >90% of glomeruli. Additional morphological characteristics such as crescent formation and periglomerular fibrosis were also noted. Proteinuria was assessed in selected MRL/Mp+/+ mice using Haema-combistix (Bayer Diagnostics, Newbury, U.K.). Apoptotic bodies present in 50 glomeruli/section were quantified by light microscopy on coded sections. A cell was considered apoptotic when it showed loss of cell volume, chromatin condensation along the nuclear membrane with intensely basophilic staining, and/or nuclear fragmentation into spherical structures containing condensed chromatin.
Immunofluorescence staining for glomerular IgG and C3 deposits was conducted on selected samples of tissue that were snap-frozen in liquid nitrogen-cooled isopentane. Frozen sections (5 µm) were cut and fixed in acetone and air-dried before incubation with FITC-conjugated anti-mouse IgG (1/40 dilution in PBS; Sigma-Aldrich, Poole, U.K.) or anti-mouse C3 (1/50 dilution; ICN Pharmaceuticals, Costa Mesa, CA). Sections were subsequently washed, and the slides were mounted in Permafluor reagent (Immunon, Pittsburgh, PA) and viewed under a fluorescence microscope.
In vivo apoptotic cell clearance by peritoneal macrophages
Phagocytosis of apoptotic cells by peritoneal macrophages was
investigated in vivo as previously described (5). Briefly,
inflammatory macrophages were recruited into the peritoneum by
injecting 1 ml of sterile 4% thioglycolate. Four days later the mice
were injected with 1 x 107 apoptotic
Jurkat T cells or 3 x 107 apoptotic murine
thymocytes. Jurkat T cells were induced to undergo apoptosis by
exposure to UV radiation, followed by 2-h culture in RPMI 1640/0.4%
BSA. This resulted in a population of cells that was 40% apoptotic
and >95% trypan blue negative. Mouse thymocytes were obtained by
mechanical dissociation of thymi from 3- to 5-wk-old mice and were
induced to undergo apoptosis by 3-h culture in RPMI 1640/0.4% BSA in
the presence of 1 µM dexamethasone (Sigma-Aldrich). This resulted in
a population of cells that was 30% apoptotic and >95% viable.
Apoptosis was confirmed by annexin V binding, propidium iodide staining
(assessed by flow cytometry), and morphological changes, including
nuclear fragmentation and condensation, loss of cell volume, and
membrane blebbing (assessed on cytospin preparations). Cells were
considered viable when they excluded propidium iodide and trypan blue.
After 30 min the mice were sacrificed, the peritoneal cells were
recovered by lavage, and phagocytosis was scored on coded cytospins
stained with DiffQuick (Dade Behring, Marburg, Germany).
Phagocytosis was expressed as the percentage of macrophages ingesting
apoptotic cells.
Statistics
Statistics were calculated using GraphPad Prism version 2.0 (GraphPad Software, San Diego, CA). Nonparametric statistical tests were applied throughout. Differences were considered significant for p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Three cohorts consisting of 54 C1qa-/- (25 males and 29 females), 48 C1qa+/- (23 males and 25 females), and 45 wild-type (22 males and 23 females) C57BL/6 mice were analyzed. ANA titers were measured at 6, 9, and 12 mo of age, and all samples tested were negative. In view of this result, no further autoantibody analyses were conducted. Renal tissue obtained at 12 mo was assessed for the presence of GN. The great majority of mice in all three cohorts showed normal morphology, and no significant differences among the three groups were observed (data not shown). Similarly, the quantification of glomerular apoptotic bodies in the kidneys of these mice did not show a significant difference among any of the three experimental cohorts (data not shown).
Analysis of C57BL/6.lpr/lpr.C1qa-/- mice
A total of 33 C57BL/6.lpr/lpr.C1qa-/- animals (16 males and 17 females) and 44 C57BL/6.lpr/lpr controls (21 males and 23 females) were studied. At 3 mo of age low ANA titers (range, 1/80 to 1/160) were detected, but no significant difference between the two groups was found. A similar picture was seen in the analysis of anti-ssDNA Abs (range, 7–57.6 AEU, in 15% of the C1qa-/- and 20% of the wild-type mice). A similar analysis was conducted at 4 and 6 mo of age. As expected, the overall prevalence and titer of autoantibodies were increased at these later time points, although no significant differences between the two groups were found. GN was assessed in renal tissue collected at 8–10 mo of age. Severe GN was detected in a small proportion of animals from both groups, and overall no significant difference in the prevalence or severity of GN existed between the two groups. Apoptotic bodies (expressed as the number found in 50 glomeruli) were counted in 10 C57BL/6.lpr/lpr.C1qa-/- and 10 wild-type C57BL/6.lpr/lpr mice with no histological evidence of GN at 8 mo of age, and significantly greater numbers were found in C1q-deficient kidneys (C57BL/6.lpr/lpr.C1qa-/-, 1.1 ± 0.27 (mean ± SEM); wild-type, 0; by Mann-Whitney U test, p < 0.012). However, at 10 mo of age in 12 C57BL/6.lpr/lpr.C1qa-/- and 10 wild-type C57BL/6.lpr/lpr mice, no significant difference was found (C57BL/6.lpr/lpr.C1qa-/-, 0.539 ± 0.22; wild-type, 0.818 ± 0.38).
Analysis of MRL/Mp-lpr/lpr.C1qa-/- mice
The MRL/Mp-lpr/lpr model develops a highly accelerated
and aggressive autoimmune disease. Therefore, ANA titers and the
presence of GN were assessed in a small sentinel group of 1.5-mo-old
mice (11
MRL/Mp-lpr/lpr.C1qa-/- and 10
MRL/Mp-lpr/lpr wild-type mice). All the samples analyzed
were ANA negative, and no statistically significant difference in the
prevalence or severity of GN was observed between the two groups. More
extensive analysis was conducted in a group consisting of 19
MRL/Mp-lpr/lpr.C1qa-/- and 24
MRL/Mp-lpr/lpr wild-type animals at the later time point of
2 mo of age. Although at this time high ANA titers (range, 1/80 to
1/1280) were found in 84% of the
MRL/Mp-lpr/lpr.C1qa-/- and in
64% of the MRL/Mp-lpr/lpr wild-type mice, there was no
significant difference between the two groups. Similarly, no
differences were seen with regard to measurements of anti-ssDNA Ab
levels or anti-dsDNA titers. At 2 mo of age severe GN (grades
I–IV) was detected in both groups, but no significant difference in
the prevalence or the severity of disease was seen. Glomerular
apoptotic bodies were not detected in any of the GN-negative kidneys
analyzed. In addition to the phenotypic analysis, a survival study,
consisting of 17
MRL/Mp-lpr/lpr.C1qa-/- (10
males and 7 females) and 17 MRL/Mp-lpr/lpr wild-type (9
males and 8 females) mice, was established. All the animals were kept
in the same specific pathogen-free environment. The pattern of
mortality within both groups was similar, with the onset of death
occurring after 3 mo of age, and 50% mortality being reached at
6–7 mo. The experiment was fully resolved after 16 mo, and a
significant increase in mortality, although not marked, was observed
within the C1q-deficient group (by log-rank test, p =
0.022; Fig. 1
).
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In contrast to the results obtained from the study of the above
cohorts, analysis of the MRL/Mp+/+ strain revealed marked
differences between C1q-deficient and wild-type animals. Studies were
conducted in 47
MRL/Mp+/+.C1qa-/- (29 males
and 18 females) and 34 MRL/Mp+/+ controls (22 males and 12
females). The initial analysis was conducted on serum obtained at 3 mo
of age, at which point no ANA titers were detected in either of the two
groups. However, by 6 mo of age a discernable phenotype began to
emerge, in which the presence and titer of ANA in the
MRL/Mp+/+.C1qa-/- group were
significantly greater than those found in controls (by Mann-Whitney
U test, p = 0.0001; Fig. 2a). In addition,
significantly higher levels of anti-ssDNA Abs were detected in
MRL/Mp+/+.C1qa-/- mice (by
Mann-Whitney U test, p = 0.0057; Fig. 2b). Analysis of the distribution of autoantibody levels
within the individual male and female populations measured at 6 mo
showed that in both experimental groups the females had a higher
incidence of autoantibody production compared with the males. At 6 mo
of age MRL/Mp+/+.C1qa-/-
mice developed significantly higher, although not marked, levels
of rheumatoid factor (by Mann-Whitney U test,
p = 0.0422; Fig. 2c). However, no
significant levels of anti-dsDNA and anti-erythrocyte Abs were
detected in either of the two groups of mice at 6 mo (data not shown).
In the course of the study after 5 mo of age an accelerated mortality
and morbidity within the female
MRL/Mp+/+.C1qa-/- group was
noticed. The clinical presentation of disease in these mice was
characterized by kidney failure, resulting in heavy proteinuria and
anasarca. Mortality data were collected up to 12 mo of age, at which
time point the mice were sacrificed. From this analysis it emerged that
significantly greater mortality was recorded within the
MRL/Mp+/+.C1qa-/-female
group, in which there was 41% mortality by 12 mo compared with no
mortality in the wild-type group (by log-rank test, p =
0.014; Fig. 3).
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Assessment of GN was conducted on renal tissue obtained at 12 mo
of age, with the exception of a number of female
MRL/Mp+/+.C1qa-/- mice that
died or had to be sacrificed prematurely due to the development of
severe anasarca. The prevalence and severity of GN were significantly
greater in the
MRL/Mp+/+.C1qa-/- group
compared with the controls (by Mann-Whitney U test,
p < 0.0001) regardless of gender (Table I). However, within each experimental
group females suffered a higher incidence of severe GN compared with
males. In a number of cases of diseased females light microscopy
revealed the presence of grossly abnormal glomeruli showing crescent
formation and periglomerular fibrosis (Fig. 4). Simple dipstick tests before
sacrifice showed marked proteinuria (>20 mg/ml) in all female
MRL/Mp+/+.C1qa-/- mice
assessed positive for severe GN. Immunofluorescence staining in
selected GN-positive kidneys revealed the presence of extensive IgG and
C3 deposits distributed both within the mesangium and along capillary
walls (data not shown).
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). Comparison of the phagocytic uptake
of an equivalent number of viable thymocytes confirmed that the
peritoneal macrophages preferentially engulfed apoptotic cells
(percentage of macrophages ingesting apoptotic thymocytes, 30.1 ±
1.4% (n = 5) compared with 3.4 ± 1.86%
(n = 4) with viable cells (mean ± SEM);
p = 0.0159, by Mann-Whitney U test).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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However, our findings with the C1q-deficient mice appear to contradict a number of previous studies investigating the roles of other complement deficiencies in the modification of disease expression in MRL/Mp-lpr/lpr and C57BL/6.lpr/lpr animals. The generation and subsequent phenotyping of factor B-deficient MRL/Mp-lpr/lpr mice showed a partial amelioration of disease compared with controls, leading investigators to hypothesize that the blockade of the alternative pathway in some way inhibited the full expression of autoimmunity (20). Another study showed that homozygous deficiencies of C4 and CD21/CD35 (CR1/CR2) accelerated disease in C57BL/6.lpr/lpr mice, although paradoxically C3-deficient C57BL/6.lpr/lpr mice behaved in a similar fashion as controls (21). Furthermore, C3 deficiency in MRL/Mp-lpr/lpr mice has been shown to have minimal effects on disease expression (22). In light of all these observations, it can be speculated that the underlying explanation for these apparently conflicting reports may lie in the nature of the genetic background of the mice used for these various analyses or may reflect the complexity of the multiple biological roles of the complement system in inflammatory diseases. In the case of the factor B-deficient MRL/Mp-lpr/lpr mice a significant difference between the knockouts and controls was the H2 haplotype. The factor B-deficient mice were all typed as H2b/b, whereas the controls were all H2k/k (20). The MHC is known to play a major role in autoimmune pathogenesis in murine SLE models, and therefore this discrepancy in H2 haplotype may have had an influence on the observed phenotype. All the MRL/Mp mice analyzed in our experiments were determined as H2k/k (data not shown), and C1q is not linked to the H2 locus, whereas factor B and C4 are. However, the protective effects on disease expression observed in the factor B-deficient mice compared with the absence of modifying effects of C1q or C3 deficiency (22) on the same MRL/Mp-lpr/lpr genetic background may be due to different biological effects of the complement system on tissue according to the pathway of activation. As shown in other experimental models of induced renal injury the complement system may play a dual role, with both injurious and protective roles (23). Thus, it can be postulated that it is the lack of an amplification loop for C3 activation by factor B deficiency that induced the beneficial effects observed in the factor B-deficient mice, and not the absence of C3 activation or C3 in itself.
With regard to the analysis of C4- and CD21/CD35-deficient
C57BL/6.lpr/lpr mice, the genetic background was a hybrid of
129 and C57BL/6. It is known that the hybrid (129 x C57BL/6)
genetic background is predisposed to the development of SLE (2, 24). This raises the possibility that the modification of
disease in this case could have been influenced primarily by
combinations of uncharacterized background genes interacting with the
lpr mutation and not necessarily due to the action of the
targeted deletions. In addition, recent data have suggested that the
capacity of C4 to protect from the development of autoimmunity in the
permissive (129 x C57BL/6) host strain operates independently of
CD21/CD35 function (25). This supports the hypothesis that
early classical pathway complement proteins, upstream from C3
activation, are the principal components of the complement system
involved in the prevention of autoimmune responses, a mechanism for
which may involve the handling of apoptotic cells (5). In
this context it is of note that the
MRL/Mp+/+.C1qa-/- mice
exhibited an in vivo impairment in the phagocytic uptake of
heterologous and autologous apoptotic cells by elicited peritoneal
macrophages compared with the wild-type animals (Fig. 5
).
In conclusion, the effect of genetic background on the expression of disease in gene-targeted C1q-deficient animals has been found to be critical. Analysis of C1q deficiency in C57BL/6, C57BL/6.lpr/lpr, MRL/Mp-lpr/lpr, and MRL/Mp+/+ mice only showed evidence of disease acceleration in MRL/Mp+/+ animals. The MRL/Mp+/+.C1qa-/- strain may prove be a very useful tool with which to dissect the contributions of C1q deficiency to autoimmune pathogenesis in light of the genetic uniformity of this model. In addition to the relevance of this work to the relationship between C1q deficiency and autoimmunity, this study also illustrates the importance of the genetic background in the analysis of gene-targeted mice in general. The majority of the original reports describing SLE-like disease in gene-targeted mice have presented data obtained from hybrid mouse strains.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Mark J. Walport, Rheumatology Section, Imperial College School of Medicine, Division of Medicine, Hammersmith Hospital, Du Cane Road, London, U.K. W12 ONN. E-mail address: m.walport{at}ic.ac.uk
3 Abbreviations used in this paper: SLE, systemic lupus erythematosus; ANA, antinuclear Ab; GN, glomerulonephritis; AEU, arbitrary ELISA unit.
Received for publication April 18, 2001. Accepted for publication December 19, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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