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* Division of Rheumatology, Department of Medicine, and
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110;
Veteran’s Administration Medical Center, Minneapolis, MN 55417 and
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610
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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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Abnormalities in CR1 and CR2 have been described in different autoimmune diseases (19). CR1 expression is reduced on erythrocytes, polymorphonuclear leukocytes, and B lymphocytes from patients with systemic lupus erythematosus (SLE), autoimmune hemolytic anemia, and Sjögren’s syndrome (19, 20, 21). Expression of CR2 on B cells is also reduced in patients with SLE (22). The decrease in cell surface levels of CR1 and CR2 is usually an acquired phenomenon secondary to disease progression and not a primary genetic defect responsible for disease development (19). Nevertheless, it is not clear how this acquired reduction in the expression of these CRs modifies the autoimmune disorder present in these diseases.
Recent studies in animal models have also suggested that genetically determined abnormalities in these receptors may also have a causative role in SLE. For example, in the MRL/Mpj-Faslpr mouse, a model of murine SLE, markedly reduced levels of CR1 and CR2 are found on B cells before the appearance of clinical overt disease (23). In another mouse model of SLE, NZM2410/NZW mice have a single nucleotide polymorphism in the Cr2 gene (24). This polymorphism is located in the region encoding for the C3d binding site and introduces a new glycosylation site that affects ligand binding and receptor-mediated cell signaling. In addition, a (129Sv/J x C57BL/6).lpr hybrid mouse strain with a Cr2 gene-targeted mutation develops a progressive fatal SLE-like autoimmune disorder (22). Thus, decreased expression of these CRs in patients with SLE, or in susceptible mouse strains, may be important in the development or acceleration of autoimmune disease.
However, it is unclear how the difference in CR2 function found in the NZM2410/NZW mice specifically relates to distinct SLE clinical manifestations. Currently, the Cr2 polymorphism in NZM2410/NZW has not been studied in association with other SLE susceptibility loci (24). Furthermore, although the (129Sv/J x C57BL/6).lpr Cr2-/- hybrid mouse strain develops a SLE-like syndrome, the widespread genetic polymorphism between the 129Sv/J and C57BL/6 mouse strains makes it difficult to determine what precise autoimmune phenotype is related to abnormalities in Cr2 expression by itself, or in relation to other unique genetic loci combinations that can supply epistatic effects (22, 25).
To clarify this matter we have analyzed congenic C57BL/6 mice either with an isolated gene targeted mutation in Cr2 (C57BL/6.Cr2-/- mice) or with a concomitant deficiency in Fas (C57BL/6.lpr Cr2-/- mice). C57BL/6 mice are not susceptible to the development of autoimmune disease (26). In contrast, C57BL/6.lpr mice have a mild autoimmune disease characterized by the presence of lymphadenopathy and splenomegaly, as well as increased concentration of IgM and IgG Abs, but limited amounts of anti-dsDNA Abs (26, 27). C57BL/6.lpr mice also develop high levels of rheumatoid factor associated with this indolent autoimmune disorder, but without the development of arthritis (27). Renal disease is not present in this mouse strain (28). In this study we found limited amounts of anti-dsDNA IgG Abs in the sera of C57BL/6.Cr2-/- mice and no other signs of autoimmune disease. Interestingly, the Cr2null mutation in a C57BL/6.lpr background induces increased serum concentrations of IgG and increased serum levels of antinuclear Abs (ANA) and IgG anti-dsDNA Abs. However, it does not affect the degree of splenomegaly and lymphadenopathy usually found in C57BL/6.lpr controls. Furthermore, renal function is not compromised. In summary, these results indicate that mutations in the Cr2 gene, especially when combined with mutations in the Fas gene, increase the production of autoantibodies. Phenotypic expression of other disease manifestations need additional Cr2-independent genetic factors that modify clinical presentation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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F1(129Sv/J x C57BL/6) Cr2-/- mice were generated using standard gene-targeting techniques as previously described (15). C57BL/6 and C57BL/6-Faslpr/Faslpr (C57BL/6.lpr) mice were purchased from The Jackson Laboratory (Bar Harbor, ME). Mice carrying both the lpr and Cr2-/- homozygous mutations were generated by crossing to the C57BL/6 background for eight generations, and then to the C57BL/6.lpr background for two generations. They were maintained under specific pathogen-free conditions.
Genomic screening of the extent of the 129Sv/J retention in the C57BL/6.Cr2-/- mice was done by screening DNA obtained from two mice with a panel of 40 microsatellite markers that are polymorphic between C57BL/6 and 129Sv/J as previously described (29). These markers were distributed on the entire autosomal genome, including at the positions of three known SLE susceptibility loci (Sle1, Sle2, Sle3) on C57BL/6 background (30). Ten additional polymorphic markers were typed in the Sle1 region on telomeric chromosome 1, where Cr2 is located.
Genotyping
C57BL/6.lpr littermates were typed as previously described using the PCR technique (31). The following oligonucleotides were designed to distinguish the lpr allele from the wild-type Fas allele: Fas1, 5'-GATTCCATTTGCTGCTGTGT-3'; Fas2, 5'-CTTCATAACTGGTGTCGCAA-3'; and Fas3, 5'-CAGGGAAATGTAGCAAGATG-3'. Amplification was conducted using 3 mM magnesium chloride and cycling 35 times (10 s at 94°C, 10 s at 55°C, and 80 s at 72°C). The following oligonucleotides were designed to distinguish Cr2-/- mice: 5'-TGTCAGGCTCCTCCTAAAATTAT-3' and 5'-CTTTACAAAGACGGATTTCTATA-3'. PCR conditions are 4 min at 94°C, and then 35 cycles (30 s at 94°C, 30 s at 55°C, 60 s at 72°C), with a final extension for 6 min at 72°C. The amplified products were visualized on a 1.3% agarose gel. Template DNA was obtained from splenocytes and tail DNA using a PUREGENE DNA Isolation kit (Gentra Systems, Minneapolis, MN).
Abs and flow cytometry
7G6 is a rat anti-mouse CR1/CR2 mAb (32). FITC-conjugated 7G6, PE-conjugated anti-mouse B220, and PE-conjugated anti-mouse CD95 were obtained from BD PharMingen (San Diego, CA). For flow cytometric analysis, single-cell suspensions were prepared from spleen. A total of 1 µg of Ab was added to 1 x 106 cells for 60 min in 100 µl of PBS/0.1% BSA/0.01% NaN3 at 4°C. Flow cytometry was performed on a FACScan (BD Biosciences, San Jose, CA).
Northern blot
Total RNA was isolated by homogenizing tissue samples in TRIzol reagent (Life Technologies, Rockville, MD) using a power homogenizer according to the manufacturer’s instructions. Electrophoresis was performed in 0.9% agarose and 0.6% formaldehyde in a buffer containing 0.02 M morpholinopropanesulfonic acid, 5 mM sodium acetate, and 1 mM EDTA. RNA was transferred to a nylon membrane and probed with a Cr2 cDNA fragment encoding functional short consensus repeats 7 and 8 (2). Hybridization and washing were performed using the same conditions as above except that 50% formamide was added to the hybridization buffer and hybridization was done at 42°C and washing was done at 56°C.
Western blot
Mouse splenic cells were lysed in buffer containing 1% Nonidet P-40, 2 mM PMSF, 150 mM NaCl2, 2 mM EDTA, and protease inhibitors. Ten microliters (3 x 106 cell equivalents) of this solution were analyzed by 7.5% SDS-PAGE. Proteins were transferred to nitrocellulose. Nitrocellulose membranes were blocked by using 0.1% Tween 20 and 5% (w/v) nonfat dry milk (pH 7.5) and then incubated overnight at 4°C. Afterward, the membrane was incubated with a 1/500 dilution of 0.5 mg/ml 7G6 anti-mouse CR1/CR2 Ab at 37°C for 1.5 h. The membrane was washed with PBS and 0.1% Tween 20, and bound Ab was detected by using a 1/2500 dilution of goat anti-rat IgG conjugated to HRP (Southern Biotechnology Associates, Birmingham, AL), followed by detection using the Western Blot Chemiluminescence Reagent Plus (NEN Life Science Products, Boston, MA).
Urine protein excretion
Urine protein levels were determined every 6 wk starting at 6 wk of age by colorimetric analysis using dipsticks (Chemstrip 4OB; Boehringer Mannheim, Indianapolis, IN) as previously described (33).
Renal pathology
At the time of sacrifice (38 wk), the kidneys were removed. Kidneys were fixed with 10% buffered formalin, embedded in paraffin, sectioned, and stained with H&E.
Measurement of IgG isotypes
Serum IgM and IgG isotype levels were measured by ELISA using the SBA Clonotyping System/HRP (Southern Biotechnology Associates). The relative concentration of Ig in individual samples was calculated by comparing the mean OD obtained from triplicate wells to a standard curve using linear regression analysis (15).
Measurement of autoantibodies
ANA were measured by indirect immunofluorescence using human epithelial cell (Hep-2) tissue culture substrate fixed on microscopy slides (Sigma-Aldrich, St. Louis, MO). Different serum dilutions were added and incubated for 30 min at room temperature. After washing in PBS, FITC-conjugated goat anti-mouse IgG was added and incubated for 30 min. Slides were evaluated on a fluorescence microscope and the highest serum dilution that still stained the Hep-2 tissue culture substrate was recorded. Anti-dsDNA Abs were measure by ELISA. Ninety-six-well ELISA plates were coated with 5 µg/ml calf thymus dsDNA (Sigma-Aldrich) at 4°C overnight. Serum dilutions were added and incubated overnight at 4°C. The detecting Ab was 100 µl of a 0.2 µg/ml HRP-conjugated goat anti-mouse IgG Ab (Southern Biotechnology Associates) added for 1 h at 37°C, followed by 1-Step Turbo TMB-ELISA (Pierce, Rockford, IL). The mean OD450 from serum dilution wells was compared with a standard curve of titrated serum derived from a 6-mo-old MRL.lpr mouse to calculate the relative units (RU) (13, 15). Rheumatoid factor was measured by ELISA. Plates were coated with mouse IgG (Southern Biotechnology Associates), then a 1/1600 serum dilution was added and incubated at room temperature for 2 h. After washing, goat anti-mouse IgM-HRP (Southern Biotechnology Associates), 1/500 diluted in blocking buffer, was added and incubated at room temperature for 1 h, followed by 1-Step Turbo TMB-ELISA (Pierce).
Statistical analysis
Values are expressed as mean ± SEM. Levels of statistical significance were determined using the Student t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We bred our (129Sv/J x C57BL/6)Cr2-/- mice eight generations into the C57BL/6 mouse strain and two additional generations into the C57BL/6.lpr mouse strain to generate mice deficient in Fas, CR1, and CR2, in a C57BL/6 background. C57BL/6.lpr littermates derived from the breeding of C57BL/6.lpr Cr2+/- mice were used as controls. To verify the genotype, we performed a genomic screening using PCR-based markers polymorphic between the C57BL/6 and 129Sv/J mouse strains. Of the 50 polymorphic markers screened, 48 were C57BL/6 derived and only two, D3 Mit100 located at 46 cM from the centromere and D13 Mit130 located at 42.6 cM from the centromere, were found to be 129Sv/J derived. These markers correspond to the positions of potential SLE susceptibility loci in the BXSB strain (Bxs5 on chromosome 3 and Bxs6 on chromosome 13) (34). However, these two Bxs loci are dependent of the expression of the Yaa locus and are therefore unlikely to play a role in our model. In addition, D3 Mit100 corresponds to the position of the New Zealand White-negative modifier locus Sles3 (35). However, we have shown that this locus is epistatic to New Zealand White-derived Sle1 and is therefore not likely again to play a role in our model. All major SLE susceptibility loci were C57BL/6 derived in our model. Most importantly, typing of the telomeric chromosome 1 with 10 markers showed that the 129Sv/J genomic interval containing the targeted mutation in Cr2, which corresponds to Sle1c (29), did not extend to Sle1a and Sle1b, which are C57BL/6 derived in our model.
To verify that the Cr2-/- genotype was
expressed phenotypically, we measured the levels of CR1 and CR2 mRNA by
Northern blotting and the protein expression on the surface of cells by
Western blot and FACS analysis. As previously reported, several bands
hybridized to the Cr2 probe in Northern blots from C57BL/6
and C57BL/6.lpr mice (1, 2) (Fig. 1
). No detectable levels of CR1 or CR2
mRNA or protein were found in
C57BL/6.Cr2-/- and C57BL/6.lpr
Cr2-/- mice (Fig. 1).
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). In fact, H&E staining of kidney
sections from C57BL/6.lpr and C57BL/6.lpr
Cr2-/- mice have similar appearance to tissue
sections derived from C57BL/6 and
C57BL/6.Cr2-/- mice.
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F1(129Sv/J x C57BL/6) Cr2-/- mice have no abnormalities in the overall levels of IgM or IgG and, although no significant changes are detected in the levels of particular IgG isotypes, there is a trend for lower serum levels of IgG2a and IgG3 (15). In contrast, increased serum levels of IgM and IgG subclasses are found in C57BL/6.lpr mice (26). To determine how the combined Cr2 and lpr mutation affected the Ig serum levels, we measured serum levels of IgM and specific IgG isotypes in nonimmunized 36-wk-old C57BL/6.lpr and C57BL/6.lpr Cr2-/- mice.
Significant increases in the serum concentrations of IgG1 and IgG2b
were noted in the C57BL/6.lpr Cr2-/- as
compared with C57BL/6.lpr mice (Table I). There was also a trend for higher
concentrations of IgG2a (1.6-fold increase) and IgG3 (2.6-fold
increase), although it did not reach a statistically significant
difference. C57BL/6.lpr Cr2-/- mice also
had elevated levels of IgM, although no difference was noted as
compared with the C57BL/6.lpr counterparts. Surprisingly,
the isolated Cr2 mutation significantly increased the
baseline IgM levels found in the serum of aged animals.
C57BL/6.Cr2-/- mice had a 4-fold increase
in the baseline levels of IgM as compared with C57BL/6 controls,
although levels were still low as compared with
C57BL/6.lpr and C57BL/6.lpr
Cr2-/- animals. There was no notable difference
in the levels of IgG1, IgG2a, and IgG2b between the C57BL/6 and the
C57BL/6.Cr2-/- mice although, as
previously reported, there was a significant decrease in the amount of
IgG3 in the serum of C57BL/6.Cr2-/- mice
(15).
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To determine whether deficiency in CR1 and CR2 had any effect on
the production of ANA and anti-dsDNA Ab production, serum levels of
these autoantibodies were measured. Both C57BL/6.lpr and
C57BL/6.lpr Cr2-/- mice generated ANA
(data not shown). Interestingly, 61% (11 of 17) of the
C57BL/6.lpr Cr2-/- mice, as
compared with only 33% (4 of 12) of the C57BL/6.lpr
mice, had titers higher than a 1/2560 serum dilution at 24 wk of age
(Fig. 3A). Moreover, 82% of the C57BL/6.lpr
Cr2-/- females had high ANA titers compared
with only 14% of C57BL/6.lpr females (Fig. 3B).
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).
At this age there was a trend among C57BL/6.lpr
Cr2-/- males to have lower amounts of these
autoantibodies as compared with controls. In contrast, from 24 to 36 wk
of age, C57BL/6.lpr Cr2-/- mice had
6-fold higher average titers of anti-dsDNA Abs as compared with
controls (7 ± 1.7 RU in C57BL/6.lpr; 39.6 ± 14.6
RU in C57BL/6.lpr Cr2-/- at 36 wk of age;
p < 0.025). This difference was more pronounced among
females, with only small differences between 30- and 36-wk-old
males.
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). No difference was
noted between the background levels detected by our ELISA system in the
6-wk-old C57BL/6 wild-type mice (3.6 ± 1 RU) as compared with the
36-wk-old C57BL/6 wild-type mice (3.7 ± 0.8 RU). The 36-wk-old
C57BL/6.Cr2-/- mice and the 36-wk-old
C57BL/6.lpr mice have a small 2-fold increase in the levels
of anti-dsDNA Abs as compared with 36-wk-old C57BL/6 controls
(6.2 ± 1 RU in C57BL/6.Cr2-/- mice,
p < 0.025; 7 ± 1.7 RU in C57BL/6.lpr,
p < 0.05). Thus, these results demonstrate that there
is a small but statistically significant increase in anti-dsDNA
production in the C57BL/6.Cr2-/- mice,
comparable to the C57BL/6.lpr mice, but that the combined
deficiency in CR1, CR2, and Fas results in a marked increase in serum
autoantibody levels as compared with each mutation alone.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To further assure that the increase in autoantibodies we observed in the C57BL/6.lpr Cr2-/- mice is directly related to the deficiency in CRs, and not to the potential effect of 129Sv/J and C57BL/6-derived gene combinations on disease presentation, we performed an extensive genomic screening using PCR-based markers polymorphic between these two mouse strains. The SLE susceptibility loci corresponded to the C57BL/6 background, including genomic intervals linked to the Cr2 gene in chromosome 1.
An unexpected finding is the increase in IgM serum levels present in
nonimmunized C57BL/6.Cr2-/- mice as
compared with wild-type controls. In our original paper, we did not
find any differences in IgM levels between the
F1(129Sv/J x C57BL/6)
Cr2-/- and controls (15).
Although we do not have a clear explanation for this finding, we do not
think that this discrepancy is related to strain differences. At 8 wk
of age C57BL/6.Cr2-/- and C57BL/6 mice
have comparable levels of total IgM (data not shown). Conversely,
36-wk-old C57BL/6.Cr2-/- have a 4-fold
increase in the IgM serum levels (Table I
). Thus, this is an effect
that apparently becomes evident when the mouse ages.
The experimental results presented herein differ from previous studies performed in (129Sv/J x C57BL/6).lpr mice with a gene targeted mutation in Cr2 (22). (129Sv/J x C57BL/6).lpr Cr2-/- mice develop a severe form of autoimmune disease characterized by high titers of ANA and anti-dsDNA Abs, severe splenomegaly, and early mortality due to immune complex-mediated glomerulonephritis. One possible explanation for this difference may relate to the widespread genetic polymorphism between the 129Sv/J and C57BL/6 mouse strains. There are no detailed studies describing the phenotype due to the lpr mutation on 129Sv/J or (129Sv/J x C57BL/6)F1 mice. Nevertheless, previous studies have shown that the (129Sv/J x C57BL/6) background has an autoimmune phenotype, indicating that genetic factors derived from this hybrid strain combination modify disease manifestation as compared with the same autoimmune-predisposing mutation in a pure background (25, 36). These observations complicate the analysis of the autoimmune disease due to a combined Cr2 and lpr mutation using a (129Sv/J x C57BL/6) hybrid mouse strain. It is difficult to determine which disease phenotypes are directly related to the Cr2 mutation and which disease phenotypes are secondary to other genetic factors that affect how the autoimmune disease, induced by the combined Cr2 and lpr mutations, is manifested.
C57BL/6.lpr Cr2-/- female mice have increased ANA and anti-dsDNA Ab titers as compared with males. In contrast, the levels of anti-dsDNA Abs between C57BL/6.lpr males and females are comparable. We do not have a clear explanation for this observation, although it may relate to a sex-related epistatic effect that other genes may have in autoantibody production, and not a direct result of the Cr2 mutation. In comparison, there is also an effect of gender on the incidence and prevalence rate of human SLE (37). The disease incidence is higher in women.
The reason for the increase in IgG titers and autoantibody production related to the combined CR and Fas deficiency is unclear. One possible explanation relates to the role of CR1 and CR2 in B cell activation. It is known that these receptors form part of a multimolecular protein complex on the surface of B cells that includes CD19 and CD86 (9, 10). Engagement of these receptors by C3-containing Ag or C3-containing immune complexes provides costimulatory signals that facilitate B cell receptor-mediated B cell activation (11). It is also known that signals involved in clonal deletion and clonal anergy of autoreactive B cells involved interaction of the B cell receptor with Ag (38). It is possible that optimal B cell receptor-mediated signals for the development of these tolerogenic events are also dependent on the costimulatory effects of cell surface CR2/CD19/CD86. In fact, using a transgenic mouse model of B cell tolerance, Prodeus et al. (22) have described that autoreactive Cr2-/- B cells are not adequately anergized by interacting with soluble self-Ag. The contribution of the lpr mutation on the increased autoantibody production observed in the C57BL/6.lpr Cr2-/- mice may relate to the survival of autoreactive T cells that facilitates the full development of the autoreactive Cr2-/- B cells described above. It may also abolish Fas-mediated apoptotic signals that otherwise control the population of these autoreactive Cr2-/- B cells.
It is interesting that the autoimmune process becomes evident at
18–24 wk of age. If the mechanism of autoimmunity is solely related
to the development of central anergy by self-reactive B cells, we
should expect an early onset of autoantibody production. The fact that
we do not see an early autoimmune process underscores the epistatic
effects of protective genes in the induction of autoimmunity. Genetic
influences are already protecting the C57BL/6.lpr mice from
the more severe disease found in the MRL/lpr mice (26, 28). The specific genes involved in this protective effect are
still largely unknown, but they may be also affecting the autoimmune
manifestations in the C57BL/6.lpr Cr2-/-
mice. The role of Cr2 in peripheral tolerance induction
cannot be excluded. Although speculative, it is intriguing to consider
that optimal peripheral tolerance acquisition may also be dependent on
the expression of CR1 and/or CR2. More work needs to be done to
specifically define the role of these CRs in the development of
autoimmune disease.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Hector D. Molina, Division of Rheumatology, Department of Medicine, Box 8045, Washington University School of Medicine, 4940 Parkview Place, St. Louis, MO 63110. E-mail address: hmolina{at}imgate.wustl.edu
3 Abbreviations used in this paper: CR, complement receptor; ANA, antinuclear Ab; RU, relative unit; SLE, systemic lupus erythematosus.
Received for publication February 4, 2002. Accepted for publication May 24, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2-microglobulin dependence of the lupus-like autoimmune syndrome of MRL-lpr mice. J. Immunol. 156:4932.[Abstract]
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) and C57BL/6.lpr
Cr2-/- (
) mice at 18, 24, 30, and 36 wk of
age. 
, The average anti-dsDNA IgG titer in
C57BL/6.lpr; •, the average anti-DNA IgG titer in
C57BL/6.lpr Cr2-/-. Left
panel, Female population. Middle panel, Male
population. Right panel, Total population of males and
females together. At 36 wk of age, C57BL/6.lpr
Cr2-/- mice had 