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,
Departments of
*
Medicine and
Immunology, University of Colorado Health Sciences Center, Denver, CO 80262;
Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206; and
§
Department of Pathology, Centre Medical Universitaire, Geneva, Switzerland
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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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Although only lupus-prone strains produce autoantibodies to gp70, all murine strains tested have measurable levels of virus-free serum gp70 Ag (19, 20). Studies indicate that serum gp70 levels are genetically determined and vary among different inbred strains. Strains with low levels (<5 µg/ml) include C57BL/6 (B6) and BALB/c, whereas strains with high levels (>20 µg/ml) include DBA/2 and the lupus-prone strains NZB, NZW, MRL, and BXSB (20). The genes responsible for production of serum gp70 most likely represent past integrations of murine leukemia viruses, which have yielded nonfunctional (i.e., virus-free) sites of envelope expression. Studies suggest that most of the serum gp70 is produced by hepatic cells and levels can further increase as an acute phase reactant more than 10-fold in high-producing strains (20, 21). It seems likely that higher circulating gp70 levels in the lupus-prone strains may affect the quantity and size of gp70 IC and the development of nephritis. Genetic loci linked to higher gp70 levels therefore may be a subset of lupus-susceptibility loci in NZB or NZW mice.
In the present study, we utilized genetic crosses of NZB (high gp70 levels) and B6 (low gp70 levels) to analyze the effect of serum gp70 levels on the quantity of gp70 IC and the development of lupus nephritis. In both a backcross and intercross analysis, we noted a much stronger association of nephritis with gp70 IC compared with anti-chromatin Abs. Elevated serum gp70 levels were correlated with higher levels of gp70 IC, although the effect on disease appeared to be small. We also mapped three NZB loci strongly linked with elevated levels of gp70 and analyzed their contributions to nephritogenic immune complex formation. The results characterize a set of potential susceptibility loci separate from those involved in autoantibody production.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Parental NZB/BINJ (designated NZB) and C57BL/6J (designated B6) were obtained from The Jackson Laboratory (Bar Harbor, ME) and were maintained in the animal care facilities at the National Jewish Medical and Research Center and/or the University of Colorado Health Sciences Center (Denver, CO). All mice were bred and maintained in these facilities. B6 mice were made congenic for H2z (B6.H2z), as previously described (22, 23). For the present study, 152 female (B6.H2z x NZB)F1 x NZB backcross mice and 163 female (NZB x B6)F2 were analyzed for serum gp70 Ag levels and followed for expression of disease.
Collection of sera and evaluation of renal disease
Study mice were bled at monthly intervals beginning at 2 mo for
the F2 mice and 5 mo for the backcross mice until
12 mo of age or death of the animal. The blood was allowed to clot at
room temperature, and the serum was stored at -20° until analyzed
for serum gp70 and autoantibody levels. Mice were also evaluated for
proteinuria at monthly intervals using Chemstrip (Boehringer Mannheim,
Indianapolis, IN), as described (9, 10, 16). Urine samples
were graded 0 to 3+, corresponding to approximate
protein concentrations as follows: 0/trace, <0.3 g/L;
1+, 
0.3 g/L; 2+, 1
g/L; 3+, >3 g/L. Mice with
2+ or greater proteinuria, on at least two
consecutive occasions before 12 mo of age, were designated as positive
for high-grade proteinuria and severe renal disease. Mice with negative
or trace determinations for the entire 12-mo period were designated as
negative for renal disease. The validity of using proteinuria to
document severe renal disease in New Zealand hybrid mice has been
studied previously (9, 10, 16, 22, 24). As in previous
studies, the majority of mice with proteinuria died before the end of
the study period. All remaining animals were sacrificed at 1 yr of
age.
Serological assays
Serum levels of IgG anti-chromatin Abs were measured as previously described (10, 23). Briefly, wells of Immulon II microtiter plates (Dynatech Laboratories, Chantilly, VA) were coated with calf thymus chromatin at 2.5 µg/ml and postcoated with 1 mg/ml gelatin. Serum samples were tested at a dilution of 1/300, and after washing, bound Ab was detected with a peroxidase-conjugated goat anti-mouse IgG reagent (Kirkegaard & Perry Laboratories, Gaithersburg, MD). After incubation with substrate, OD (405) was determined with an automated spectrophotometer (Dynatech). Assays were performed in duplicate, and OD values were converted to a unit scale by comparison with a standard curve.
Serum levels of gp70 and autoantibodies to gp70 were quantitated as previously described (25). Since the excess of gp70 in serum makes free anti-gp70 Abs difficult to detect, these autoantibodies are measured as gp70-anti-gp70 IC. Complexes were measured by ELISA after precipitation of the serum with polyethylene glycol (average m.w. 6000), which precipitates only the Ab-bound gp70. Results are expressed as µg/ml of gp70 complexed with anti-gp70 Abs by referring to a standard curve using a serum with known amounts of gp70. The concentration of total serum gp70 (free and complexed forms) in serum samples was determined by the same ELISA.
Genetic mapping using simple sequence length polymorphisms
Oligonucleotides flanking simple sequence repeats were either purchased (Research Genetics, Huntsville, AL) or synthesized at the National Jewish Molecular Resource Center using an Applied Biosystems (Foster City, CA) model 392 DNA synthesizer. The sequences of the primers used can be found at the internet address: http://www.genome.wi.mit.edu/. Amplification of the simple sequence repeats was achieved by the PCR in a PTC-100 thermal cycler (MJ Research, Watertown, MA). PCRs (20 µl) generally utilized 35 cycles of: 30 s at 94°C, 1 min at 55°C, 30 s at 72°C. After amplification, 10–15 µl of product was loaded onto a 15% polyacrylamide gel (Bio-Rad MiniProtean II, Richmond, CA) and electrophoresed at 12 V/cm for 2–4 h. The PCR products were visualized by ethidium bromide staining and UV transillumination (254 nm). The animals were then scored as either NN (NZB homozygous), BB (B6 homozygous), or NB (heterozygous) for each marker. The positions of the simple sequence length polymorphism markers (and genetic loci) with respect to the centromere are given in accordance with the Mouse Chromosome Committee Reports (obtained at http://www.informatics.jax.org/).
A genome-wide search for loci linked with serum gp70 levels was performed with 90 markers in (B6.H2z x NZB)F1 x NZB backcross mice. Loci showing at least trends for linkage (Lod > 1.4; p < 0.01) with elevated gp70 or autoantibody levels or nephritis in this backcross were also tested in the (NZB x B6)F2 cross for linkage with the same traits. In addition, all loci previously suggested to be lupus-susceptibility loci in New Zealand mice (reviewed in Refs. 26 and 27) were also tested in the (NZB x B6)F2 cross.
Statistical analysis
The association of a specific serological trait with renal
disease (positive or negative) was quantified by the Mann-Whitney test
without any prior grouping of mice based on serological results. In
addition, associations were determined by 
2
analysis, using a standard (3 x 2) contingency matrix
(28) after mice were divided into three groups of equal
number based on the serum levels of autoantibodies or gp70. Mice were
grouped without knowledge of the distribution of renal disease. The
association of serum gp70 levels with autoantibody levels was also
analyzed by two methods. First, mice were grouped into discrete sets
(designated low, medium, or high) on the basis of serum gp70 levels and
an ANOVA was performed. In addition, serum gp70 and gp70 IC levels were
correlated on linear scales and r2
values were obtained using Cricket Graph (Computer Associates
International, Islandia, NY).
Linkage of particular genetic loci with serological traits was also calculated using the linkage program MAPMAKER/QTL (29). This program was used to determine quantitative trait loci (QTL) in linkage with serum gp70, gp70 IC, and anti-chromatin levels. These levels were log10 transformed before analysis because this tended to normalize their frequency distribution, which improves the accuracy of MAPMAKER/QTL.
Because of the multiple hypothesis testing that is inherent in a
genome-wide search, a threshold for suggestive linkage was set at
Lod > 1.9, (2 > 8.6, p
< 0.0034), based on the recommendation of Lander and Kruglyak
(30). The threshold for linkage was Lod > 3.3,
(2 > 15.1, p < 0.0001). Loci
were also considered to be linked to a trait if a locus previously
mapped at p < 0.01 was confirmed in a separate data
set at the same statistical cutoff (30).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A previous analysis of the (B6.H2z x
NZB)F1 x NZB backcross showed that the
development of nephritis was linked with inheritance of
H2z and a NZB locus on distal chromosome 1
(named Nba2 for NZB autoimmunity 2) (22, 23).
Overall, 20% of the backcross mice (n = 152) developed
severe nephritis by 12 mo of age. Peak autoantibody production occurred
at about 7–9 mo of age. We compared the levels of gp70 IC and
anti-chromatin autoantibodies in backcross mice with and
without nephritis (Table I
). In
addition to comparing 7-mo values using a nonparametric t
test (Mann-Whitney U test), backcross mice were divided into
three equal size groups on the basis of levels of gp70 IC or
anti-chromatin autoantibodies, and the distribution of nephritis
within each group was compared. Using either type of analysis, a much
stronger association of nephritis with gp70 IC compared with
anti-chromatin Abs was apparent. For this backcross, serum levels
of gp70 were quantitated at 5 mo of age, the earliest available blood
samples, to minimize the influence of anti-gp70 autoantibodies on
free Ag levels. In contrast to gp70 IC, there was no association of
serum gp70 levels with nephritis in the backcross mice and mean levels
were similar (Table I).
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).
Again, we found a remarkable association of nephritis with gp70 IC
compared with anti-chromatin autoantibodies. For this cross, serum
gp70 levels were measured at 2 mo of age, which is after levels reach
maximal concentrations (14) and well before there is any
evidence of autoantibody production or autoimmune disease. Therefore,
the genetically determined variation in gp70 levels in
F2 mice was determined in the absence of
potential effects of anti-gp70 autoantibodies and/or inflammation.
A weak but significant association of serum gp70 concentration with
nephritis was observed in the F2 mice when
comparing mice without prior grouping (p =
0.02) or after grouping mice based on gp70 levels
(p = 0.05) (Table II). The latter association
appeared to be related to a lower frequency of disease in mice with the
lowest levels of gp70.
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To examine the influence of serum gp70 levels on autoantibody
production, animals were initially placed into three groups based on
serum gp70 level, as described above. Mean (±SE) levels of gp70 IC and
anti-chromatin Abs for each group are shown in Fig. 1. An association of serum gp70 with gp70
IC levels was observed in both crosses (backcross mice,
p = 0.05; F2 mice,
p = 0.002). In contrast, no association was apparent
for anti-chromatin levels (Fig. 1). To further analyze the
relationship between serum gp70 and gp70 IC, serological values for
each mouse were plotted on linear scales and
r2 and p values were
calculated (Fig. 2). When all mice were
considered, correlations were either not present or barely detectable.
However, this appeared to be influenced by mice with undetectable
levels of serum gp70 IC, perhaps reflecting an inability to generate
autoantibodies. When the subset of mice with above background levels of
gp70 IC (>0.6 µg/ml) was considered separately, weak but
statistically significant correlations between serum gp70 and gp70 IC
levels were apparent (backcross mice, r2 =
0.23, p = 7.1 x
10-5;
F2 mice, r2 =
0.17, p = 0.006).
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A genome-wide scan was performed in (B6.H2z
x NZB)F1 x NZB backcross mice for QTL linked
with higher serum levels of gp70. Ninety markers were tested, covering
over 90% of the genome with minimal gaps. Two relatively broad regions
on chromosomes 4 and 13 with strong linkage were noted (Table III and Fig. 3). Another region on chromosome 6 showed
a trend for linkage in the backcross.
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Each of the three gp70-linked loci showed a gene-dosage effect on serum
gp70 levels in (NZB x B6)F2 mice (Fig. 4). Thus, mice with two NZB alleles and
two B6 alleles showed the highest and lowest levels, respectively, and
intermediate levels were observed in mice heterozygous for one NZB
allele. Mice homozygous for NZB alleles at both chromosome 4 and 13
loci (n = 9) had strikingly elevated gp70 levels
compared with mice homozygous for B6 alleles at these loci
(n = 10) (mean ± SE, 38.2 ± 6.35 vs
5.7 ± 0.7, respectively; p = 2.4 x
10-5). We also analyzed
these three loci for evidence of interaction (epistasis) using the
MAPMAKER/QTL (29). However, for all possible combinations,
the sum of Lod scores was less than the Lod score for simultaneous
contribution, suggesting independent (i.e., additive) contributions
from each locus.
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and Fig. 3
). In addition,
the contribution of this locus to levels of gp70 IC was supported by
association studies. Consistent with the effect on free gp70 levels, we
observed a significant gene-dosage effect on gp70 IC levels; mean
(±SE) gp70 IC levels for mice with NZB/NZB, NZB/B6, and B6/B6
genotypes were 4.5 ± 0.87, 2.6 ± 0.52, and 1.4 ± 0.47
µg/ml, respectively; p = 0.004. The effect of the
chromosome 13 locus on gp70 IC levels was selective in that there was
no influence on levels of anti-chromatin Ab levels by linkage
(Table IV) or association analyses (data not shown). Despite the effect
on gp70 IC levels, no linkage of chromosome 13 markers with nephritis
was apparent (Table V). The gp70-linked
locus on chromosome 2 showed no effect on gp70 IC in the
F2 mice (Table IV). However, suggestive linkage
with gp70 IC was noted in the backcross mice. Interestingly, chromosome
4 markers did not show even a trend for linkage with gp70 IC in either
cross (Table IV), and no association of gp70 IC levels with chromosome
4 genotypes was discernible (data not shown; p = 0.6).
Suggestive linkage with anti-chromatin Abs (Table IV) and a
possible trend for linkage with nephritis (Table V) in
F2 mice may reflect separate NZB susceptibility
loci previously mapped to this chromosome (31, 32, 33, 34, 35).
Finally, we examined whether combinations of gp70-linked loci
strengthened their linkage or association with gp70 IC or nephritis.
However, no combination of NZB alleles at these loci increased the
linkage or association of chromosome 13 loci with gp70 IC or chromosome
4 loci with nephritis.
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). In the F2
mice, however, Nba2 showed no detectable influence on any of
the traits measured. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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For the current studies, backcross and intercross progeny of NZB and B6 parental mice were utilized to examine the effect of serum gp70 levels on gp70 IC formation and nephritis. In both crosses, we observed a much stronger association of nephritis with gp70 IC compared with anti-chromatin autoantibodies. Similar results were found in previous analyses of (NZB x NZW)F2 (6), (NZB x NZW)F1 x NZW backcross (10), (B10 x NZB)F1 x NZB backcross (16), and B6 x (NZW x B6.Yaa)F1 backcross mice (14), in which levels of gp70 IC were compared with anti-DNA Abs. In both crosses analyzed in the current study, we also noted a significant association of serum gp70 levels with gp70 IC. However, overall correlations between these two serologic traits were weak. Importantly, an association of gp70 levels with nephritis was observed in the F2 analysis, although the strength of this association was much less than that with gp70 IC.
NZB, NZW, and (NZB x NZW)F1 mice all make high levels of serum gp70, whereas only F1 mice generate high levels of autoantibodies and develop severe nephritis (4, 5, 6, 8). Our data suggest that the production level of autoantibodies rather than the relative level of autoantigen is the determining feature in immune complex formation and pathogenicity in these genetic crosses. This hypothesis is also supported by the genetic mapping data reported herein. NZB loci on chromosomes 4 and 13, which were strongly linked to serum gp70 levels, showed little to no linkage with gp70 IC levels. In contrast, loci that contributed to disease on the basis of IgG autoantibody production, such as H2 and Nba2 on distal chromosome 1, had a much greater impact on gp70 IC levels and disease. A number of genetic crosses involving only NZB and NZW mice have demonstrated that the risk of disease is greater in mice that are heterozygous for the H2d/z haplotype compared with H2z/z or H2d/d mice (8, 9, 10, 34, 42, 43, 44 ; reviewed in Ref. 26). Separate studies (14, 16, 24, 33) have shown that inheritance of H2b, in the context of either H2d or H2z, also enhances IgG autoantibody production and nephritis. The association of H2b with disease is further demonstrated in the current F2 study with mice homozygous for H2b/b having the highest incidence of disease. A second gene, Nba2, on distal chromosome 1, has been implicated in both the production of autoantibodies and nephritis in previous backcross analyses (22, 23, 32). To our surprise, we did not observe any detectable linkage of Nba2 with either autoantibodies or nephritis in the (NZB x B6)F2 animals. Although we do not have a straightforward explanation for these results at present, it should be stressed that B6 mice congenic for a 10 cM region encompassing Nba2 demonstrate markedly elevated levels of IgG anti-chromatin Abs (S. J. Rozzo, T. J. Vyse, E. Roper, S. Izui, and B. L. Kotzin, unpublished observations).
The impact of serum gp70 Ag on disease could have been underestimated in the current study for several reasons. First, the serum levels of gp70 in B6 mice, although lower than NZB levels, may still be high enough for adequate formation of complexes and hence, development of lupus nephritis. If so, a stronger correlation of Ag levels with disease might have been observed if production was more completely reduced or eliminated by genetic breeding, knockout, or other gene suppression technologies. It is also possible that with the onset of disease and the corresponding systemic inflammation, genetically low levels of gp70 are subsequently boosted to levels that are adequate for optimal immune complex formation, since gp70 acts as an acute phase reactant (20, 21, 45, 46). One may also have to consider the possible heterogeneity of serum gp70 proteins, most of which are closely related to gp70 on xenotropic virus isolated from NZB mice (5, 7). Differences in immunogenicity or antigenicity among gp70 proteins could affect the formation of gp70 IC and their pathogenicity (5, 7, 9, 47). Finally, our inability to observe a larger role for serum gp70 levels may relate to the complexities of immune complex formation and the possibility that above a certain level, higher Ag levels may lead to smaller and less pathogenic complexes (37).
The results of our genetic mapping studies revealed that the level of serum gp70 among different inbred strains is a complex genetic trait. At least three NZB loci on chromosomes 2, 4, and 13 were found to be linked with elevated gp70 levels. Multiple linked markers over broad regions on chromosomes 4 and 13 were noted in both backcross and intercross mice, and it is possible that these chromosomes carry more than one locus each. In a recent genetic analysis of B6 x (NZW x B6.Yaa)F1 backcross mice, an NZW locus in a nearly identical position on chromosome 13 was also found to be linked with elevated serum gp70 levels (14), and the underlying allele at this position may therefore be shared between NZB and NZW. Similar to our results, linkage of that NZW locus with gp70 was out of proportion to linkage with gp70 IC, and no influence on the development of lupus nephritis was detected. The chromosome 13 NZB (and NZW) locus maps close to Gv1, a locus that coordinately regulates the expression of multiple murine retroviral sequences (48). B6 mice are known to have a Gv1 allele that results in low expression. The NZB loci mapped in the current analysis are distinct from other previously mapped loci that affect retroviral expression such as Gv2 and Sgp2 located on the telomeric end of chromosome 7 and Sgp1 linked to the H2 locus on chromosome 17 (49, 50). It seems likely that many of the genetic contributions to gp70 levels reflect old insertions of murine leukemia viruses into the mouse genome and that mutation has allowed the expression of the envelope gene without other viral genes (51). Although NZB and NZW strains have not been studied, other strains have been found to carry many insertion sites scattered over the genome. At this time, it is unknown whether the different genetic contributions may also have different gp70 sequences with perhaps different antigenic properties.
The present study confirms the strong association of anti-gp70 autoimmunity with nephritis in murine lupus. While autoantibodies to human retroviral envelope proteins have yet to be described in SLE patients, a comprehensive study of such individuals has not been done. Several studies in human SLE patients have suggested that retroviral proteins may play a role in the production of autoantibodies (52, 53, 54 ; reviewed in Ref. 55).
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Footnotes |
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2 R.M.T. and T.J.V. contributed equally to this paper.
3 Current address: Imperial College School of Medicine, Hammersmith Campus, London, W12 ONN, U K.
4 Address correspondence and reprint requests to Dr. Brian L. Kotzin, Division of Clinical Immunology (B-164), University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262.
5 Abbreviations used in this paper: NZB, New Zealand Black; gp, glycoprotein; gp70 IC, gp70-anti-gp70 immune complex; Lod, log likelihood of the odds; NZW, New Zealand White; QTL, quantitative trait loci; SLE, systemic lupus erythematosus.
Received for publication February 9, 2000. Accepted for publication May 17, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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