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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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In this study, we provide evidence for B10 lupus-susceptibility loci, especially one chromosome 13 locus that is strongly linked with nephritogenic anti-gp70 autoantibodies and involved in the development of lupus nephritis. Although microsatellite mapping revealed only one marker polymorphic between B6 and B10 in the linked chromosome 13 interval, this region in B6 mice was devoid of any contribution to disease.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Parental NZB/BINJ, NZW/LacJ mice, C57BL/6J (B6), and C57BL/10J (B10) were obtained from The Jackson Laboratory (Bar Harbor, ME) and were bred and maintained in the animal care facility at the National Jewish Medical and Research Center or University of Colorado Health Sciences Center (Denver, CO). Two different lines of B6 mice transgenic for Ez genes (13), two different lines of B10 mice transgenic for Az genes (14), and one line of B6 mice congenic for H2z (15, 16) have been previously described. B6 transgenic mice were generated by direct injection into B6 eggs and then continued breeding with B6 mice. The B10.Azlo and B10.Azhi transgenic lines were initially generated by injection into (SWR x B10.M)F2 or (CBA/J x B10.M)F2 eggs, respectively, and then repeated backcrossing with B10 mice for at least seven generations. These transgenic lines are maintained by continued backcrossing to B10 mice.
In the current work, (B6.Ez x NZB)F1 x NZB and (B10.Az x NZB)F1 x NZB backcross mice are designated B6.Ez and B10.Az backcross mice, respectively. These backcrosses were bred in the Denver animal facilities, and all groups of mice used in these studies were housed in the same room and fed an identical diet. Only female backcross mice were studied. The generation of (B10.Azlo x NZB)F1 x NZB and (B10.Az x NZB)F1 x NZB backcross mice utilized 13 different transgenic breeders. In genetic mapping studies of these backcross progeny, including analysis of four informative markers in the linked chromosome 13 interval, no alleles of CBA/J or SWR origin have been identified.
Mice were evaluated for proteinuria at monthly intervals using
tetrachlorophenol-tetrabromosulfophthalein paper (Chemstrip; Boehringer
Mannheim, Indianapolis, IN), as previously described (17).
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. A negative
nephritis phenotype was ascribed to mice that did not exhibit
proteinuria during the 12 mo of follow-up, and these mice appeared
healthy at the time of sacrifice. Previous studies have documented a
strong correlation between high grade proteinuria, histologic severity
of glomerulonephritis, and death from renal failure before 1 year of
age in New Zealand hybrid mice (11, 13, 14, 17) (T.
J. Vyse and B. L. Kotzin, unpublished observations). In the
B10.Az backcross, 206 mice were initially
followed, of which 145 demonstrated a clear positive or negative
phenotype for renal disease. The other mice showed lower and
intermittent levels of proteinuria and were excluded from the present
analysis for linkage with nephritis. The development of severe
proteinuria also predicted early mortality in the current study. For
example, 36 (85%) of 43 mice with high grade proteinuria before 9 mo
of age died by 12 mo of age. In contrast, during the entire study, only
5 (8%) of 65 mice with no proteinuria died, and all but one of these
mice showed obvious evidence for a cause of death unrelated to
nephritis.
Study mice were also bled from the tail at monthly intervals from the age of 5 mo. The blood was allowed to clot at room temperature, and the serum was stored at -20°C degrees until assayed for autoantibody levels. In the current study, 160 B6.Ez backcross mice were followed for the development of nephritis and serial autoantibody levels. In the B10.Az backcross, serial autoantibody levels were determined for 175 of the 206 total mice, including all 145 with a definite positive or negative nephritis phenotype.
Genetic mapping using microsatellite polymorphisms
A genome-wide scan for loci linked with disease traits was conducted using microsatellite markers polymorphic between NZB and B10 (or B6) and techniques previously described (11, 15, 18). The animals were then scored as either heterozygous for NZB and B10 (or B6) alleles or homozygous for NZB alleles for each marker. In separate studies, microsatellite markers on chromosome 13 available from Research Genetics (Huntsville, AL) were compared for polymorphisms between B10 and B6 genomes. The positions of all microsatellite markers (and other genetic loci) with respect to the centromere are given in accordance with the Mouse Chromosome Committee Reports, obtainable from the Mouse Genome Database (MGD) at http://www.informatics.jax.org.
Serological assays
Serum levels of autoantibodies to calf thymus chromatin, prepared as described (19), were determined by ELISA, as previously reported (11, 16). All assays were performed in duplicate and were quantified against a standard curve obtained with mAbs or sera. Values for the different anti-nuclear Abs are reported as U/ml. The production of autoantibodies to gp70 was quantitated as serum levels of gp70-anti-gp70 immune complexes (gp70 IC), because the relative excess of gp70 in sera makes free anti-gp70 Abs difficult to detect (7, 8, 9, 20). These complexes were measured by ELISA after precipitation of the serum with polyethylene glycol (average m.w. 6000), as described (20). The results are expressed as µg/ml of gp70 complexed with anti-gp70 Abs. The cutoffs used to segregate mice with negative/low vs high/positive levels in the current study are the same as previously defined in studies of (NZB x NZW)F1 x NZW backcross mice and other backcrosses (11, 13, 14, 16). Cutoffs were <1 U/ml and >4.6 U/ml for IgG anti-chromatin Abs, and <0.5 and >3.5 µg/ml for gp70 IC.
Statistical analyses
The linkage of a particular locus with nephritis (categorized as
positive or negative) was quantified by 
2
analysis, using a standard (2 x 2) contingency matrix
(21). Quantitative trait loci (QTL) in linkage with
autoantibody levels were determined by using the linkage program,
MAPMAKER/QTL (22, 23, 24), and the data are presented as log
likelihood of the odds (lod) scores. The autoantibody levels were
log10 transformed before analysis with
MAPMAKER/QTL, because this tended to normalize their frequency
distribution (11, 14, 16), 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
and linkage was set at lod > 1.9 (2 >
8.6, p < 0.0034) and at lod > 3.3
(2 > 15.1, p < 1 x
10-4), respectively (25). Loci were
considered to be confirmed if a locus, previously shown to be linked
with a disease trait at lod > 1.5 (2 >
6.6, p < 0.01), was linked in the present study at the
same statistical level. Odds ratios were calculated as: [(number of
diseased mice with gene) x (number of healthy mice without
gene)]/[(number of diseased mice without gene) x (number of
healthy mice with gene)].
Comparisons of the frequency of nephritis or frequency of elevated
autoantibody levels between groups of mice were determined using
2 analysis. Comparisons of autoantibody levels
between groups of mice were determined by the Wilcoxon rank-sum test,
unless as indicated.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Based on the above comparison, we set out to map a B10 effect on disease expression that was not evident in B6 backcross mice. Whole genome scans using microsatellite markers have shown greater than 98% genetic identity between B6 and B10 mice, which have been bred separately at The Jackson Laboratory since approximately 1937 (26). Six genomic regions on chromosomes 2, 4, 11, 12, proximal 13, and 16 have been mapped as different in these two strains (27, 28). An unmapped minor histocompatibility locus, termed H9, has also been shown to be different in these strains (26). Based on this knowledge, we first mapped these known polymorphic chromosomal regions in the B10.Az backcrosses for disease-susceptibility loci. However, not one B10 marker tested in these intervals showed a trend (at p < 0.01) for linkage with nephritis or IgG autoantibody production.
The above results suggested that the B10 nephritis-susceptibility loci
were possibly located in regions not previously known to be polymorphic
between B10 and B6. We therefore completed a genome scan of the
B10.Az backcross mice for loci linked with
nephritis (Table I
). We used 83 markers
that covered over 90% of the genome without major gaps. This linkage
analysis completely covered chromosomal regions corresponding to
previously implicated lupus-susceptibility loci in NZB and/or NZW mice
on chromosomes 1, 3, 4, 5, 6, 7, 9, 11, 13, 14, 18, 19, and at the MHC
on chromosome 17 (reviewed in Refs. 12 and
29). The B10 MHC (H2b) was
strongly linked with nephritis (Table I and Ref. 14) in
the B10.Az backcross mice. However, MHC could not
solely explain the increased frequency of disease in B10 vs B6
backcrosses because it is identical in B10 and B6. Also shown in Table I, loci on distal chromosome 1 at Crp (previously named
Nba2 for New Zealand black autoimmunity 2),
chromosome 4, and chromosome 7 showed trends (p
< 0.05) for linkage with nephritis. At these positions, however, NZB
homozygosity was associated with greater disease risk. Therefore, these
loci did not appear to explain the much greater frequency of nephritis
in the B10 vs B6 crosses. In contrast, suggestive linkage (Table I) and
association (Fig. 1) of a mid-chromosome
13 locus with nephritis were related to inheritance of B10 allelic
markers. Inheritance of the B10 allele at D13Mit226 resulted
in a 3.1-fold increased risk of nephritis. In the B10 backcrosses, 72%
of the mice inheriting this B10 chromosome 13 interval developed severe
nephritis compared with 48% of the NZB homozygous mice
(p < 0.01; Fig. 1). In the B6 backcross mice,
nephritis did not occur at a sufficient frequency to allow mapping for
linked loci.
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shows that the B10 backcross mice
also demonstrated higher levels of IgG autoantibodies to chromatin and
to gp70 compared with B6 backcross mice. This appeared to correlate
with the increased percentage of B10 backcross mice developing
nephritis. Levels of both autoantibodies were significantly higher in
nephritic B10 backcross mice compared with B6 backcross mice
(p = 3 x 10-7 for
anti-chromatin and 6.6 x 10-4 for gp70
IC, as determined by Dunn’s nonparametric procedure of the
Kruskal-Wallis test; two tailed). A genome scan revealed several QTL
linked with production of these autoantibodies (Table II). However, inheritance of the B10
allele was linked with increased autoantibody production at only three
loci: MHC (H2b), a locus on chromosome 10,
and the mid-chromosome 13 locus that showed suggestive linkage with
nephritis, as described above. H2b was
linked with serum levels of anti-chromatin and anti-gp70
autoantibodies, and it is apparent that the effect of MHC on nephritis
in these backcrosses, as in previous studies of New Zealand hybrid mice
(11, 12, 13, 14, 16, 17, 30), is at the level of IgG autoantibody
production. The chromosome 10 locus was suggestively linked with
anti-chromatin Abs, but showed no linkage with gp70 IC. As shown in
Table I
, this locus did not have a measurable effect on nephritis.
Similar to MHC, the chromosome 13 locus also showed striking linkage
with gp70 IC (Table II). Separate analyses of the two different
B10.Az backcrosses (i.e.,
B10.Az and B10.Azlo) for
linkage of D13Mit226 with gp70 IC showed lod scores of 2.4
(p = 1 x 10-3) and
3.3 (p = 1 x
10-4), respectively. As shown in Fig. 2B, heterozygosity for the B10 chromosome 13 locus was
associated with higher mean levels of gp70 IC compared with mice
homozygous for NZB alleles at this position (p
= 6.8 x 10-7). Surprisingly, the
chromosome 13 locus did not show even a trend for linkage with
anti-chromatin autoantibodies (Table II). Mean levels of
anti-chromatin Abs were also not statistically different
(p > 0.1) in mice with or without a B10 allele
at the chromosome 13 locus (Fig. 2A).
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A). In the B6
backcross, homozygosity for NZB alleles on proximal chromosome 13
showed a trend for linkage with anti-chromatin Abs and gp70 IC
(Fig. 3B). As predicted by the genome scan data, we noted
strong linkage of several mid-chromosome 13 markers with gp70 IC levels
in the B10 backcross mice (Fig. 3B). Maximal linkage was
predicted to be closest to D13Mit226 (13, 59) with a maximum
lod score of 5.5 (p = 4.8 x
10-7). Markers covering the same region in
B6.Ez backcross mice did not show even a trend
for linkage with gp70 IC (Fig. 3B). In addition, using
previously defined cutoffs to categorize mice with negative/low vs high
levels of gp70 IC, we found that 30% of B10 heterozygous group vs
5.6% of the NZB homozygous group had elevated gp70 IC levels
(p =4.7 x 10-7),
but no comparisons showed any effect of this chromosomal region from
the B6 strain in the B6.Ez backcross. It is
emphasized that although expression of gp70 IC and
anti-chromatin Abs was lower in the B6 compared with B10
backcrosses, autoantibody levels were adequate in both sets of crosses
to identify QTL. Thus, in our previous work, we were able to show
the effects of Nba2 and H2 on gp70 IC and on
anti-chromatin Abs in B6.Ez backcross mice
(13).
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If B10/NZB heterozygosity at a non-MHC locus (or loci) and the MHC (H2b/d) together provide significant risk for disease, it is possible that a subset of (B10 x NZB)F1 mice would develop disease. This possibility depends on the importance of contributions from recessive NZB loci (e.g., Nba2) for which NZB homozygosity has been linked with increased disease susceptibility and which would be absent in the F1 mice (15, 16). In a preliminary analysis, 4 of 11 female (B10.Az x NZB)F1 mice developed severe nephritis within the first 12 mo of life. These preliminary studies did not include control (B6 x NZB)F1 mice.
Because this genetic region does not harbor genes known to be involved
in specific immune recognition (Fig. 4),
we wondered whether a gene that affected gp70 Ag levels might be
involved. Serum gp70 glycoprotein levels were analyzed as described
(31), but no chromosome 13 markers linked with levels of
free Ag were identified in a QTL analysis (maximal lod = 0.06;
p = 0.61).
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). Only
one polymorphic marker (D13Mit290; 59 cM) was found.
Nucleotide sequence analysis of the PCR products showed that the B10
product contained one more TTTC tetranucleotide repeat unit compared
with B6. It is likely that this marker is closely linked with a
lupus-susceptibility locus on chromosome 13. Importantly, the limited
number of polymorphic markers between the two strains predicts a small
chromosomal interval different in B10 vs B6. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The likelihood of B10 susceptibility loci, not present in B6 mice, is also supported by our previous studies of (B6.H2z x NZB)F1 x NZB backcross mice (15, 16). Expression of disease in this backcross was found to be linked with inheritance of H2z. In H2z-negative (B6.H2z x NZB)F1 x NZB backcross mice, there was a low (7.2%) incidence of nephritis, which was significantly different (p < 1 x 10-8) compared with B10.Az backcross mice, and is consistent with the hypothesis that the B6 and B10 genetic backgrounds differ in their effects on disease expression. We also have completed a whole genome scan of the B6.H2z backcross, but found no non-MHC disease-susceptibility loci with strong contributions other than the NZB-derived Nba2 locus on chromosome 1 (T. J. Vyse, S. J. Rozzo, S. Izui, and B. L. Kotzin, unpublished observations). No B6 markers, including those on mid-chromosome 13, were linked to lupus nephritis, autoantibodies to chromatin, or gp70 IC.
Perusal of the genetic maps in the region of the mid-chromosome 13
locus has not disclosed likely candidate(s) for the
disease-susceptibility gene. Several genes involved in signaling as
well as immune responses have been mapped to this region (Fig. 4), but
it is not clear how polymorphism in such genes would lead to a
selective increase in one type of autoantibody response. It is of
interest that the linked phenotype involves increased levels of gp70 IC
and enhanced nephritis, but not increased anti-chromatin Abs.
Increased levels of gp70 Ag could affect anti-gp70 immune responses
and gp70 IC in a selective fashion. However, a QTL analysis disclosed
no B10 chromosome 13 markers linked with levels of free Ag. This lack
of effect on serum gp70 levels distinguishes the current B10 locus from
a NZW-derived locus located slightly more proximal on chromosome 13
described by Santiago et al. (31) and from a slightly
proximal NZB-derived locus (R. M. Tucker, T. J. Vyse, S.
J. Rozzo, S. Izui, and B. L. Kotzin, unpublished observations). In
the latter case, levels of gp70 were associated with inheritance of NZB
alleles in a gene dose-dependent fashion. It is still possible that
this region in B10 vs B6 has a structurally different retroviral
insert. Although Xmv-13 was originally mapped to
mid-chromosome 13 (32), it has been more recently
positioned at 39cM (Mouse Genome Database (MGD) at
http//:www.informatics.jax.org), which is too proximal to be
colocalized with our B10 locus. At this time, we are not aware of any
xenotropic retroviral gene that has been localized to the region of the
B10 locus on chromosome 13.
The genetic contribution identified in these studies is derived from a nonautoimmune strain. In this regard, alleles from strains not themselves displaying a significant autoimmune phenotype have been linked with autoimmune traits and disease in previous analyses of crosses with New Zealand mice. For example, loci from the nonautoimmune SM/J mice were linked with accelerated nephritis and autoantibody production in an analysis of backcross mice and in NZB x SM/J (NXSM) recombinant inbred strains (18). In a separate backcross study of NZW contributions, BALB/c loci on chromosomes 1 and 9 were linked with increased production of IgM anti-nuclear autoantibodies, although BALB/c mice themselves do not demonstrate these autoimmune traits (33). In several previous genetic studies, inheritance of the MHC from the nonautoimmune strain was linked with enhanced autoimmune manifestations (13, 14, 34). Finally, recent studies of NZW genetic contributions to disease showed that inheritance of one B6 allele vs two NZW alleles at certain non-MHC loci was linked with increased IgG autoantibody production and lupus nephritis (34). Such results emphasize that the lupus-prone strains only harbor a subset of disease-susceptibility loci and that nonautoimmune strains may show contributions to disease in backcrosses and intercrosses. It seems likely that a subset of these loci, from both autoimmune and nonautoimmune backgrounds, may turn out to be relevant to human systemic lupus. These contributions to autoimmunity may not be surprising when one considers that multiple loci control related traits in nonautoimmune strains, such as the magnitude of the immune response. For example, loci from the A.SW/snJ strain (in a backcross with SJL/snJ) on chromosomes 1, 5, 7, 13, 16, and 19 were linked with increased IgG Ab production to a test Ag, rhodopsin (35). Interestingly, these QTL appear to colocalize with lupus-susceptibility loci mapped to the corresponding chromosomes (12, 29).
The B10 locus on chromosome 13 is referred to as a disease-susceptibility locus in these studies, and thus is considered to operate in a dominant or codominant fashion. Alternatively, this region on chromosome 13 could be regarded as a NZB disease-suppressor locus (34), because homozygosity for an NZB allele in this region is linked with decreased expression of disease. NZB mice do not demonstrate full expression of the lupus-like disease that is expressed in (NZB x NZW)F1 mice or in a large subset of (B10.Az x NZB)F1 x NZB backcross mice. Renal disease in NZB mice is usually mild and rarely is manifest before 1 year of age. In addition, high levels of autoantibodies to chromatin, dsDNA, and gp70 are unusual. Our results indicate that NZB homozygosity compared with B10/NZB heterozygosity at the chromosome 13 locus and possibly other loci are responsible. Whether a locus is disease susceptibility vs disease suppressor in nature may be mostly a semantic issue. How such a locus is ultimately regarded may depend on identifying the etiologic gene and defining the mechanism.
The current studies are also consistent with a large body of evidence that autoantibodies to gp70 are important in the pathogenesis of nephritis in this murine model (7, 8, 9, 10, 11, 14, 30, 31). In several backcrosses, including the B10 backcross analyzed in this work, levels of gp70 IC were shown to have stronger associations with nephritis compared with anti-nuclear Abs (9, 11, 30, 31). Furthermore, we found that the B10 mid-chromosome 13 locus was linked with gp70 IC, but not with anti-chromatin responses, and yet inheritance of this B10 locus was associated with the development of severe nephritis. Although not measured in the current study, it is unlikely that an effect on anti-dsDNA Abs was missed because the production of anti-chromatin and anti-dsDNA is highly correlated and coordinately regulated (11). These studies, however, do not preclude an important role for anti-dsDNA (and/or anti-chromatin) in the pathogenesis of murine lupus nephritis (12, 30). In the present study, we noted that B10 backcross mice with nephritis had higher levels of anti-chromatin Abs compared with B6 backcross mice, which did not develop nephritis. However, the locus on chromosome 10 was the only B10 locus with a selective effect on anti-chromatin Abs, and it appeared to have only a small effect on nephritis.
The results of our current analysis also suggested that the markedly increased frequency of severe nephritis in B10 vs B6 backcross mice is not explained totally by the added contribution of the B10 chromosome 13 locus in combination with H2b. Analysis of genotypic risk ratios and variance explained by these loci predict that other B10 loci also contribute to enhanced nephritis, possibly through increased autoantibody production. The results of our genome-wide linkage analysis, however, indicate that other individual loci with contributions as strong as the chromosome 13 locus are extremely unlikely. Instead, it appears that the full B10 effect on disease stems from the contribution of H2b, the chromosome 13 locus, and its interaction with H2b, and multiple small contributions from other loci that will be more difficult to map with surety and more difficult to fully characterize.
In summary, we have mapped a locus on chromosome 13 linked with lupus disease traits when contributed by B10, but not B6, mice. This locus is named Nba4 (New Zealand black autoimmunity 4) related to its apparent distinction from other mapped loci in New Zealand mice (12, 29) and because it was mapped in the context of NZB genes. The results also suggest that epistatic interactions occur between Nba4 and the MHC in mice of the H2b/d haplotype. Importantly, the limited number of polymorphic markers between the B10 and B6 strains at this locus predicts a small chromosomal interval different in B10 vs B6, and therefore a unique opportunity to identify the linked disease-susceptibility locus. The extreme genetic similarity and the availability of at least one polymorphic microsatellite marker have essentially created a mouse congenic for the susceptibility locus and may afford a unique opportunity to expedite discovery of the etiologic allele.
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Footnotes |
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2 Current address: Rheumatology Section, Imperial College School of Medicine, Hammersmith Campus, Du Cane Road, London W12 ONN, U.K.
3 Address correspondence and reprint requests to Dr. Brian L. Kotzin, Department of Clinical Immunology (B-164), University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262.
4 Abbreviations used in this paper: NZB, New Zealand Black; gp70 IC, gp70-anti-gp70 immune complexes; lod, log likelihood of the odds; NZW, New Zealand White; QTL, quantitative trait loci; cM, centiMorgan.
Received for publication June 11, 1999. Accepted for publication March 7, 2000.
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) and mice without renal disease (
). The
solid line represents the mean level for all mice in each group. gp70
IC levels were significantly different between B10.Az
backcross mice with the B10 chromosome 13 locus compared with mice
without this locus (p = 6.8 x
10-7).
) backcross mice. Each data point represents the
lod score determined for a different marker along chromosome 13.
Homozygosity for NZB alleles at a marker (D13Mit16) on
proximal chromosome 13 showed a trend for linkage with
anti-chromatin Abs and gp70 IC. In contrast, heterozygosity for B10
alleles at the other markers (D13Mit98,
D13Mit147, D13Mit226,
D13Mit213, and D13Mit150) more distal on
chromosome 13 (