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* Institut National de la Santé et de la Recherche Médicale Unité 399, Faculté de Médecine, Marseille, France; and
Department of Pathology, Centre Médical Universitaire, Geneva, Switzerland
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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12 megabases (Mb)) interval between markers D13Mit142 and D13Mit254 mediates increased basal serum levels of gp70 in B6.NZW-Sgp3/1 and B6.NZW-Sgp3/2 mice and with a higher degree in males (15 µg/ml) than in females (9 µg/ml) as compared with B6 (2 µg/ml), revealing a gender effect. However, their gp70 levels are still lower than that of NZW mice (60 µg/ml). In addition, B6.NZW-Sgp3/1 and B6.NZW-Sgp3/2 mice showed a moderate 2- to 3-fold increase in serum gp70 in response to LPS, which contrasted with over a 10-fold increase in NZW mice. Although both B6.NZW-Sgp3/1 and B6.NZW-Sgp3/2 mice failed to produce significant amounts of gp70 anti-gp70 immune complexes, unexpectedly, aged B6.NZW-Sgp3/2 congenic males bearing the Yaa gene developed increased titers of IgG autoantibodies to DNA and chromatin. Our data indicate that Sgp3 is involved in a complex process of gp70 production under polygenic control and may provide a significant contribution to lupus susceptibility not only through up-regulation of gp70 autoantigen production but also predisposition to autoimmunity. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The gp70 autoantigen is produced by liver cells and secreted in the blood circulation of all mouse strains, although at various levels among the different inbred strains (2). Noteworthy, all systemic lupus erythematosus-prone strains have relatively high concentrations of gp70 in their sera (>20 µg/ml), whereas C57BL/6 (B6) and C57BL/10 (B10) produce low levels of serum gp70 (2 µg/ml). However, several normal strains have equally high levels of serum gp70, indicating that the gp70 autoantigen is not nephritogenic by itself. By studying the progeny of crosses of lupus-prone NZB, NZW and BXSB with B6 or B10 strains, we (5) and others (10, 11) mapped a quantitative trait locus (QTL) on chromosome 13 at 37 centiMorgans (cM) from the centromere that was strongly linked with basal levels of serum gp70. This locus mapped to a chromosomal location different from that of previously identified loci, Sgp1 linked to the H2 locus on chromosome 17 (12), and Sgp2 located at the telomeric end of chromosome 7 (13). In our analysis of B6 x (NZW x B6.Yaa)F1 backcross mice, this region of the genome, here designated as Sgp3, appeared to be a major determinant of quantitative variation of gp70 Ag. A trend of linkage of the Sgp3 locus with gp70 IC levels and the lack of apparent influence on the production of IgG anti-DNA Abs and development of severe GN suggested that its contribution to levels of nephritogenic gp70 IC could be a consequence of increased concentrations of circulating gp70. In the NZB genetic crosses, in which two other loci contributing to serum gp70 were identified on chromosomes 2 and 4, the chromosome 13 locus influence on gp70 IC similarly appeared to be related to the regulation of gp70 production. In the BXSB backcross study, this single region of the genome, named Bxs6, directing serum gp70 was also the major linkage for serum gp70 IC. Interestingly, there appeared to be a threshold of serum gp70 concentration below which high titers of gp70 IC were not produced. Thus, relatively little is known about the factors regulating expression of the murine lupus gp70 autoantigen. Moreover, the contribution of Sgp3 to gp70 production and its implication in anti-gp70 autoantibody response remain to be better defined.
Individual contributions of lupus susceptibility loci can be ascertained using congenic strains (14). Such congenic strains can be produced by introgressing chromosomal regions from lupus-prone mouse strains into the genome of normal mice by repetitive backcross procedure and using a marker-assisted selection protocol (15). Using this method, we developed three congenic B6.NZW-Sgp3 strains carrying NZW-derived regions encompassing all or part of the Sgp3 locus in the B6 background and determined their basal levels of serum gp70. Since concentrations of serum gp70 can be increased like that of acute phase reactants following LPS injection only in strains with naturally high levels of gp70 (16), we analyzed the response of the constructed congenic strains to LPS. We also tested their autoimmune phenotype by analyzing the production of Abs to gp70, DNA, and chromatin. The present results indicate that Sgp3 is involved in a complex process of gp70 production under polygenic control and reveal its potential role in autoantibody production.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Parental NZW/OlaHsd and C57BL/6JIco mice were purchased from Harlan U.K. Ltd (Oxon, U.K.) and IFFA-CREDO (Lyon, France), respectively. B6.Yaa males were established by repeated backcrosses (n >20) as described previously (17). The B6.NZW-Sgp3 congenic strains, (NZW x B6)F1 and (NZW x B6.c13NZW) F1 hybrid mice, were obtained by local breeding in our own animal facility. Congenic strains were designated according to rules for nomenclature of mouse strains obtained at Mouse Genome Informatics (www.informatics.jax.org). Males of the B6.NZW-Sgp3/2 and -Sgp3/3, but not B6.NZW-Sgp3/1, congenic strains are carrying the Yaa mutation. DNA was extracted from tail biopsies. Blood samples were collected by orbital sinus puncture and the sera were stored at -20°C until use.
LPS injection
LPS purified from Escherichia coli 055:B5 was obtained from Sigma-Aldrich (St. Louis, MO). Twenty-five micrograms of LPS dissolved in sterile PBS was injected i.p. into test mice at a final volume of 0.2 ml. Sera were collected 24 h later.
Serological assays
Concentrations of total gp70 in serum samples were determined by ELISA as described previously (18). Serum levels of gp70 IC were quantified by the same ELISA combined with the precipitation of the serum with 10% polyethylene glycol (average Mr 6000) which precipitates only the Ab-bound gp70, but not free gp70, as described elsewhere (19). Results are expressed as micrograms per milliliter of gp70 by referring to a standard curve obtained from NZB sera with known amounts of gp70.
The presence of IgG anti-DNA, anti-chromatin, and anti-DNP Abs was assessed by ELISA as previously described (20). Results are expressed in titration units (units per milliliter) in reference to a standard curve obtained from a pool serum of 3- to 4-mo-old MRL-lpr/lpr mice. Mice with anti-DNA, anti-chromatin, and anti-DNP Ab levels above the mean of age-matched B6 males plus 3 SD (36, 43, and 161 U/ml, respectively) were considered as positive.
Microsatellite genotyping
Genotypes were determined by PCR using selected simple sequence length polymorphism (SSLP) markers either purchased from Research Genetics (Huntsville, AL) or Invitrogen (Carlsbad, CA). The sequences of the primers used were found at the following internet address: http://www.informatics.jax.org/. PCR amplification was conducted with Platinum Taq polymerase (Invitrogen) using a GeneAmp PCR System 9700 thermal cycler (Applied Biosystems, Foster City, CA), as described previously (5). The positions of the SSLP markers with respect to the centromere were obtained from the Mouse Genome Database and the Ensembl Database via the internet at http://www.informatics.jax.org and http://www.ensembl.org.
Histopathology
Kidney samples were collected at 12 mo of age and histological sections were stained with periodic acid-Schiff reagent. Glomerulonephritis was evaluated based on the intensity and extent of pathological changes as described elsewhere (5).
Statistical analysis
Statistical analysis was performed with the Wilcoxon two-sample test. In addition, the incidence of mice with elevated serum titers of autoantibodies was analyzed by using the exact Fisher’s test. Probability values >5% were considered to be insignificant.
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Results |
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We established three independent B6-congenic strains in five backcross generations by following the strategy of maintaining the previously identified mid-chromosome 13 interval 12 cM distal to the D13Mit250 marker locus and selecting against the presence of other contaminating NZW genomes at each generation. We used one marker at each end of the chromosome 13 interval, D13Mit250 and D13Mit97, one internal marker, D13Mit253, and eight markers located outside this interval, D13Mit55, -275, -90, -139 centromeric and D13Mit193, -147, -76, -262 telomeric. In addition, 3 SSLP markers were used for each of the other 18 autosomes and a set of 15 markers was used to screen against the NZW lupus susceptibility loci localized on chromosomes 1, 4, 7, 11, and 17 (21, 22). The resulting B6.NZW-Sgp3/1-, -Sgp3/2-, and -Sgp3/3-congenic lines were subsequently maintained by brother-sister mating. A schematic representation of congenic strains is shown in Fig. 1.
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11 cM interval of the NZW-derived region encompassing the entire confidence interval that extended 3 cM toward the centromeric and telomeric ends, respectively. In the B6.NZW-Sgp3/2 and B6.NZW-Sgp3/3 strains, a larger congenic interval extended toward the centromeric end to 34 and 37 cM, respectively. These two latter strains were selected for the presence of a recombination event that occurred within the interval at one or the other side of the internal D13Mit253 marker. A further characterization of their genotype using eight additional SSLP markers located inside the locus Sgp3 allowed localization of the recombination events between D13Mit313 and D13Mit254 and between D13Mit142 and D13Mit318, respectively. Mice of the B6.NZW-Sgp3/1- and -Sgp3/2-, but not B6.NZW-Sgp3/3-, congenic strains show increased levels of serum gp70
Concentration of circulating gp70 Ag has been shown to remain constant throughout life after 1–3 mo of age (2). Therefore, levels of serum gp70 were determined once in 3- to 6-mo-old mice. As shown in Fig. 2, B6.NZW-Sgp3/1 and B6.NZW-Sgp3/2 male homozygotes had significantly higher gp70 concentrations (15.1 ± 5.4 µg/ml and 15.0 ± 3.7 µg/ml, respectively) than those of control B6 males (2.6 ± 1.0 µg/ml; p < 0.001). As previously reported, female counterparts of these two congenic strains had relatively smaller amounts of serum gp70 (8.2 ± 1.6 µg/ml and 10.5 ± 3.1 µg/ml; p < 0.001 and p < 0.05, respectively), yet much higher than that of B6 female mice (2.1 ± 0.8 µg/ml; p < 0.001). Production of serum gp70 was markedly reduced, but still substantially augmented in heterozygote B6.NZW-Sgp3/1 and B6.NZW-Sgp3/2 males (5.1 ± 1.9 µg/ml; p < 0.005 and 5.9 ± 1.1 µg/ml; p < 0.001, respectively) and female (3.7 ± 1.1 µg/ml; p < 0.005 and 3.9 ± 1.3 µg/ml; p < 0.001, respectively) mice. This result is consistent with our previous finding that Sgp3 is expressed in a dominant manner but indicates that allele dosage markedly affects the levels of serum gp70. In contrast, none of B6.NZW-Sgp3/3 male and female mice displayed increased levels of serum gp70 (homozygote: 2.4 ± 0.8 µg/ml and 1.5 ± 0.2 µg/ml, respectively; heterozygote: 2.5 ± 0.8 µg/ml and 1.5 ± 0.5 µg/ml, respectively; Fig. 2). It should be noted that serum levels of gp70 in B6.NZW-Sgp3/2 male mice carrying the autoimmune acceleration gene Yaa were comparable to those in B6.NZW-Sgp3/1 male mice lacking the Yaa mutation, arguing against any participation of the Yaa gene in gp70 production.
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12 Mb) between D13Mit142 and D13Mit254 shared in the B6.NZW-Sgp3/1 and B6.NZW-Sgp3/2 strains. Although assessment of gp70 production in Yaa--Sgp3/1 and Yaa+-Sgp3/2 males might not be adequate for fine mapping of the Sgp3 locus, comparison of their female counterparts supports this conclusion. Comparative analysis of serum gp70 production in B6.NZW-Sgp3/1-congenic mice and their F1 hybrids with NZW
The relatively low levels of serum gp70 observed in B6.NZW-Sgp3/1- and -Sgp3/2-congenic strains were not expected from the previous B6 x (NZW x B6.Yaa)F1 backcross study, which identified Sgp3 as a major contribution to serum gp70. As shown in Fig. 3, B6.NZW-Sgp3/1 heterozygotes (5.1 ± 1.9 µg/ml) and homozygotes (15.1 ± 5.4 µg/ml) had much lower levels of serum gp70 than Sgp3 heterozygous (NZW x B6)F1 hybrids (24.2 ± 4.8 µg/ml; p < 0.001) and Sgp3-homozygous NZW mice (64.5 ± 4.0 µg/ml; p < 0.05), respectively. This indicates the participation of genetic loci other than Sgp3 in the regulation of gp70 expression. This was further supported by the demonstration that serum gp70 levels in Sgp3 homozygous (NZW x B6.NZW-Sgp3/1)F1 hybrid mice were moderately increased (34.7 ± 4.2 µg/ml), as compared with Sgp3 heterozygous (NZW x B6)F1 hybrids, but still lower than those of NZW mice.
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Given that serum gp70 increases after injection of LPS with a peak production at 24 h only in murine strains whose basal content is high, including NZW, we next examined whether our B6.NZW-Sgp3-congenic strains could exhibit an enhanced gp70 production following LPS stimulation. As shown in Fig. 4, B6.NZW-Sgp3/1 and -Sgp3/2 homozygotes of both sexes displayed a moderate 2.2- and 2.6-fold increase of serum gp70, respectively, in response to LPS. Concentrations of serum gp70 hardly up-regulated in B6.NZW-Sgp3/1 and -Sgp3/2 heterozygotes (0.9- to 1.6-fold in each sex) or in B6.NZW-Sgp3/3 homozygotes (0.9- to 1.8-fold in each sex), as in the case of control B6 mice (1.3-fold). By contrast, in NZW mice, the LPS stimulation resulted in a marked 11.5-fold increase of serum gp70, as previously reported (16). Thus, although B6.NZW-Sgp3/1 and -Sgp3/2 strains had increased basal levels of serum gp70, their serum gp70 responses induced by LPS were rather limited, indicating a minimal role of the Sgp3 locus for acceleration of serum gp70 production following LPS stimulation.
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Increased levels of serum IgG anti-DNA and anti-chromatin autoantibodies in B6.NZW-Sgp3/2-congenic mice bearing the Yaa mutation
Since Sgp3 was in the trend of linkage with gp70 IC levels in our previous backcross analysis (5) and an identical region on chromosome 13, Bxs6, was identified as a major contribution to the Ab response to the gp70 Ag in BXSB male mice bearing the Yaa gene (11), we investigated its possible implication in the production of anti-gp70 Abs by determination of the serum levels of gp70 IC. As shown in Fig. 5, levels of circulating gp70 IC in 6- to 11-mo-old Yaa-bearing B6.NZW-Sgp3/2 male homozygotes and heterozygotes (0.6 ± 0.2 µg/ml and 0.6 ± 0.3 µg/ml, respectively) were not different from those found in either their female counterparts (0.6 ± 0.4 µg/ml and 0.4 ± 0.2 µg/ml, respectively) or B6 controls (0.6 ± 0.3 µg/ml).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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12 cM region, Sgp3 was here localized to a 3 cM (12 Mb) interval between markers D13Mit142 and D13Mit254. Furthermore, congenic strains containing disease-susceptibility alleles provide important information about the contribution of each locus to specific phenotypes of the disease. Our data indicate that Sgp3 is involved in the susceptibility to lupus-like disease through regulation of gp70 autoantigen expression but may also provide a significant contribution through predisposition to autoimmunity. Sgp3 was the strongest locus detected in our original cross, with a logarithm of odds score of 12.8, 43.4% of the phenotypic variance explained, and no additional significant gp70-associated loci identified, suggesting that it provides a contribution that is key to the production of serum gp70. Yet despite the strong linkage of gp70 Ag production, Sgp3 by itself has only a small effect on serum gp70 production, resulting in levels of gp70 in Sgp3 homozygotes only one-quarter as high those of NZW mice. Notably, similar differences are observed between Sgp3 heterozygous B6.NZW-Sgp3 and (NZW x B6)F1 hybrids. A likely explanation is that Sgp3 plays a primary role in production of serum gp70 but that modifier genes at other genetic loci are able to markedly promote, or potentially suppress (12), its effect. This would be consistent with the previous observation that only mouse strains with elevated basal levels of gp70 respond to LPS (16) and the present finding that acceleration of serum gp70 production in response to LPS is critically dependent on other genetic loci. Noteworthy, in studying the correlation between expression of serum gp70 and the retroviral GIX thymocyte Ag regulated by a locus close to Sgp3 on chromosome 13, Gv1 (23), Hara et al. (16) reported that 129 (GIX-) mice, obtained by backcrossing the prototype GIX+ strain 129 (high gp70 levels) to the GIX- strain B6 (low gp70 levels), produced low basal levels of serum gp70 and did not respond to LPS. Unfortunately, the 129 (GIX-) strain is no longer available to determine whether it differed from the 129 strain at Sgp3. The development of reciprocal NZW.B6-Sgp3-congenic strains would be of major interest to answer this question. In addition, examination of the lupus-like disease in (NZW.B6-Sgp3 x B6.Yaa)F1 male mice would be helpful to evaluate the extent of the Sgp3 impact on the autoimmune disease.
Whatever the role played by Sgp3 in the genetic regulation of gp70 Ag production, our data clearly support the participation of other genetic loci and are consistent with previous reports that expression of the gp70 Ag in sera is a complex genetic trait. Maruyama and coworkers (12, 13) have reported that serum gp70 is controlled by at least two other loci, Sgp1 on chromosome 17 and Sgp2 on chromosome 7; Sgp2 contributing to the process of serum gp70 production in response to LPS. Noteworthy, Tucker et al. (10) identified a second NZB locus on distal chromosome 4 that was strongly linked with elevated gp70 levels in (B6 x NZB)F2 intercross mice and (B6 x NZB)F1 x NZB backcross mice with logarithm of odds scores of 10.8 and 5.1 at marker D4Mit33, respectively. Since in our B6 x (NZW x B6.Yaa)F1 backcross study D4Mit33 showed no influence on gp70, this suggests that the high gp70 phenotype may be produced by distinct genetic combinations among the different inbred strains. In this regard, it is also significant that the Sgp1 locus closely linked to the H2 region on chromosome 17, responsible for increased serum gp70 concentrations in B10.D2-congenic mice with a H2d haplotype derived from DBA/2 (12), had no influence on gp70 levels in the intercross and backcross study involving the H2d-bearing NZB strain (10). It should be also noted that BXSB x (B10 x BXSB)F1 backcross mice homozygous for the Bxs6 interval on chromosome 13, implicated as a major locus responsible for the production of gp70 in BXSB mice with a variance of 85%, spread with values overlapping the parental B10 and BXSB strains (11), consistent with multiple genetic effects.
In addition to the genetic crosses related to regulation of serum gp70 Ag, other genetic mapping studies have highlighted the significance of this chromosome 13 locus in expression of endogenous retroviral sequences. As stated above, Gv1 is a genetic locus that controls the GIX phenotype of thymocytes at the transcription level and lies 37 cM from the centromere on chromosome 13 (23). The Gv1 locus was also described as regulating the abundance of multiple endogenous murine leukemia virus-related transcripts in liver and spleen (24). Another locus present at this region of chromosome 13, termed Rsl for regulator of sex limitation, enhances serum levels of the sex-limited protein Slp in males and enables its expression in females (25). Interestingly, the Slp gene under control of Rsl is a duplicate of the C4 complement component gene containing an upstream provirus which imposes androgen-dependent expression of the adjacent Slp gene (26). It should be noted that as for gp70 Ag production, the liver is the major source of Slp and males produce higher levels of Slp in serum compared with females. Moreover, the B10 haplotype at Rsl is associated with a null to low Slp phenotype, whereas the NZB haplotype results in high levels of Slp. Thus, the properties of the Sgp3 gene involved in gp70 Ag expression appear concordant with those of Gv1 and Rsl. Under the assumption of identity between Gv1, Rsl, and Sgp3, we are most likely following a factor functioning in trans to control the transcription of retroviral sequences rather than the inheritance of structural genes encoding retroviral proteins present at this locus. The observation that low but detectable quantities of serum gp70 are present in B6 and B10 mice is consistent with this hypothesis. This region is rich in genes encoding zinc finger proteins with potential transcriptional activity and could be candidate genes for the Sgp3 gene effect. It will be of interest to test whether any of these candidates is Sgp3.
Strikingly, the combination of the NZW allele for the Sgp3 locus with the autoimmune acceleration gene Yaa appears to predispose to autoimmunity. This conclusion is based on the finding that Yaa-bearing males of the B6.NZW-Sgp3/2, but not B6.NZW-Sgp3/3, strain produce increased serum levels of IgG autoantibodies to DNA and chromatin. Since the congenic interval present in the B6.NZW-Sgp3/2 strain is shorter than that in B6.NZW-Sgp3/3, except within Sgp3, the Sgp3 locus is most likely the contributing factor underlying this effect. A role for Sgp3 in autoantibody production was not predicted by our previous backcross study, since the chromosome 13 interval showed no influence on anti-DNA Ab production (5). The weak linkage with gp70 IC was interpreted as a consequence of increased concentrations of circulating gp70. It is intriguing that the autoimmune phenotype of the B6.NZW-Sgp3/2 mice involves antinuclear, but not anti-gp70, autoantibody formation. The current lack of effect on serum gp70 IC supports the need for other susceptibility alleles that may specifically control the production of anti-gp70 Abs (7). The mechanism by which Sgp3 confers enhanced predisposition to autoimmunity is however unclear. Although we do not have a straightforward explanation, it should be stressed that the absence of IgG autoantibodies in B6.NZW-Sgp3/2 females and B6.NZW-Sgp3/1 males carrying a normal Y chromosome suggests that Sgp3 does not induce an autoimmune phenotype per se, but may contribute to humoral autoimmunity when combined with genes that potentiate such responses. It should be noted that our present data cannot rule out the possibility that two genes within Sgp3 may account for autoantibody production in interaction with the Yaa gene and for gp70 production.
In conclusion, our results fine-mapped the Sgp3 locus on mouse chromosome 13 involved in gp70 Ag expression, reducing the number of potential candidate genes from several hundred to 112. This is an important step toward identification of the actual gene or genes underlying Sgp3, allowing candidate genes to be assessed for differential expression and polymorphisms in the coding sequence. Identification of genes implicated in expression of retroviral gp70 Ag may give access to important regulatory elements that govern coordinate expression of secondary loci. Moreover, the congenic strategy used in the current study has proved to be an effective approach for dissecting the specific components to which the Sgp3 locus contributes. It must be kept in mind that several genes may contribute all of the Sgp3 effects. We are therefore continuing our fine-mapping efforts to further reduce the QTL interval. Clearly, elucidation of the mode of action of Sgp3 will impact on our understanding of murine lupus-like autoimmune disease.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Luc Reininger, Institut National de la Santé et de la Recherche Médicale Unité 399, Faculté de Médecine, 27 bd Jean Moulin, F-13385 Marseille, Cedex 05, France. E-mail address: luc.reininger{at}medecine.univ-mrs.fr
3 Abbreviations used in this paper: GN, glomerulonephritis; IC, immune complex; QTL, quantitative trait locus; SSLP, simple sequence length polymorphism; Mb, megabase; cM, centiMorgan.
Received for publication April 21, 2003. Accepted for publication July 22, 2003.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, Sgp3 heterozygous mice; •, Sgp3 homozygous mice. Horizontal lines indicate median values for each group of mice.
) and b/b (
) and w/w (
), homozygote mice at Sgp3.
