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The Journal of Immunology, 2003, 171: 6442-6447.
Copyright © 2003 by The American Association of Immunologists

Genetic Complementation in Female (BXSB x NZW)F2 Mice 1

Dwight H. Kono2, Miyo S. Park and Argyrios N. Theofilopoulos

Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
F1 hybrids among New Zealand Black (NZB), New Zealand White (NZW), and BXSB lupus-prone strains develop accelerated autoimmunity in both sexes regardless of the specific combination. To identify BXSB susceptibility loci in the absence of the Y chromosome accelerator of autoimmunity (Yaa) and to study the genetics of this complementation, genome-wide quantitative trait locus (QTL) mapping was performed on female (BXSB x NZW)F2 mice. Six QTL were identified on chromosomes 1, 4, 5, 6, 7, and 17. Survival mapped to chromosomes 5 and 17, anti-chromatin Ab to chromosomes 4 and 17, glomerulonephritis to chromosomes 6 and 17, and splenomegaly to chromosomes 1, 7, and 17. QTL on chromosomes 4 and 6 were new and designated as Lxw1 and -2, respectively. Two non-MHC QTL (chromosomes 1 and 4) were inherited from the BXSB and the rest were NZW-derived, including two similar to previously defined loci. Only two of 11 previously defined non-MHC BXSB QTL using male (Yaa+) crosses were implicated, suggesting that some male-defined BXSB QTL may require coexpression of the Yaa. Findings from this and other studies indicate that BXSB and NZB backgrounds contribute completely different sets of genes to complement NZW mice. Identification of susceptibility genes and complementing genes in several lupus-prone strain combinations will be important for defining the epistatic effects and background influences on the heterogeneous genetic factors responsible for lupus induction.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Systemic lupus erythematosus is a genetically heterogeneous disease inherited as a polygenic threshold trait with manifestations dependent on the number and specific combinations of predisposing alleles (reviewed in Refs. 1, 2, 3). Due to the complexity of defining this type of inheritance in humans, inbred mouse strains that spontaneously develop lupus-like disease are being studied to determine the nature of the genetic contributions to disease induction, severity, and the diversity of manifestations. This approach has enabled the identification of several susceptibility genes, including Fas (Tnfrsf6; lpr and lprcg mutations), Fasl (Tnfsf6; gld mutation), Src homology domain 2-containing tyrosine phosphatase-1 (Hcph; me and mev mutations) and a putative gene that has not yet been cloned, the Y chromosome accelerator of autoimmunity and lymphoproliferation (Yaa)3 (1). These genes had mutations with specific phenotypes that provided the basis for their identification. Because most lupus susceptibility alleles do not exhibit such distinguishing phenotypes, however, genome-wide searches have been performed as the initial step toward identifying genes based on chromosomal location.

Several genomic intervals from lupus-prone and nonautoimmune backgrounds have been linked to a variety of lupus traits with varying degrees of confidence. Among the lupus-prone strains, five quantitative trait loci (QTL) have been identified for the New Zealand Black (NZB) (chromosomes 1, 4, 5, 11, and 17) (3, 4, 5), eight for the New Zealand White (NZW) (chromosomes 1, 6, 7, 13, 16, 17, 18, and 19) (3, 4, 5, 6), eight for the MRL-Faslpr (chromosomes 2, 4, 5, 7, 10, 11, 12, and 16) (7, 8, 9), and at least 11 loci for the Yaa+ BXSB (possibly four regions on chromosome 1, possibly two on chromosome 4, and a single locus each on chromosomes 3, 7, 8, 10, 13, 14, and 17) (10, 11, 12). Although some of the overlapping loci from different strains may represent the same gene, it is evident from this and other studies of gene knockout animals (reviewed in Ref. 1) that a substantial number of genes can contribute to the induction of systemic autoimmunity. Little, however, is known about the relative strength and interaction of these loci to the autoimmune process, which will be important for determining the significance of these loci.

F1 complementation studies have shown that acceleration of disease occurs not only in the BWF1 hybrid, but also in male and female F1 hybrids of the BXSB with either the NZB or NZW strains (13). In contrast, minimal complementation is observed between these strains and the MRL-Faslpr, with the sole exception of the male, but not female, (MRL-Faslpr x BXSB)F1 hybrid, which develops accelerated disease because of the Yaa gene (13). These findings raise the possibility of shared susceptibility genes or mechanisms between the BXSB and NZ strains that may not apply to the MRL background. Because the NZB and NZW strains have different sets of susceptibility genes (1, 2, 3), complementation of either strain by the BXSB background suggests that at least some of the BXSB QTL responsible for complementation are unique. Furthermore, because F1 hybrids of autoimmune strains with nonautoimmune strains develop less severe to no autoimmune disease (3, 4, 13), it is likely that complementation is from predisposing genes contributing positively to disease rather than recessive suppressor genes that are negated by the F1 heterozygosity.

The BXSB is a recombinant inbred strain generated from crossing C57BL/6 and SB/Le strains that develops a severe form of systemic autoimmunity (1, 13). Male BXSB mice develop severe lupus-like disease by 5 mo of age characterized by lymphoproliferation, high levels of Mac1-positive peripheral blood cells, high titers of autoantibodies, glomerulonephritis (GN) and vasculitis. Genetic susceptibility, however, is highly dependent on the Yaa gene because female BXSB mice develop only very mild disease. The Yaa gene alone can promote disease in other lupus backgrounds. Consomic NZB.Yaa and NZW.Yaa that differ from the parental strains by only the BXSB Y chromosome develop accelerated autoimmune disease similar to Yaa containing male F1 crosses of NZB or NZW to BXSB mice (14). The Yaa gene, however, requires other background genes for disease because C57BL/6.Yaa or CBA/J.Yaa mice are largely unaffected (13, 14, 15). The Yaa gene has a greater effect on mice with mild lupus than in those with severe disease (15). Expression of Yaa on T cells is not required for disease acceleration (16, 17), and double bone marrow chimera experiments using mixtures of Yaa+ and Yaa- cells demonstrated selective production of anti-DNA and hypergammaglobulinemia by Yaa+ B cells (18). The Ab promoting effect of the Yaa gene was observed not only for self Ags, but also for foreign Ags, particularly those that elicit low T cell-dependent Ab responses (19). Thus, weak autoimmune promoting genes might be expected to be most affected by the Yaa gene.

Thus far, BXSB QTL have been mapped only in Yaa+ mice (10, 11, 12) and therefore, the extent to which these loci are dependent on the Yaa is not known. In this study, a genome-wide QTL scan of female (BXSB x NZW)F2 (XWF2) intercross mice was performed to identify BXSB (H-2b) susceptibility loci in the absence of the Yaa gene and to determine whether complementation of NZW (H-2z) to BXSB or to NZB (H-2d) involves similar or diverse QTL. Multiple QTL from both parental strains were found to predispose to lupus-like disease, including two new loci on chromosomes 4 and 6. Furthermore, BXSB QTL that complemented the NZW genome to promote lupus were completely different from the NZW-complementing NZB QTL.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Mice

NZW/LacScr, BXSB/Scr, (BXSB x NZW)F1 (XWF1), and (BXSB x NZW)F2 (XWF2) intercross mice were bred and maintained in The Scripps Research Institute animal facility (La Jolla, CA). Female mice were used in this study. Mice were autopsied at 1 year of age or earlier if moribund.

Lupus phenotypes

Mice were bled at monthly intervals from 5 mo of age. Autopsies and histologic procedures were performed as previously described (5, 7). Briefly, tissue sections were fixed in Bouin’s solution and stained with periodic acid-Schiff (PAS) reagent. Severity of GN was graded blindly on a 0 to 4 scale as previously described (5), with scores >2 considered pathologic. Severity of degenerative vascular disease of coronary vessels, myocardial infarction, and necrotizing polyarteritis was graded on a 0–3 scale as previously described (20). Briefly, for degenerative vascular disease, grade 1 contained minimal PAS-positive deposits along and within one coronary blood vessel wall, grade 2 had PAS-positive deposits with narrowing of the lumen in two or three vessels, and grade 3 involved four or more affected vessels. For myocardial infarction, the size of myocardial necrosis was 1–2 mm for grade 1, 2–3 mm for grade 2, and >3 mm for grade 3. Arteritis was graded on the number of affected small and medium-sized muscular arteries and the number of organs involved. Only arteries with necrotizing and exudative inflammation of the intima and media were included. Grade 1 was limited to one organ, grade 2 required involvement of three vessels in at least two different organs, and grade 3 involved vessels in at least three different organs. The ELISA for serum anti-chromatin Abs was performed as described (5).

Microsatellite analysis

Genome-wide microsatellite scanning was performed by PCR of tail DNA using 132 simple sequence length polymorphisms (list available on request) selected from 361 microsatellite markers (Research Genetics, Huntsville, AL). PCRs used standard reagents containing 1.5 mM MgCl2 and 0.4 µM primers under the following conditions: 40 cycles of 92°C for 20 s, 42°C to 60°C (depending on primers) for 1.5 min and 72°C for 2 min. Products were visualized on agarose gels stained with ethidium bromide.

Statistics and linkage analysis

Survival was analyzed by the Kaplan-Meier statistic. Comparisons of traits between parental strains and crosses were performed with the two-tailed unpaired t test or ANOVA. Associations between quantitative traits in F2 mice were determined by regression coefficients with p values derived from Fisher’s transformation.

The linkage map for the (BXSB x NZW)F2 cross was created with Mapmaker3 (http://waldo.wi.mit.edu/ftp/distribution/software/mapmaker3) (21). QTL were identified using QTL Cartographer version 1.17 (http://statgen.ncsu.edu/qtlcart). Likelihood ratios (LR) were calculated using the LRmapqtl program. Composite interval mapping was performed using model 6 of the Zmapqtl program with options set at 2-cM intervals, 10-cM window size, and five background parameters. The experiment-wise significance level for each trait was determined by analyzing 1000 random shuffling permutations of the actual phenotype data. Log transformations of quantitative traits were used when they resulted in more normalized distributions. GN scores were normalized by regrouping into five categories as previously described for QTL (7): GN scores <=1 were scored as 1 (n = 11), between 1 and <2 as 2 (n = 65), 2 to <2.5 as 3 (n = 122), 2.5 to <3 as 4 (n = 42), and >=3 as 5 (n = 24). New loci were designated Lxw for lupus BXSB x NZW.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Disease traits in female BXSB, NZW, F1, and F2 intercross mice

The incidence and severity of major disease manifestations for female BXSB, NZW, XWF1, and XWF2 mice are summarized on Table I and Fig. 1. Traits examined included those previously tested in a BWF2 linkage study (survival, GN, anti-chromatin Ab levels, and spleen weight) (5), as well as others that have high incidence in XWF1 hybrids, including myocardial infarction (MI), degenerative vascular disease (DVD), arteritis, and thymic atrophy (13). For all traits, disease was significantly worse in XWF1 hybrid mice than in one or both parental strains.


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  		Table I. Summary of lupus manifestations in female BXSB, NZW, XWF1, and XWF2 micea

 


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  		FIGURE 1. Cumulative survival and anti-chromatin Ab levels for female BXSB, NZW, and crosses. A, Percent cumulative mortality (p < 0.006 for XWF1 and NZW, p < 0.0002 for XWF1 and BXSB). B, Mean and SE ELISA OD units for anti-chromatin Ab levels. A value of p < 0.05 for BXSB vs NZW (at 9–12 mo of age, by unpaired two-tailed t test), NZW vs XWF1 (8–12 mo), BXSB vs XWF1 (12 mo), BXSB vs XWF2 (11 and 12 mo), NZW vs XWF2 (9–12 mo). The number of mice in each group was 14 BXSB, 8–9 NZW, 7–16 XWF1, and 93–123 XWF2. Mortality of NZW mice was reported previously (5 ).

 
The 1-year survival for female BXSB mice was 100% (14 mice) and 89% (8 of 9) for NZW mice, but only 31% (5 of 16) for female XWF1 mice (p < 0.01). The female XWF2 mice had an intermediate survival of 66% (81 of 123) consistent with multigenic inheritance of this trait. The average IgG anti-chromatin Ab levels in BXSB mice and XWF1 hybrids were elevated, whereas, average levels in NZW mice were nearly normal throughout the 1-year observation period (Fig. 1). The average anti-chromatin Ab levels in XWF1 mice at older ages (11 and 12 mo) were likely reduced as a result of death or renal insufficiency of the most severely affected individuals. The XWF2 female mice had slightly higher anti-chromatin Ab levels than the BXSB and XWF1 early in disease and lower levels at later time points, consistent with additive polygenic inheritance. Spleen weights were in the normal range for both BXSB and NZW mice, but were more than 2-fold greater in XWF1 mice (Table I). Interestingly, while there was no evidence of GN in BXSB mice, 22% (2 of 9) of NZW mice developed GN (score >2.0) despite the much lower anti-chromatin Ab levels. The XWF1 hybrid had significantly more GN than the NZW (p < 0.01) and BXSB (p < 0.0001) strains. MI and DVD occurred more frequently in the XWF1 hybrid (58%) than the BXSB (none) and NZW (11%) mice. Thymic atrophy was present in all groups, but to a significantly lower extent in BXSB mice (p < 0.01 compared with XWF1 hybrids). Arteritis was present in 40% of XWF1 mice, but in none of the parental strains (p < 0.05). Overall, the findings suggest that NZW mice may be more susceptible than BXSB mice to most of the traits including mortality, GN, MI, DVD, arteritis, and thymic atrophy, although BXSB mice are clearly more susceptible to anti-chromatin Ab production.

Among the XWF2 mice, significant correlation (r >0.65) between traits was observed only for DVD and MI (r = 0.85, p < 0.0001) consistent with DVD as the major cause of MI. The lack of correlation between some of the other traits considered pathogenically related, e.g., survival, GN, and anti-chromatin Ab production, suggests that to some extent, independent immunopathologic or additional pathways may be involved.

Loci with linkage to survival

Two loci associated with survival were identified on chromosomes 5 (D5Mit55, p < 0.007) and 17 (Tnf, p < 0.0016) (Table II). The locus on chromosome 5 accounts for 18.0% of the variance and the chromosome 17 locus for 6.8%. The chromosome 5 locus maps to the proximal-mid portion of the chromosome (Fig. 2) and the Tnf marker on chromosome 17 is located within the MHC complex <1 cM from the class II genes and will be considered equivalent to the MHC. The predisposing allele for the chromosome 5 locus was inherited from NZW strain, whereas, for the MHC, the heterozygous genotype (H-2b/z) conferred somewhat higher susceptibility than the homozygous BXSB genotype (H-2b/b), while the NZW genotype (H-2z/z) was resistant (Table II). The contributions of the two loci were additive (p < 0.0005), and when all combinations of alleles were examined, appeared dependent on specific combinations (epistasis) (Fig. 3). Thus, the locus on chromosome 5 had a strong effect on survival when the MHC (Tnf) was heterozygous (70, 43, and 25%, when D5Mit55 was of the X, F, and W genotypes, respectively, Fig. 2); however, there was minimal effect when the MHC was of the least susceptible NZW genotype (83–100% survival for all D5Mit55 genotypes).


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  		Table II. Susceptibility loci for (BXSB x NZW)F2 mice

 


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  		FIGURE 2. QTL scans for chromosomes 1, 4, 5, 6, 7, and 17. Composite interval maps of LR test (LRT) are shown for the following traits: chromosome (Chr) 1: spleen weight; Chr 4: anti-chromatin Ab; Chr 5: survival; Chr 6: GN; Chr 7: spleen weight; Chr 17: GN, anti-chromatin Ab; and spleen weight. For chromosomes 1–7, horizontal lines are the experiment-wise significance levels {alpha} = 0.1 (dotted line) and 0.05 (solid line) obtained by analyzing 1000 random permutations of the experimental data (QTL Cartographer). For Chr 17, QTL scans for the three different traits are: spleen weight (thin line), GN (bold line), and anti-chromatin Ab (dotted line), along with corresponding horizontal lines for the experiment-wise significance levels {alpha} = 0.05. {blacktriangleup}, Positions of the following markers in order from the acromere. Chr 1: D1Mit294, D1Nds4, D1Mit212, D1mit302, D1Mit46, D1Mit10, D1Mit54, D1Mit105, D1Mit115, D1Mit17; Chr 4: D4Mit1, D4Mit2, D4Mit53, D4Mit9, D4mit28, D4Mit258, D4Mit54, D4Mit14, D4Mit48; Chr 5: D5Mit48, D5Mit348, D5Mit55, D5Mit254, D5Nds2, D5Mit312, D5Mit371, D18Mit7, D5Mit31, D5Mit43; Chr 6: D6Mit138, D6Mit33, D6Mit70, D6Mit10, D6Mit256, D6Mit291, D6Mit14; Chr 7: D7Mit152, D7Mit56, D7Mit294, cd22, D7Mit55, D7Mit227, D7Nds5, D7Mit211, D7Mit84, D7Mit281, D7Mit12, D7Nds4, D7Mit259; Chr 17: D17Mit97, Tnf, D17Mit10, D17Mit42, D17Mit129.

 


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  		FIGURE 3. Cumulative survival of XWF2 mice segregated by the chromosome 5 QTL and MHC genotypes. Cumulative survival of all combinations of the chromosome 5 QTL (probably Sle6) and MHC (chromosome 17) genotypes from 4 to 12 mo (left panel). Percent survival at 12 mo is shown on the right panel. First letter of genotype is the chromosome 5 QTL and second is the MHC; F = F1, X = BXSB, and W = NZW. The genotype of the chromosome 5 locus was defined at D5Mit55 (28 cM from centromere) and the MHC at Tnf (19 cM from centromere).

 
Mapping of QTL predisposing to anti-chromatin Ab production

The MHC (Tnf, p = 5.1 x 10-6) and a QTL on proximal chromosome 4 (D4Mit2, p = 0.0002) were linked to IgG anti-chromatin Ab production at 6 mo (Table II, Fig. 2). The MHC accounted for 29.7% and the chromosome 4 locus for 13.0%. In both cases, the susceptibility allele was inherited from the BXSB strain. When analysis was performed for anti-chromatin Ab production at later time points (10 and 11 mo), there was linkage to the MHC and a NZW allele on chromosome 1 (D1Mit54, p = 4.2 x 10-4), but not to the chromosome 4 QTL. This is consistent with the early anti-chromatin Ab production observed in the BXSB, but not NZW strain, and may have been affected by the earlier sacrifice of more severely diseased XWF2 mice (~20% of mice at 10 mo).

QTL predisposing to GN

Two QTL were identified for GN, one was the MHC (Tnf, p = 4.3 x 10-5) and the other a proximal interval on chromosome 6 (D6Mit33, p = 0.004) (Table II, Fig. 2). The susceptible allele on the chromosome 6 QTL was recessively inherited from the NZW, whereas the H-2b/b haplotype was associated with worse disease. Chromosome 6 QTL appears to be novel. The chromosome 6 locus accounted for 16.0% of the variance and the MHC for 25.7%.

QTL predisposing to splenomegaly

Three QTL predisposing to splenomegaly were identified on mid-proximal chromosome 1 (D1Mit46, p = 0.03), the acrocentric end of chromosome 7 (D7Mit152, p = 5.5 x 10-5) and the MHC (Tnf, p = 1.1 x 10-3) (Table II, Fig. 2). These loci accounted for 19.0, 15.5, and 21.5% of variance, respectively. The susceptible locus on chromosome 1 was inherited from the BXSB strain and appeared to be additive. The susceptible allele for the chromosome 7 QTL was recessively inherited from the NZW. The H-2b/b haplotype was again associated with the greatest severity. The chromosome 7 QTL overlaps and is probably identical to Lbw5 and Sle3/Sle5, which were previously identified in BWF2 intercross (5) and NZM/Aeg2410 x (NZM/Aeg2410 x C57BL/6)F1 backcross (4) studies, respectively.

QTL predisposing to other traits

Three QTL were identified for arteritis on chromosomes 1 (D1Mit54, p = 2.9 x 10-4), 6 (D6Mit256, p = 7 x 10-4), and 17 (D17Mit42, p = 1.2 x 10-3), however, none of these reached the 0.1 level of genome-wide significance. The susceptibility alleles for QTL on chromosomes 1 and 6 were from the NZW strain and for the chromosome 17 QTL from the BXSB. Genome-wide searches of DVD and MI failed to identify any QTL. This may be due to the contribution of a large number of genes and a relatively low incidence of DVD and MI in the XWF2 intercrosses in this study (Table I).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Herein, lupus-predisposing QTL for NZW and BXSB backgrounds were identified in the absence of the Yaa gene by analyzing female XWF2 mice. Six significant QTL linked to one or more traits were found on chromosomes 1, 4, 5, 6, 7, and 17, including two potentially new QTL and four previously defined loci. Non-MHC QTL from the NZW strain included loci on chromosomes 5, 6, and 7, while there were two non-MHC QTL on chromosomes 1 and 4 from the BXSB background. The BXSB-derived QTL on chromosome 1 (at ~43 cM), was linked to splenomegaly and mapped between two previously reported loci, Bxs1 (at 32.8 cM) and Bxs2 (at 63 cM). Both of these QTL were identified using male BXSB x B10 crosses and interestingly both were linked to splenomegaly, although at a suggestive level of significance (10, 12). Both loci were also linked to GN and autoantibody production. Thus, it is likely that the chromosome 1 locus identified in this study represents the same locus. This locus mapped centromeric to previously described NZB (Lbw7/Nba2) (3, 5) and NZW (Sle1) (4) chromosome 1 QTL and is likely distinct from these.

The BXSB-inherited chromosome 4 locus, designated Lxw1 (for lupus BXSB x NZW), was linked to early anti-chromatin production consistent with the predilection of female BXSB, but not female NZW, mice to this trait (Fig. 1). Lxw1 maps proximal to another BXSB locus (Acla-2) that was linked to the production of anti-cardiolipin IgG Ab (11) and a more distal BXSB chromosome 4 locus that was linked to lymphadenopathy (10). This raises the possibility that Lxw1 and Acla-2, although appearing to be distinct because of their locations, may represent a single BXSB QTL that broadly enhances autoantibody production even in the absence of the Yaa gene, but this will need to be determined. Lxw1, because of its proximal location, does not overlap the chromosome 4 NZB locus, Nba1/Sle2/Lbw2 (4, 5, 22), and clearly represents a distinct QTL.

The chromosome 5 locus was linked to mortality and appeared strongly dependent on the MHC haplotype (Fig. 3). This locus likely represents the NZW chromosome 5 QTL, Sle6 (23). The chromosome 6 locus linked to GN is novel and will be designated Lxw2. The NZW QTL on chromosome 7 overlaps and is probably the same as a NZW locus previously defined as Sle3/5 or Lbw5 (4, 5). This QTL has been verified in C57BL/6 mice congenic for the Sle3/Sle5 region of NZM/Aeg2410 (24) and in NZB backgrounds congenic for the Lbw5 fragment of NZW (our unpublished observations). The fact that this locus can contribute to some disease manifestations in both autoimmune and nonautoimmune backgrounds (Refs. 4 , 5 , and this study) suggests its involvement in a common or fundamental mechanism in the autoimmune process.

Several BXSB QTL were previously defined in mapping studies of male Yaa+ crosses. Hogarth et al. (10, 12) using BXSB x (B10 x BXSB)F1 and B10 x (B10 x BXSB)F1 backcross mice, identified four regions on chromosome 1 with significant linkage to nephritis or anti-dsDNA Ab (Bxs1–4) and another to ANA/anti-ssDNA on chromosome 3 (Bxs5). In addition, other QTLs of suggestive linkage were also described, including a region on distal-mid chromosome 4 to lymphadenopathy, proximal-mid chromosome 10 to anti-dsDNA Ab and chromosome 13 to anti-ssDNA Ab. In another study, Ida et al. (11), analyzing NZW x (NZW x BXSB)F1 backcross mice identified BXSB QTL in mid chromosome 4 (Acla-2) with linkage to anti-cardiolipin Ab, distal chromosome 7 (Myo-1) to MI, proximal chromosome 8 (Pbat-2) to anti-platelet Ab and thrombocytopenia, mid chromosome 14 (Myo-2) to MI, and the MHC region to anti-cardiolipin (Acla-1) and anti-platelet (Pbat-1) Abs. Strikingly, of these 11 or more potential BXSB QTL identified in male (Yaa+) mice, only the MHC and a chromosome 1 locus were linked to disease in this study of female XWF2 mice. Some of these loci may not have been identified because they were mapped to different traits, while others may be dependent on the Yaa mutation. Other sex-related factors may also play a role although predisposition of male BXSB mice to lupus is dependent on the Yaa gene and not sex hormones (13).

Previous studies using (NZW x BXSB)F1 (H-2z/b), (NZW.H-2d x BXSB) F1 (H-2d/b), and NZW x (NZW x BXSB) F1 backcross mice have shown that H-2b/z confers increased autoimmune susceptibility compared with the z/d, z/z, or d/b haplotypes (11, 25). In addition to two of these haplotypes (b/z and z/z), the current XWF2 analysis examined linkage of the homozygous b/b haplotype to disease severity. Strikingly, H-2b/b was linked to all mapable traits except for arteritis and was the haplotype associated with worse disease in all cases except for survival in which case the heterozygous H-2b/z haplotype was associated with a slightly worse outcome. This suggests that expression of the H-2b/b haplotype on the NZW background might result in significant disease acceleration in a manner similar to the autoimmune-enhancing effect of H-2bm12 in NZB mice (26).

Without exception, the development of lupus-like disease in predisposed mouse models requires the additive contributions of multiple genetic defects that vary in strength, associated traits, and dependence on other genes. Although identification of susceptibility genes and definition of their effects on the immune system are paramount, understanding the overall contribution of these genes to disease in a variety of genetic backgrounds is also important. Classification of lupus-predisposing genes in such a manner should also aid in the selection of potential gene targets for diagnosis and intervention. Further studies of complementation among lupus-prone strains will be important for defining relative contributions and epistatic interactions of susceptibility alleles.


   Acknowledgments
 
We thank Daniel G. Owens, Dimitrios Theofilopoulos, and Agnieszka Szydlik for excellent technical assistance.


   Footnotes
 
1 This work was supported in part by National Institutes of Health Grants AR42242, ES08666, and AR39555. This is Scripps Research Institute Publication 12241-IMM. Back

2 Address correspondence and reprint requests to Dr. Dwight H. Kono, Department of Immunology, The Scripps Research Institute-IMM3, 10550 North Torrey Pines Road, La Jolla, CA 92037. E-mail address: dkono{at}scripps.edu Back

3 Abbreviations used in this paper: Yaa, Y chromosome accelerator of autoimmunity and lymphoproliferation; QTL, quantitative trait locus; GN, glomerulonephritis; PAS, periodic acid-Schiff; DVD, degenerative vascular disease; MI, myocardial infarction. Back

Received for publication August 1, 2003. Accepted for publication October 15, 2003.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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