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Proc Natl Acad Sci U S A. Jun 27, 2006; 103(26): 9970–9975.
Published online Jun 15, 2006. doi:  10.1073/pnas.0603912103
PMCID: PMC1502563
From the Cover
Immunology

A Tlr7 translocation accelerates systemic autoimmunity in murine lupus

Abstract

The y-linked autoimmune accelerating (yaa) locus is a potent autoimmune disease allele. Transcription profiling of yaa-bearing B cells revealed the overexpression of a cluster of X-linked genes that included Tlr7. FISH analysis demonstrated the translocation of this segment onto the yaa chromosome. The resulting overexpression of Tlr7 increased in vitro responses to Toll-like receptor (TLR) 7 signaling in all yaa-bearing males. B6.yaa mice are not overtly autoimmune, but the addition of Sle1, which contains the autoimmune-predisposing Slam/Cd2 haplotype, causes the development of fatal lupus with numerous immunological aberrations. B6.Sle1yaa CD4 T cells develop the molecular signature for TFH cells and also show expression changes in numerous cytokines and chemokines. Disease development and all component autoimmune phenotypes were inhibited by Sles1, a potent suppressor locus. Sles1 had no effect on yaa-enhanced TLR7 signaling in vitro, and these data place Sles1 downstream from the lesion in innate immune responses mediated by TLR7, suggesting that Sles1 modulates the activation of adaptive immunity in response to innate immune signaling.

Keywords: Sle1, Sles1, Toll-like receptor 7, yaa

Susceptibility to systemic lupus erythematosus is mediated by complex genetic and environmental interactions (1, 2). Because of this complexity, we and others have used congenic dissection of lupus-prone mouse strains to characterize the underlying immune abnormalities responsible for lupus susceptibility (311). These analyses have provided important insights into the component phenotypes associated with individual disease alleles and allowed an assessment of genetic interactions that mediate severe lupus. In addition, congenic dissection can be a key step in the identification of causative alleles, as demonstrated by the association of polymorphisms in the SLAM/CD2 gene cluster with Sle1b, the most potent lupus susceptibility locus in Sle1 (12).

The BXSB lupus model is a recombinant inbred mouse strain produced from an intercross of C57BL/6J (B6) and SB/Le (13, 14). BXSB male mice develop a severe form of murine lupus because of interactions between the y-linked autoimmune accelerator (yaa) locus on the Y chromosome and other autoimmune disease alleles in the BXSB genome (reviewed in ref. 15). yaa is the most potent disease allele detected in the BXSB strain (14). Previous studies found that yaa dysregulated the B cell lineage and that CD4 T cells were necessary for disease but need not carry the yaa mutation (1618). Introgression of yaa onto the nonautoimmune C57BL/6J (B6) background revealed that yaa could produce disease only when combined with other autoimmune-promoting genes (3, 8, 1921). In our B6 congenic system we found that the bicongenic B6.Sle1yaa strain developed severe disease, indicative of strong epistatic interactions between these two susceptibility loci (8).

We previously described four suppressive modifier loci, Sles1–4, which suppressed autoimmunity in NZW mice (22). Sles1 was the most potent of these loci, and we recently fine-mapped it into an ≈956-kb region at the proximal end of the murine MHC. Genetic complementation studies indicated that the suppressive effects of Sles1 were not mediated by MHC class II molecules and that mice expressing Sles1 mounted normal immune responses to exogenous stimulation, indicating that this suppressive modifier did not broadly inhibit the immune system (23).

Here we present data demonstrating that the causative genetic lesion for yaa involves a translocation of the Toll-like receptor (TLR) Tlr7 from the X chromosome onto the yaa Y chromosome. This translocation causes a 2-fold overexpression of Tlr7 in male mice bearing yaa, which is sufficient to dysregulate TLR7-mediated activation of innate immune responses. We further demonstrate that the introduction of Sle1 synergizes with this regulatory lesion in innate signaling to cause profound dysregulation of the adaptive immune system. Finally, the introduction of Sles1 onto the B6.Sle1yaa lupus model (B6.Sle1yaaSles1) eliminated pathogenic autoimmunity and associated phenotypes without suppressing the hyperresponsive properties of the TLR7 dysregulation caused by yaa.

Results

Genetic Interactions Among yaa, Sle1, and Sles1 Modulate Systemic Autoimmunity.

To characterize the genetic interactions among these loci, we compared the immunologic phenotypes in a congenic series consisting of B6.yaa, B6.Sle1, B6.Sle1yaa, and B6.Sle1yaaSles1. As shown in Fig. 1A, B6.Sle1yaa mice had significant cumulative mortality by 9 months, with all surviving mice exhibiting severe kidney pathology characterized by hyalanized end-stage disease in most kidney glomeruli (Fig. 5, which is published as supporting information on the PNAS web site). In contrast, B6.yaa, B6.Sle1, and B6.Sle1yaaSles1 mice had normal lifespans, with little or no evidence of kidney disease by 9 months (Figs. 1A and 5) (5). The production of serum IgM and IgG anti-chromatin, anti-dsDNA, and anti-GBM (glomerular basement membrane) autoAbs was also impacted by these genetic interactions. Relative to B6, B6.yaa mice had increased levels of IgM autoAbs by 4–6 months, and B6.Sle1 mice produced high IgG titers against chromatin. Significant levels of autoAbs were detectable in B6.Sle1yaa by 6–8 weeks, and, consistent with the incidence of severe glomerulonephritis, the titers dramatically increased by 4–6 months (Fig. 5). The autoantigen microarray profiling of these sera (shown in Fig. 1B) revealed that B6.Sle1yaa mice at 4–6 months preferentially produced high titers of IgG autoAbs against dsDNA and kidney glomerular antigens, which strongly correlated with severe kidney pathology (24). These data indicate that yaa and Sle1 dictate independent contributions to the development of autoAbs, and combining the two loci amplified these phenotypes, resulting in accelerated production of disease-associated IgG autoAbs.

Fig. 1.
Genetic interactions among yaa, Sle1, and Sles1 modulate systemic autoimmunity. (A) Cohorts of male mice of the various yaa strains indicated were aged to 9 months to assess for spontaneous mortality (n = 15–23). (B) Sera were obtained from 4- ...

yaa Contains a Translocation of the X-Linked Tlr7 Gene.

Modulations in global gene transcription ensuing from the epistatic interactions among these susceptibility loci were measured with the Sentrix Mouse-6 (48,000) array (Illumina). This analysis compared expression profiles from three biological replicas of sorted splenic CD19+ and CD4+ cells from B6, B6.yaa, B6.Sle1yaa, and B6.Sle1yaaSles1 mice at 4–6 months of age. A Boolean comparison identified 18 genes that were differentially expressed in yaa-bearing B cells at a corrected significance of P < 0.01 compared with B6 (Fig. 6, which is published as supporting information on the PNAS web site). Four of these genes (Trappc2, Rab9, Tlr7, and Prps2) are located in an ≈1-Mb segment, just proximal to the pseudoautosomal region at the telomeric end of the X chromosome (Fig. 2A Upper) (www.ensembl.org/Mus_musculus) (25). The expression of these four genes was 2-fold greater in CD19 B cells from yaa strains compared with B6 (Fig. 2A Upper). The up-regulation of Tlr7 was verified by real-time quantitative PCR (Fig. 2B). Tlr8, which is located just distal to Tlr7, was not detectably expressed in the B or CD4 T cells from any of these mice (data not shown).

Fig. 2.
yaa contains a translocation of the X-linked Tlr7 gene. (A) Expression-level fold changes of the indicated X chromosome genes in B cells from 4- to 6-month-old mice of the different yaa strains relative to B6 controls, as determined by using Illumina ...

Based on these data, we hypothesized that yaa contained a translocation of this segment of distal X to the Y chromosome, resulting in aberrant overexpression of genes that normally undergo X inactivation in females. An X-to-Y translocation was confirmed by using two-color FISH with bacterial artificial chromosome (BAC) probes specific for the Y chromosome (RP24-208N6; pink) and the X chromosome region containing Tlr7 and Prps2 (RP23-92P6; green). As shown in Fig. 2C, hybridization of metaphase chromosome spreads identified Tlr7 and Prps2 (labeled in green) on the X chromosomes of both B6 and B6.yaa mice. However, an additional copy of Tlr7 and Prps2 was found on the Y chromosome only in B6.yaa mice (Fig. 2C Right). This additional copy on the Y chromosome caused a 2-fold increase in Tlr7 gene expression in purified B cells from males in comparison to littermate females from yaa strains, consistent with the circumvention of normal X inactivation mechanisms by genes in the translocated segment (Fig. 6). DNA sequencing of both Tlr7 and Rab9 detected no polymorphisms within the coding regions of these genes between B6 and B6.yaa males, indicating that the translocated copies on yaa encode proteins that are identical to those on the X chromosome (data not shown). In addition, no changes in the tissue specificity for Tlr7 have been detected (data not shown), indicating that the primary consequence of this translocation is the 2-fold increase in gene transcription.

Functional Changes Associated with the Tlr7 Translocation in yaa Mice.

Recent work has documented the roles of TLR7 and TLR9, which are nucleic acid-binding members of the innate immune system family of TLRs, in the molecular interactions that lead to a breach in tolerance to nuclear antigens in different systems (2633). TLR7 recognizes viral ssRNA (3436), thus making it an excellent candidate for involvement in autoimmunity to RNA-containing antigens. Furthermore, TLR7 is expressed on B and myeloid lineage cells, but not in CD4 T cells, consistent with the documented functional properties of yaa (1618). Given these data, Tlr7 emerged as a strong candidate for the autoimmune phenotypes mediated by yaa.

The functional effects of a 2-fold increase in the transcription of TLR7 were tested in vitro by using the synthetic TLR7 agonist R837. Splenocytes from 6- to 8-week-old male mice were cultured for 24 and 48 h with various concentrations of R837 and assayed for differences in activation markers, proliferation, and IL12p40 secretion after stimulation. As shown in Fig. 3A, splenocytes from B6.yaa mice responded significantly more strongly to stimulation with R837 than B6 controls. Analogous experiments assessing responses of these strains to stimulation through TLR4 (LPS) and TLR9 (CpG ODN 1826) indicated that yaa enhances the proliferative responses of B cells to TLR4, but not TLR9. In this regard, stimulation by R837 in strains expressing yaa was inhibited by chloroquine, consistent with the maintenance of the specific expression of TLR7 in endocytic vesicles (Fig. 7, which is published as supporting information on the PNAS web site) (37). Taken together, these data indicate that the enhanced stimulation with the TLR7 agonist was not due to aberrant subcellular localization or generalized aberrancies in the stimulation properties of receptors located within such vesicles.

Fig. 3.
Functional changes associated with the Tlr7 translocation in yaa. (A) Sterile splenocyte suspensions from 6- to 8-week-old mice were plated in quadruplicate at 0.5 × 106 cells per ml in complete RPMI medium 1640 with varying concentrations of ...

As discussed above, B6.yaa mice develop a minimal autoimmune phenotype involving the production of low titers of IgM autoAbs (Fig. 5). However, as shown in the heat map in Fig. 3B, both the B6.yaa and B6.Sle1yaa strains produced IgM autoAbs that recognized RNA-associated autoantigens, including Ro and La, as well as a variety of small nuclear ribonucleoproteins (SnRNPs). Whereas B6.yaa produced only IgM autoAbs against these antigens, B6.Sle1yaa mice transitioned to the production of IgG (Fig. 1). In contrast, sera from autoimmune B6.Sle1 mice did not preferentially recognize this subset of antigens. These results support the hypothesis that dsyregulated TLR7 signaling may be directly involved in mediating the breach in B cell immune tolerance to RNA-containing antigens in yaa-bearing mice.

Finally, the in vivo phenotypes of B6.yaa mice were concentrated in the B cell compartment, as evidenced by significant decreases in the percentages of both T2 (B220+CD23+CD21hiIgMhi) and MZ (B220+CD23CD21+IgM+) B cells in B6.yaa mice relative to B6 (Fig. 8, which is published as supporting information on the PNAS web site) (38). Although previous studies reported the absence of monocytosis and other associated immunological abnormalities in B6.yaa mice (20, 39), we found mild myeloid and B lymphocyte dysregulations compared with B6 (Fig. 8). Overall, B6.yaa mice have subtle immune phenotypes, indicating that the deleterious consequences of the up-regulation of Tlr7 are predominantly modulated by immunoregulatory mechanisms present in B6 mice.

Interactions of Sle1 with yaa Drives Severe Autoimmune Disease.

The addition of Sle1 to B6.yaa causes a transition to severe autoimmunity accompanied by the development of a variety of immune system aberrations, including extensive splenomegaly and a tremendous increase in splenic cellularity. To assess the origins of this dysregulation, the cell lineage distributions in thymic, bone marrow, and splenic populations in the entire congenic panel were analyzed at 6–8 weeks and at 4–6 months (Tables 1 and 2, which are published as supporting information on the PNAS web site). This analysis revealed an extensive expansion of all immune cell lineages, detectable by 6–8 weeks of age and dramatically increasing by 4–6 months. Most notably, a dramatic increase in the splenic CD11b+ population was observed, with a striking expansion in the monocyte and neutrophil populations. These phenotypes are consistent with many of the immunologic dysregulations described in the parental BXSB.yaa strain (15).

A comparison of the immune cell populations of B6.yaa and B6.Sle1yaa revealed dramatic increases in the activation of the T cell lineage as a major consequence of the genetic interaction between these two disease loci. T lymphocytes from B6.Sle1yaa mice showed early and progressive activation, such that by 4–6 months ≈50% of the CD3 T cells from B6.Sle1yaa mice were CD69+ (Table 2). Both CD4 and CD8 T cells exhibited this chronic activation, along with a marked differentiation toward a CD62LCD44hi memory phenotype (Table 2). Fig. 4A presents a short list of genes with expression profiles specifically associated with B6.Sle1yaa CD4 T cells among the congenic series. Most notably, expression of Il21, Il4, Ifnγ, and many other chemokine and cytokine genes were strongly up-regulated at this point in disease development. B6.Sle1yaa T cells at this stage of disease also had a replicative senescent phenotype, which is commonly a consequence of the chronic activation associated with severe autoimmunity in lupus-prone mouse strains (Fig. 9, which is published as supporting information on the PNAS web site) (8, 4042).

Fig. 4.
TFH cell signature and cytokine dysregulations observed in B6.Sle1yaa T cells. (A and B) Heat map of gene-expression profiles of different cytokines, chemokines, and their receptors (A) and TFH cell genes (B) in sorted CD4 cells from 4- to 6-month-old ...

As shown in Fig. 4B, this expanded population of CD4+ effectors exhibited a molecular signature characteristic of the follicular T helper (TFH) cell population [up-regulated Icos, Pdcd1, Blr1 (Cxcr5), Ccl5 (Rantes), Il21, Cd200, Cd84, Tiam1, and neuropilin], which was confirmed by flow cytometry (Fig. 4C). Examination of younger mice revealed that the dysregulated expression of these molecules occurs early in the course of disease, most notably for ICOS and PD1, and can be detected by 6 weeks of age in B6.Sle1yaa splenic CD4 T cells and by 9 weeks in the peripheral blood (data not shown). There was no evidence for a TFH molecular signature in CD4 cells from B6.yaa. Thus, the expansion of the TFH population seen in B6.Sle1yaa mice is associated with the development of severe pathology and may result from the specific interactions between Sle1 and yaa.

Sles1 Inhibits Disease Development in B6.Sle1yaa Mice.

As shown in Figs. 1, ,3,3, and and44 and in the supporting information, B6.Sle1yaaSles1 mice exhibited no signs of pathogenic autoimmunity and had ex vivo phenotypes completely analogous to B6. These results demonstrated that Sles1 fully suppresses the autoimmune phenotypes and immune cell dysregulations mediated by both Sle1and yaa. As shown in Fig. 3A, Sles1 did not impact the increased responsiveness to R837 that was associated with the TLR7 up-regulation mediated by yaa. Similarly, Sles1 did not affect the inherent expression differences of the SLAM/CD2 family members mediated by the autoimmune Slam/Cd2 haplotype of Sle1b. These results indicate that Sles1 operates downstream from both of these primary genetic lesions and operates to reestablish normal tolerance and immune regulation within an immune system that has dysregulations in genes involved in both innate and adaptive responses.

Discussion

These studies demonstrate that a translocation between the X and Y chromosomes is the genetic lesion underlying the ability of the BXSB-derived yaa locus to mediate systemic autoimmunity in specific genomic contexts. This translocation results in 2-fold overexpression of the translocated genes, which includes the ssRNA-recognizing TLR7 member of the TLR family of receptors (3436). This dysregulation caused increased in vitro responses to a TLR7 agonist in yaa-bearing strains and potentiated the preferential recognition of RNA-associated autoantigens in the B6.yaa mouse. Taken together, these data provide compelling evidence that the overexpression of Tlr7 is causal for the autoimmune phenotypes associated with yaa, although contributions from other genes within the translocated genomic segment cannot be ruled out without further studies. In this regard, murine TLR8 does not appear to recognize ssRNA or the synthetic agonist R837, which contrasts with the properties of human TLR8 (43, 44).

These analyses provide important insights into how synergistic interactions between the innate and adaptive immune responses may be a key element in genetic susceptibility to autoimmunity. B6.yaa mice are not autoimmune, despite the enhanced signaling mediated by the translocated copy of Tlr7. B6.Sle1 mice develop a benign autoimmunity characterized by the production of IgG anti-chromatin autoAbs. When these two loci are combined, they interact to drive a profound and chronic activation of both innate and adaptive immune responses, culminating in fatal glomerulonephritis associated with the production of high-titered pathogenic IgG autoAbs. The immune systems of these mice are dramatically transformed as a consequence of such unregulated immune activation, which can be detected as early as 6 weeks of age, well before the development of significant autoimmune pathology.

The CD4 T cell lineage in B6.Sle1yaa is profoundly dysregulated, exhibiting an early and progressive activation that leads to a dramatic increase in IFNγ-secreting cells and ultimately a phenotype resembling that of chronic activation-induced “replicative senescence” (Fig. 9). Although B6.Sle1 mice also show similar aberrations, the introgression of yaa profoundly amplifies both the kinetics and magnitude of these phenotypes. Because CD4 cells do not express TLR7 (37), this activation is likely impacted by the dysregulation of TLR7-bearing populations in combination with the inherent B and T lymphocyte defects caused by Sle1. In this regard, the yaa-mediated increase in the secretion of IL12p40 by splenocytes stimulated in vitro with R837 is consistent with the dramatic expansion of the IFNγ-secreting CD4 T cells. The precise nature of these cellular interactions remains to be elucidated; however, it is reasonable to predict that a TLR7-mediated dysregulation of the myeloid lineage is responsible for the increased production of IL12p40 in yaa-bearing mouse strains.

The molecular signature of TFH cells found in B6.Sle1yaa mice is intriguing given the recent association of this phenotype with severe disease in the san roque lupus model (45, 46). Interestingly, key characteristics of TFH cells include the increased expression of members of the SLAM/CD2 gene family. We recently associated extensive polymorphisms of the SLAM/CD2 gene cluster with Sle1b, which is the most potent autoimmune locus identified within Sle1 (12, 47). Furthermore, Sle1b was recently identified as the predominant locus responsible for interactions between yaa and Sle1 (19). The Slam/Cd2 genes, which encode adhesion/costimulatory molecules, participate in cellular interactions between both innate and adaptive immune cells, like yaa, thus making them ideal candidates for modulating “crosstalk” between these cells. Consequently, the autoimmune-prone Slam//Cd2 haplotype expressed by Sle1, coupled with the yaa-associated enhancement in TLR7 expression, may be the key to the early chronic activation of the immune system that precedes disease development.

Sles1 remains the most intriguing element delineated in this congenic dissection of systemic autoimmunity. Our findings indicate that this modifier fully suppresses the development of chronic immune activation and autoimmune pathologies in B6.Sle1yaa mice. Because Sles1 neither suppresses the enhanced TLR7 stimulatory capacity nor impacts the polymorphic expression of the Slam/Cd2 gene cluster, and yet fully abrogates lupus in this model, we postulate that Sles1 acts downstream from the initiating trigger mediated by the interactions between these two alleles. Importantly, B6.Sle1yaaSles1 mice respond appropriately in vitro to immunogenic stimuli. Thus, this modifier reestablishes a balance between the innate and adaptive immune systems without suppressing normal functions of the immune system. In this regard, B6.Sle1yaaSles1 mice do not express the mild autoimmune phenotypes associated with B6.yaa, indicating that this suppressive modifier can regulate the enhanced TLR7 signaling mediated by yaa more effectively than the B6 genome. Consequently, the pathway modulated by Sles1 is an outstanding target for therapeutic intervention in human lupus.

Materials and Methods

Mice.

Mice were housed in the University of Texas Southwestern Medical Center Animal Resources Center’s specific pathogen-free facility with the approval of the Institutional Animal Care and Use Committee of the University of Texas Southwestern Medical Center. Original breeders for all strains were obtained from The Jackson Laboratory. The B6.Sle1yaa line was derived by breeding female B6.Sle1 mice to male B6.yaa and subsequent intercrossing of progeny (8). The introgression of the NZW-derived Sles1 interval was performed in a similar manner. The primers used to select for and identify the intervals have been previously reported (48).

Serology.

Autoantigen arrays were performed on serum samples in the University of Texas Southwestern Medical Center Microarray Core, as recently described (24).

Illumina BeadChip Gene Expression Analyses.

CD19+ and CD4+ B and T cells were sorted from the spleens of three mice per genotype using the MoFlo Flow Cytometer (DakoCytomation) and antibodies against CD19, CD4, CD8, CD11b, and B220 (BD Pharmingen/eBiosciences). Purity achieved was >95%. RNA was isolated from the sorted cells and hybridized to Illumina Sentrix Mouse 6 BeadChip arrays.

BAC FISH Hybridizations.

Slides of metaphase spreads were prepared from stimulated splenocyte cultures as described previously (49). BAC clones (BACPAC Resources, Oakland, CA) were cultured, and BAC DNA was isolated by using the PhasePrep BAC DNA kit (Sigma). DNA was labeled by using the Prime-It Fluor Fluorescence Labeling Kit (Stratagene) and Spectrum Orange (Vysis, Downers Grove, IL) according to the manufacturers’ instructions, precipitated, resuspended in LSI/WCP hybridization buffer (Vysis), and hybridized to slides overnight at 37°C. Washed and dehydrated slides were mounted by using Vectashield Mounting Medium with DAPI (Vector Laboratories) and visualized with an AX70 light microscope (Olympus, Melville, NY) using isis 5.0 FISH imaging software (MetaSystems, Altlussheim, Germany).

In Vitro TLR Splenocyte Stimulation Assays.

Sterile splenocyte suspensions were plated in quadruplicate at 0.5 × 106 cells per milliliter in complete RPMI medium 1640 with varying concentrations of the following stimuli: anti-IgM (Jackson ImmunoResearch), LPS (Sigma), CpG ODN 1826 (Coley Pharmaceuticals, Ottawa, ON, Canada) and Imiquimod-R837 (InvivoGen, San Diego). In some assays, cells were preincubated with 2 μg/ml chloroquine (InvivoGen) for 30 min at 37°C before the stimuli addition. Plates were set up in duplicate, and cells were cultured at 37°C for 24 and 48 h. Either plates were pulsed with [3H]thymidine for the last 9 h and [3H]thymidine incorporation was measured to assay for cell proliferation or cells and supernatants were collected for flow cytometric and ELISA analyses.

Cytokine ELISAs.

Supernatant and serum concentrations of the cytokines IL12p40 and IL6 were determined by using OptEIA ELISA kits (BD Biosciences) according to the manufacturer’s instructions.

Statistical Analysis.

Data were analyzed by using instat3 (GraphPad, San Diego). Unless otherwise indicated, error bars represent SEMs.

Supplementary Material

Supporting Information:

Acknowledgments

We are grateful to Dr. Jose Casco for excellent management of the mouse colony and to Angie Mobley for cell sorting. We thank the members of the E.K.W. laboratory for discussions, critical comments, and technical advice, in particular Alice Chan and Miwako Yamamoto. These studies were supported by grants from the National Institutes of Health, the Lupus Research Institute, and the Alliance for Lupus Research (to E.K.W.).

Abbreviations

TLR
Toll-like receptor
BAC
bacterial artificial chromosome
TFH
follicular T helper.

Footnotes

Conflict of interest statement: No conflicts declared.

References

1. Wakeland E. K., Liu K., Graham R. R., Behrens T. W. Immunity. 2001;15:397–408. [PubMed]
2. Wandstrat A. E., Wakeland E. K. Nat. Immunol. 2001;2:802–809. [PubMed]
3. Hudgins C. C., Steinberg R. T., Klinman D. M., Reeves M. J., Steinberg A. D. J. Immunol. 1985;134:3849–3854. [PubMed]
4. Liu K., Liang C., Liang Z., Tus K., Wakeland E. K. J. Immunol. 2005;174:1630–1637. [PubMed]
5. Mohan C., Alas E., Morel L., Yang P., Wakeland E. K. J. Clin. Invest. 1998;101:1362–1372. [PMC free article] [PubMed]
6. Mohan C., Yu Y., Morel L., Yang P., Wakeland E. K. J. Immunol. 1999;162:6492–6502. [PubMed]
7. Morel L., Mohan C., Croker B. P., Tian X.-H., Wakeland E. K. J. Immunol. 1997;158:6019–6028. [PubMed]
8. Morel L., Croker B. P., Blenman K. R., Mohan C., Huang G., Gilkeson G., Wakeland E. K. Proc. Natl. Acad. Sci. USA. 2000;97:6670–6675. [PMC free article] [PubMed]
9. Rozzo S. J., Allard J. D., Choubey D., Vyse T. J., Izui S., Peltz G., Kotzin B. L. Immunity. 2001;15:435–443. [PubMed]
10. Vidal S., Kono D. H., Theofilopoulos A. N. J. Clin. Invest. 1998;101:696–702. [PMC free article] [PubMed]
11. Zhang D., Fujio K., Jiang Y., Zhao J., Tada N., Sudo K., Tsurui H., Nakamura K., Yamamoto K., Nishimura H., et al. Proc. Natl. Acad. Sci. USA. 2004;101:13838–13843. [PMC free article] [PubMed]
12. Wandstrat A. E., Nguyen C., Limaye N., Chan A. Y., Subramanian S., Tian X. H., Yim Y. S., Pertsemlidis A., Garner H. R., Jr., Morel L., et al. Immunity. 2004;21:769–780. [PubMed]
13. Andrews B. S., Eisenberg R. A., Theofilopoulos A. N., Izui S., Wilson C. B., McConahey P. J., Murphy E. D., Roths J. B., Dixon F. J. J. Exp. Med. 1978;148:1198–1215. [PMC free article] [PubMed]
14. Murphy E. D., Roths J. B. Arthritis Rheum. 1979;22:1188–1194. [PubMed]
15. Izui S. Autoimmunity. 1990;6:113–129. [PubMed]
16. Fossati L., Sobel E. S., Iwamoto M., Cohen P. L., Eisenberg R. A., Izui S. Eur. J. Immunol. 1995;25:3412–3417. [PubMed]
17. Lawson B. R., Koundouris S. I., Barnhouse M., Dummer W., Baccala R., Kono D. H., Theofilopoulos A. N. J. Immunol. 2001;167:2354–2360. [PubMed]
18. Merino R., Fossati L., Lacour M., Izui S. J. Exp. Med. 1991;174:1023–1029. [PMC free article] [PubMed]
19. Croker B. P., Gilkeson G., Morel L. Genes Immun. 2003;4:575–585. [PubMed]
20. Izui S., Higaki M., Morrow D., Merino R. Eur. J. Immunol. 1988;18:911–915. [PubMed]
21. Kikuchi S., Fossati-Jimack L., Moll T., Amano H., Amano E., Ida A., Ibnou-Zekri N., Laporte C., Santiago-Raber M. L., Rozzo S. J.., et al. J. Immunol. 2005;174:1111–1117. [PubMed]
22. Morel L., Tian X.-H., Croker B. P., Wakeland E. K. Immunity. 1999;11:131–139. [PubMed]
23. Subramanian S., Wakeland E. K. Novartis Found. Symp. 2005;267:76–88. [PubMed]
24. Li Q. Z., Xie C., Wu T., Mackay M., Aranow C., Putterman C., Mohan C. J. Clin. Invest. 2005;115:3428–3439. [PMC free article] [PubMed]
25. Perry J., Palmer S., Gabriel A., Ashworth A. Genome Res. 2001;11:1826–1832. [PMC free article] [PubMed]
26. Barrat F. J., Meeker T., Gregorio J., Chan J. H., Uematsu S., Akira S., Chang B., Duramad O., Coffman R. L. J. Exp. Med. 2005;202:1131–1139. [PMC free article] [PubMed]
27. Boule M. W., Broughton C., Mackay F., Akira S., Marshak-Rothstein A., Rifkin I. R. J. Exp. Med. 2004;199:1631–1640. [PMC free article] [PubMed]
28. Krieg A. M. Nat. Immunol. 2002;3:423–424. [PubMed]
29. Vollmer J., Tluk S., Schmitz C., Hamm S., Jurk M., Forsbach A., Akira S., Kelly K. M., Reeves W. H., Bauer S., et al. J. Exp. Med. 2005;202:1575–1585. [PMC free article] [PubMed]
30. Lau C. M., Broughton C., Tabor A. S., Akira S., Flavell R. A., Mamula M. J., Christensen S. R., Shlomchik M. J., Viglianti G. A., Rifkin I. R., et al. J. Exp. Med. 2005;202:1171–1177. [PMC free article] [PubMed]
31. Leadbetter E. A., Rifkin I. R., Hohlbaum A. M., Beaudette B. C., Shlomchik M. J., Marshak-Rothstein A. Nature. 2002;416:603–607. [PubMed]
32. Marshak-Rothstein A., Busconi L., Rifkin I. R., Viglianti G. A. Rheum. Dis. Clin. North Am. 2004;30:559–574. [PubMed]
33. Viglianti G. A., Lau C. M., Hanley T. M., Miko B. A., Shlomchik M. J., Marshak-Rothstein A. Immunity. 2003;19:837–847. [PubMed]
34. Diebold S. S., Kaisho T., Hemmi H., Akira S., Reis e Sousa C. Science. 2004;303:1529–1531. [PubMed]
35. Heil F., Hemmi H., Hochrein H., Ampenberger F., Kirschning C., Akira S., Lipford G., Wagner H., Bauer S. Science. 2004;303:1526–1529. [PubMed]
36. Lund J. M., Alexopoulou L., Sato A., Karow M., Adams N. C., Gale N. W., Iwasaki A., Flavell R. A. Proc. Natl. Acad. Sci. USA. 2004;101:5598–5603. [PMC free article] [PubMed]
37. Sioud M. Trends Mol. Med. 2006;12:167–176. [PubMed]
38. Amano H., Amano E., Moll T., Marinkovic D., Ibnou-Zekri N., Martinez-Soria E., Semac I., Wirth T., Nitschke L., Izui S. J. Immunol. 2003;170:2293–2301. [PubMed]
39. Amano H., Amano E., Santiago-Raber M. L., Moll T., Martinez-Soria E., Fossati-Jimack L., Iwamoto M., Rozzo S. J., Kotzin B. L., Izui S. Arthritis Rheum. 2005;52:2790–2798. [PubMed]
40. Chu E. B., Ernst D. N., Hobbs M. V., Weigle W. O. J. Immunol. 1994;152:4129–4138. [PubMed]
41. Mohan C., Morel L., Yang P., Watanabe H., Croker B. P., Gilkeson G. S., Wakeland E. K. J. Clin. Invest. 1999;103:1685–1695. [PMC free article] [PubMed]
42. Shi X., Xie C., Kreska D., Richardson J. A., Mohan C. J. Exp. Med. 2002;196:281–292. [PMC free article] [PubMed]
43. Hemmi H., Kaisho T., Takeuchi O., Sato S., Sanjo H., Hoshino K., Horiuchi T., Tomizawa H., Takeda K., Akira S. Nat. Immunol. 2002;3:196–200. [PubMed]
44. Jurk M., Heil F., Vollmer J., Schetter C., Krieg A. M., Wagner H., Lipford G., Bauer S. Nat. Immunol. 2002;3:499. [PubMed]
45. Vinuesa C. G., Tangye S. G., Moser B., Mackay C. R. Nat. Rev. Immunol. 2005;5:853–865. [PubMed]
46. Vinuesa C. G., Cook M. C., Angelucci C., Athanasopoulos V., Rui L., Hill K. M., Yu D., Domaschenz H., Whittle B., Lambe T., et al. Nature. 2005;435:452–458. [PubMed]
47. Morel L., Blenman K. R., Croker B. P., Wakeland E. K. Proc. Natl. Acad. Sci. USA. 2001;98:1787–1792. [PMC free article] [PubMed]
48. Subramanian S., Yim Y. S., Liu K., Tus K., Zhou X. J., Wakeland E. K. J. Immunol. 2005;175:1062–1072. [PubMed]
49. McDaniel L. D., Chester N., Watson M., Borowsky A. D., Leder P., Schultz R. A. DNA Repair (Amsterdam) 2003;2:1387–1404. [PubMed]

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