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Murine lupus susceptibility locus Sle1a requires the expression of two sub-loci to induce inflammatory T cells.

Cuda CM, Zeumer L, Sobel ES, Croker BP, Morel L - Genes Immun. (2010)

Bottom Line: Sle1a.1, and to a lesser extent Sle1a.2, significantly affected CD4(+) T-cell activation as well as Treg differentiation and function.As the Sle1a.1 and Sle1a.2 intervals contain only 1 and 15 known genes, respectively, this study considerably reduces the number of candidate genes responsible for the production of autoreactive T cells.These results also show that the Sle1 locus is an excellent model for the genetic architecture of lupus, in which a major obligate phenotype results from the coexpression of multiple genetic variants with individual weak effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, 32610-0275, USA.

ABSTRACT
The NZM2410-derived Sle1a lupus susceptibility locus induces activated autoreactive CD4(+) T cells and reduces the number and function of Foxp3(+) regulatory T cells (Tregs). In this study, we first showed that Sle1a contributes to autoimmunity by increasing antinuclear antibody production when expressed on either NZB or NZW heterozygous genomes, and by enhancing the chronic graft versus host disease response indicating an expansion of the autoreactive B-cell pool. Screening two non-overlapping recombinants, the Sle1a.1 and Sle1a.2 intervals that cover the entire Sle1a locus, revealed that both Sle1a.1 and Sle1a.2 were necessary for the full Sle1a phenotype. Sle1a.1, and to a lesser extent Sle1a.2, significantly affected CD4(+) T-cell activation as well as Treg differentiation and function. Sle1a.2 also increased the production of autoreactive B cells. As the Sle1a.1 and Sle1a.2 intervals contain only 1 and 15 known genes, respectively, this study considerably reduces the number of candidate genes responsible for the production of autoreactive T cells. These results also show that the Sle1 locus is an excellent model for the genetic architecture of lupus, in which a major obligate phenotype results from the coexpression of multiple genetic variants with individual weak effects.

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Sle1a expression increased autoAb production on NZB or NZW heterozygous genomes. Anti-chromatin (A) and anti-dsDNA (B) IgG in 12 month old mice. Time course production of anti-chromatin (C) and anti-dsDNA (D) IgG in (NZB X B6.Sle1a)F1 (black symbols) and (NZW × B6.Sle1a)F1 (white symbols). For E and F, means and standard errors are shown and statistical significance is indicated for t tests between the cohorts at each time point. *: p < 0.05; **: p < 0.01; ***: p < 0.001.
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Figure 1: Sle1a expression increased autoAb production on NZB or NZW heterozygous genomes. Anti-chromatin (A) and anti-dsDNA (B) IgG in 12 month old mice. Time course production of anti-chromatin (C) and anti-dsDNA (D) IgG in (NZB X B6.Sle1a)F1 (black symbols) and (NZW × B6.Sle1a)F1 (white symbols). For E and F, means and standard errors are shown and statistical significance is indicated for t tests between the cohorts at each time point. *: p < 0.05; **: p < 0.01; ***: p < 0.001.

Mentions: Sle1 induces the production of anti-chromatin IgG and triggers autoimmune pathology when expressed on an NZW heterozygous genome.22Sle1c by itself leads to a very modest autoAb production, but significantly increased autoAb production and renal pathology when expressed on a NZB heterozygous genome.23 Using the same strategy for Sle1a, we compared (NZB X B6.Sle1a)F1 and (NZW X B6.Sle1a)F1 to (NZB X B6)F1 and (NZW X B6)F1 mice, respectively, up to 12 months of age. (NZW X B6.Sle1a)F1 mice produced significantly more anti-chromatin IgG than (NZW X B6)F1 controls (Fig. 1A), and the amount of anti-dsDNA IgG was significantly greater in both (NZB X B6.Sle1a)F1 and (NZW X B6.Sle1a)F1 compared to controls (Fig. 1B). Interestingly, (NZB X B6.Sle1a)F1 mice produced significantly more anti-dsDNA IgG than the (NZW X B6.Sle1a)F1, while the reverse was observed for anti-chromatin IgG (Fig. 1C and D). This difference could be due to the differential effect of NZW/NZW vs. NZW/NZB Sle1a alleles or to differences between the NZB and NZW alleles on the rest of the genome. No significant renal pathology was observed in either (NZB X B6.Sle1a)F1 or (NZW X B6.Sle1a)F1. Nonetheless, this experiment shows that Sle1a expression significantly enhances anti-nuclear autoAb production.


Murine lupus susceptibility locus Sle1a requires the expression of two sub-loci to induce inflammatory T cells.

Cuda CM, Zeumer L, Sobel ES, Croker BP, Morel L - Genes Immun. (2010)

Sle1a expression increased autoAb production on NZB or NZW heterozygous genomes. Anti-chromatin (A) and anti-dsDNA (B) IgG in 12 month old mice. Time course production of anti-chromatin (C) and anti-dsDNA (D) IgG in (NZB X B6.Sle1a)F1 (black symbols) and (NZW × B6.Sle1a)F1 (white symbols). For E and F, means and standard errors are shown and statistical significance is indicated for t tests between the cohorts at each time point. *: p < 0.05; **: p < 0.01; ***: p < 0.001.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2958247&req=5

Figure 1: Sle1a expression increased autoAb production on NZB or NZW heterozygous genomes. Anti-chromatin (A) and anti-dsDNA (B) IgG in 12 month old mice. Time course production of anti-chromatin (C) and anti-dsDNA (D) IgG in (NZB X B6.Sle1a)F1 (black symbols) and (NZW × B6.Sle1a)F1 (white symbols). For E and F, means and standard errors are shown and statistical significance is indicated for t tests between the cohorts at each time point. *: p < 0.05; **: p < 0.01; ***: p < 0.001.
Mentions: Sle1 induces the production of anti-chromatin IgG and triggers autoimmune pathology when expressed on an NZW heterozygous genome.22Sle1c by itself leads to a very modest autoAb production, but significantly increased autoAb production and renal pathology when expressed on a NZB heterozygous genome.23 Using the same strategy for Sle1a, we compared (NZB X B6.Sle1a)F1 and (NZW X B6.Sle1a)F1 to (NZB X B6)F1 and (NZW X B6)F1 mice, respectively, up to 12 months of age. (NZW X B6.Sle1a)F1 mice produced significantly more anti-chromatin IgG than (NZW X B6)F1 controls (Fig. 1A), and the amount of anti-dsDNA IgG was significantly greater in both (NZB X B6.Sle1a)F1 and (NZW X B6.Sle1a)F1 compared to controls (Fig. 1B). Interestingly, (NZB X B6.Sle1a)F1 mice produced significantly more anti-dsDNA IgG than the (NZW X B6.Sle1a)F1, while the reverse was observed for anti-chromatin IgG (Fig. 1C and D). This difference could be due to the differential effect of NZW/NZW vs. NZW/NZB Sle1a alleles or to differences between the NZB and NZW alleles on the rest of the genome. No significant renal pathology was observed in either (NZB X B6.Sle1a)F1 or (NZW X B6.Sle1a)F1. Nonetheless, this experiment shows that Sle1a expression significantly enhances anti-nuclear autoAb production.

Bottom Line: Sle1a.1, and to a lesser extent Sle1a.2, significantly affected CD4(+) T-cell activation as well as Treg differentiation and function.As the Sle1a.1 and Sle1a.2 intervals contain only 1 and 15 known genes, respectively, this study considerably reduces the number of candidate genes responsible for the production of autoreactive T cells.These results also show that the Sle1 locus is an excellent model for the genetic architecture of lupus, in which a major obligate phenotype results from the coexpression of multiple genetic variants with individual weak effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, 32610-0275, USA.

ABSTRACT
The NZM2410-derived Sle1a lupus susceptibility locus induces activated autoreactive CD4(+) T cells and reduces the number and function of Foxp3(+) regulatory T cells (Tregs). In this study, we first showed that Sle1a contributes to autoimmunity by increasing antinuclear antibody production when expressed on either NZB or NZW heterozygous genomes, and by enhancing the chronic graft versus host disease response indicating an expansion of the autoreactive B-cell pool. Screening two non-overlapping recombinants, the Sle1a.1 and Sle1a.2 intervals that cover the entire Sle1a locus, revealed that both Sle1a.1 and Sle1a.2 were necessary for the full Sle1a phenotype. Sle1a.1, and to a lesser extent Sle1a.2, significantly affected CD4(+) T-cell activation as well as Treg differentiation and function. Sle1a.2 also increased the production of autoreactive B cells. As the Sle1a.1 and Sle1a.2 intervals contain only 1 and 15 known genes, respectively, this study considerably reduces the number of candidate genes responsible for the production of autoreactive T cells. These results also show that the Sle1 locus is an excellent model for the genetic architecture of lupus, in which a major obligate phenotype results from the coexpression of multiple genetic variants with individual weak effects.

Show MeSH
Related in: MedlinePlus