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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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Related in: MedlinePlus

Map of Sle1a and its two recombinant intervals. From top to bottom are shown: a scale in Mb, the location of the microsatellite markers or SNPs mapping the interval termini, and the Sle1a, Sle1a.1 and Sle1a.2 intervals, in which the black rectangles show the regions of known NZW allelic derivation, and the hatched rectangles on each side indicate the regions of recombination between the NZW and B6 genomes.
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Figure 3: Map of Sle1a and its two recombinant intervals. From top to bottom are shown: a scale in Mb, the location of the microsatellite markers or SNPs mapping the interval termini, and the Sle1a, Sle1a.1 and Sle1a.2 intervals, in which the black rectangles show the regions of known NZW allelic derivation, and the hatched rectangles on each side indicate the regions of recombination between the NZW and B6 genomes.

Mentions: The entire Sle1a interval is covered by the combination of the Sle1a.1 and Sle1a.2 intervals (Fig. 3). The Sle1a.1 interval contains only one gene, Pbx1, while the Sle1a.2 interval contains 15 known genes and 3 ESTs or predicted peptides, 7 of them expressed in CD4+ T cells, 9 expressed in B cells, and 11 expressed in myeloid cells (Table 1). The Sle1a.1 and Sle1a.2 intervals potentially overlap between rs31413434 and rs30711102 (< 100 Kb) upstream of the Pbx1 transcriptional start site, in a region that does not contain any gene. The Sle1a.2 interval extends on the telomeric end beyond the Sle1a interval, resulting in the Fcgr2b gene having the B6 and NZW alleles in B6.Sle1a and B6.Sle1a.2, respectively.26


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)

Map of Sle1a and its two recombinant intervals. From top to bottom are shown: a scale in Mb, the location of the microsatellite markers or SNPs mapping the interval termini, and the Sle1a, Sle1a.1 and Sle1a.2 intervals, in which the black rectangles show the regions of known NZW allelic derivation, and the hatched rectangles on each side indicate the regions of recombination between the NZW and B6 genomes.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: Map of Sle1a and its two recombinant intervals. From top to bottom are shown: a scale in Mb, the location of the microsatellite markers or SNPs mapping the interval termini, and the Sle1a, Sle1a.1 and Sle1a.2 intervals, in which the black rectangles show the regions of known NZW allelic derivation, and the hatched rectangles on each side indicate the regions of recombination between the NZW and B6 genomes.
Mentions: The entire Sle1a interval is covered by the combination of the Sle1a.1 and Sle1a.2 intervals (Fig. 3). The Sle1a.1 interval contains only one gene, Pbx1, while the Sle1a.2 interval contains 15 known genes and 3 ESTs or predicted peptides, 7 of them expressed in CD4+ T cells, 9 expressed in B cells, and 11 expressed in myeloid cells (Table 1). The Sle1a.1 and Sle1a.2 intervals potentially overlap between rs31413434 and rs30711102 (< 100 Kb) upstream of the Pbx1 transcriptional start site, in a region that does not contain any gene. The Sle1a.2 interval extends on the telomeric end beyond the Sle1a interval, resulting in the Fcgr2b gene having the B6 and NZW alleles in B6.Sle1a and B6.Sle1a.2, respectively.26

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