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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 or Sle1a.2 expression increased the cGVHD response. Anti-dsDNA IgG (A); spleen weight (B); ratio of AA4.1+ IgM+ CD21lo CD23lo T1 over AA4.1− IgM+ CD21int CD23+ follicular B cells; percentage of CD86+ (D) and CD22 expression (E) in B220+ gated cells; and ratio of CD62L+ CD44− naïve over CD62L− CD44+ memory CD4+ T cells five weeks after cGVHD induction in B6, B6.Sle1a and B6.Sle1a sub-congenic mice. G. Additive semi-quantitative scores of glomerular C3 and IgG deposits in B6.Sle1a and B6 mice five weeks after cGVHD induction. H. Anti-dsDNA IgG production in BM chimeras expressing Sle1a in both B and T cells (1a T + 1a B), in T cells only (1a T + B6 B), in B cells only (B6 T + 1a B), or in neither B nor T cells (B6 T + B6 B) one week after cGVHD induction. I. Anti-dsDNA IgG production in BM chimeras grouped according to the Sle1a or B6 origin of their T cells (1a T or B6 T), or B cells (1a B or B6 B). *: p < 0.05; **: p < 0.01; ***: p < 0.001. J. Representative C3 immunofluorescence staining in B6.Sle1a and B6 mice five weeks after cGVHD induction (100x). K. Representative ANA stain and corresponding titer in 9–12 month old mice.
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Figure 2: Sle1a or Sle1a.2 expression increased the cGVHD response. Anti-dsDNA IgG (A); spleen weight (B); ratio of AA4.1+ IgM+ CD21lo CD23lo T1 over AA4.1− IgM+ CD21int CD23+ follicular B cells; percentage of CD86+ (D) and CD22 expression (E) in B220+ gated cells; and ratio of CD62L+ CD44− naïve over CD62L− CD44+ memory CD4+ T cells five weeks after cGVHD induction in B6, B6.Sle1a and B6.Sle1a sub-congenic mice. G. Additive semi-quantitative scores of glomerular C3 and IgG deposits in B6.Sle1a and B6 mice five weeks after cGVHD induction. H. Anti-dsDNA IgG production in BM chimeras expressing Sle1a in both B and T cells (1a T + 1a B), in T cells only (1a T + B6 B), in B cells only (B6 T + 1a B), or in neither B nor T cells (B6 T + B6 B) one week after cGVHD induction. I. Anti-dsDNA IgG production in BM chimeras grouped according to the Sle1a or B6 origin of their T cells (1a T or B6 T), or B cells (1a B or B6 B). *: p < 0.05; **: p < 0.01; ***: p < 0.001. J. Representative C3 immunofluorescence staining in B6.Sle1a and B6 mice five weeks after cGVHD induction (100x). K. Representative ANA stain and corresponding titer in 9–12 month old mice.

Mentions: To better define the role of Sle1a in autoimmunity, we used the chronic graph versus host disease (cGVHD) model in which I-Aβ-mismatched CD4+ T cells transferred from B6.bm12 mice provide bystander help to resident autoreactive B cells that are otherwise tolerized.24 B6.bm12 splenocytes induced significantly more anti-chromatin and anti-dsDNA IgG, lymphoid expansion, expansion of T1 B cells to the expense of follicular B cells, and T and B cell activation in B6.Sle1a than in B6 mice (Fig. 2A–F). C3 and IgG deposition was also significantly increased in B6.Sle1a as compared to B6 glomeruli (Fig. 2G and J). These results indicate that Sle1a expression expands the pool of autoreactive B cells, which, in this model, require interactions with CD4+ T cells during their development.25 To determine whether Sle1a enhanced cGVHD through T or B cells, we induced cGVHD in mixed bone-marrow (BM) chimeras reconstituted with a mixture of BM from two of the B6.Sle1a.Tcrb−/−.Tcrd−/−, B6.Sle1a.Igh6, B6.Tcrb−/−.Tcrd−/− or B6.Igh6 strains in such a way that the T and B cell origin was either from Sle1a or B6. Activation of either CD4+ T cells or B cells in these chimeras tracked with the Sle1a origin of each of these cell types (data not shown). The chimeras in which both T and B cells expressed Sle1a produced significantly more anti-dsDNA IgG (Fig. 2H) and showed an increase in spleen weight (data not shown) compared to chimeras in which both T and B cells were of B6 origin. The expression of Sle1a in B cells only, but not in T cells, showed a similar trend. A significant difference was obtained when all chimeras were grouped according to the origin of their B cells, either Sle1a or B6, but not their T cells (Fig. 2I), suggesting an intrinsic B cell effect of Sle1a expression. Taken together, these data showed that Sle1a increases the number of autoreactive B cells that respond to alloreactive T cell help, at least partially in an intrinsic B cell manner.


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 or Sle1a.2 expression increased the cGVHD response. Anti-dsDNA IgG (A); spleen weight (B); ratio of AA4.1+ IgM+ CD21lo CD23lo T1 over AA4.1− IgM+ CD21int CD23+ follicular B cells; percentage of CD86+ (D) and CD22 expression (E) in B220+ gated cells; and ratio of CD62L+ CD44− naïve over CD62L− CD44+ memory CD4+ T cells five weeks after cGVHD induction in B6, B6.Sle1a and B6.Sle1a sub-congenic mice. G. Additive semi-quantitative scores of glomerular C3 and IgG deposits in B6.Sle1a and B6 mice five weeks after cGVHD induction. H. Anti-dsDNA IgG production in BM chimeras expressing Sle1a in both B and T cells (1a T + 1a B), in T cells only (1a T + B6 B), in B cells only (B6 T + 1a B), or in neither B nor T cells (B6 T + B6 B) one week after cGVHD induction. I. Anti-dsDNA IgG production in BM chimeras grouped according to the Sle1a or B6 origin of their T cells (1a T or B6 T), or B cells (1a B or B6 B). *: p < 0.05; **: p < 0.01; ***: p < 0.001. J. Representative C3 immunofluorescence staining in B6.Sle1a and B6 mice five weeks after cGVHD induction (100x). K. Representative ANA stain and corresponding titer in 9–12 month old mice.
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Figure 2: Sle1a or Sle1a.2 expression increased the cGVHD response. Anti-dsDNA IgG (A); spleen weight (B); ratio of AA4.1+ IgM+ CD21lo CD23lo T1 over AA4.1− IgM+ CD21int CD23+ follicular B cells; percentage of CD86+ (D) and CD22 expression (E) in B220+ gated cells; and ratio of CD62L+ CD44− naïve over CD62L− CD44+ memory CD4+ T cells five weeks after cGVHD induction in B6, B6.Sle1a and B6.Sle1a sub-congenic mice. G. Additive semi-quantitative scores of glomerular C3 and IgG deposits in B6.Sle1a and B6 mice five weeks after cGVHD induction. H. Anti-dsDNA IgG production in BM chimeras expressing Sle1a in both B and T cells (1a T + 1a B), in T cells only (1a T + B6 B), in B cells only (B6 T + 1a B), or in neither B nor T cells (B6 T + B6 B) one week after cGVHD induction. I. Anti-dsDNA IgG production in BM chimeras grouped according to the Sle1a or B6 origin of their T cells (1a T or B6 T), or B cells (1a B or B6 B). *: p < 0.05; **: p < 0.01; ***: p < 0.001. J. Representative C3 immunofluorescence staining in B6.Sle1a and B6 mice five weeks after cGVHD induction (100x). K. Representative ANA stain and corresponding titer in 9–12 month old mice.
Mentions: To better define the role of Sle1a in autoimmunity, we used the chronic graph versus host disease (cGVHD) model in which I-Aβ-mismatched CD4+ T cells transferred from B6.bm12 mice provide bystander help to resident autoreactive B cells that are otherwise tolerized.24 B6.bm12 splenocytes induced significantly more anti-chromatin and anti-dsDNA IgG, lymphoid expansion, expansion of T1 B cells to the expense of follicular B cells, and T and B cell activation in B6.Sle1a than in B6 mice (Fig. 2A–F). C3 and IgG deposition was also significantly increased in B6.Sle1a as compared to B6 glomeruli (Fig. 2G and J). These results indicate that Sle1a expression expands the pool of autoreactive B cells, which, in this model, require interactions with CD4+ T cells during their development.25 To determine whether Sle1a enhanced cGVHD through T or B cells, we induced cGVHD in mixed bone-marrow (BM) chimeras reconstituted with a mixture of BM from two of the B6.Sle1a.Tcrb−/−.Tcrd−/−, B6.Sle1a.Igh6, B6.Tcrb−/−.Tcrd−/− or B6.Igh6 strains in such a way that the T and B cell origin was either from Sle1a or B6. Activation of either CD4+ T cells or B cells in these chimeras tracked with the Sle1a origin of each of these cell types (data not shown). The chimeras in which both T and B cells expressed Sle1a produced significantly more anti-dsDNA IgG (Fig. 2H) and showed an increase in spleen weight (data not shown) compared to chimeras in which both T and B cells were of B6 origin. The expression of Sle1a in B cells only, but not in T cells, showed a similar trend. A significant difference was obtained when all chimeras were grouped according to the origin of their B cells, either Sle1a or B6, but not their T cells (Fig. 2I), suggesting an intrinsic B cell effect of Sle1a expression. Taken together, these data showed that Sle1a increases the number of autoreactive B cells that respond to alloreactive T cell help, at least partially in an intrinsic B cell manner.

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