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Regulation of B cell tolerance by 129-derived chromosome 1 loci in C57BL/6 mice.

Fossati-Jimack L, Cortes-Hernandez J, Norsworthy PJ, Cook HT, Walport MJ, Botto M - Arthritis Rheum. (2008)

Bottom Line: The combination of V(H)3H9R/Vkappa8R with the 129chr1b interval resulted in impaired B cell anergy, and transgenic IgM and IgG anti-ssDNA antibodies were found in the circulation.The gene-targeted animals showed a similar phenotype.The presence of a single 129chr1b locus on the B6 background impaired B cell anergy, prevented deletion of anti-DNA transgenic B cells, and induced receptor revision.

View Article: PubMed Central - PubMed

Affiliation: Molecular Genetics and Rheumatology Section, Faculty of Medicine, Imperial College, London, UK. l.fossati@imperial.ac.uk

ABSTRACT

Objective: Systemic lupus erythematosus is a multifactorial disease with a strong genetic component. Previous studies have shown that a 129-derived chromosome 1 interval (Sle16) on the C57BL/6 (B6) background is sufficient to induce humoral autoimmunity. The aim of the present study was to elucidate the mechanisms by which this locus contributes to the loss of peripheral tolerance.

Methods: Anti-single-stranded DNA (anti-ssDNA)-knockin transgenic mice (V(H)3H9R/Vkappa8R and V(H)3H9R) were crossed with a B6 congenic line named B6.129chr1b that carries the Sle16 locus. A parallel study of a gene-targeted animal, whose mutated gene is located within the 129chr1b interval on chromosome 1, was also performed.

Results: The combination of V(H)3H9R/Vkappa8R with the 129chr1b interval resulted in impaired B cell anergy, and transgenic IgM and IgG anti-ssDNA antibodies were found in the circulation. The presence of IgG2a(a) anti-ssDNA and IgM(a) anti-Sm antibodies in sera indicated that the autoreactive transgenic B cells underwent class switching and epitope spreading. The 129chr1b locus appeared to have a dominant effect, since transgenic antibodies were also detected in mice carrying a single allele. The gene-targeted animals showed a similar phenotype.

Conclusion: The presence of a single 129chr1b locus on the B6 background impaired B cell anergy, prevented deletion of anti-DNA transgenic B cells, and induced receptor revision. The findings of this study also emphasize that the autoimmune phenotype observed in mice with targeted genes located on chromosome 1 may simply arise from epistatic interactions between the 129 and B6 parental strains.

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IgMa anti–single-stranded DNA (anti-ssDNA), antihistone, antichromatin, and anti-Sm autoantibodies (autoAb) in VH3H9R/VLκ8R.B6, VH3H9R/VLκ8R.B6.129chr1b129/129, VH3H9R/VLκ8R.B6.129chr1b129/B6, and VH3H9R/VLκ8R.B6. Apcs−/− mice at ages A, 2 months, B, 5 months, and C, 10 months. Values are the mean and SEM arbitrary enzyme-linked immunosorbent assay units (AEU).
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fig03: IgMa anti–single-stranded DNA (anti-ssDNA), antihistone, antichromatin, and anti-Sm autoantibodies (autoAb) in VH3H9R/VLκ8R.B6, VH3H9R/VLκ8R.B6.129chr1b129/129, VH3H9R/VLκ8R.B6.129chr1b129/B6, and VH3H9R/VLκ8R.B6. Apcs−/− mice at ages A, 2 months, B, 5 months, and C, 10 months. Values are the mean and SEM arbitrary enzyme-linked immunosorbent assay units (AEU).

Mentions: VH3H9R/Vκ8R mice can generate only antibodies against ssDNA. However, previous studies of VH3H9R/VLκ8R.MRL. lpr/lpr mice have shown that when tolerance is broken, VH3H9R/VLκ8R-transgenic B cells can undergo receptor editing in order to change the specificity of the transgenic B cells toward other autoantigens (32). In light of these previous observations, we measured IgMa autoantibodies against different nuclear antigens at different time points in the VH3H9R/VLκ8R.B6 cohorts (Figure 3). At an early stage of the disease (age 2 months) in mice carrying the 129chr1b locus, IgMa autoantibodies were mainly directed against ssDNA. However, at later time points (ages 5 months and 10 months), IgMa against other autoantigens (Sm and chromatin) were detectable, indicating an expansion of the autoantibody repertoire.


Regulation of B cell tolerance by 129-derived chromosome 1 loci in C57BL/6 mice.

Fossati-Jimack L, Cortes-Hernandez J, Norsworthy PJ, Cook HT, Walport MJ, Botto M - Arthritis Rheum. (2008)

IgMa anti–single-stranded DNA (anti-ssDNA), antihistone, antichromatin, and anti-Sm autoantibodies (autoAb) in VH3H9R/VLκ8R.B6, VH3H9R/VLκ8R.B6.129chr1b129/129, VH3H9R/VLκ8R.B6.129chr1b129/B6, and VH3H9R/VLκ8R.B6. Apcs−/− mice at ages A, 2 months, B, 5 months, and C, 10 months. Values are the mean and SEM arbitrary enzyme-linked immunosorbent assay units (AEU).
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2658014&req=5

fig03: IgMa anti–single-stranded DNA (anti-ssDNA), antihistone, antichromatin, and anti-Sm autoantibodies (autoAb) in VH3H9R/VLκ8R.B6, VH3H9R/VLκ8R.B6.129chr1b129/129, VH3H9R/VLκ8R.B6.129chr1b129/B6, and VH3H9R/VLκ8R.B6. Apcs−/− mice at ages A, 2 months, B, 5 months, and C, 10 months. Values are the mean and SEM arbitrary enzyme-linked immunosorbent assay units (AEU).
Mentions: VH3H9R/Vκ8R mice can generate only antibodies against ssDNA. However, previous studies of VH3H9R/VLκ8R.MRL. lpr/lpr mice have shown that when tolerance is broken, VH3H9R/VLκ8R-transgenic B cells can undergo receptor editing in order to change the specificity of the transgenic B cells toward other autoantigens (32). In light of these previous observations, we measured IgMa autoantibodies against different nuclear antigens at different time points in the VH3H9R/VLκ8R.B6 cohorts (Figure 3). At an early stage of the disease (age 2 months) in mice carrying the 129chr1b locus, IgMa autoantibodies were mainly directed against ssDNA. However, at later time points (ages 5 months and 10 months), IgMa against other autoantigens (Sm and chromatin) were detectable, indicating an expansion of the autoantibody repertoire.

Bottom Line: The combination of V(H)3H9R/Vkappa8R with the 129chr1b interval resulted in impaired B cell anergy, and transgenic IgM and IgG anti-ssDNA antibodies were found in the circulation.The gene-targeted animals showed a similar phenotype.The presence of a single 129chr1b locus on the B6 background impaired B cell anergy, prevented deletion of anti-DNA transgenic B cells, and induced receptor revision.

View Article: PubMed Central - PubMed

Affiliation: Molecular Genetics and Rheumatology Section, Faculty of Medicine, Imperial College, London, UK. l.fossati@imperial.ac.uk

ABSTRACT

Objective: Systemic lupus erythematosus is a multifactorial disease with a strong genetic component. Previous studies have shown that a 129-derived chromosome 1 interval (Sle16) on the C57BL/6 (B6) background is sufficient to induce humoral autoimmunity. The aim of the present study was to elucidate the mechanisms by which this locus contributes to the loss of peripheral tolerance.

Methods: Anti-single-stranded DNA (anti-ssDNA)-knockin transgenic mice (V(H)3H9R/Vkappa8R and V(H)3H9R) were crossed with a B6 congenic line named B6.129chr1b that carries the Sle16 locus. A parallel study of a gene-targeted animal, whose mutated gene is located within the 129chr1b interval on chromosome 1, was also performed.

Results: The combination of V(H)3H9R/Vkappa8R with the 129chr1b interval resulted in impaired B cell anergy, and transgenic IgM and IgG anti-ssDNA antibodies were found in the circulation. The presence of IgG2a(a) anti-ssDNA and IgM(a) anti-Sm antibodies in sera indicated that the autoreactive transgenic B cells underwent class switching and epitope spreading. The 129chr1b locus appeared to have a dominant effect, since transgenic antibodies were also detected in mice carrying a single allele. The gene-targeted animals showed a similar phenotype.

Conclusion: The presence of a single 129chr1b locus on the B6 background impaired B cell anergy, prevented deletion of anti-DNA transgenic B cells, and induced receptor revision. The findings of this study also emphasize that the autoimmune phenotype observed in mice with targeted genes located on chromosome 1 may simply arise from epistatic interactions between the 129 and B6 parental strains.

Show MeSH
Related in: MedlinePlus