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A lupus-susceptibility C57BL/6 locus on chromosome 3 (Sle18) contributes to autoantibody production in 129 mice

Genes & Immunity volume 10, pages 47–55 (2009)Cite this article

Abstract

Epistatic interactions between the non-autoimmune strains 129 and C57BL/6 (B6), used for generating gene-targeted animals, can induce a lupus-like disease. Genome-wide scan analyses of testcross progeny between these two strains have identified several lupus susceptibility loci, with the strongest linkage to the production of autoantibodies (auto-Abs) displayed by an interval on chromosome 1 of 129 origin (Sle16). However, the contribution of B6 loci to the lupus phenotype remained unknown. We used a congenic approach to deduce the contribution to the autoimmune traits of the B6 genomic interval on chromosome 3 (Sle18), previously shown to be linked to antinuclear Ab production. This interval, when transferred on a 129 background (a strain termed 129.B6–Sle18), promoted auto-Ab production targeting a broad spectrum of autoantigens, expansion of activated CD4+T and B cells and mild glomerulonephritis. Surprisingly, these immunological and serological defects were accompanied by a significant increase in the percentage of regulatory T cells (Tregs; CD4+ Foxp3+). However, these cells, that expressed lower levels of Foxp3, had no impaired regulatory function when tested in vitro. These findings illustrate further the efficacy of congenic dissection for functional characterisation of individual lupus susceptibility loci and highlight the contribution of loci derived from non-autoimmune strains to the disease pathogenesis.

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Acknowledgements

We thank Mrs Margarita Lewis for technical assistance with the processing of tissue for histological studies and the staff of the Biological Services Unit at our institution for the care of the animals involved in this study. We are grateful to Dr Dumitriu for her technical help with the T-suppressor assays. This study was supported by the Wellcome Trust (Grant no. 071467).

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  1. M J Walport

    Present address: 3Current address: The Wellcome Trust, London, UK.,

Authors and Affiliations

  1. Faculty of Medicine, Molecular Genetics and Rheumatology Section, Imperial College, Hammersmith Campus, London, UK

    Y Heidari, L Fossati-Jimack, F Carlucci, M J Walport & M Botto

  2. Department of Histopathology, Imperial College, Hammersmith Campus, London, UK

    H T Cook

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  1. Y Heidari
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Correspondence to M Botto.

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Heidari, Y., Fossati-Jimack, L., Carlucci, F. et al. A lupus-susceptibility C57BL/6 locus on chromosome 3 (Sle18) contributes to autoantibody production in 129 mice. Genes Immun 10, 47–55 (2009). https://doi.org/10.1038/gene.2008.78

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