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Murine lupus susceptibility locus Sle2 activates DNA-reactive B cells through two sub-loci with distinct phenotypes

Genes & Immunity volume 12, pages 199–207 (2011)Cite this article

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Abstract

The NZM2410-derived Sle2 lupus susceptibility locus induces an abnormal B-cell differentiation, which most prominently leads to the expansion of autoreactive B1a cells. We have mapped the expansion of B1a cells to three Sle2 sub-loci, Sle2a, Sle2b and Sle2c. Sle2 also enhances the breach of B-cell tolerance to nuclear antigens in the 56R anti-DNA immunoglobulin transgenic (Tg) model. This study used the Sle2 sub-congenic strains to map the activation of 56R Tg B cells. Sle2c strongly sustained the breach of tolerance and the activation of anti-DNA B cells. The production of Tg-encoded anti-DNA antibodies was more modest in Sle2a-expressing mice, but Sle2a was responsible for the recruitment for Tg B cells to the marginal zone, a phenotype that has been found for 56R Tg B cells in mice expressing the whole Sle2 interval. In addition, Sle2a promoted the production of endogenously encoded anti-DNA antibodies. Overall, this study showed that at least two Sle2 genes are involved in the activation of anti-DNA B cells, and excluded more than two-thirds of the Sle2 interval from contributing to this phenotype. This constitutes an important step toward the identification of novel genes that have a critical role in B-cell tolerance.

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Acknowledgements

This work was supported by a National Institutes of Health grant RO1 AI068965 to LM. We thank Dr Chandra Mohan for the generous gift of B6.56R and B6.Sle2.56R breeders, Xuekun Su for outstanding animal care and members of the Morel lab for stimulating discussions.

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  1. H Niu

    Present address: 2Current address: Center For Autoimmune and Musculoskeletal Disease, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 32610-0275, USA.,

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  1. Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, USA

    L Zeumer, A Sang, H Niu & L Morel

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  1. L Zeumer
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  2. A Sang
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Correspondence to L Morel.

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Zeumer, L., Sang, A., Niu, H. et al. Murine lupus susceptibility locus Sle2 activates DNA-reactive B cells through two sub-loci with distinct phenotypes. Genes Immun 12, 199–207 (2011). https://doi.org/10.1038/gene.2010.69

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