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BXSB/long-lived Is a Recombinant Inbred Strain Containing Powerful Disease Suppressor Loci¹

Michelle E. K. Haywood^2,*, Luisa Gabriel^2,*, S. Jane Rose^*, Nicola J. Rogers, Shozo Izui and Bernard J. Morley^3,*

^* Rheumatology Section and Department of Immunology, Imperial College, London, United Kingdom; and Department of Pathology and Immunology, Centre Medical Universitaire, Geneva, Switzerland

The BXSB strain of recombinant inbred mice develops a spontaneous pathology that closely resembles the human disease systemic lupus erythematosus. Six non-MHC loci, Yaa, Bxs1–4, and Bxs6, have been linked to the development of aspects of the disease while a further locus, Bxs5, may be a BXSB-derived disease suppressor. Disease development is delayed in a substrain of BXSB, BXSB/MpJScr-long-lived (BXSB/ll). We compared the genetic derivation of BXSB/ll mice to the original strain, BXSB/MpJ, using microsatellite markers and single nucleotide polymorphisms across the genome. These differences were clustered and included two regions known to be important in the disease-susceptibility of these mice, Bxs5 and 6, as well as regions on chromosomes 5, 6, 9, 11, 12, and 13. We compared BXSB/ll to >20 strains including the BXSB parental SB/Le and C57BL/6 strains. This revealed that BXSB/ll is a separate recombinant inbred line derived from SB/Le and C57BL/6, but distinctly different from BXSB, that most likely arose due to residual heterozygosity in the BXSB stock. Despite the continued presence of the powerful disease-susceptibility locus Bxs3, BXSB/ll mice do not develop disease. We propose that the disappearance of the disease phenotype in the BXSB/ll mice is due to the inheritance of one or more suppressor loci in the differentially inherited intervals between the BXSB/ll and BXSB strains.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Arthritis Research Campaign (U.K.) (to B.J.M.) and from the Swiss National Foundation for Scientific Research (to S.I.).

² M.E.K.H. and L.G. contributed equally to this manuscript.

³ Address correspondence and reprint requests to Prof. Bernard J. Morley, Rheumatology Section, Faculty of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London, U.K. E-mail address: b.morley{at}imperial.ac.uk

⁴ Abbreviations used in this paper: SLE, systemic lupus erythematosus; B6, C57BL/6; BXSB/ll, BXSB/MpJScr-long-lived; B10, C57BL/10; Mb, megabase; NZB, New Zealand Black; NZW, New Zealand White; qPCR, quantitative real-time PCR; SNP, single nucleotide polymorphism; Yaa, Y chromosome accelerator of autoimmunity.