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Characterization of Reciprocal Lmb1–4 Interval MRL-Fas^lpr and C57BL/6-Fas^lpr Congenic Mice Reveals Significant Effects from Lmb3¹

Marie-Laure Santiago-Raber^*, M. Katarina Haraldsson, Argyrios N. Theofilopoulos and Dwight H. Kono^2,

^* Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland; and Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037

Susceptibility to severe lupus in MRL-Fas^lpr mice requires not only the lpr mutation but also other predisposing genes. Using (MRL-Fas^lpr x B6-Fas^lpr)F2 (where B6 represents C57BL/6) intercrosses that utilize the highly susceptible MRL and poorly susceptible B6 backgrounds, we previously mapped CFA-enhanced systemic lupus-like autoimmunity to four loci, named Lmb1–4, on chromosomes 4, 5, 7, and 10. In the current study, we generated and analyzed reciprocal interval congenic mice for susceptibility to CFA-enhanced autoimmunity at all four Lmb loci. Although all loci had at least a slight effect on lymphoproliferation, only Lmb3 demonstrated a major effect on lymphoproliferation and anti-chromatin Ab levels. Further characterization of Lmb3, primarily by comparing MRL-Fas^lpr with MRL.B6-Lmb3 Fas^lpr congenic mice, revealed that it also played a significant role in spontaneous lupus, modifying lymphoproliferation, IgG and autoantibody levels, kidney disease, and survival. The less susceptible B6 Lmb3 locus was associated with a marked reduction in numbers of CD4⁺ and double-negative (CD4^–CD8^–) T cells, particularly in lymph nodes, as well as reduced T cell proliferation and enhanced T cell apoptosis, both in vivo and in vitro. IFN--producing CD4⁺ T cells were also reduced in MRL.B6-Lmb3 Fas^lpr mice. Further mapping using subinterval congenic mice placed Lmb3 in the telomeric portion of chromosome 7. Thus, Lmb3, primarily through its effects on CD4⁺ and double-negative T cells, appears to be a highly penetrant lupus-modifying locus. Identification of the underlying genetic alteration responsible for this quantitative trait locus should provide new insights into lupus-modifying genes.

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¹ This is publication 18691-IMM from the Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. The work reported herein was supported by National Institutes of Health Grants AR39555, AR42242, AR31203, and AI051977.

² Address correspondence and reprint requests to Dr. Dwight H. Kono, Department of Immunology/IMM3, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. E-mail address: dkono{at}scripps.edu

³ Abbreviations used in this paper: DN, double negative (CD4^–CD8^–); GN, glomerulonephritis; B6, C57BL/6; cM, centimorgan; LN, lymph node; Mb, megabase; NZW, New Zealand White; QTL, quantitative trait locus; RF, rheumatoid factor; SLE, systemic lupus erythematosus.