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* Rheumatology Section and
Department of Histopathology, Faculty of Medicine, Imperial College, London, United Kingdom
Extensive evidence indicates that genetic predisposition is a central element in susceptibility to systemic lupus erythematosus both in humans and animals. We have previously shown that a congenic line carrying a 129-derived chromosome 1 interval on the C57BL/6 background developed humoral autoimmunity. To further dissect the contribution to autoimmunity of this 129 interval, we have created six subcongenic strains carrying fractions of the original 129 region and analyzed their serological and cellular phenotypes. At 1 year of age the congenic strain carrying a 129 interval between the microsatellites D1Mit15 (87.9 cM) and D1Mit115 (99.7 cM) (B6.129chr1b) had high levels of autoantibodies, while all the other congenic lines were not significantly different from the C57BL/6 controls. The B6.129chr1b strain displayed only mild proliferative glomerulonephritis despite high levels of IgG and C3 deposited in the kidneys. FACS analysis of the spleens revealed that the B6.129chr1b mice had a marked increase in the percentage of activated T cells associated with a significant reduction in the proportion of CD4+CD25high regulatory T cells. Moreover, this analysis showed a significantly reduced percentage of marginal zone B cells that preceded autoantibody production. Interestingly the 129chr1b-expressing bone marrow-derived macrophages displayed an impaired uptake of apoptotic cells in vitro. Collectively, our data indicate that the 129chr1b segment when recombined on the C57BL/6 genomic background is sufficient to induce loss of tolerance to nuclear Ags. These findings have important implication for the interpretation of the autoimmune phenotype associated with gene-targeted models.
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1 This work was supported by The Wellcome Trust (Grant 071467). L.F.-J. was a recipient of a fellowship from the Arthritis Research Campaign (U.K.).
2 F.C. and J.C.-H. equally contributed to the work.
3 Current address: The Wellcome Trust, London, U.K.
4 Address correspondence and reprint requests to Prof. Marina Botto, Rheumatology Section, Faculty of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London W12 0NN, U.K. E-mail address: m.botto{at}imperial.ac.uk
5 Abbreviations used in this paper: SLE, systemic lupus erythematosus; ANA, antinuclear Ab; AP, alkaline phosphatase; AEU, arbitrary ELISA unit; BMDM, bone marrow-derived macrophage; AFU, arbitrary fluorescent unit; PI, phagocytic index; SLAM, signaling lymphocytic activating molecule.
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