Altered selection processes of B lymphocytes in autoimmune NZB/W mice, despite intact central tolerance against DNA.
Anti-DNA autoantibodies are the hallmark of systemic lupus erythematosus and the (NZBxNZW)F1 (NZB/W) murine model. To investigate potential defects in B cell tolerance, we followed the development of anti-DNA-specific B cells in 2-5-month-old mice transgenic for an unmutated muH chain in the normal C57BL/6 and in the NZB/W background. When the transgenic H chain was combined with a random kappa L chain repertoire about 60% of the antibodies bound to DNA. The analysis of the B cell repertoire in the spleen showed extensive receptor editing and a deletion of DNA reactivity in the C57BL/6 as well as in the autoimmune NZB/W background. NZB/W compared to C57BL/6 transgenic mice had a higher frequency of anti-DNA B cells among follicular B cells that were not censored by central tolerance mechanisms. Furthermore, positive selection of B cells with a recurrent rearrangement into the marginal zone compartment was more pronounced in NZB/W mice. Serum levels of transgenic IgM and of anti-DNA autoantibodies indicate a polyclonal activation of hyperactive B cells in the transgenic NZB/W mice. We propose different B cell receptor signaling thresholds for the NZB/W compared to C57BL/6 B cells. This could explain the quantitative differences in the B cell repertoire as well as the hyperactivity of B cells from NZB/W mice.
Wellmann
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Division of Molecular Immunology, Department of Medicine III, University of Erlangen-Nürnberg, Erlangen, Germany.
Werner
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Winkler
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TH
D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D001853:Bone Marrow / Q000276:immunology; D004247:DNA / Q000276:immunology*; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain; D006825:Hybridomas; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007075:Immunoglobulin M / Q000097:blood / Q000235:genetics; D007135:Immunoglobulin Variable Region; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology*; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D008822:Mice, Transgenic; D017634:Self Tolerance; D013154:Spleen / Q000276:immunology; D014407:Tumor Cells, Cultured
D000974:Antibodies, Antinuclear; D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D004247:DNA