Accelerated autoimmunity and lupus nephritis in NZB mice with an engineered heterozygous deficiency in tumor necrosis factor.
Development of autoimmunity and lupus nephritis in New Zealand (NZB x NZW)F1 mice, a model for human systemic lupus erythematosus (SLE), involves both MHC- and non-MHC-linked contributions. A characteristic reduced responsiveness of the Tnf gene, which derives from the NZW parent, has been considered contributory since replacement therapy modifies the course of disease. It has remained unclear whether imbalances in TNF production operate early at the level of autoimmune induction, or, whether TNF interferes with the development of glomerulonephritis independent of the ensuing autoimmunity. To directly assess if reduced TNF production alone is sufficient to exacerbate the innocuous autoimmune responses present in NZB mice, we crossed NZB mice with Tnf-deficient and normal background control mice. Unlike control groups, (NZB x Tnf(0))F1 hemizygous mice develop enhanced autoimmunity and severe renal disease similar to the (NZB x NZW)F1 mice. Autoimmune responses are associated with an early spontaneous increase in serum levels of anti-nuclear autoantibodies and hyperproliferating B cells which readily express anti-dsDNA specificities in response to polyclonal and T helper stimuli. These findings demonstrate a physiological role for TNF in suppressing the emergence of autoreactive lymphocytes in the NZB model, and indicate that defective TNF function may be causative of the autoimmune and pathological phenomena in lupus.
Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece.
D
D
Kontoyiannis
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G
Kollias
D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D005818:Genetic Engineering; D006801:Humans; D008181:Lupus Nephritis / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D018345:Mice, Knockout; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*
D014409:Tumor Necrosis Factor-alpha