IFN-gamma AUrich element removal promotes chronic IFN-gamma expression and autoimmunity in mice q

We generated a mouse model with a 162 nt AU-rich element (ARE) region deletion in the 30 untranslated region (30UTR) of the interferon-gamma (IFN-g) gene that results in chronic circulating serum IFN-g levels. Mice homozygous for the ARE deletion (ARE-Del) / present both serologic and cellular abnormalities typical of patients with systemic lupus erythematosus (SLE). ARE-Del / mice display increased numbers of pDCs in bone marrow and spleen. Addition of IFN-g to Flt3-ligand (Flt3L) treated in vitro bone marrow cultures results in a 2-fold increase in pDCs with concurrent increases in IRF8 expression. Marginal zone B (MZB) cells and marginal zone macrophages (MZMs) are absent in ARE-Del / mice. ARE-Delþ/ mice retain both MZB cells and MZMs and develop no or mild autoimmunity. However, low dose clodronate treatment in ARE-Delþ/ mice specifically eliminates MZMs and promotes anti-DNA antibody development and glomerulonephritis. Our findings demonstrate the consequences of a chronic IFN-gmilieu on B220þ cell types and in particular the impact of MZB cell loss on MZM function in autoimmunity. Furthermore, similarities between disease states in ARE-Del / mice and SLE patients suggest that IFN-gmay not only be a product of SLE but may be critical for disease onset and progression. Published by Elsevier Ltd. the U.S. Government to retain a nonexclusive, royalty-free license in and to any copyright covering the article. l Immunology, Cancer & Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, 105

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