Autoimmunity in interferon-gamma AU-rich element deleted-mice is associated with loss of marginal zone B cells and macrophages. (BA15P.217)

Abstract We generated a mouse model with a 162 nt AU-rich element (ARE) region deletion in the 3’ untranslated region (3’UTR) of the interferon (IFN)-gamma gene that results in chronic circulating serum IFN-gamma levels. Mice homozygous for the ARE deletion present both serologic and cellular abnormalities typical of patients with systemic lupus erythematosus (SLE). Marginal zone B (MZB) cells and marginal zone macrophages (MZMs) are absent in ARE-deleted (ARE-Del)-/- mice. ARE-Del+/- mice retain both MZB cells and MZMs and develop no or mild autoimmunity. However, low dose clodronate treatment in ARE-Del+/- mice specifically eliminates MZMs and promotes anti-DNA antibody development and glomerulonephritis. Our findings demonstrate the consequences of a chronic IFN-gamma milieu on MZB cell loss and MZM function in autoimmunity. Furthermore, similarities between disease states in ARE-Del-/- mice and SLE patients suggest that IFN-gamma may not only be a product of SLE but may be critical for disease onset and progression.