| First Author | Hodge DL | Year | 2014 |
| Journal | J Autoimmun | Volume | 53 |
| Pages | 33-45 | PubMed ID | 24583068 |
| Mgi Jnum | J:298798 | Mgi Id | MGI:6488237 |
| Doi | 10.1016/j.jaut.2014.02.003 | Citation | Hodge DL, et al. (2014) IFN-gamma AU-rich element removal promotes chronic IFN-gamma expression and autoimmunity in mice. J Autoimmun 53:33-45 |
| abstractText | 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-gamma (IFN-gamma) gene that results in chronic circulating serum IFN-gamma 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-gamma 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-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 B220(+) 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-gamma may not only be a product of SLE but may be critical for disease onset and progression. |
