IFN-gamma AU-rich element removal promotes chronic IFN-gamma expression and autoimmunity in mice

IFN-gamma AU-rich element removal promotes chronic IFN-gamma expression and autoimmunity in mice

Journal of Autoimmunity

10.1016/j.jaut.2014.02.003

http://dx.doi.org/10.1016/j.jaut.2014.02.003

Deborah L. Hodge, Cyril Berthet, Vincenzo Coppola, Wolfgang Kastenmüller, Matthew D. Buschman, Paul M. Schaughency, Hidekazu Shirota, Anthony J. Scarzello, Jeff J. Subleski, Miriam R. Anver, John R. Ortaldo, Fanching Lin, Della A. Reynolds, Michael E. Sanford, Philipp Kaldis, Lino Tessarollo, Dennis M. Klinman, Howard A. Young

28 February 2014

Deborah L. Hodge, Cyril Berthet, Vincenzo Coppola, Wolfgang Kastenmüller, Matthew D. Buschman, Paul M. Schaughency, Hidekazu Shirota, Anthony J. Scarzello, Jeff J. Subleski, Miriam R. Anver, John R. Ortaldo, Fanching Lin, Della A. Reynolds, Michael E. Sanford, Philipp Kaldis, Lino Tessarollo, Dennis M. Klinman, Howard A. Young, IFN-gamma AU-rich element removal promotes chronic IFN-gamma expression and autoimmunity in mice, Journal of Autoimmunity, Volume 53, September 2014, Pages 33-45, ISSN 0896-8411, http://dx.doi.org/10.1016/j.jaut.2014.02.003. (http://www.sciencedirect.com/science/article/pii/S0896841114000420)

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-γ) gene that results in chronic circulating serum IFN-γ 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-γ 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-γ 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-γ may not only be a product of SLE but may be critical for disease onset and progression.

http://creativecommons.org/licenses/by-nc-nd/4.0/

https://oar.a-star.edu.sg/communities-collections/articles/12445

0896-8411

Institute of Molecular and Cell Biology