title: IFN-gamma AU-rich element removal promotes chronic IFN-gamma expression and autoimmunity in mice.
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-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.
authors.affiliation: Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, MD 21702, USA. Electronic address: hodged@mail.nih.gov.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Hodge
authors.affiliation: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702, USA; Oncodesign, 20 Rue Jean Mazen, Dijon 21076, France. Electronic address: cberthet@oncodesign.com.
authors.forename: Cyril
authors.initials: C
authors.lastname: Berthet
authors.affiliation: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702, USA; Department of Molecular Virology, Immunology and Medical Genetics at The Ohio State University, 460 W. 12th Street, Columbus, OH 43210, USA. Electronic address: Vincenzo.Coppola@osumc.edu.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Coppola
authors.affiliation: Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Cellular Interactions and Immunimaging Institutes of Molecular Medicine and Experimental Immunology (IMMEI), University of Bonn, Sigmund-Freud Str. 25, Bonn 53105, Germany. Electronic address: wkastenm@uni-bonn.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kastenmüller
authors.affiliation: Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, MD 21702, USA; Division of Endocrinology and Metabolism, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. Electronic address: mbuschman@ucsd.edu.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Buschman
authors.affiliation: Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, MD 21702, USA; Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: pschaugh@jhmi.edu.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Schaughency
authors.affiliation: Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, MD 21702, USA; Department of Clinical Oncology, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan. Electronic address: shirotah@idac.tohoku.ac.jp.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Shirota
authors.affiliation: Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, MD 21702, USA. Electronic address: scarzean@mail.nih.gov.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Scarzello
authors.affiliation: Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, MD 21702, USA. Electronic address: subleskj@mail.nih.gov.
authors.forename: Jeff J
authors.initials: JJ
authors.lastname: Subleski
authors.affiliation: Laboratory Animal Science Program (LASP), Science Applications International Corporation (SAIC), National Cancer Institute, Frederick, MD 21702, USA. Electronic address: anvermr@mail.nih.gov.
authors.forename: Miriam R
authors.initials: MR
authors.lastname: Anver
authors.affiliation: Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, MD 21702, USA. Electronic address: ortaldoj@mail.nih.gov.
authors.forename: John R
authors.initials: JR
authors.lastname: Ortaldo
authors.affiliation: Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, MD 21702, USA. Electronic address: fanching.lin@nih.gov.
authors.forename: Fanching
authors.initials: F
authors.lastname: Lin
authors.affiliation: Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, MD 21702, USA. Electronic address: reynoldd@mail.nih.gov.
authors.forename: Della A
authors.initials: DA
authors.lastname: Reynolds
authors.affiliation: Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, MD 21702, USA. Electronic address: sanfordm@mail.nih.gov.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Sanford
authors.affiliation: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702, USA; Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Proteos, 61 Biopolis Drive, Singapore 138673, Republic of Singapore. Electronic address: kaldis@imcb.a-star.edu.sg.
authors.forename: Philipp
authors.initials: P
authors.lastname: Kaldis
authors.affiliation: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702, USA. Electronic address: tessarol@mail.nih.gov.
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarollo
authors.affiliation: Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, MD 21702, USA. Electronic address: klinmand@mail.nih.gov.
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Klinman
authors.affiliation: Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, MD 21702, USA. Electronic address: YoungHow@mail.nih.gov.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Young
mesh_terms: D063307:AU Rich Elements / Q000235:genetics*; D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D001483:Base Sequence; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D017384:Sequence Deletion; D000099185:Interferon Regulatory Factor-8
chemical_list: D000974:Antibodies, Antinuclear; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma; D008565:Membrane Proteins; D000099185:Interferon Regulatory Factor-8; C084881:flt3 ligand protein
keywords: Autoimmunity; Glomerulonephritis; Interferon gamma; Systemic lupus erythematosus