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

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

doi:10.1016/j.jaut.2014.02.003

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

J Autoimmun. 2014 Sep:53:33-45. doi: 10.1016/j.jaut.2014.02.003. Epub 2014 Feb 28.

Authors

Deborah L Hodge¹, Cyril Berthet², Vincenzo Coppola³, Wolfgang Kastenmüller⁴, Matthew D Buschman⁵, Paul M Schaughency⁶, Hidekazu Shirota⁷, Anthony J Scarzello⁸, Jeff J Subleski⁹, Miriam R Anver¹⁰, John R Ortaldo¹¹, Fanching Lin¹², Della A Reynolds¹³, Michael E Sanford¹⁴, Philipp Kaldis¹⁵, Lino Tessarollo¹⁶, Dennis M Klinman¹⁷, Howard A Young¹⁸

Affiliations

¹ 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.
² 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.
³ 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.
⁴ 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.
⁵ 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.
⁶ 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.
⁷ 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.
⁸ 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.
⁹ 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.
¹⁰ Laboratory Animal Science Program (LASP), Science Applications International Corporation (SAIC), National Cancer Institute, Frederick, MD 21702, USA. Electronic address: anvermr@mail.nih.gov.
¹¹ 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.
¹² 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.
¹³ 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.
¹⁴ 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.
¹⁵ 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.
¹⁶ Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702, USA. Electronic address: tessarol@mail.nih.gov.
¹⁷ 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.
¹⁸ 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.

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.

Keywords: Autoimmunity; Glomerulonephritis; Interferon gamma; Systemic lupus erythematosus.

Published by Elsevier Ltd.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

AU Rich Elements / genetics*
Animals
Antibodies, Antinuclear / immunology
B-Lymphocytes / immunology
B-Lymphocytes / pathology
Base Sequence*
Gene Expression Regulation / genetics
Gene Expression Regulation / immunology
Humans
Interferon Regulatory Factors / genetics
Interferon Regulatory Factors / immunology
Interferon-gamma* / genetics
Interferon-gamma* / immunology
Lupus Nephritis / genetics
Lupus Nephritis / immunology*
Macrophages / immunology
Macrophages / pathology
Membrane Proteins / genetics
Membrane Proteins / immunology
Mice
Mice, Knockout
Sequence Deletion*

Substances

Antibodies, Antinuclear
Interferon Regulatory Factors
Membrane Proteins
flt3 ligand protein
interferon regulatory factor-8
Interferon-gamma

Abstract

Publication types

MeSH terms

Substances

Grants and funding