title: Essential Requirement for IFN Regulatory Factor 7 in Autoantibody Production but Not Development of Nephritis in Murine Lupus.
abstract: Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by the production of autoantibodies against nuclear components. Recent genetic studies of SLE patients have revealed that IFN regulatory factor (IRF) 7 gene polymorphisms are associated with an increased risk of SLE, but the precise role of IRF7 in SLE development is not fully understood. We investigated the role of IRF7 in the pathogenesis of SLE using a mouse model and saw a curious dissociation of autoantibody production and development of glomerulonephritis. SLE was chemically induced into IRF7-deficient mice, and glomerulonephritis with deposits of IgG and lipogranulomas were observed after 10 mo. However, these mice failed to produce anti-dsDNA, ssDNA, ribonucleoprotein, and Sm autoantibodies. Following the chemical induction, IRF7-deficient mice expressed substantially lower levels of IFN-stimulated genes than did wild-type mice, but NF-κB target genes were equally upregulated in both strains. Therefore, the type I IFN pathway seems critical for the autoantibody production, but the NF-κB activation is sufficient for the development of glomerulonephritis in this model. Our study thus demonstrates a specific requirement for IRF7 in autoantibody production and uncovers a new layer of complexity in the pathogenesis of SLE.
authors.affiliation: Department of Dermatology, Nara Medical University School of Medicine, Kashihara, Nara 634-8522, Japan; fumim@naramed-u.ac.jp.
authors.forename: Fumi
authors.initials: F
authors.lastname: Miyagawa
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201; and.
authors.forename: Yutaka
authors.identifier: 0000-0002-1342-9282
authors.initials: Y
authors.lastname: Tagaya
authors.affiliation: Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Keiko
authors.identifier: 0000-0001-7013-2728
authors.initials: K
authors.lastname: Ozato
authors.affiliation: Department of Dermatology, Nara Medical University School of Medicine, Kashihara, Nara 634-8522, Japan;
authors.forename: Hideo
authors.identifier: 0000-0003-1971-9835
authors.initials: H
authors.lastname: Asada
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D017209:Apoptosis / Q000187:drug effects; D001323:Autoantibodies / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000502:physiology; D005260:Female; D005921:Glomerulonephritis / Q000209:etiology; D050839:Interferon Regulatory Factor-7 / Q000502:physiology*; D008181:Lupus Nephritis / Q000209:etiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology; D009504:Neutrophils / Q000502:physiology; D010847:Picolines / Q000494:pharmacology
chemical_list: C524030:1-(3-picolinium)-12-triethylammonium-dodecane dibromide; D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D050839:Interferon Regulatory Factor-7; C494235:Irf7 protein, mouse; D016328:NF-kappa B; D010847:Picolines