title: The Expression of BAFF Is Controlled by IRF Transcription Factors.
abstract: Patients with systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS) are typically characterized by the presence of autoantibodies and an IFN-signature. The strength of the IFN-signature positively correlates with disease severity, suggesting that type I IFNs are active players in these diseases. BAFF is a cytokine critical for development and proper selection of B cells, and the targeting of BAFF has emerged as a successful treatment strategy of SLE. Previous reports have suggested that BAFF expression is directly induced by type I IFNs, but the precise mechanism for this remains unknown. In this article, we demonstrate that BAFF is a bona fide ISG and that IFN regulatory factors (IRFs) control the expression of BAFF. We identify IRF1 and IRF2 as positive regulators of BAFF transcription and IRF4 and IRF8 as potent repressors; in addition, we have mapped the precise binding site for these factors in the BAFF promoter. IFN-β injections induced BAFF expression mainly in neutrophils and monocytes, and BAFF expression in neutrophils from pSS patients strongly correlated with the strength of the IFN-signature. In summary, we show that BAFF expression is directly induced by type I IFNs via IRF1 and IRF2, whereas IRF4 and IRF8 are negative regulators of BAFF expression. These data suggest that type I IFN blockade in SLE and pSS patients will lead to downregulation of BAFF and a consequential reduction of autoreactive B cell clones and autoantibodies.
authors.affiliation: Unit of Experimental Rheumatology, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden;
authors.forename: Maria
authors.initials: M
authors.lastname: Sjöstrand
authors.affiliation: Unit of Experimental Rheumatology, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden;
authors.forename: Alina
authors.initials: A
authors.lastname: Johansson
authors.affiliation: Broegelmann Research Laboratory, The Gade Institute, University of Bergen, N-5201 Bergen, Norway; and.
authors.forename: Lara
authors.identifier: http://orcid.org/0000-0002-3666-842X
authors.initials: L
authors.lastname: Aqrawi
authors.affiliation: Unit of Neuroimmunology, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Olsson
authors.affiliation: Unit of Experimental Rheumatology, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden;
authors.forename: Marie
authors.identifier: http://orcid.org/0000-0002-0915-7245
authors.initials: M
authors.lastname: Wahren-Herlenius
authors.affiliation: Unit of Experimental Rheumatology, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden; alexander.espinosa@ki.se.
authors.forename: Alexander
authors.initials: A
authors.lastname: Espinosa
mesh_terms: D001323:Autoantibodies / Q000276:immunology; D053264:B-Cell Activating Factor / Q000097:blood / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000276:immunology*; D050836:Interferon Regulatory Factor-2 / Q000276:immunology*; D050835:Interferon Regulatory Factors / Q000276:immunology*; D016899:Interferon-beta / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology; D008297:Male; D008969:Molecular Sequence Data; D009000:Monocytes / Q000276:immunology; D009103:Multiple Sclerosis / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D012859:Sjogren's Syndrome / Q000276:immunology; D014158:Transcription, Genetic / Q000235:genetics; D000099185:Interferon Regulatory Factor-8; D000099218:Interferon Regulatory Factor-4
chemical_list: D001323:Autoantibodies; D053264:B-Cell Activating Factor; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; D050835:Interferon Regulatory Factors; D016899:Interferon-beta; D000099185:Interferon Regulatory Factor-8; D000099218:Interferon Regulatory Factor-4; C494257:IRF1 protein, human; C494229:IRF2 protein, human; C505719:TNFSF13B protein, human