title: IRF9 and STAT1 are required for IgG autoantibody production and B cell expression of TLR7 in mice.
abstract: A hallmark of SLE is the production of high-titer, high-affinity, isotype-switched IgG autoantibodies directed against nucleic acid-associated antigens. Several studies have established a role for both type I IFN (IFN-I) and the activation of TLRs by nucleic acid-associated autoantigens in the pathogenesis of this disease. Here, we demonstrate that 2 IFN-I signaling molecules, IFN regulatory factor 9 (IRF9) and STAT1, were required for the production of IgG autoantibodies in the pristane-induced mouse model of SLE. In addition, levels of IgM autoantibodies were increased in pristane-treated Irf9 -/- mice, suggesting that IRF9 plays a role in isotype switching in response to self antigens. Upregulation of TLR7 by IFN-alpha was greatly reduced in Irf9 -/- and Stat1 -/- B cells. Irf9 -/- B cells were incapable of being activated through TLR7, and Stat1 -/- B cells were impaired in activation through both TLR7 and TLR9. These data may reveal a novel role for IFN-I signaling molecules in both TLR-specific B cell responses and production of IgG autoantibodies directed against nucleic acid-associated autoantigens. Our results suggest that IFN-I is upstream of TLR signaling in the activation of autoreactive B cells in SLE.
authors.affiliation: Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Donna L
authors.initials: DL
authors.lastname: Thibault
authors.forename: Alvina D
authors.initials: AD
authors.lastname: Chu
authors.forename: Kareem L
authors.initials: KL
authors.lastname: Graham
authors.forename: Imelda
authors.initials: I
authors.lastname: Balboni
authors.forename: Lowen Y
authors.initials: LY
authors.lastname: Lee
authors.forename: Cassidy
authors.initials: C
authors.lastname: Kohlmoos
authors.forename: Angela
authors.initials: A
authors.lastname: Landrigan
authors.forename: John P
authors.initials: JP
authors.lastname: Higgins
authors.forename: Robert
authors.initials: R
authors.lastname: Tibshirani
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Utz
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D020869:Gene Expression Profiling; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000145:classification / Q000276:immunology*; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010954:Plasmacytoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D001323:Autoantibodies; D007074:Immunoglobulin G; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D050794:STAT1 Transcription Factor; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9